@article {pmid42294596, year = {2026}, author = {Thomas, CE and Wesselink, E and Takashima, Y and Huyghe, JR and Buchanan, DD and Grant, RC and Costa, AD and Ugai, T and Ogino, S and Nowak, JA and Peters, U and Phipps, AI and Hsu, L}, title = {Evaluating statistical models for overdispersed multi-omics data: a multiplex immunofluorescence case study.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwag127}, pmid = {42294596}, issn = {1476-6256}, abstract = {Multi-omic data analysis poses statistical challenges. We evaluated statistical models for our multiplex immunofluorescence study of T cell subset densities in colorectal cancer. Using 1235 cases, we compared seven models- ordinal logistic regression, Poisson, quasi-Poisson, quadratic negative binomial (NB), linear NB, zero-inflated NB (ZINB) and hurdle NB models- assessing associations with a strong (microsatellite instability, MSI) and a weak (calcium intake) exposure. Simulation studies assessed type I error and power. Effect estimates were generally consistent for the strong exposure (MSI) but varied for the weaker exposure (calcium). Simulations revealed inflated false-positive rates for the Poisson and NB-based models, including quadratic NB, zero-inflated and hurdle, but not for ordinal logistic regression or the linear NB model. The quasi-Poisson model showed modest inflation of low p-values, but the overall p-value distribution remained approximately uniform under the null. Ordinal logistic, linear NB, and quasi-Poisson models achieved the best or near-best power across a range of zero proportions, dispersion levels, and distributions. The ordinal logistic, linear NB, and quasi-Poisson models are useful and robust options for epidemiologic analyses of overdispersed, right-skewed multi-omic data with a nontrivial proportion of zero counts.}, }
@article {pmid42294841, year = {2026}, author = {Mina, R and Beksac, M and Rodríguez-Otero, P and Chen, W and Mateos, MV and Li, J and Moreau, P and Cohen, YC and Min, CK and Jelinek, T and Ye, JC and Magen, H and Rubinstein, SM and Fu, W and Hungria, V and Cengiz Seval, G and Farias, JS and Radocha, J and Maral, S and Turgut, M and Koh, Y and O'Leary, D and Schmidt Filho, J and Thertulien, R and An, G and Huang, SY and Grosicki, S and Tyczyńska, A and Banerjee, R and Pianko, MJ and Martínez-López, J and Steckiewicz, P and Maruyama, D and Fukushima, K and Oriol, A and Lopez Pardo, J and Goldschmidt, H and Pawlyn, C and Perrot, A and Zamagni, E and Dimopoulos, MA and Rasche, L and Tolbert, J and Terry, W and Courtoux, C and Liu, X and Vasey, SY and Connors, K and Festa, M and Heuck, C and Langlois, A and O'Rourke, L and Zhou, J and Qin, X and Lu, J and Gong, J and Vieyra, D and Voorhees, PM and , }, title = {Talquetamab-Daratumumab in Relapsed or Refractory Myeloma.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2604657}, pmid = {42294841}, issn = {1533-4406}, abstract = {BACKGROUND: Talquetamab, a bispecific antibody targeting GPRC5D and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma in phase 1-2 trials, with a limited effect on normal B cells.<br><br>METHODS: In a phase 3 trial, we randomly assigned patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy to receive talquetamab plus daratumumab and pomalidomide (Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). The primary end point was progression-free survival as assessed by an independent review committee. Key secondary end points were overall response, complete response or better (complete or stringent complete response), measurable residual disease-negative complete response, and overall survival.<br><br>RESULTS: A total of 287, 287, and 290 patients were assigned to the Tal-DP, Tal-D, and DPd groups, respectively. At the interim analysis (median follow-up, 24.6 months), progression-free survival was significantly longer with Tal-DP and Tal-D than with DPd (24-month estimate, 81.3% and 77.6% vs. 51.2%; hazard ratio for disease progression or death, Tal-DP vs. DPd, 0.28 [95% confidence interval {CI}, 0.20 to 0.40], and Tal-D vs. DPd, 0.33 [95% CI, 0.24 to 0.46]; P<0.001 for both comparisons). The overall response was higher with Tal-DP and Tal-D than with DPd (88.2% and 88.5% vs. 77.6%), as was complete response or better (71.1% and 69.0% vs. 34.5%) and measurable residual disease-negative complete response (52.3% and 46.3% vs. 15.9%) (P<0.001 for all comparisons). Overall survival at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd (hazard ratio for death, Tal-DP vs. DPd, 0.47 [95% CI, 0.30 to 0.73], and Tal-D vs. DPd, 0.51 [95% CI, 0.33 to 0.78]). Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the patients in the Tal-DP, Tal-D, and DPd groups, respectively; fatal adverse events occurred in 1.8%, 4.0%, and 4.6%.<br><br>CONCLUSIONS: Among patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy, both Tal-DP and Tal-D led to significantly longer progression-free survival than DPd. (Funded by Johnson &amp; Johnson; MonumenTAL-3 ClinicalTrials.gov number, NCT05455320.).}, }
@article {pmid42296457, year = {2026}, author = {Barac, A and Guha, A and Fleming, TR and Bonaca, M and Thavendiranathan, P and Deswal, A and Amiri-Kordestani, L and Bhatnagar, V and Cordoba, R and Hurvitz, S and Adjei, AA and Agarwal, N and , }, title = {Defining Cardiovascular Endpoints in Oncology Trials: Challenges and Opportunities: A Scientific Statement From the American Heart Association.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2501647}, doi = {10.1200/JCO-25-01647}, pmid = {42296457}, issn = {1527-7755}, abstract = {The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular toxicities that manifest through vascular, myocardial, or metabolic pathways, potentially limiting the use of cancer therapeutics and adversely affecting outcomes. Oncology clinical trials provide an important opportunity to evaluate cardiovascular safety signals by generating data on the incidence, timing, and spectrum of toxicities. However, progress has been limited by inconsistent definitions and variable approaches to event characterization. This scientific statement aligns the advances in cardiovascular medicine and cardiovascular clinical trials to provide criteria for systematic selection, rigorous characterization, and adjudication of cardiovascular endpoints in contemporary oncology trials. The proposed framework links drug-specific mechanisms to endpoint selection and standardizes the approach to definitions of adverse cardiovascular events, including heart failure, arrhythmias, myocarditis, and thrombotic events. Definitions of major adverse cardiac events, clinical events, and surrogate endpoints are discussed, along with strategies for alignment with the Common Terminology Criteria for Adverse Events and patient-reported outcomes. Practical guidance is provided for prospective surveillance, decentralized and hybrid clinical trial designs, independent endpoint adjudication, and statistical approaches to competing risks and late-emerging toxicities. By harmonizing cardiovascular endpoint assessment across oncology trials, this scientific statement aims to enhance risk stratification, facilitate regulatory acceptance, and inform clinical decision making, ultimately improving patient safety while supporting innovation in cancer therapeutics.}, }
@article {pmid42145593, year = {2026}, author = {Yeh, CH and Walsh, SR and Parsons, R and Zhang, E and Thakur, B and Song, K and Van Ltallie, E and Clark, M and Williams, W and Edwards, RJ and Hahn, WO and Song, S and Lin, L and Huang, HI and Lugo, J and Quan, A and Xue, Y and Chen, Y and Tuck, R and Mansouri, K and Spence, T and Laukaitis, H and Parks, R and Barr, M and Schweer, E and Levering, N and Eaton, A and Shen, S and Janowska, K and Johnson, G and Wang, P and Cain, D and Arus-Altuz, A and Donahue, E and Kirshner, HF and Zhbannikov, I and Berry, M and Venkatayogi, S and Martin Beem, JS and Hyrien, O and Yu, PC and Parks, R and Polakowski, LL and Tindale, I and Yurdadon, C and Burnham, R and Andriesen, J and Wage, K and Seaman, MS and Montefiori, D and Kelsoe, G and Wiehe, K and Saunders, KO and McElrath, MJ and Corey, L and Mayer, K and Acharya, P and Baden, L and Haynes, BF}, title = {Induction of multiple HIV-1 neutralizing B Cell Precursors in Humans.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42145593}, abstract = {Induction of broadly neutralizing antibodies (bnAbs) remains a central goal of HIV vaccine development. In the HVTN300 clinical trial (NCT04915768), we evaluated an HIV CH505 transmitted/founder (TF) envelope trimer designed to prime naïve B cell precursors of the CD4 binding site (CD4bs) class of bnAbs that use a CDRH3-dominated binding mode. Autologous tier 2 serum neutralizing activity was detected in 9 of 11 vaccinees, and neutralizing B cells were isolated from all participants. CD4bs-directed, CDRH3-binder bnAb precursors were identified in 8 of 11 vaccinees (73%), including one lineage with nascent heterologous breadth that neutralized 6% of global HIV isolates. Cryo-EM structures confirmed CD4bs CDRH3-binder modes of engagement and additionally revealed vaccine-induced V1/V3-directed antibodies and a neutralizing lineage targeting the gp120/gp41 interface. Together, these results demonstrate that the CH505 TF trimer primes a diverse, polyclonal neutralizing B cell repertoire in humans, providing multiple entry points for sequential boosting strategies to achieve HIV bnAb breadth.}, }
@article {pmid42239153, year = {2026}, author = {Wu, W and Greene, JE and Ahmad, K and Henikoff, S}, title = {KAS-CUT&amp;Tag for direct mapping of transcription bubbles.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42239153}, issn = {2692-8205}, abstract = {Transcription by RNA Polymerase II (Pol II) generates dynamic transcription bubbles as it moves forward, but existing methods map transcriptional activity in vivo only indirectly. We introduce KAS-CUT&amp;Tag, a method that combines N3-kethoxal labeling of exposed guanines with CUT&amp;Tag to directly map transcription bubbles. We find that bubble density varies across Pol II-bound genes at transcription start sites, gene bodies, and termination sites. Transcription bubbles are enriched at genes marked by the H3K36me3 histone modification and chromatin-bound splicing factor U2AF2, but the highest enrichment is at replication-coupled histone genes throughout the cell cycle. KAS-CUT&amp;Tag also detects colocalization of the histone gene transcription factor NPAT with Pol II at the Histone Locus Body, suggesting NPAT is juxtaposed to transcription bubbles via interaction with Pol II. Together, KAS-CUT&amp;Tag enables direct mapping of Pol II and regulatory interactions at transcription bubbles, providing a powerful tool for precise analysis of transcriptional activity.}, }
@article {pmid42239335, year = {2026}, author = {Kishishita, A and Cismoski, S and Grant, T and Deo, R and Prudhvi, S and Sue, C and Barpanda, A and Yu, C and Shenoy, S and Berman, S and Reeves, AG and Li, H and Liu, T and Naik, A and Biswas, D and Jiao, F and He, Y and Hancock, M and Dalal, R and Zalevsky, A and Hoopmann, MR and Ye, CJ and Viner, R and Feng, F and Mandal, K and Moritz, RL and Riesco, IE and Sali, A and Wells, JA and Srivastava, S and Huang, L and Wiita, AP}, title = {Extending structural surfaceomics to identify aberrant conformations of tumor surface proteins as potential immunotherapy targets.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42239335}, issn = {2692-8205}, abstract = {The complement of tumor cell surface proteins, or "surfaceome", is a rich source of potential immunotherapy targets. To move beyond expression-based target discovery, we previously described "structural surfaceomics," combining crosslinking mass spectrometry (XL-MS) with surface protein biotinylation to identify conformation-selective targets. In our prior work, we applied this method to a single model of acute myeloid leukemia (AML), identifying active integrin beta-2 as a promising target. Here, we expand structural surfaceomics to identify additional immunotherapy targets and surface protein biology across additional models of AML, multiple myeloma, and prostate cancer, as well as donor peripheral blood mononuclear cells. Utilizing these models and different chemical crosslinkers, we compile an extensive database of 5,209 crosslinks. We characterize both shared and unique crosslink-based features, identifying 1,612 disease model-specific crosslinks, including 212 potentially defining tumor-specific conformations based on distance constraint violations relative to AlphaFold predictions. We further implement a suite of emerging modeling tools to predict tumor-specific protein structures. We probe crosslinking patterns suggesting multiple myeloma-specific CD48 and AML-specific integrin α1/β4 heterodimer conformations. This work establishes a resource for cancer structural biology by implementation of structural surfaceomics. Our findings also point toward more realistic protein design models, potentially enabling systematic detection of targetable cancer-specific epitopes for next-generation immunotherapies.}, }
@article {pmid42279418, year = {2026}, author = {Sujichantararat, S and Biswas, D and Kazerouni, AS and Tsang, ED and Sathe, A and Hippe, DS and Park, VY and Chung, M and Specht, JM and Dintzis, SM and Rahbar, H and Holmes, JH and Huang, W and Partridge, SC}, title = {Deep Learning-Based Synthetic Contrast-Enhanced Breast MRI for Monitoring Response to Neoadjuvant Therapy.}, journal = {Cancers}, volume = {18}, number = {11}, pages = {}, pmid = {42279418}, issn = {2072-6694}, support = {1R01CA248192-04/NH/NIH HHS/United States ; 1R01CA190299-05/NH/NIH HHS/United States ; }, abstract = {Background/Objectives: Contrast-enhanced (CE) breast MRI is highly sensitive for evaluating breast cancer extent and response to neoadjuvant therapy (NAT) but requires intravenous administration of gadolinium-based contrast agents (GBCA), increasing cost, time, patient discomfort, and health concerns. This study explored the feasibility of reducing GBCA use in treatment monitoring using a deep learning (DL) model to synthesize CE-MRI from non-contrast MRI. Methods: This IRB-approved retrospective pilot study evaluated women with breast cancer enrolled in an ongoing trial using serial MRI to monitor NAT prior to surgery. A pre-trained DL model was used to synthesize CE-MRI from T1-, T2-, and diffusion-weighted MRI. Changes in tumor volume at early (post-1-cycle NAT) and mid-treatment were measured on synthetic and acquired CE-MRI. Performance for predicting residual cancer burden (RCB) class 0/1 was evaluated using AUC and compared with DeLong's test. Results: 27 women were included in the study (median age, 47 years [range = 28-75]); 14 (52%) achieved RCB class 0 and six (22%) achieved class 1. Synthetic CE-MRI-derived tumor volumes showed strong correlation with those from acquired CE-MRI at pre-treatment (ρ = 0.92, p < 0.001) and early treatment (ρ = 0.83, p < 0.001), but lower agreement at mid-treatment (ρ = 0.57, p = 0.002). Change in tumor volume on synthetic CE-MRI was numerically similar to acquired CE-MRI for predicting RCB class 0/1 vs. 2/3 at both early (AUC = 0.84 vs. 0.86, p = 0.83) and mid-treatment (AUC = 0.73 vs. 0.75, p = 0.80). Conclusions: Synthetic CE-MRI demonstrates preliminary feasibility as a non-contrast surrogate for predicting favorable outcomes (RCB class 0/1) in this pilot study, but inconsistencies in tumor volume measurement vs. acquired CE-MRI warrant further model refinement and validation.}, }
@article {pmid42280448, year = {2026}, author = {Bodenrader, A and Sotres-Alvarez, D and Dao, MC and Scott, TM and Aytur, SA and Noel, SE and Qi, Q and Gallo, LC and Daviglus, M and Tarraf, W and Kaplan, R and Bigornia, SJ}, title = {Dairy Products Are Not Adversely Associated with Depressive Symptoms over 6 Years in the Hispanic Community Health Study/Study of Latinos.}, journal = {Nutrients}, volume = {18}, number = {11}, pages = {}, pmid = {42280448}, issn = {2072-6643}, support = {HHSN268201300001I/N01-HC-65233//National Heart Lung and Blood Institute/ ; HHSN268201300004I/N01-HC-65234//National Heart Lung and Blood Institute/ ; HHSN268201300003I/ N01-HC-65236 Northwestern Univ//National Heart Lung and Blood Institute/ ; HHSN268201300005I/N01-HC-65237//National Heart Lung and Blood Institute/ ; Grant Numbers not applicable//National Dairy Council/ ; }, mesh = {Humans ; *Dairy Products/adverse effects ; *Hispanic or Latino/psychology ; Female ; Male ; *Depression/ethnology/epidemiology/etiology ; Prospective Studies ; Adult ; Middle Aged ; *Diet ; United States/epidemiology ; }, abstract = {Background/Objectives: Current evidence suggests that Hispanic/Latino adults experience a disproportionate burden of depression. Dairy consumption has been associated with fewer depressive symptoms, but examinations in Hispanic/Latino cohorts are unavailable. Our objective was to measure the 6-year prospective associations between dairy consumption and depressive symptoms among Hispanic/Latino adults. Methods: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a prospective population-based cohort study of 16,415 Hispanic/Latino adults residing in the US. We estimated daily dairy product consumption from two 24 h baseline dietary recalls using the National Cancer Institute method. The 10-item Center for Epidemiological Studies Depression Scale (CESD10) administered at baseline and follow-up assessed depressive symptoms. Survey multiple linear regression models adjusted for baseline CESD10 and other covariates, including sociodemographic, dietary and health factors. Standardized β coefficients represent the standard deviation difference in 6-year CESD10 score per one standard deviation increase in daily dairy intake at baseline. Complete data were available among 10,618 participants. Results: Neither baseline total dairy consumption (standardized β (95% CI); -0.019 (-0.048, 0.011)), nor milk (-0.006 (-0.029, 0.018)), cheese (0.038 (-0.006, 0.081)), or cream (-0.005 (-0.037, 0.028), p > 0.05 for all) consumption was significantly associated with the follow-up CESD10 score. Conversely, we observed a significant and inverse association between yogurt (-0.036 (-0.058, -0.013), p = 0.002) and butter (-0.049 (-0.092, -0.006), p = 0.027) with the CESD10 score. Conclusions: Total dairy, fat-based dairy groupings, milk, cheese, and cream were not associated with CESD10 score at 6-year follow-up; yogurt and butter showed inverse associations that require cautious interpretation due to very small effect sizes. Although additional prospective analyses in other diverse cohorts are needed to confirm these results, our findings suggest that dairy consumption is not adversely associated with depressive symptoms in Hispanic/Latino adults.}, }
@article {pmid42281185, year = {2026}, author = {Gray, SL and Piccorelli, AV and Hart, LA and Cook, AJ and Williamson, BD and Balderson, BH and Phelan, EA}, title = {Substitution Patterns After Discontinuation of CNS-Active Medications in Older Adults in Primary Care.}, journal = {Journal of the American Geriatrics Society}, volume = {}, number = {}, pages = {}, doi = {10.1111/jgs.70514}, pmid = {42281185}, issn = {1532-5415}, support = {U01CE002967/CC/CDC HHS/United States ; }, abstract = {BACKGROUND: Little is known about substitution of alternative medications in the context of deprescribing. The objectives were to: (1) determine the frequency of medication substitutions among those who discontinued a central nervous system (CNS)-active medication, and (2) characterize substitutions as potentially inappropriate (as per the 2023 Beers Criteria) versus not.<br><br>METHODS: We conducted a secondary analysis that combined data from the intervention and usual care arms from the STOP-FALLS deprescribing trial that tested a health-system-embedded intervention designed to reduce prescription of CNS-active medications. This analysis focused on participants followed for 360&#x2009;days following baseline with chronic use of opioids, benzodiazepines, tricyclic antidepressants, skeletal muscle relaxants, or Z-drugs. Discontinuation was defined as the first date when there was no evidence of a prescription fill for 90&#x2009;days, thus only participants with a discontinuation that occurred in the first 270&#x2009;days were included. A list of likely alternative treatments was developed for each target medication. A substitution was operationalized as a new alternative medication prescribed during the 30&#x2009;days prior to or 60&#x2009;days after discontinuation of a target medication.<br><br>RESULTS: The study sample included 2182 individuals (average age 70.5&#x2009;years, 63.1% female). At baseline, a total of 2415 target medications were prescribed, of which 442 (18.3%) were discontinued. Discontinuation rates varied from 122 (8.0%) for users of opioids to 86 (49.7%) for users of skeletal muscle relaxants. Substitutions were made for 42 (9.5%) drug discontinuations. Of these substitutions, 11 of 42 (26.2%) were to a potentially inappropriate medication: tricyclic antidepressants (n&#x2009;=&#x2009;5), benzodiazepines (n&#x2009;=&#x2009;3) and hydroxyzine (n&#x2009;=&#x2009;3). Other common substitutions included gabapentin, selective serotonin norepinephrine reuptake inhibitors, and trazodone.<br><br>DISCUSSION: Of medication discontinuations with a substitution, one-quarter were to at least one potentially inappropriate medication. This finding highlights the need for additional guidance for prescribers to ensure safe deprescribing of CNS-active medications.}, }
@article {pmid42284622, year = {2026}, author = {Aragon-Ching, JB and Gupta, S and Grivas, P and Park, SH and Petrylak, DP and Sridhar, SS and Gurney, H and Jacob, N and Tyroller, K and Hoffman, J and Bellmunt, J}, title = {Avelumab first-line maintenance for advanced urothelial carcinoma: long-term outcomes from the JAVELIN Bladder 100 trial in patients with high body mass index or diabetes mellitus.}, journal = {ESMO open}, volume = {11}, number = {7}, pages = {107776}, doi = {10.1016/j.esmoop.2026.107776}, pmid = {42284622}, issn = {2059-7029}, abstract = {BACKGROUND: Avelumab first-line maintenance is the recommended treatment option for patients with advanced urothelial carcinoma (UC) without progression following platinum-based chemotherapy (PBC), based on the phase III JAVELIN Bladder 100 trial. High body mass index (BMI; ≥30 kg/m[2]) and diabetes mellitus (DM) are risk factors for bladder cancer. We report exploratory analyses from JAVELIN Bladder 100 in patients with high BMI or documented controlled DM at the time of random assignment.<br><br>PATIENTS AND METHODS: JAVELIN Bladder 100 enrolled patients with advanced UC without progression after first-line PBC, who were randomly assigned to receive avelumab plus best supportive care (BSC; n = 350) or BSC alone (n = 350). The primary endpoint was overall survival (OS) from the time of random assignment.<br><br>RESULTS: Overall, 122 patients (17.4%) had high BMI and 114 (16.3%) had DM. After a median follow-up of &#x2265;38 months in both arms, hazard ratios for OS with avelumab plus BSC versus BSC alone were 0.77 [95% confidence interval (CI) 0.49-1.21] in patients with high BMI and 0.60 (95% CI, 0.37-0.95) in patients with DM. Long-term safety of avelumab maintenance in these subgroups was generally consistent with that of the overall population.<br><br>CONCLUSIONS: Exploratory analyses support the use of avelumab first-line maintenance in patients with advanced UC without progression following PBC, including those with high BMI or DM.}, }
@article {pmid42286308, year = {2026}, author = {Rogers, JR and Ward, ZJ and Stratton, KL and Leisenring, WM and Taylor, CS and Armstrong, GT and Chow, EJ and Feraco, AM and Howell, RM and Hudson, MM and McMahon, M and Morton, LM and Oeffinger, KC and Smith, SA and Diller, L and Yeh, JM}, title = {Modeling long-term mortality and morbidity in pediatric Hodgkin lymphoma survivors after reduced radiotherapy exposure.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag186}, pmid = {42286308}, issn = {1460-2105}, abstract = {BACKGROUND: Long-term survivors of pediatric Hodgkin lymphoma are at risk of late treatment-related mortality, cancer, and heart disease. While modified treatments have reduced radiation exposure, long-term risks in late adulthood are unknown.<br><br>METHODS: Using a simulation model based on data from the Childhood Cancer Survivor Study and national databases, we projected overall survival and cumulative incidence of breast cancer and heart failure for 5-year survivors treated with extended-field RT, chest RT&#x2009;&#x2265;&#x2009;35&#x2009;Gy, chest RT&#x2009;<&#x2009;35&#x2009;Gy, or chemotherapy only. Estimates were compared with general population individuals who faced only age-related risks. We report the mean and 95% uncertainty intervals (UIs) among 1000 iterations.<br><br>RESULTS: At age 65, projected overall survival ranged from 24.7% (95% UI, 17.7 to 32.5) after extended-field RT to 71.8% (44.9 to 81.8) after chemotherapy only, compared with 86.4% (83.8 to 88.8) in the general population. Cumulative breast cancer incidence among female survivors was 61.1% for extended-field RT, 59.7% for chest RT&#x2009;&#x2265;&#x2009;35&#x2009;Gy, 49.8% for chest RT&#x2009;<&#x2009;35&#x2009;Gy, and 17.9% for chemotherapy only, respectively, versus 6.1% in the general population. Heart failure risks among all survivors were 34.8%, 33.4%, 28.4%, and 16.0, respectively, versus 4.3%. Across all subgroups, breast cancer and heart failure were projected to occur 16.1-31.7 and 21.0-25.9 years earlier, respectively, relative to general population risks at age 65.<br><br>CONCLUSIONS: Although historical reductions in RT dose and field have substantially improved long-term survival, survivors treated with lower-dose or chemotherapy alone remain at markedly elevated risk for early-onset breast cancer and heart failure.}, }
@article {pmid42286829, year = {2026}, author = {Mage, PL and Konecny, AJ and Mair, F}, title = {Measurement and Prediction of Unmixing-Dependent Spreading due to Collinearity in Spectral Flow Cytometry.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {}, number = {}, pages = {}, doi = {10.1002/cyto.a.70044}, pmid = {42286829}, issn = {1552-4930}, abstract = {Advances in spectral cytometry instrumentation and fluorescent reagents have led to the possibility of ultra-high-parameter panels exceeding 50 colors. However, panel size is limited in practice by unmixing-dependent spreading (UDS), a phenomenon which leads to a progressive deterioration of unmixed signal-to-noise ratios in panels that contain fluorochrome combinations with significant spectral overlap. So far, choosing spectrally compatible sets of fluorochromes that avoid UDS has been a complex and labor-intensive task involving substantial trial-and-error experimentation. Here, we provide a detailed explanation of UDS and practical strategies for handling UDS in large spectral panels. We describe the empirical hallmarks of UDS, demonstrate how to quantify its impact, and dissect its underlying mathematical cause in terms of spectral collinearity. We present practical tools derived from the regression literature that can be used to select optimal combinations of fluorochromes in a platform-agnostic fashion based on publicly available reference data, providing a general tool for spectral panel design.}, }
@article {pmid42288368, year = {2026}, author = {Fogh, SE and Greenlee, H and Langley, B and Gillespie, EF and Wonders, KY and Marshall, N}, title = {Exercise in Oncology Patients: A Call for Strategies to Address the Critical Gap Between Evidence-Based Recommendations and Implementation.}, journal = {Seminars in radiation oncology}, volume = {38}, number = {}, pages = {151025}, doi = {10.1016/j.semradonc.2026.151025}, pmid = {42288368}, issn = {1532-9461}, mesh = {Humans ; *Neoplasms/therapy ; Quality of Life ; Evidence-Based Medicine ; *Exercise ; *Exercise Therapy/methods ; Practice Guidelines as Topic ; }, abstract = {Physical activity has demonstrated positive impact on cancer outcomes, including survival and quality of life, in patients throughout the trajectory of cancer treatment. Government and leading health organizations have included exercise among cancer-prevention guidelines based on substantial evidence demonstrating clear benefits, including reductions in treatment-related side effects, higher chemotherapy completion rates, improved physical fitness and functionality, and increases in health-related quality of life. Despite clear consensus-based recommendations, a gap exists between what is known to benefit patients with cancer and the implementation of an intervention which has consistently demonstrated a positive impact on patient outcomes. It is critical to develop customized programming, reimbursement and thoughtful strategies that consider both patient and provider barriers to implementing exercise as part of cancer treatment.}, }
@article {pmid42288371, year = {2026}, author = {Astaphan, DJ and Blanco, MM and Riviere, P and Fogh, SE and Greenlee, H and Gillespie, EF}, title = {Clinical Trials of Integrative Oncology Interventions for Radiation Therapy: Emerging Evidence and Opportunities.}, journal = {Seminars in radiation oncology}, volume = {38}, number = {}, pages = {151045}, doi = {10.1016/j.semradonc.2026.151045}, pmid = {42288371}, issn = {1532-9461}, mesh = {Humans ; *Neoplasms/radiotherapy/psychology ; *Clinical Trials as Topic ; *Integrative Oncology/methods ; Quality of Life ; *Radiotherapy/adverse effects ; }, abstract = {Integrative oncology interventions for patients undergoing radiation therapy (RT) may relieve symptoms (including procedural anxiety) and improve quality of life, though gaps remain in the evidence base to adequately guide implementation efforts. In this article we review clinical trials specifically for psychological (ie, mindfulness), physical (ie, exercise, acupuncture), and combination approaches (ie, yoga, tai chi, and qigong), in which several symptom-based clinical outcomes are impacted (ie, fatigue, sleep disturbance, pain, mood, and xerostomia). We identified at least 90 clinical trials and 15 systematic reviews and meta-analyses related to this topic, but note the predominance of early-phase investigations and some heterogeneity in study findings. We also assess opportunities across the radiation treatment continuum, noting most interventions were targeted during active radiation treatment. Future research ought to leverage novel hybrid study designs and multi-center community-based clinical settings (including cooperative groups) to confirm effectiveness and generalizability of findings of existing earlier phase clinical trials. Meanwhile, opportunities to improve clinical trial efficiency such as integrating advanced practice providers and patient-reported outcomes in routine care should be considered. As a field with procedural elements, established symptom trajectories, and often daily patient engagement, radiation oncology is poised to develop and implement interventions that advance symptom science and clinical outcomes for patients with cancer.}, }
@article {pmid42288686, year = {2026}, author = {Lange, JM and Ahmad, I and Dengos, IJ and Ryan, A and Apostolidou, S and Gentry-Maharaj, A and Holloway, S and Ryser, MD and Menon, U and Etzioni, R}, title = {Can ovarian cancer screening work? A secondary analysis of the UK collaborative trial of ovarian cancer screening.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {42288686}, issn = {1532-1827}, support = {NIHR HTA grant 16/46/01//DH | National Institute for Health Research (NIHR)/ ; NIHR HTA grant 16/46/01//DH | National Institute for Health Research (NIHR)/ ; NIHR HTA grant 16/46/01//DH | National Institute for Health Research (NIHR)/ ; C1479/A2884//Cancer Research UK (CRUK)/ ; C1479/A2884//Cancer Research UK (CRUK)/ ; C1479/A2884//Cancer Research UK (CRUK)/ ; G9901012 and G0801228//RCUK | Medical Research Council (MRC)/ ; G9901012 and G0801228//RCUK | Medical Research Council (MRC)/ ; G9901012 and G0801228//RCUK | Medical Research Council (MRC)/ ; R35CA274442//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R35CA274442//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R35CA274442//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {BACKGROUND: The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; 2001-2020) showed no reduction in disease mortality in its primary intervention arm using multimodal screening (MMS) with longitudinal Cancer Antigen 125 (CA125) and transvaginal ultrasound. Whether this null result reflects the stop-screen design, screening performance, or ovarian cancer natural history remains unclear.<br><br>METHODS: Using individual-level screening and diagnosis data from the MMS arm, we estimated ovarian cancer natural history, focusing on high-grade serous ovarian cancer (HGSC), the most common and lethal subtype. We then simulated trial outcomes under (1) continued screening beyond the trial screening interval and (2) high sensitivity for early-stage detection over an extended time period.<br><br>RESULTS: The estimated window for detecting early-stage HGSC under MMS was <6 months. Continued screening yielded at most a 15% relative mortality reduction. Achieving a&#x2009;&#x2265;20% mortality reduction required extending the detectable early-stage window to 1 year and attaining &#x2265;70% sensitivity during this period.<br><br>CONCLUSION: Current screening modalities offer a very limited opportunity to intercept HGSC at an early stage. Clinically effective ovarian cancer screening will require first- and second-line tests capable of detecting HGSC substantially earlier in its natural history.}, }
@article {pmid42292132, year = {2026}, author = {Cassidy, T and Belluccini, G and Iyaniwura, SA and Ribeiro, RM and Perelson, AS}, title = {INHERITANCE OF INTRACELLULAR VIRAL RNA IN A MULTISCALE MODEL OF HEPATITIS C INFECTION.}, journal = {SIAM journal on applied mathematics}, volume = {86}, number = {3}, pages = {791-813}, pmid = {42292132}, issn = {0036-1399}, abstract = {Multiscale mathematical models of hepatitis C infection have been instrumental in our understanding of direct acting antivirals. These models include the mechanisms driving intracellular viral production and explicitly model the intracellular concentration of viral RNA. However, incorporating proliferation of infected hepatocytes in these models can be subtle, as infected daughter cells inherit viral RNA from the proliferating mother cell. Here, we show how to incorporate this inheritance within a multiscale model of HCV infection. As in typical multiscale models of HCV infection, we show that this model is mathematically equivalent to a system of ordinary differential equations and perform bifurcation analysis of the resulting ODE that demonstrates that proliferation of infected hepatocytes can lead to infection persistence even if the basic reproductive number is less than one.}, }
@article {pmid42294510, year = {2026}, author = {Blackmore, SJ and Gala, N and Fraser-Purdy, H and Moore, IC and Olaogun, D and Ovtsyn, D and Allick, C and Arola, K and Aspin, C and Burack, JA and Garneau, AB and Campbell, ANC and Efimoff, I and Fetter, AK and Gone, JP and Greenfield, BL and Iyer, SN and Kirmayer, L and Kropp, FB and Melro, C and Nelson, LA and O'Connor, RM and Paul, J and Phillips, M and Pride, T and Skewes, MC and Stoor, JPA and Tremblay, MC and Ullrich, JS and Walls, ML and Warne, D and Wendt, DC}, title = {Indigenous Research Sovereignty Within Academia: Challenges and Opportunities.}, journal = {SSM. Mental health}, volume = {9}, number = {}, pages = {}, pmid = {42294510}, issn = {2666-5603}, abstract = {Indigenous Peoples' inherent right to self-determination includes authority over research, yet university systems centralize control in ways that constrain Indigenous sovereignty. This article examines how academic institutional structures and processes-well beyond the actions of individual researchers-shape the possibilities and limitations of Indigenous-focused research within universities. Drawing on a collaborative, story-based process involving Indigenous and non-Indigenous researchers working with Indigenous communities across diverse regions and contexts internationally, we synthesize shared experiences to identify recurrent challenges and the systemic conditions that produce them. We describe both barriers and solutions within five themes: governance, institutional fit, burden, capacity, and relationships. Examples of barriers include paternalizing ethics boards, cumbersome financial systems, rigid timelines, and narrow evaluation metrics, which often conflict with community-defined governance and relational approaches to research. Examples of solutions include Indigenous-governed funding pathways, community ethics bodies, Indigenous-led research units, and institution-level efforts to embed relational accountability. We argue that strengthening Indigenous research sovereignty requires universities and funders to redesign their infrastructures (not simply adjust procedures), meaningfully share authority, align practices with Indigenous governance, and support long-term relationship building. By centering community leadership and relational accountability, universities can move beyond symbolic or superficial commitments to Indigenous self-determination in research, toward research environments rooted in respect, reciprocity, and community-defined outcomes.}, }
@article {pmid42279178, year = {2026}, author = {Anderson, LJ and Okamura, L and Dhunjishah, N and Gowrisankar, R and Song, J and Chauncey, TR and Garcia, JM}, title = {Baseline Functional Performance Predicts Better Long-Term Self-Reported Physical Function After Auto-HSCT.}, journal = {Journal of clinical medicine}, volume = {15}, number = {11}, pages = {}, doi = {10.3390/jcm15114318}, pmid = {42279178}, issn = {2077-0383}, abstract = {Background/Objectives: Determination of baseline predictors of longer-term quality of life (QOL) after autologous hematopoietic stem cell transplantation (Auto-HSCT) may identify patients with the greatest supportive care needs. We hypothesized that baseline older age, weight loss, and worse functional performance would negatively predict QOL over two years post-HSCT. Methods: Physical function, body composition, and QOL were assessed before (PRE) and one month (1MO) after Auto-HSCT in U.S. Veterans (N = 23). QOL and survival were also assessed approximately every six months for two years after Auto-HSCT (5MO, 1YR, 1.5YR, and 2YR). Changes over time were tested via Generalized Estimating Equation regression analyses (p < 0.05 = significant). The impact of PRE variables on QOL at each follow-up was tested via Spearman's correlations (p < 0.01 = significant). Results: Relative to PRE, depression and anxiety significantly improved (p ≤ 0.039) at 1MO while fatigue and vitality significantly worsened (p ≤ 0.024) 1MO to 5MO post-HSCT. Vitality, depression, and anxiety returned to PRE levels thereafter, while fatigue trajectory varied depending on the survey used. Bone-Marrow-Transplant-related QOL significantly improved at 5MO (p = 0.014) while self-reported function (p ≤ 0.021) and physical activity (p ≤ 0.045) significantly improved 1-2YR post-HSCT. Greater PRE 30 s chair stand test performance consistently correlated with better self-reported function 1-2YR (r = 0.76-0.91, p ≤ 0.007) post-HSCT. Greater PRE 6 min walk test performance consistently correlated with better symptom burden 1-2YR (r = 0.71-0.81, p ≤ 0.01) post-HSCT. Conclusions: In support of our hypothesis, baseline functional performance was associated with QOL during two years of recovery after Auto-HSCT; older age and recent weight loss at baseline only predicted worse baseline QOL. Our data indicates that evaluation of the 30 s chair stand and 6 min walk tests as rehabilitation targets and/or predictors of QOL, fitness, or mortality after Auto-HSCT are warranted. Larger, controlled studies are needed to confirm the findings from this exploratory analysis.}, }
@article {pmid41984995, year = {2026}, author = {Lee-Miller, CA and Kairalla, JA and Hibbitts, E and Winick, NJ and Rabin, KR and Angiolillo, A and Schore, RJ and Salzer, WL and Burke, MJ and Loh, ML and Raetz, EA and Hunger, SP and Devidas, M and Teachey, DT and Gupta, S and McNeer, JL}, title = {Adding induction intrathecal cytarabine in newly diagnosed CNS2 B-acute lymphoblastic leukemia does not improve outcomes.}, journal = {Blood advances}, volume = {10}, number = {12}, pages = {4184-4192}, doi = {10.1182/bloodadvances.2026019660}, pmid = {41984995}, issn = {2473-9537}, mesh = {Humans ; *Cytarabine/administration &amp; dosage/therapeutic use ; Injections, Spinal ; Female ; Male ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/mortality/diagnosis ; Child ; Child, Preschool ; Treatment Outcome ; Adolescent ; *Central Nervous System Neoplasms/drug therapy ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Antimetabolites, Antineoplastic/administration &amp; dosage/therapeutic use ; Prognosis ; }, abstract = {Patients with central nervous system (CNS) disease at diagnosis on Children's Oncology Group (COG) B-acute lymphoblastic leukemia (B-ALL) trials AALL0331 and AALL0232 had inferior outcomes, largely secondary to CNS relapse. In response, for patients with newly diagnosed B-ALL enrolled on COG studies AALL0932 and AALL1131, therapy was adjusted to incorporate additional intrathecal cytarabine during induction for patients with low-level CNS involvement (CNS2). We evaluated the impact of this intervention.Event-free survival, overall survival, and cumulative incidence of relapse were compared among patients with CNS2 B-ALL before vs after amendment, stratified by receipt of a 3-drug (standard-risk) or 4-drug (high-risk) induction. Multivariable models were constructed to adjust for demographic and disease variables. When stratified by trial, preamendment and postamendment patients with CNS2 status did not differ significantly by demographic or disease factors. Additional intrathecal cytarabine doses during induction did not improve outcomes for patients with B-ALL. Multivariate analyses adjusting for disease prognosticators, race/ethnicity, and leukemia cytogenetics did not identify any subpopulation that significantly benefited from additional intrathecal cytarabine. Additional intrathecal cytarabine during induction for patients with CNS2 B-ALL did not improve outcomes or mitigate the adverse prognostic impact of CNS2 status in B-ALL. Future COG B-ALL studies will not include additional intrathecal cytarabine in induction for patients with CNS2 disease. Alternative treatment strategies are needed for patients with CNS2 disease.}, }
@article {pmid41985005, year = {2026}, author = {Wang'ondu, R and Kairalla, JA and Shago, M and Angiolillo, AL and Breidenbach, H and Burke, MJ and Carroll, AJ and Rabin, KR and Salzer, WL and Schore, RJ and Wang, C and Hunger, SP and Teachey, DT and Raetz, EA and Loh, ML and Davis, KL and Rau, RE}, title = {Chromosome 15q deletions confer inferior outcomes among children with ETV6::RUNX1 B-cell acute lymphoblastic leukemia.}, journal = {Blood advances}, volume = {10}, number = {12}, pages = {4109-4112}, doi = {10.1182/bloodadvances.2026019599}, pmid = {41985005}, issn = {2473-9537}, }
@article {pmid42274313, year = {2026}, author = {Wang, N and DiCorpo, DA and Zhang, Y and Kleinbrink, E and Arnett, DK and Barnard, J and Blangero, J and Bowden, DW and Carson, AP and Chen, YI and Chung, MK and Curran, JE and Darbar, D and Duggirala, R and Ellinor, PT and Fatkin, D and Fornage, M and Heard-Costa, N and He, J and Hou, L and Kardia, SLR and Kooperberg, C and Loos, RJF and McManus, DD and Mitchell, BD and Minster, RL and North, KE and Psaty, BM and Raffield, LM and Redline, S and Rich, SS and Roden, D and Rotter, JI and Shoemaker, MB and Smith, JD and Van Wagoner, DR and Aguet, F and Ardlie, K and Bis, JC and Brody, JA and Cade, BE and Clish, CB and de Vries, PS and Floyd, JS and Freedman, BI and Gabriel, S and Gerzsten, RE and Goodarzi, MO and Gu, C and Guo, X and Gupta, N and Heckbert, SR and Hsu, S and Hung, YJ and Kalyani, RR and Kelly, TN and Kinney, GL and Li, C and Liu, S and Liu, Y and Lloyd-Jones, DM and Manson, JE and Mathias, RA and Mercader, JM and Morrison, AC and Naseri, T and Onengut, S and Palmer, ND and Peyser, PA and Qi, Q and Raghavan, S and Reiner, AP and Rooney, MR and Sevilla-Gonzalez, M and Sarnowski, C and Smith, JD and Smith, JA and Spartano, NL and Tahir, U and Taylor, KD and Tobias, DK and Tracy, RP and Viali, S and Wang, H and Wood, AC and Yanek, LR and Zhao, W and Zheng, Y and Dupuis, J and Liu, CT and Sladek, R and Wessel, J and Meigs, JB and Manning, AK and , }, title = {Colocalization of eQTLs With Type 2 Diabetes and Glycemic Traits Using Whole-Genome Sequences in Diverse Populations From the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.}, journal = {Diabetes}, volume = {}, number = {}, pages = {}, doi = {10.2337/db25-0557}, pmid = {42274313}, issn = {1939-327X}, support = {UM1DK078616/DK/NIDDK NIH HHS/United States ; }, abstract = {We aimed to improve understanding of the genetic architecture of type 2 diabetes and glycemic traits by leveraging whole-genome sequencing in diverse populations. Our goal was to identify novel variants, refine known loci, and link genetic signals to regulatory mechanisms through colocalization with expression quantitative trait loci. We discovered novel variants, significantly improved fine-mapping resolution, and identified 80 regulatory colocalization signals in diabetes-relevant tissues. These findings support precision medicine approaches by connecting genetic variation to functional biology in type 2 diabetes.}, }
@article {pmid42274332, year = {2026}, author = {Zhang, J and Bellocco, R and Jia, Y and Nasrollahzadeh, D and Zagai, U and Jeske, R and Waterboer, T and Wu, AH and Anderson, LA and Risch, HA and Vaughan, TL and Ye, W}, title = {The role of gastric atrophy in the association between Helicobacter pylori infection and esophageal adenocarcinoma.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-1312}, pmid = {42274332}, issn = {1538-7755}, abstract = {BACKGROUND: The mechanism underlying pathways between H. pylori infection, gastric atrophy, and esophageal adenocarcinoma (EAC) is yet to be quantitatively investigated.<br><br>METHODS: 435 patients with EAC and 1298 cancer free subjects were included from the International Barrett's and Esophageal Adenocarcinoma Consortium (BEACON). Samples collected from 1993 to 2004. Gastric atrophy was determined by serum pepsinogens. H. pylori infection was assessed by antibodies against 15 antigens. Logistic regression models were fitted to estimate odds ratio, to quantify the association between antibodies and gastric atrophy. The 4-way decomposition of the overall effect in natural direct and indirect effects was used to measure the intermediate effects of mediators between H. pylori and EAC, while also considering their role as effect modifiers.<br><br>RESULTS: Seropositivity for 15 H. pylori antigens was associated with a lower risk of EAC; the ORs ranged from 0.44 (95% CI; 0.40-0.49) to 0.91 (95% CI; 0.84-0.98). Seropositivity for multiple antigens was also associated with a reduced risk of EAC. The effect of H. pylori infection was not mediated through gastric atrophy, body mass index (BMI), and gastroesophageal reflux disease (GERD), whether these factors were examined individually or jointly, as the estimates of natural indirect effects were close to 0.<br><br>CONCLUSIONS: This study confirmed the inverse association between H. pylori and EAC, which was not mediated by gastric atrophy nor the combination with BMI and GERD.<br><br>IMPACT: It suggests refining EAC risk prediction models and exploring other potential mediators and pathways between H. pylori and EAC.}, }
@article {pmid42274978, year = {2026}, author = {Shadman, M and Munir, T and Xu, S and Yang, K and Mohseninejad, L and Guthrie, G and Hirata, J and Lefebure, M and Williams, R and Tam, CS}, title = {Indirect Comparison of the Efficacy of Zanubrutinib vs Ibrutinib and Acalabrutinib in Treatment-Naive Chronic Lymphocytic Leukemia: 6-Year Follow-Up.}, journal = {Advances in therapy}, volume = {}, number = {}, pages = {}, pmid = {42274978}, issn = {1865-8652}, abstract = {INTRODUCTION: Zanubrutinib, acalabrutinib, and ibrutinib each demonstrated improved investigator-assessed progression-free survival (PFS-INV) and overall survival (OS) versus chemotherapy-based regimens in treatment-naive chronic lymphocytic leukemia (CLL) in the phase 3 trials SEQUOIA (NCT03336333), ELEVATE-TN (NCT02475681), and RESONATE-2 (NCT01722487), respectively. In the absence of head-to-head studies, this analysis compared the efficacy of zanubrutinib vs ibrutinib and vs acalabrutinib in treatment-naive CLL via indirect naive comparisons.<br><br>METHODS: Eligibility criteria were aligned to improve cross-trial comparability. The zanubrutinib vs ibrutinib comparison included COVID-19-adjusted PFS-INV and OS in arm A of SEQUOIA (n = 241; median follow-up, 73.4 months) and the ibrutinib arm of RESONATE-2 (n = 136; median follow-up, 88.5 months). The zanubrutinib vs acalabrutinib comparison included PFS-INV and OS in subgroups of patients without del(17p) and/or TP53 mutations from arm A of SEQUOIA (n = 215; median follow-up, 73.6 months) and the acalabrutinib arm of ELEVATE-TN (n = 156; median follow-up, 74.5 months).<br><br>RESULTS: Baseline characteristics were similar for each comparison. Zanubrutinib significantly prolonged PFS-INV (hazard ratio [HR], 0.65; 95% CI, 0.44-0.97; P = 0.0330) and showed a trend toward improved OS (HR, 0.60; 95% CI, 0.36-1.01; P = 0.0532) vs ibrutinib. At the 72-month landmark, PFS-INV and OS rates were significantly higher with zanubrutinib vs ibrutinib, with a risk difference of 15.3% (95% CI, 8.3-22.2%) for PFS and 9.9% (95% CI, 3.0-16.7%) for OS. Compared with acalabrutinib, zanubrutinib trended toward improved PFS-INV (HR, 0.76; 95% CI, 0.52-1.11; P = 0.1553) and OS (HR, 0.66; 95% CI, 0.41-1.06; P = 0.0836). The 72-month landmark PFS-INV and OS rates were significantly higher with zanubrutinib vs acalabrutinib, with a risk difference of 9.9% (95% CI, 3.0-16.9%) for PFS-INV and 8.8% (95% CI, 2.0-15.5%) for OS.<br><br>CONCLUSION: These findings inform the long-term comparative efficacy of Bruton tyrosine kinase inhibitors and suggest that zanubrutinib may confer sustained PFS and OS benefits compared with ibrutinib and acalabrutinib in similar treatment-naive CLL populations. Graphical abstract and video available for this article. Overview of the Comparative Efficacy of Covalent BTK Inhibitors in Treatment-Na&#xef;ve CLL/SLL With Six-Year Follow-Up (MP4 345006 kb).}, }
@article {pmid42275226, year = {2026}, author = {St Germain, R and Sholukh, AM}, title = {Protocol for antibody-dependent cellular phagocytosis assay with controlled IgG concentrations in tested samples.}, journal = {STAR protocols}, volume = {7}, number = {2}, pages = {104626}, doi = {10.1016/j.xpro.2026.104626}, pmid = {42275226}, issn = {2666-1667}, abstract = {Here, we present a protocol to equalize antibody concentrations between samples to focus analysis on IgG properties rather than phagocytosis driven by antibody concentration. We describe steps for quantitating antigen-specific IgG in serum using a suitable binding assay, diluting samples to equalize IgG concentration, and using the antibody-dependent cellular phagocytosis (ADCP) assay. We then detail procedures for measuring differences in antibody properties between experimental groups by running diluted samples in the ADCP assay or other effector function assays. For complete details on the use and execution of this protocol, please refer to St. Germain et al.[1].}, }
@article {pmid42276049, year = {2026}, author = {Liang, J and Jiang, X and Reitsam, NG and Lenz, T and Zhang, L and Gustav, M and Carrero, ZI and Muti, HS and Neidlinger, P and Clusmann, J and Žigutytė, L and Sainath, V and Wolf, F and Boardman, LA and French, AJ and Goode, EL and Gsur, A and Brezina, S and Gunter, MJ and Steinfelder, R and Harrison, T and Peters, U and Phipps, AI and Quirke, P and West, NP and Hoffmeister, M and Brenner, H and Wankhede, D and Jonnagaddala, J and Hawkins, N and Ward, RL and Fountzilas, E and Papadopoulou, K and Fountzilas, G and André, T and Taieb, J and Emile, JF and Svrcek, M and Kong, L and Kather, JN}, title = {Spatial biomarker discovery via interpretable semantic learning in histopathology.}, journal = {Cancer cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ccell.2026.05.014}, pmid = {42276049}, issn = {1878-3686}, abstract = {Spatial biomarkers are critical for precision oncology but remain challenging to systematically discover due to the complexity of whole-slide images. We present PathPrism, an interpretable AI framework for spatial biomarker discovery and virtual experimentation. Unlike black-box models, PathPrism encodes tissue architecture into pathologically informed spatial features, enabling transparent modeling of prognosis, molecular alterations, and therapy response. Applied to 7,000 patients with colorectal cancer across 11 cohorts, PathPrism uncovered hundreds of biomarkers predictive of survival, MSI, BRAF, and TP53 mutations, and stratified chemotherapy benefit in stage II/III disease. Building on these interpretable findings, PathPrism uses large language models as auxiliary tools to generate hypotheses grounded in spatial semantics. We further introduce VirtualWSI, a platform for semantic perturbation within an interpretable spatial biomarker atlas. PathPrism provides a scalable and interpretable framework for spatial biomarker discovery.}, }
@article {pmid42276543, year = {2026}, author = {Noyd, DH and Coons, L and Bank, JD and Larimer, E and Garson, G and Aliferakis, V and Giovannetti, T and Villavicencio, C and Lin, YH and Leu, MG and Chow, EJ and Heike, CL}, title = {An Informatics Approach to Enhance Care for Childhood, Adolescent and Young Adult Cancer Survivors Through Population Health Management.}, journal = {Cancer control : journal of the Moffitt Cancer Center}, volume = {33}, number = {}, pages = {10732748261460117}, doi = {10.1177/10732748261460117}, pmid = {42276543}, issn = {1526-2359}, abstract = {IntroductionAdolescent and young adult (AYA) cancer survivors are at significant risk for late treatment-related effects yet face challenges when transitioning to survivorship-focused care and longitudinal follow-up. Population-level tools in the electronic health record (EHR) offer a pragmatic approach to track patients and optimize care.MethodsThe Seattle Children's Hospital Cancer Survivor Program created a population health management system, using tools embedded within the EHR, based on a validated registry of AYA survivors. We developed a dynamic dashboard to make care gaps visible survivorship care, provide exposure-based pulmonary and cardiac toxicity surveillance, and support transition to adult care. We also built reports to facilitate real-world data analysis of the transition to survivorship care and longitudinal follow-up in a retrospective cohort of AYA survivors. We analyzed data from the cohort to explore subgroup differences in survivorship care.ResultsAmong survivors who finished treatment between January 1, 2021, and April 30, 2022 (n=220), 47% completed a long-term follow-up visit. There were no differences in the likelihood of follow-up based on age categories (p=0.36). For survivors with established long-term follow-up (n=743), 76% received longitudinal care. Compared with children, adolescent survivors (OR 0.51, 95% CI 0.29-0.9), emerging young adults (OR 0.39, 95% CI 0.24-0.63), and young adults (OR 0.10, 95% CI 0.05-0.18) were less likely to have a survivorship visit in the preceding 30 months. This difference was attenuated when analysis was restricted to survivors <22 years old and adjustment for years off therapy, with OR of 0.67 (95%CI 0.37-1.21) and 0.82 (0.45-1.50) among AYAs compared to children as the referent group.ConclusionAn EHR embedded population health platform represents a feasible approach to measure longitudinal follow-up care and transitions among AYA survivors. Clinical informatics tools have the potential to drive innovation and enhance evidence-based, guideline-concordant care to mitigate late effects in this population.}, }
@article {pmid41758961, year = {2026}, author = {Wang, Y and Liu, S and Ghamlouch, H and Gagler, DC and Blaney, P and Nabet, B and Davies, FE and Morgan, GJ}, title = {Study of NSD2 using a dTAG system reveals its molecular mechanism and oncogenic implications in t(4;14) multiple myeloma.}, journal = {Blood}, volume = {147}, number = {24}, pages = {2916-2929}, doi = {10.1182/blood.2025031663}, pmid = {41758961}, issn = {1528-0020}, abstract = {The histone H3 lysine 36 dimethylation (H3K36me2) methyltransferase NSD2 is deleted in Wolf-Hirschhorn syndrome and is aberrantly expressed in 10% to 15% of patients with multiple myeloma (MM) because of a t(4;14) translocation. Although NSD2 is thought to be a primary driver in MM, the exact molecular mechanisms by which it regulates transcription remain unclear. We applied the degradation tag (dTAG) system to acutely degrade NSD2 and used this, in combination with time-resolved thiol-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), to identify 307 transcriptional targets of NSD2. Reconstitution with either wild-type NSD2 or a catalytically inactive mutant (NSD2Y1179A) showed that NSD2's transcriptional effects are almost exclusively dependent on its SET domain activity. Mechanistically, H3K36me2 deposition by NSD2 antagonizes H3K27me3 levels, and treatment with 2 distinct Polycomb repressive complex 2 inhibitors demonstrated that approximately half of the NSD2 target genes are regulated in an H3K27me3-dependent manner. Cleavage under targets and tagmentation (CUT&amp;Tag) analysis showed that upon NSD2 depletion, there was an increase in H3K27me3 that occurred at genome-wide intergenic regions rather than at the promoters or gene bodies of NSD2 target genes. These data suggest that NSD2, via H3K36me2, antagonizes H3K27me3 deposition likely at distal regulatory elements, including enhancers, creating a chromatin landscape favorable for target gene transcription. Importantly, NSD2 target genes were enriched for key oncogenic pathways, and 24 transcription factors (TFs) implicated in neurodevelopment and acute leukemia, consistent with its role in Wolf-Hirschhorn syndrome and MM. Eight of these TFs are known oncogenic drivers in acute leukemia or MM, highlighting a novel molecular mechanism for NSD2's role in t(4;14) MM.}, }
@article {pmid42182279, year = {2026}, author = {Zhai, Z and Wang, C and Jiang, C and Rong, Z and Li, JJ}, title = {IntegrateRigor: annotation-free integration optimization for cell identity recovery reveals cancer-immune interface niches.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42182279}, issn = {2692-8205}, abstract = {Integrating single-cell and spatial transcriptomics data across batches is essential for recovering comparable cell identities-including cell types, subtypes, and states-as a prerequisite for downstream analyses in multi-condition and large-scale studies. This task remains challenging because between-batch variation removal often conflicts with cell identity preservation, and current methods typically rely on generic highly variable gene selection and lack principled metrics for hyperparameter tuning when cell identity annotations are unavailable. Together, these limitations often lead to over-integration, which merges biologically distinct cell identities, or under-integration, which leaves cells separated by batch rather than identity. Here we introduce IntegrateRigor, a data-driven, annotation-free, method-agnostic framework that optimizes integration specifically for reliable cell identity recovery across batches. IntegrateRigor first selects genes whose expression patterns are stable across batches using a gene-wise likelihood-based batch stability score, excluding batch-sensitive genes that can bias cell identity alignment during integration. It then identifies the optimal integration configuration across methods and hyperparameters by defining a dataset-level integration score that explicitly balances between-batch variation removal against cell identity preservation, without requiring prior annotations. In a colorectal cancer single-cell and spatial transcriptomics dataset, IntegrateRigor revealed previously uncharacterized cancer-immune interface niches in the tumor microenvironment that were masked by under-integration under default settings and by over-integration in previous literature. Across diverse datasets spanning multiple sources of between-batch variation, IntegrateRigor consistently improved cell identity recovery by mitigating both over-integration and under-integration across five state-of-the-art methods. By transforming integration from a heuristic preprocessing step into a statistically principled, dataset-adaptive procedure for cell identity recovery, IntegrateRigor improves the reproducibility and biological discovery power of large-scale single-cell and spatial transcriptomics analyses.}, }
@article {pmid42263665, year = {2026}, author = {Ueland, K and Elahi, T and Rasmussen, M and Wolfe, AE and Purcell, H and Chakka, SR and Mirimo-Martinez, M and Persinger, H and Johnson, K and Boynton, AM and McMillen, K and Byelykh, M and Biernacki, MA and Yeh, AC and Ali, N and Manjappa, S and Wuliji, N and Fredricks, D and Bleakley, M and Holmberg, LA and Peled, JU and Schenk, J and Raftery, D and Ma, J and Hill, GR and Neuhouser, ML and Lee, SJ and Markey, KA}, title = {Plant-based whole-food diets are feasible during auto-HCT and are associated with dose-dependent microbiome modulation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026020270}, pmid = {42263665}, issn = {2473-9537}, abstract = {Plant-based whole foods may represent a tractable approach to mitigating microbiome disruption and improving outcomes in patients undergoing auto-HCT for multiple myeloma, a population in whom intestinal dysbiosis has been linked with inferior survival. We conducted a single-arm clinical trial at our center, in which participants undergoing auto-HCT (n = 22) received fresh, pre-prepared, plant-based meals for 5 weeks spanning conditioning, neutropenia, and early recovery, with the goal of supporting the consumption of nutrient-dense, high-fiber foods. The primary endpoints were feasibility and tolerability, defined by successful enrollment, and patient-reported intake of study meals. Dietary intake was quantified using prospective food diaries and 24‑hour dietary recall surveys. Secondary endpoints included changes in gut microbiome composition and function assessed by shotgun metagenomic sequencing and stool short-chain fatty acid (SCFA) measurements. The intervention was feasible and generally well tolerated, with all participants consuming delivered meals to some degree, with adherence sufficient to support planned dietary and correlative analyses. Greater intake of study meals was associated with more pronounced shifts in gut microbial communities, including enrichment of SCFA-producing taxa and compositional changes consistent with a fiber-responsive microbiome. Stool SCFA concentrations increased from baseline to the end of the intervention, suggesting a functional impact of the dietary strategy on microbial metabolite production during the peri-transplant period. These findings demonstrate that a plant-based meal delivery intervention is implementable during auto-HCT and suggest dose-dependent modulation of the gut microbiome and its metabolic output. The trial is registered at ClinicalTrials.gov (NCT06559709).}, }
@article {pmid42263667, year = {2026}, author = {Bashey, A and Logan, BR and Hill, LC and Symons, HJ and Farhadfar, N and Grunwald, MR and Pidala, JA and Dehn, JG and Brunstein, C and Arai, S and Leifer, E and He, N and Shaw, BE and Juckett, MB and Devine, SM and Uberti, J and Westervelt, P and Srour, SA and Pusic, I and Vasu, S and Hayes-Lattin, B and Ciurea, SO and Horowitz, MM and Lee, SJ and Hogan, WJ}, title = {Donor-Specific Transplant Outcomes from BMTCTN 1702: A Multi-Center Prospective Biological-Assignment Trial.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026020355}, pmid = {42263667}, issn = {2473-9537}, abstract = {Newer approaches to control alloreactivity may produce similar transplant outcomes using HLA-mismatched donors versus HLA-matched unrelated donors. However, prospective comparisons are lacking. BMT CTN 1702 used a donor search prognosis score to assign patients without matched sibling donors, to transplant using an 8/8 HLA-matched unrelated donor (MUD) or the center's preference of haploidentical-related (HAPLO), mismatched unrelated (MMUD), or umbilical cord blood (UCB) donors. Outcomes using MUD were compared to HAPLO, MMUD and UCB while adjusting for relevant covariates. Patients (n=1179) (93% adults) underwent transplantation with a MUD (n=772), HAPLO (n=254), MMUD (n=112) and UCB (n=41) at a median of 3.7, 3.4, 3.9 and 3.8 months from enrollment. Post-transplant cyclophosphamide (PTCy) was used in 23.9%, 83.9%, 65.2% and 0% of MUD, HAPLO, MMUD and UCB HCT. In multivariate analysis, compared to MUD, survival after HCT was significantly lower for patients receiving UCB (HR 2.65, p<0.001) but not statistically different for HAPLO and MMUD HCT recipients (HR 1.08 and 1.18). The risk of relapse was not significantly different by donor type, but treatment-related mortality (TRM) (HR 3.31, p<0.001) and disease-free survival (DFS) (HR 1.99, p=0.002) were inferior for UCB but not different for HAPLO and MMUD than MUD. In PTCy patients, HAPLO and MMUD were associated with increased grade 3/4 acute GVHD (HR 2.39, p=0.017 and 2.53, p=0.038) and chronic GVHD (HR 1.71 each, p=0.028 and 0.080) than MUD, but other outcomes were not different. HAPLO or MMUD may effectively be used to expedite transplantation when finding MUD is unlikely. NCT03904134.}, }
@article {pmid42264569, year = {2026}, author = {Fonseca, GA and Triplette, M}, title = {Lung Cancer Screening Guidelines: Moving Beyond Pack-Years for Equity and Efficiency.}, journal = {Chest}, volume = {169}, number = {6}, pages = {1457-1458}, doi = {10.1016/j.chest.2026.02.029}, pmid = {42264569}, issn = {1931-3543}, }
@article {pmid42265107, year = {2026}, author = {Agrawal, P and Feng, J and Kallur Siddaramaiah, L and Khechaduri, A and Salladay, KR and Hinton, K and Means, M and Rose, JA and Cohen, L and Tian, M and Baboo, S and Diedrich, JK and Reese, T and Kara, D and Yates, JR and Paulson, JC and Alt, FW and Pancera, M and Stamatatos, L}, title = {Diverse germline-targeting HIV Env immunogens select for distinct mutations in the same knock-in mice B cell receptors.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-74183-w}, pmid = {42265107}, issn = {2041-1723}, support = {P01 AI138212/AI/NIAID NIH HHS/United States ; R01 AI177095/AI/NIAID NIH HHS/United States ; }, abstract = {VRC01-class HIV broadly neutralizing antibodies have been isolated from people living with HIV. Their unmutated (germline) forms do not bind Env and do not neutralize HIV. They acquire their broadly neutralizing potentials through the accumulation of specific somatic mutations. Here, we identify key modifications that allow Env-derived proteins from diverse HIV clades to effectively engage germline VRC01-class B cell receptors (BCRs) expressed by naive B cells. Noticeably, these germline-targeting Env proteins interact with VRC01-class BCRs differently depending on the specific Env background. When used as immunogens in a knock-in mouse model, all germline-targeting Envs successfully activate VRC01-class B cells. However, the resulting BCRs accumulate distinct mutations at key positions. Thus, while the same BCRs are initially activated, they follow different maturation pathways depending on the immunogen used. These findings have important implications not only for HIV vaccine design efforts but also for other immunogens aiming to direct specific BCR maturation pathways.}, }
@article {pmid42265755, year = {2026}, author = {Cheng, HH and Maxwell, KN and Salari, K and Cooperberg, MR and Follmer, K and Jeter, JM and Jun, G and Lee, DJ and Patel, HD and Schaeffer, EM and Sokolova, AO and Wolff, EM and Lin, DW}, title = {The 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) study.}, journal = {BJU international}, volume = {}, number = {}, pages = {}, doi = {10.1111/bju.70334}, pmid = {42265755}, issn = {1464-410X}, support = {P50CA097186/NH/NIH HHS/United States ; P50CA180995/NH/NIH HHS/United States ; P50CA272390/NH/NIH HHS/United States ; W81XWH-17-2-0043//DOD Prostate Cancer Research Program/ ; W81XWH-22-2-0021//DOD Prostate Cancer Research Program/ ; HT9425-25-1-0498//DOD Prostate Cancer Research Program/ ; HT9425-25-1-0747//DOD Prostate Cancer Research Program/ ; HT9425-25-1-0544//DOD Prostate Cancer Research Program/ ; //The Canary Foundation/ ; //The Basser Center for BRCA/ ; //BRCA Research and Cure Alliance (CureBRCA)/ ; //The Institute for Prostate Cancer Research/ ; //Polsky Urologic Cancer Institute/ ; //Prostate Cancer Foundation/ ; }, abstract = {BACKGROUND: Inherited (germline) pathogenic and likely pathogenic variants (gPVs) in key genes associated with increased risk of prostate cancer (PCa) now warrant more attentive PCa screening per National Comprehensive Cancer Network (NCCN) guidelines-e.g., BRCA2, HOXB13, ATM, BRCA1, MSH2, MSH6, CHEK2 and TP53. However, the optimal early detection strategy for gPV carriers, including use of age-adjusted PSA thresholds and prostate imaging may be refined. and as a means to investigate novel biomarkers.<br><br>STUDY DESIGN: 'Prostate Cancer Screening for People at Genetic Risk of Aggressive Disease' (PATROL) is a multicentre, prospective early detection study for individuals at increased risk for PCa due to carrying a gPV in a PCa risk gene.<br><br>ENDPOINTS: The primary endpoint is to determine the positive predictive value of pre-defined age-directed prostate-specific antigen (PSA) level thresholds and prostate-specific imaging, e.g., multiparametric magnetic resonance imaging (MRI) for clinically significant PCa on biopsy for individuals at risk of PCa due to a gPV. Exploratory endpoints include characterising clinicopathological characteristics of PCa and patient-reported outcomes. Biospecimens will be collected to evaluate emerging clinical and research biomarkers.<br><br>PATIENTS AND METHODS: Key eligibility includes: individuals aged &#x2265;40&#x2009;years who carry a gPV in an eligible gene, who have no prior diagnosis of PCa, do not have another active malignancy, and provide informed consent. Study procedures include annual physical examination and PSA. Imaging with MRI is optional at baseline and recommended if the PSA level is above the protocol-recommended PSA level threshold. Participants will be offered prostate biopsy for any clinical concern, PSA level >1.0&#x2009;ng/mL if aged <50&#x2009;years; PSA level >1.5&#x2009;ng/mL if aged 50-59&#x2009;years; PSA level >2.0&#x2009;ng/mL if aged &#x2265;60&#x2009;years. If PCa is diagnosed, clinical care is determined by the participant and treating physician. If opting for active surveillance, study procedures will be collected annually for 10&#x2009;years or until definitive treatment. If definitive treatment, study procedures will be collected for an additional 1&#x2009;year. Long-term clinical outcomes will be collected annually until the study closes.}, }
@article {pmid42266673, year = {2026}, author = {Kirtane, K and Niu, J and Blumenschein, G and Massarelli, E and Hanna, GJ and Lee, S and Bishop, MR and Konecny, GE and Mao, D and Zheng, Y and Rodriguez, K and Kim, JJ and Williams, C and Schweitzer, C and Adhikary, S and Jung, AS and Klebanoff, CA}, title = {A phase 1 trial of HPV16 E7 T-cell receptor-engineered T cells in patients with relapsed/refractory HPV16-positive cancers (KITE-439 trial).}, journal = {Frontiers in oncology}, volume = {16}, number = {}, pages = {1809354}, pmid = {42266673}, issn = {2234-943X}, abstract = {Patients with relapsed/refractory (r/r) HPV-associated epithelial cancers have a poor prognosis. Engineered T cells expressing a T cell receptor (TCR) specific for HPV16 E7 can induce tumor regression. We conducted a Phase 1 trial of KITE-439, an investigational autologous T-cell product expressing TCR specific for HPV16 E7 in patients with r/r HPV16+ epithelial cancers. CD4+ and CD8+ T cells selected from leukapheresed peripheral blood mononuclear cells were stimulated with anti-CD3/anti-CD28 antibodies followed by retroviral transduction and expansion in the presence of interleukin-7/15 and an AKT inhibitor. Patients received lymphodepleting chemotherapy (cyclophosphamide 30 mg/kg/day for 2 days and fludarabine 25 mg/m[2]/day for 5 days) followed by a single infusion of KITE-439 with daily IL-2 (2.5×10[5] IU/kg, up to 7 doses). The primary objectives were safety, tolerability, and efficacy; the primary endpoint was dose-limiting toxicities (DLTs). Eight HLA-A*02:01+ patients received KITE-439 (1×10[6]-1×10[8] cells/kg). No DLTs occurred during the trial. In all patients, KITE-439 cells were detected in peripheral blood within 7 days post-infusion. Three patients experienced Grade 1-2 cytokine release syndrome related to KITE-439 (resolved within 1-5 days) and 4 had KITE-439-related Grade 1-2 neurologic events (resolved within a day). One patient achieved a partial response (from Day 35 to Month 3) and 7 had a best response of stable disease. These results suggest that KITE-439 has an acceptable safety profile for the treatment of patients with HPV-associated epithelial cancers. Further studies are needed to determine optimal manufacturing conditions and T-cell characteristics required for enhanced antitumor activity.}, }
@article {pmid42268934, year = {2026}, author = {Guzmán-Solís, AA and Ouizougun-Oubari, M and Escaffre, O and Larsen, BB and Lopez, M and Locklear, S and Kumar, M and Juelich, TL and Smith, JK and Zhang, L and Haas, GD and Roenicke, R and Brambilla, L and Oguntuyo, KY and Patel, AR and Sapse, IA and Bowden, TA and Tortorella, D and Bloom, JD and Freiberg, AN and Bajic, G and Duty, JA and Lee, B}, title = {A cocktail of human mAbs targeting the henipavirus fusion and receptor binding proteins provides cross-species neutralization.}, journal = {Science translational medicine}, volume = {18}, number = {853}, pages = {eadw8573}, doi = {10.1126/scitranslmed.adw8573}, pmid = {42268934}, issn = {1946-6242}, mesh = {Humans ; Animals ; *Antibodies, Monoclonal/immunology ; *Henipavirus/immunology ; *Viral Fusion Proteins/immunology ; *Antibodies, Neutralizing/immunology ; Mice ; Neutralization Tests ; Mice, Transgenic ; Cross Reactions/immunology ; *Receptors, Virus/metabolism ; Amino Acid Sequence ; }, abstract = {The Nipah and Hendra viruses (NiV and HeV, respectively) are highly pathogenic, with case fatality rates of 40 to 75%, representing substantial public health threats. Although one monoclonal antibody (mAb), mAb102.4, has advanced through phase 1 clinical trials, there remains a critical need for approved therapeutic options against these henipaviruses (HNVs). Development of human mAbs has been constrained by limited access to convalescent patient samples. Here, we describe human mAbs derived from transgenic humanized mice that cross-neutralize extant NiV and HeV strains by binding to their fusion protein (F) or receptor binding protein (RBP). Deep mutational scanning and functional studies demonstrated that the anti-RBP mAb (8G3) targets the receptor binding site and requires multiple simultaneous mutations for escape. Sequence analysis of our anti-F mAbs identified a clonally expanded VH3-33 family with evidence of somatic hypermutation, yielding high-affinity antibodies. Cryo-electron microscopy revealed that our most potent F antibody (2A1) recognizes a conserved quaternary epitope spanning two protomers in trimeric prefusion NiV-F and stabilized, rather than displaced, a key glycan shield, distinguishing it from previously described antibodies targeting this region. The 8G3 and 2A1 mAbs exhibited additive neutralization when combined and provided complete protection against lethal NiV challenge in hamsters when administered individually or as a cocktail, even when treatment was delayed. Using a pseudovirus system, we show that this dual-targeting approach was resilient against a suite of escape mutants compared with monotherapy. Our findings establish a candidate therapeutic strategy that minimizes development of resistance, providing a foundation for next-generation countermeasures against emerging HNVs.}, }
@article {pmid42268936, year = {2026}, author = {Malek, R and Matassoli, F and Gordon, K and Shimberg, GD and Mantus, GE and Spangler, A and Chopde, AJ and Teng, IT and Zhou, T and Lin, BC and Carroll, R and Kazmierski, R and Wang, L and Posavad, CM and Rouphael, NG and Branche, AR and Roberts, PC and Serebryannyy, L and Andrews, SF}, title = {SARS-CoV-2 variant booster vaccination and infection alter the breadth of the memory B cell repertoire.}, journal = {Science translational medicine}, volume = {18}, number = {853}, pages = {eaeb9847}, doi = {10.1126/scitranslmed.aeb9847}, pmid = {42268936}, issn = {1946-6242}, abstract = {Evolving endemic viruses such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain major health threats. Although variant updated vaccines aim to enhance protection, preexisting immunity shapes memory B cell (MBC) responses. To assess how SARS-CoV-2 spike protein variant-based vaccine boosters and infections alter the MBC repertoire, we analyzed MBC responses in the COVAIL vaccine trial, where participants previously vaccinated with SARS-CoV-2 Wuhan-1 spike immunogen were boosted with Wuhan-1, variant, or bivalent spike immunogens. Some participants also experienced a subsequent infection with an Omicron variant. We determined that variant vaccine boosters and SARS-CoV-2 infections led to transiently greater recall of cross-reactive MBCs compared with a Wuhan-1 vaccine booster. Long term, we detected little change in the MBC repertoire after an Omicron vaccine booster, but MBCs evaluated several months after Omicron variant infection had higher neutralization capacity to both Wuhan-1 and BA.1 compared with those from individuals who had not experienced an infection. However, these Wuhan-1/BA.1 cross-reactive MBCs from infected individuals displayed less breadth toward the more distant BA.2.86 lineage than MBCs from uninfected individuals. Thus, SARS-CoV-2 variant boosters and infections differentially shape the long-term MBC repertoire.}, }
@article {pmid42269282, year = {2026}, author = {Gazeau, S and Byrne, C and Coombs, D and Kunzweiler, C and Calheiros, RC and Diaz-Decaro, J and Gantt, S and Craig, M}, title = {Mathematical modelling highlights the crucial role of early childhood immunization in preventing congenital CMV in countries with high CMV seroprevalence.}, journal = {Vaccine}, volume = {88}, number = {}, pages = {128788}, doi = {10.1016/j.vaccine.2026.128788}, pmid = {42269282}, issn = {1873-2518}, abstract = {BACKGROUND: Congenital cytomegalovirus infection (cCMVi) is a major global health problem and a leading cause of childhood hearing, visual, and intellectual disability. Development of an effective vaccine against CMV is a high priority, and there is optimism that one will be achieved soon. Previous mathematical modelling to predict the impact of CMV vaccination in low CMV seroprevalence, high-income populations indicate that vaccinating infants could be a highly efficient strategy to prevent cCMVi, even with only a modestly effective vaccine (i.e., <50% protective against primary infection). However, whether vaccinating infants is optimal in high CMV seroprevalence settings, where rates of cCMVi are correspondingly higher, is unclear.<br><br>METHODS: We adjusted our existing agent-based stochastic model to study CMV vaccine efficacy in high seroprevalence settings (reaching 90%) with Brazil as a test case.<br><br>RESULTS: Our results suggest that vaccinating 12-year-old girls and women of childbearing age would have limited ability to reduce cCMVi rates in Brazil, even with a vaccine conferring complete life-long protection against CMV infection. In contrast, vaccinating infants was predicted to provide substantial long-term reductions in the number of cCMVi cases in Brazil, even if it only induced protection equivalent to natural immunity against CMV reinfection and reactivation. Further, our model predicted that if two-thirds of Brazilian infants were vaccinated, a modestly effective vaccine would reduce the number of cCMVi cases by up to 76%.<br><br>CONCLUSION: Together with results from other studies, this analysis underscores that infancy is likely the optimal target age for CMV vaccination to prevent cCMVi in all populations, regardless of the CMV seroprevalence. Furthermore, our findings predict large reductions in disease due to cCMVi worldwide through attainable vaccination scenarios.}, }
@article {pmid42270451, year = {2026}, author = {Schwartz, J and Meehan, K and Cohn, EB and Bacci, JL and Calo, WA and Ko, LK and Shah, PD}, title = {Current practices, opportunities to improve, and behavioral targets related to HPV vaccination in community pharmacies: A qualitative study of pharmacy staff and parents.}, journal = {Human vaccines &amp; immunotherapeutics}, volume = {22}, number = {1}, pages = {2685449}, doi = {10.1080/21645515.2026.2685449}, pmid = {42270451}, issn = {2164-554X}, abstract = {Human papillomavirus (HPV) causes 39,300 cancers annually in the United States, yet adolescent vaccination coverage remains suboptimal. Community pharmacies are highly accessible and authorized to vaccinate adolescents but remain underutilized for HPV vaccination. This study examined how current pharmacy vaccination practices align with parent expectations and identified modifiable behavioral and implementation targets to improve uptake. We conducted a qualitative study using key informant interviews with pharmacy staff (n = 11) and parents of adolescents ages 9-17 (n = 13) between February - March 2021. Interview guides were informed by the 5As Behavioral Counseling Framework and Theoretical Domains Framework (TDF). Data were analyzed using framework-guided rapid content analysis to identify themes related the vaccination workflow stages. Analyses identified 31 current practices and 35 opportunities for improvement across the 5As, as well as 20 behavioral constructs spanning 12 domains. Key gaps identified by pharmacy staff included inconsistent adolescent vaccine assessment, limited proactive recommendations, lack of standardized communication, insufficient documentation and follow-up for hesitancy, and fragmented reminder and scheduling systems. Parents valued convenience and clear, concise recommendations, while staff highlighted workflow and system constraints. Opportunities centered on standardizing assessment and communication, expanding technician roles, implementing proactive prompts and reminders, improving care coordination with primary care providers, and strengthening follow-up processes. Pharmacy-based HPV vaccination can be strengthened through targeted behavioral and workflow changes across the vaccination continuum. These findings provide a theory-informed, practice-ready framework to guide intervention design and evaluation aimed at increasing HPV vaccine uptake and series completion in community pharmacy settings.}, }
@article {pmid42273705, year = {2026}, author = {Monaco, F and Tran, DT and Sandmaier, BM and Tykodi, SS}, title = {Case Report: donor cell-derived leukemia after allogeneic stem cell transplantation for metastatic renal cell carcinoma.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1830323}, pmid = {42273705}, issn = {1664-3224}, abstract = {Donor cell-derived leukemia (DCL) is a rare complication of allogeneic hematopoietic cell transplantation (allo-HCT), previously described in patients receiving allo-HCT for hematologic malignancies. Allo-HCT has also been investigated as an immunotherapy platform for solid tumors including clear cell renal cell carcinoma (RCC). Herein, we describe a unique patient case treated by allo-HCT for RCC who subsequently developed DCL. A 40-year-old man was diagnosed with metastatic clear cell RCC treated surgically by left nephrectomy plus metastasectomy of a rib lesion. He was referred to the Fred Hutchinson Cancer Center and treated by allo-HCT as part of a clinical trial (NCT00005851). His initial allograft following fludarabine/2 Gy total body irradiation (TBI) conditioning was complicated by graft failure. After collecting a G-CSF-mobilized autologous hematopoietic stem cell product as a failsafe for repeated graft failure, he was re-transplanted from the same donor following cyclophosphamide/antithymocyte globulin (ATG) conditioning, resulting in successful engraftment. Fourteen months later, he developed donor origin acute myelomonocytic leukemia with central nervous system (CNS) involvement. He was treated by 7 + 3 induction with intrathecal methotrexate and was able to achieve complete remission. He subsequently underwent autologous hematopoietic cell transplantation (auto-HCT) without further leukemia relapse. Unfortunately, 4 years after his auto-HCT, he developed recurrent RCC, initially managed by surgical resections. Upon further progression, he was then treated with sequential lines of systemic therapy that included pazopanib, nivolumab, cabozantinib, and lenvatinib/everolimus. He died from complications of his RCC 17 years after his second successful allograft. The absence of pre-transplant systemic therapies for the patient's metastatic RCC and ongoing good health of the donor implicates a leukemogenic potential of his transplant-associated therapies including TBI, cyclophosphamide, and ATG. His uncommonly long survival from metastatic RCC suggests clinical benefit was derived from the 14-month duration of allo-HCT associated with T-cell allo-immunity previously shown capable of targeting RCC-associated minor histocompatibility antigens.}, }
@article {pmid42124731, year = {2026}, author = {Harari, S and Eguia, RT and Dadonaite, B and Radford, CE and Stewart, C and Veesler, D and Bloom, JD}, title = {Mutations to the HCoV-229E spike have counterbalancing effects on serum antibody neutralization and receptor binding.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42124731}, issn = {2692-8205}, abstract = {Human coronavirus 229E (HCoV-229E) is an endemic pathogen that causes repeated "common-cold" infections throughout life. Like other coronaviruses, it accumulates spike mutations that erode antibody immunity and enable reinfection. Here, we use pseudovirus deep mutational scanning to measure how mutations to the HCoV-229E spike affect its cell entry function, binding to its human APN receptor, and neutralization by human sera with a range of sensitivities to erosion by viral evolution. We find that both receptor binding and serum neutralization are affected by mutations across spike, including many that modulate these properties by affecting the balance of up versus down conformations of the spike receptor-binding domain (RBD). In particular, some mutations increase both receptor binding and serum neutralization by shifting the RBD to a more up conformation, suggesting that the HCoV-229E spike has evolved to shield key RBD neutralizing epitopes at the cost of less efficient receptor binding.}, }
@article {pmid42256204, year = {2026}, author = {Yang, Y and Ronsley, R and Kilburn, L and Kim, A and Wechsler-Reya, RJ and Yang, ZJ}, title = {Differentiation-inducing triiodothyronine enhances chemotherapy and suppresses post-treatment tumor regrowth in medulloblastoma.}, journal = {Molecular therapy. Oncology}, volume = {34}, number = {2}, pages = {201235}, pmid = {42256204}, issn = {2950-3299}, abstract = {Medulloblastoma (MB), the most common malignant pediatric brain tumor, is treated with intensive multimodal regimens that cause substantial long-term toxicity and fail to prevent recurrence in up to 30% of patients. We investigated triiodothyronine (T3), an FDA-approved thyroid hormone, as a differentiation-based therapeutic strategy for MB. Using a Sonic Hedgehog (SHH)-driven mouse model, two patient-derived xenografts (SHH and group 3), and drug-resistant TP53-mutant MB cells, we found that T3 and cytotoxic chemotherapy suppress tumor growth through complementary biological mechanisms: T3 promotes terminal differentiation of tumor cells, whereas cyclophosphamide (CTX) and irinotecan (CPT-11) induce caspase-3-dependent apoptosis. In vitro, T3 enhanced the tumor inhibitory effects of CTX and CPT-11, suppressed proliferation in chemotherapy-resistant cells, and promoted differentiation across MB subgroups. In vivo, sequential administration of T3 following chemotherapy suppressed post-treatment tumor regrowth and prolonged survival without increasing systemic toxicity. T3-induced transient tachycardia was effectively controlled with propranolol without compromising antitumor activity. Together, these findings support the potential of T3 as a clinically accessible differentiation-based therapy that enhances chemotherapy responses and suppresses post-treatment tumor regrowth in medulloblastoma.}, }
@article {pmid42256618, year = {2026}, author = {Zane, GK and Dimitrov, D and Levin, CE and Khosropour, CM and Duerr, A}, title = {Evaluating the potential health and economic impacts of chlamydia vaccination strategies in the United States: a mathematical modeling and cost-effectiveness simulation study.}, journal = {Lancet regional health. Americas}, volume = {60}, number = {}, pages = {101502}, pmid = {42256618}, issn = {2667-193X}, abstract = {BACKGROUND: Chlamydia trachomatis (chlamydia) is the most commonly reported sexually transmitted infection in the United States (US), causing substantial morbidity and costs despite effective treatment. Vaccination may be a promising prevention strategy, but its national epidemiologic and economic impact remains understudied.<br><br>METHODS: We developed an age- and sex-structured compartmental model of heterosexual chlamydia transmission among US individuals aged 15-64 years from 2000 to 2075. The model was calibrated to adjusted annual chlamydia cases and validated against national prevalence data. We simulated routine vaccination of adolescent females or both sexes beginning in 2025, with or without a one-time catch-up campaign for unvaccinated females aged 15-24 years in 2035. Outcomes included chlamydia incidence rates, infections and sequelae averted by 2075, and incremental cost-effectiveness ratios through 2050.<br><br>FINDINGS: Without vaccination, incidence rates were projected to rise from 16.9 to 18.7 infections per 1000 person-years between 2025 and 2075. Under base-case assumptions (50% coverage, 70% efficacy, 10-year protection), incidence rates declined to 4.0 and 0.4 per 1000 person-years under female-only and sex-neutral vaccination, respectively. By 2075, female-only and sex-neutral vaccination reduced infections by 37.4% and 52.3%, respectively. Catch-up vaccination provided modest additional benefit. All strategies were cost-saving; sex-neutral vaccination yielded 145,943 additional quality-adjusted life years and $354 million in savings versus female-only vaccination by 2050. Results were robust across sensitivity analyses.<br><br>INTERPRETATION: Chlamydia vaccination could substantially reduce infections and sequelae in the US and is likely to be cost-saving or highly cost-effective across plausible scenarios.<br><br>FUNDING: This work was primarily supported by the National Institutes of Health (1F31AI181431-01A1).}, }
@article {pmid42258320, year = {2026}, author = {Kleeman, SO and Riazat-Kesh, Y and Carvajal, R and Marmarelis, ME and Schadendorf, D and Sharon, E and Othus, M and Robert, C and Skoulidis, F and Izar, B and Maki, RG and Janowitz, T}, title = {Cancer chemo-immunotherapy: time will tell.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, doi = {10.1158/2326-6066.CIR-26-0335}, pmid = {42258320}, issn = {2326-6074}, abstract = {Endogenous circadian programs coordinate physiology across tissues, including immune cell trafficking and drug metabolism. Previous retrospective studies suggested that the timing of immune checkpoint inhibitor delivery may be a modifiable determinant of survival in patients with cancer, with earlier infusions often associated with improved outcomes. Recently, the prospective randomized phase 3 LungTIME-C01 trial reported that earlier time-of-day (before 3pm) administration of chemo-immunotherapy nearly doubled progression-free survival in patients with non-small cell lung cancer. In this commentary, we examine the trial's clinical design and execution, including protocol amendments and safety reporting that warrant clarification. We consider the mechanistic interpretation of the results, highlighting that the observed effects may reflect contributions from cytotoxic chronopharmacology, circadian immune regulation, and healthcare delivery factors rather than immunotherapy timing alone. We outline implications for future trial design, including factorial approaches to disentangle the timing of immunotherapy from chemotherapy and the need for multicenter validation before scheduling recommendations are widely adopted.}, }
@article {pmid42258780, year = {2026}, author = {Unger, JM}, title = {Psychosocial Predictors of Shared Decision Making Among US Cancer Survivors.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2501143}, doi = {10.1200/OP-25-01143}, pmid = {42258780}, issn = {2688-1535}, abstract = {PURPOSE: Cancer survivors, who have unique health care needs, are projected to number nearly 19 million by 2025, over 5% of the US population. Shared decision making (SDM) between patients and providers is vital for patient-centered care. This study evaluated whether demographic, socioeconomic, behavioral, geographic, health, health information, and psychosocial factors predict the risk of cancer survivors not engaging in SDM.<br><br>METHODS: Data from the Health Information National Trends Survey (HINTS) from 2012 to 2024 were used. Participants included adults diagnosed with cancer within the past 20 years who had one or more health care visits in the past year. SDM was measured on a four-point scale by a question about involvement in health care decisions, with dichotomization (always v usually/sometimes/never) aligned with Healthy People 2030 objectives. Forty-two variables were analyzed, and a risk prediction model was developed using 60% of the participants and validated with the remaining 40%.<br><br>RESULTS: The study included 3,622 participants, predominantly older than 65 years (61.5%), with 54.8% being women and 12.9% Black. A model with four variables (distrust of health care providers, distrust of family, anxiety/depression, and fair/poor perceived health) was associated with lower SDM engagement in the training set and was confirmed in the validation set. For each increase in the quartile level of adverse risks, there was a 23% reduction in the odds of SDM. The odds of experiencing SDM were 56% lower for those with 3-4 risk factors than for those with 0 risk factors.<br><br>CONCLUSION: These findings suggest that screening for psychosocial vulnerability may help identify cancer survivors who could benefit from targeted strategies to support SDM in clinical care.}, }
@article {pmid42260942, year = {2026}, author = {Fathima, S and Wong, MM and Gonzalez-Lugo, J and Geyer, SM and Alsugair, A and Sirenko, M and Langer, KJ and Lasho, TL and Finke, C and Choi, J and Abdul-Hay, M and Ho, G and Litzow, MR and Matin, A and Durani, U and Hefazi, M and Hogan, WJ and Shah, MV and Al-Kali, A and Begna, KH and Gangat, N and Saliba, AN and Go, RS and Kewan, T and Bartoo, G and Kutzke, J and McCullough, K and Warrington, KJ and Sullivan, M and Reichard, KK and Olteanu, H and Murthy, H and Badar, T and Kusne, Y and Palmer, J and Chhabra, S and Punwani, N and Riwes, M and McGuirk, JP and Krakow, EF and Langston, A and Kourelis, T and Dingli, D and Foran, J and Koster, MJ and Patnaik, MM and Beck, DB and Alkhateeb, HB and Mangaonkar, AA}, title = {Therapeutic Outcomes in VEXAS Syndrome: A Multicenter Comparative Cohort of Allogeneic Hematopoietic Stem Cell Transplantation and Hypomethylating Agents.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70401}, pmid = {42260942}, issn = {1096-8652}, support = {Arnold and Kit Palmer Career Award in Cancer Research//Mayo Clinic Center for Clinical and Translational Science/ ; CSDG-23-1020347-01-IBCD//American Cancer Society/ ; }, abstract = {Hypomethylating agents (HMA) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have both demonstrated remissions in VEXAS; however, comparative data is lacking. We conducted a multicenter, retrospective analysis of 66 patients diagnosed with VEXAS syndrome treated with HMA (n = 35) or alloHSCT (n = 31). Baseline characteristics such as genetics, co-morbidities, and performance status were balanced between the groups, except older age in the HMA group. Median follow-up from therapy initiation was 18 months (95% CI: 11-26), and 14 (21%) deaths were reported (alloHSCT n = 3; HMA n = 11). Among all evaluable patients within the alloHSCT cohort, all patients achieved molecular remission, and a substantial proportion of patients discontinued glucocorticoids (58%). In contrast, HMA therapy was associated with lower but meaningful rates of molecular remission (22%) and glucocorticoid discontinuation (6%). In a real-world setting, HMA therapy was associated with a high discontinuation rate related to toxicity or lack of response. On multivariable analysis adjusted for age and Charlson Comorbidity Index, alloHSCT was associated with improved overall survival (HR = 0.20, 95% CI: 0.05-0.81; p = 0.024). This association remained consistent across multiple ancillary sensitivity analyses, including restriction to transplant-eligible patients, patients aged ≤ 75 years, 1:1 matching, and propensity score-based weighted analyses. Although limited by retrospective design, these findings suggest that alloHSCT remains an attractive and potentially curative strategy in selected patients with VEXAS. Prospective validation of these findings is warranted.}, }
@article {pmid42262514, year = {2026}, author = {Chlebowski, RT and Rapp, S and Aragaki, AK and Manson, JE and Pan, K and Neuhouser, ML and Johnson, KC and Snetselaar, LG and Henderson, VW and Qi, L and Hayden, KM and Baker, LD and Garcia, O and Pichardo, MD and Wactawski-Wende, J and Prentice, RL}, title = {Low-fat dietary pattern and dementia mortality: a secondary analysis of the Women's Health Initiative dietary modification randomized clinical trial with long-term follow-up.}, journal = {Menopause (New York, N.Y.)}, volume = {}, number = {}, pages = {}, pmid = {42262514}, issn = {1530-0374}, abstract = {OBJECTIVES: In the Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, the dietary intervention significantly reduced breast cancer mortality and, in a subgroup of women 65 years old or above, significantly lowered possible cognitive impairment based on Modified Mini-State Examination (3MSE) scores. Based on this background, we examined the dietary intervention association with long-term dementia mortality.<br><br>METHODS: The WHI DM clinical trial randomized 48,835 postmenopausal US women, aged 50-79 years, with dietary fat intake &#x2265;32% of energy and anticipated &#x2265;3-year survival. Cognitive function was not an eligibility criterion. Randomization was to a low-fat dietary pattern intervention (40%; n=19,541) with goals to reduce fat intake and increase fruit, vegetable, and grain intake or a usual diet comparison (60%; n=29,294). All dietary targets were significantly reduced. Mortality findings were confirmed by central medical record review enhanced by serial National Death Index findings. Dementia mortality was examined after an 8.5-year (median) dietary intervention and 20-year cumulative follow-up.<br><br>RESULTS: Dietary intervention did not influence dementia mortality (n=1,386) (HR: 0.94, 95% CI: 0.85-1.05), with similar findings for Alzheimer (HR: 1.00, 95% CI 0.85-1.17) and non-Alzheimer dementia mortality (HR: 0.90, 95% CI 0.77-1.05). Of 13 subgroup analyses, with dietary intervention, there was a trend for lower dementia mortality in younger women (50-59&#xa0;y, HR: 0.73, 95% CI: 0.44-1.21; 60-69&#xa0;y, HR: 0.85, 95% CI: 0.72-1.01; 70-79&#xa0;y, HR: 1.06, 95% CI: 0.91-1.23; P-trend 0.03).<br><br>CONCLUSIONS: A low-fat eating pattern did not reduce dementia mortality in postmenopausal women.}, }
@article {pmid42262918, year = {2026}, author = {Topalidou, I}, title = {A second life.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyag116}, pmid = {42262918}, issn = {1943-2631}, abstract = {The Genetics Society of America Mentorship Award recognizes members of the scientific community for exceptional mentoring of geneticists at any career stage. Irini Topalidou is the inaugural recipient in the nonfaculty category, honored for her outstanding contributions to mentoring within the C. elegans community and beyond. She has mentored numerous trainees who have gone on to pursue graduate and medical degrees, postdoctoral or faculty positions, and careers in biotech. The award further acknowledges her published work on STEM education and career choice, as well as her commitment to understanding and addressing trainee challenges and to improving mentorship practices. In the essay below, Irini reflects on her journey as an immigrant in the United States and how these experiences have shaped her life, career, and approach to mentorship. She also highlights how recent scientific and cultural shifts are challenging the principles of openness, diversity, and discovery in the United States, placing one of its greatest strengths at risk.}, }
@article {pmid42250885, year = {2026}, author = {Naumova, AV and Nakamura, K and Marchiano, S and Neidig, LE and Blakely, LP and Tsuchida, H and Murry, CE and Kerwin, WS}, title = {Circumferential Strain Recovery After Human Cardiomyocyte Transplantation in Minipigs Using a Novel Frequency-Based Method for Myocardial Tagging Quantification.}, journal = {Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance}, volume = {}, number = {}, pages = {102756}, doi = {10.1016/j.jocmr.2026.102756}, pmid = {42250885}, issn = {1532-429X}, abstract = {BACKGROUND: Transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is promising new method for heart remuscularization after infarction. We hypothesized that hPSC-CMs affect heart function by improving local contractility in the infarcted zones. However, there is a need for a precise non-invasive assessment of regional contractile function in the infarcted segments.<br><br>METHODS: We describe here a novel approach for rapid and robust quantification of myocardial end-systolic circumferential strain (CS). Linear tags are placed in 60-degree pattern offsets and analyzed via optimized post-processing based on local Fourier transformation of standardized American Heart Association (AHA) myocardial segmentation. This method has been implemented for the first time to evaluate transendocardial hPSC-CMs transplantation in a minipig model of myocardial infarction. Validation of the new frequency-based calculation of myocardial strain was done using two independent approaches: (1) a tag tracking, and (2) feature tracking technique.<br><br>RESULTS: In the cell-treated hearts (n=4), mean end-systolic CS in the infarcted segments (anterior and anteroseptal areas combined) at the mid-wall region decreased from -6.69 &#xb1; 1.56% (pre-MI) to -1.13 &#xb1; 1.96% at 2 weeks post-MI (pre-treatment), with subsequent improvement to -4.00 &#xb1; 0.76% by 8 weeks after cell transplantation. Conversely, CS in the infarcted segments in vehicle-control group (n=5) decreased from -5.18 &#xb1; 0.97% (pre-MI) to -1.39 &#xb1; 1.23% at 2 weeks post-MI and worsened further to 0.33 &#xb1; 1.93% by 8 weeks post-vehicle. There was no improvement in the global ejection fraction in the cell-treated group in comparison with control. It was a high correlation of the new method of myocardial strain calculation with the standard tag tracking approach and feature tracking strain analysis across the experimental conditions (normal heart, infarcted, cell/vehicle treated).<br><br>CONCLUSIONS: A novel frequency-based technique for assessment of local circumferential strain does not require specialized acquisition protocols, access to k-space data, nor highly optimized reconstruction algorithms or commercial software. It can quickly and precisely assess regional myocardial injury and recovery. Our findings support our hypothesis that transplantation of hPSC-CMs improves regional myocardial strain in infarcted minipig hearts.}, }
@article {pmid42252893, year = {2026}, author = {Mahla, RS}, title = {Identifying Antigen-Specific Autoreactive B Cells in Sjögren's Disease: Methodological Challenges and Emerging Strategies.}, journal = {International journal of rheumatic diseases}, volume = {29}, number = {6}, pages = {e70728}, doi = {10.1111/1756-185x.70728}, pmid = {42252893}, issn = {1756-185X}, }
@article {pmid42255261, year = {2026}, author = {Morris, SM and Pilat, K and Girard, EJ and Noll, A and Ang, LS and Price, J and Mhyre, AJ and Correnti, CE and Bandaranayake, AD and Mehlin, C and Clarke, M and Brasel, K and Muthuraman, P and Crook, ZR and Cole, B and Hylkema, TA and Le, Q and Meshinchi, S and Olson, JM}, title = {Fully human anti-FOLR1 T-cell engager demonstrates potent activity in CBFA2T3::GLIS2 acute megakaryoblastic leukemia.}, journal = {Blood neoplasia}, volume = {3}, number = {3}, pages = {100232}, pmid = {42255261}, issn = {2950-3280}, }
@article {pmid42079255, year = {2026}, author = {Pravica, M and Franić, D and Bazdan, M and Guzalić, D and Bedalov, A and Boban, M}, title = {Proteasome-dependent degradation and nucleus-vacuole junctions sustain proteostasis during acute glucose starvation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.04.22.720209}, pmid = {42079255}, issn = {2692-8205}, abstract = {How protein quality control is maintained during acute metabolic stress remains poorly understood. In budding yeast, abrupt glucose depletion rapidly lowers ATP levels and leads to the formation of chaperone-containing inclusions, suggesting that ATP-dependent degradation of misfolded proteins may be compromised when energy becomes limiting. Here we find that selective degradation of misfolded proteins remains active during acute glucose starvation despite reduced cellular ATP levels. Using model misfolded substrates in yeast Saccharomyces cerevisiae, we show that misfolded proteins continue to be efficiently degraded throughout both early and late phases of acute glucose depletion. This degradation requires the proteasome and depends on its functional 19S regulatory particle, indicating that ATP-dependent proteasomal activity persists during metabolic stress. We further find that nucleus-vacuole junctions (NVJs) promote efficient degradation during prolonged glucose starvation, revealing a role for organelle contact sites in supporting proteostasis under energy limitation. Together, these findings indicate that cells preserve proteasome-mediated proteostasis during acute glucose starvation, while NVJ membrane contact sites help sustain degradation capacity when metabolic resources are scarce.}, }
@article {pmid42146360, year = {2026}, author = {Nemani, K and Jaycox, JR and Akcan, U and Schuman, BM and Yeon, SM and Harano, N and Qin, K and Notestine, AA and Carroll, SM and McKenzie, BS and Furchtgott, L and Lahti, AC and Tsien, RW and Agalliu, D and Goff, DC and Ring, AM}, title = {High prevalence of CNS-directed autoantibodies in patients with schizophrenia.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42146360}, issn = {2692-8205}, abstract = {Schizophrenia is a severe neuropsychiatric disorder whose etiology and biological heterogeneity remain poorly understood. Immune dysregulation has long been implicated, but the breadth and clinical significance of autoantibody responses remain unclear beyond rare individual examples. Here we use Rapid Extracellular Antigen Profiling-a proteome-scale assay for autoantibodies against extracellular and secreted proteins-to profile 352 individuals with schizophrenia and 971 community controls. We find that schizophrenia is marked by a striking elevation in extracellular autoantibody burden, present near disease onset, and approaching nearly twice control levels in the most severely ill patients. This burden increases with age in a pattern that diverges from controls and targets central nervous system antigens, including neuroactive receptors, neuronal ion channels, proteins involved in synaptic function, and blood-brain barrier integrity. Autoantibodies against blood-brain barrier antigens impair barrier function ex vivo and are associated with broader central nervous system autoreactivity, supporting a model in which barrier disruption promotes loss of tolerance to brain antigens. At the clinical level, higher baseline autoantibody burden predicts reduced responsiveness to the antipsychotic risperidone, suggesting that autoantibodies contribute to treatment resistance. Together, these findings identify humoral autoimmunity as a pervasive component of schizophrenia and imply that therapies that reset humoral immunity or reduce autoantibody burden may benefit patients beyond those with currently recognized antibody-mediated syndromes.}, }
@article {pmid42182320, year = {2026}, author = {Deneke, VE and Suwita, JP and Wang, H and Tonai, S and Lu, Y and Panser, K and Schleiffer, A and Hollis, JA and Novatchkova, M and Dürnberger, G and Stejskal, K and Krssakova, G and Blaha, A and Andresan, AAR and Mirus, M and Marvanova, H and Chang, HY and Noda, T and Burga, A and Roitinger, E and Ikawa, M and Pauli, A}, title = {The SPARK complex forms the molecular basis of vertebrate fertilization.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42182320}, issn = {2692-8205}, abstract = {Fertilization requires gamete recognition and membrane fusion, yet the molecular basis of this process in vertebrates remains unknown. Here we identify SPARK (sperm protein assembly and receptor-binding key), a conserved multi-protein complex that integrates all known sperm fertilization factors, including TMEM81-IZUMO1-SPACA6 and DCST1/2, together with two newly identified components, TMDD1 and FAM187A. SPARK subunits are mutually dependent for stability in mature sperm, and disruption of any single component causes male sterility in zebrafish and mice. Incubating zebrafish sperm with soluble egg receptor Bouncer partially rescues fertilization of Bouncer-deficient eggs in a SPARK-dependent manner, consistent with egg receptor binding priming the complex for fusion. Thus, we propose SPARK as a conserved molecular machine that couples gamete recognition to membrane fusion.}, }
@article {pmid42244105, year = {2026}, author = {Misono, S and Fann, JR and Osazuwa-Peters, N and Marmor, S}, title = {Mental Health and Survival in Medicare Beneficiaries With Lung and Head and Neck Cancer.}, journal = {Psycho-oncology}, volume = {35}, number = {6}, pages = {e70510}, pmid = {42244105}, issn = {1099-1611}, abstract = {BACKGROUND: Mental health (MH) conditions can significantly influence cancer outcomes, yet associations with survival and potential impacts of MH care utilization remain underexplored.<br><br>AIMS: Examine associations between (1) MH diagnoses and (2) MH utilization and survival among Medicare beneficiaries with lung or head and neck (HN) cancers.<br><br>METHODS: Patients diagnosed with lung or HN cancers between 2004 and 2018 were stratified by MH diagnosis status in the two years prior to cancer diagnosis. We examined factors associated with MH diagnosis and MH services and evaluated overall and cancer specific survival analyses using Kaplan-Meier survival analyses and multivariable Cox regressions.<br><br>RESULTS: 19% of patients with a lung cancer diagnosis (n&#xa0;=&#xa0;333,875) and 15% of HN patients (n&#xa0;=&#xa0;39,253) received a MH diagnosis within two years before cancer diagnosis. Kaplan-Meier survival analysis indicated significantly worse survival among patients with a MH diagnosis and higher rates of survival among those receiving MH services. Among individuals with a MH diagnosis, the mortality hazard for individuals that received MH services was lower compared to those who did not receive MH services, in both HN and Lung cancer.<br><br>CONCLUSIONS: MH conditions were common in people with lung and HN cancers and associated with worse overall and cancer-specific survival for head and neck cancer. Among those with MH diagnoses, receipt of MH services was associated with lower hazard of death, highlighting the need for early identification of this at-risk population and integration of MH care into oncology care.}, }
@article {pmid42244233, year = {2026}, author = {Okello, P and Thuo, N and Roche, SD and Saravis, AL and Mwai, D and Naik, P and Kiptinness, C and Kareithi, T and Mugambi, ML and Sharma, M and Ngure, K and Ortbald, KF}, title = {Qualitative Insights on Client and Provider Barriers and Facilitators to Using a Novel Online HIV Pre- and Post-Exposure Delivery Model in Kenya.}, journal = {Journal of the International AIDS Society}, volume = {29}, number = {6}, pages = {e70133}, pmid = {42244233}, issn = {1758-2652}, support = {INV-037646/GATES/Gates Foundation/United States ; }, abstract = {INTRODUCTION: Online delivery of HIV pre- and post-exposure prophylaxis (PrEP and PEP) could address persistent access barriers, yet implementation across Africa remains limited. The ePrEP Kenya Pilot (NCT05377138) integrated PrEP and PEP services into an existing e-pharmacy platform and identified client- and provider-level barriers and facilitators to use.<br><br>METHODS: In the pilot, clinicians screened adults (age 18+) in Nairobi and Mombasa Counties for PrEP and PEP eligibility via telehealth; pharmaceutical technologists courier-delivered HIV testing services (including self-testing) and dispensed PrEP or PEP to eligible clients who paid 150-250 KES (&#x223c;$1-2 USD) for HIV testing, &#x2264;149 KES (&#x223c;$1 USD) for courier delivery and nothing for telehealth consultation or PrEP/PEP drugs. We conducted monthly check-in calls with providers and, near study endline, in-depth interviews (IDIs) with purposively sampled clients and all providers. We analysed verbatim call transcripts and IDIs inductively, then mapped identified barriers and facilitators to the Consolidated Framework for Implementation Research (CFIR).<br><br>RESULTS: From February to November 2023, we conducted 10 check-in calls and interviewed 30 clients (10 PEP, 10 PrEP with 1+ refill, 10 PrEP with no refills) and 10 providers (4 clinicians, 6 pharm techs). Clients had a median age of 27 years (IQR 25-30) and providers 28 years (IQR 27-31); 53% (16/30) of clients and 30% (3/10) of providers were female. In the Outer Setting CFIR domain, providers identified motorcycle manoeuvrability as a delivery facilitator but noted that traffic, poor road infrastructure, bad weather and personal safety concerns posed challenges. In the Inner Setting domain, providers identified information-sharing practices and collegiality as facilitators. In the Individuals domain, clients' capability, opportunity and motivation to use online PrEP/PEP services was reportedly facilitated by app-guided HIV self-testing, broad delivery zones and enhanced privacy, but hindered by low awareness of these services, limited access to internet-enabled devices, data security concerns and uncertainties around couriers' pharmacy credentials. Recommendations included reducing client costs, expanding delivery coverage and hours, and offering alternative delivery options (e.g. medication pick-up lockers).<br><br>CONCLUSIONS: Online PrEP and PEP delivery is a promising differentiated service model, especially if partially subsidized by third-party payers. Implementation success will require model adaptations that address logistical, infrastructural and awareness barriers.}, }
@article {pmid42244408, year = {2026}, author = {Loroña, NC and LaBrie, S and Thomas, CE and Yin, H and Huyghe, JR and Qu, C and Thomas, S and Nayemi, S and Ammar, H and Kahsai, O and Hsu, L and Curtis, KR and Koehne, A and Redwood, DG and Li, L and Li, CI and Peters, U and Thomas, TK and Phipps, AI and Figueiredo, JC and Hullar, M}, title = {Site- and age-dependent associations between Fusobacterium nucleatum and colorectal cancer mortality.}, journal = {Cancer}, volume = {132}, number = {12}, pages = {e70484}, doi = {10.1002/cncr.70484}, pmid = {42244408}, issn = {1097-0142}, support = {S10OD028685//Office of Research Infrastructure Programs, National Institutes of Health/ ; //GSF/ ; SR-202221337//M.J. Murdock Charitable Trust/ ; //V Foundation for Cancer Research/ ; P20CA252733/NH/NIH HHS/United States ; P30 CA015704/NH/NIH HHS/United States ; P50CA285275/NH/NIH HHS/United States ; R01CA155101/NH/NIH HHS/United States ; R01CA238087/NH/NIH HHS/United States ; R01CA248931/NH/NIH HHS/United States ; R01CA280639/NH/NIH HHS/United States ; R01CA284732/NH/NIH HHS/United States ; T32CA094880/NH/NIH HHS/United States ; U01CA290673/NH/NIH HHS/United States ; }, abstract = {BACKGROUND: Fusobacterium nucleatum (Fn) is a bacterium typically found in the human oral cavity that has been implicated in the development and progression of colorectal cancer (CRC).<br><br>OBJECTIVE: This study examines the association between prevalence of Fn in tumor tissue and CRC-specific mortality in a heterogeneous United States population.<br><br>METHODS: The present study includes 233 participants with stage I-III CRC who died of CRC, matched to 458 participants with CRC who did not die from their disease, within the Translational Research Program in Cancer Differences across Populations. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue samples. Droplet digital polymerase chain reaction was used to assess the prevalence of Fn. The authors fit logistic regression models for the association between Fn positivity and CRC-specific mortality, adjusting for age, year of diagnosis, sex, stage, tumor site, population group, and tumor macrodissection status.<br><br>RESULTS: Presence of Fn in CRC tumor tissue was associated with 79% greater odds (95% CI, 1.20-2.67) of CRC-specific mortality. This association was more pronounced in participants with rectal (odds ratio [OR], 7.73; 95% CI, 2.13-34.79) than proximal colon (OR, 1.17; 95% CI, 0.65-2.08) or distal colon tumors (OR, 1.51; 95% CI, 0.74-3.04, p value for interaction&#xa0;=&#xa0;.023), and more pronounced with respect to early-onset (age <50 years; OR, 10.30; 95% CI, 2.09-70.53) than later-onset CRC (age &#x2265;50 years; OR, 1.51; 95% CI, 0.98-2.33, p value for interaction&#xa0;= .010).<br><br>CONCLUSIONS: These findings support an association between presence of Fn in CRC tumor tissue and CRC-specific mortality, particularly for rectal tumors and early-onset CRC, in a heterogeneous population.}, }
@article {pmid42245734, year = {2026}, author = {Zhang, JS and Ng, JCK and Hermida de Viveiros, P and Al-Marayaty, R and Al Akoum, N and Shinglot, H and Jing, W and Vizcaino, V and Alexiev, BA and Cranmer, LD and Loggers, ET and Abrams, H and Wagner, MJ and Pillarisetty, VG and Kim, EY and Pierce, RH and Berglund, P and Jones, RL and Lu, H and Ter Meulen, J and Pollack, SM and Seo, YD}, title = {Intratumoral TLR4 agonist therapy elicits antigen-specific T cell clonal expansion in metastatic leiomyosarcoma: a case series.}, journal = {Frontiers in oncology}, volume = {16}, number = {}, pages = {1829331}, pmid = {42245734}, issn = {2234-943X}, abstract = {Metastatic soft tissue sarcomas (STSs) are a heterogeneous group of rare mesenchymal tumors whose treatment options are limited. Our group has been interested in utilizing the synthetic toll-like receptor 4 (TLR4) agonist, glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE), in patients with advanced STSs. Here, we report a case series of three patients with metastatic leiomyosarcoma who had superficial lesions amenable to intratumoral (IT) injection. We explored the safety, tolerability, and immunologic effects of IT GLA-SE given at 20 μg weekly for 12 weeks, both alone and in combination with radiotherapy. In this small case series, treatment was well tolerated, with no serious adverse events observed. Clinically, although no patient had significant tumor shrinkage, two had notable stability in their target lesions despite systemic disease progression. Immunologically, IT GLA-SE induced a clonal expansion of T cells intratumorally in one patient and in peripheral blood in another, suggesting an antitumor effect both at the site of injection and systemically. Moreover, GLA-SE elicited clonal expansion of systemic T cells targeting a well-known immunogenic cancer antigen, NY-ESO-1. The augmented expression of T cells targeting NY-ESO-1 in the systemic circulation of our patient following IT-GLA-SE warrants further investigation, given the promising role of NY-ESO-1 in current and future T-cell based immunotherapies. Together, these findings demonstrate the potential of IT GLA-SE to elicit antigen-specific T cell clonal expansion as a component of immunotherapeutic strategies to combat metastatic STSs. Expanded studies are needed to explore the clinical and immunologic effects of IT GLA-SE, particularly in combination with other immunotherapies.}, }
@article {pmid42248140, year = {2026}, author = {DeWitt, WS and Vora, AA and Araki, T and Galloway, JG and Alkutkar, T and Bortolatto, J and Castro, TBR and Dumm, W and Jennings-Shaffer, C and Jia, T and Mesin, L and Ozorowski, G and Pae, J and Ralph, DK and Bloom, JD and Nourmohammad, A and Song, YS and Ward, AB and Starr, TN and Matsen, FA and Victora, GD}, title = {Replaying germinal center evolution on a quantified affinity landscape.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2026.05.013}, pmid = {42248140}, issn = {1097-4172}, abstract = {Darwinian evolution of immunoglobulin genes within germinal centers (GCs) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the cellular mechanics of how competition between B cells increases affinity are well established, the evolutionary dynamics of this process are less clear. We developed an experimental evolution model in which we "replay" over one hundred monoclonal GC reactions, assigning affinities to each cell using deep mutational scanning. Our data reveal how GCs achieve predictable outcomes by means of noisy but persistent selection on an affinity landscape whose exploration is heavily constrained by somatic hypermutation biases. We infer a fitness landscape that quantitatively recapitulates the affinity maturation trajectory of our clone and find that apparent features of GC selection, such as permissiveness to low-affinity lineages and rapid plateauing of affinity, are likely artifacts of survivorship biases that distort our view of how B cell affinity progresses over time.}, }
@article {pmid42249080, year = {2026}, author = {Budillon, A and Lemmers, RJLF and Tapscott, SJ and van der Maarel, SM}, title = {The emergence and diversification of the DUX gene family across placental mammals.}, journal = {Communications biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s42003-026-10442-2}, pmid = {42249080}, issn = {2399-3642}, support = {R01AR045203//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; }, abstract = {The DUX gene family encodes transcription factors with paired homeodomains. It has critical roles in embryogenesis and disease, including facioscapulohumeral muscular dystrophy (FSHD) and cancer. This study conducts a comparative analysis of the DUX gene family-DUXA, DUXB (including DUXBL), and DUXC (including DUX4 and Dux)-across placental mammals, highlighting their structural diversity within macrosatellite repeat contexts. Using long-read genomes, we explore gene distribution, array patterns, and phylogenetic relationships in various vertebrate species. Our analysis reveals that DUXA and DUXB are highly conserved, with intriguing variations such as intronless forms likely arising from ancestral retrotransposition events. While DUXBL is inconsistently retained across clades, its locus-which in non-placental mammals harbors the ancestral single-homeodomain sDUX gene-served as an evolutionary hub for diversification, giving rise to DUXA, DUXB and DUXC, as well as macrosatellite tandem array structures. Sequence conservation and syntenic analyses demonstrate array adaptability, exemplified by higher-order repeats in orangutans and disrupted patterns of concerted evolution in elephants. Furthermore, analysis of human pseudo-DUX4 arrays indicates their potential role in disease mechanisms, including as possible contributors to rare cases of FSHD, warranting further investigation. This study thus provides insights into DUX-family gene evolution, offering a foundation for future research into developmental roles and disease implications.}, }
@article {pmid42243439, year = {2026}, author = {Chestnut, C and McKoy, T and Westphalen, AC and Lin, DW and Nyame, YA}, title = {The clinical utility of prostate MRI before biopsy.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, pmid = {42243439}, issn = {1759-4820}, abstract = {Approximately 1 in 8 men are diagnosed with prostate cancer during their lifetime. However, long-term data have shown that as many as half of diagnosed prostate cancers have low lethal potential. Early detection of prostate cancer relying on PSA alone is associated with potential harm to patients owing to false-positive results, prostate biopsy-related complications and over-detection and over-treatment of low-risk cancers. Multiparametric MRI offers an adjunctive strategy for improving the diagnostic yield of prostate biopsy and also for potentially reducing the need for biopsy in selected patients. Prostate MRI can increase the detection of clinically significant prostate cancer through targeted biopsy, especially in patients with a previous negative biopsy who did not undergo initial imaging. Prostate MRI improves clinically significant cancer detection, potentially reducing biopsy burden in patients on active surveillance.}, }
@article {pmid42241708, year = {2026}, author = {Meyer, LK and Ryan, K and Panetta, JC and Crews, KR and Albeituni, S and Degar, BA and Hermiston, ML and Talano, JM and Torno, LL and Zambidis, ET and Trone, DJ and Sabin, ND and Maron, G and Flerlage, T and Thomas, PG and Cheng, C and Campbell, PK and Nichols, KE and Hines, MR}, title = {HLHRUXO: A prospective trial of a ruxolitinib-containing regimen for children with hemophagocytic lymphohistiocytosis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026020265}, pmid = {42241708}, issn = {2473-9537}, abstract = {Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by excessive immune cell activation and hypersecretion of inflammatory cytokines, many of which signal via the Janus kinases (JAKs). Preclinical studies have demonstrated that the JAK1/2 inhibitor ruxolitinib ameliorates disease manifestations and prolongs survival in mouse models of HLH. Similarly, clinical studies have suggested that ruxolitinib is safe and effective for children with HLH, although prospective trials evaluating optimal ruxolitinib doses in primary (i.e., inherited/genetic) HLH are lacking. To address this gap, we developed HLHRUXO (https://clinicaltrials.gov/study/NCT04551131), a prospective multi-institutional clinical trial utilizing a ruxolitinib-containing regimen in children with newly diagnosed or relapsed/refractory HLH. Patients received ruxolitinib 25 mg/m2 twice daily combined with dexamethasone, with or without etoposide, for eight weeks, followed by continuation therapy at the discretion of the treating physician. Pharmacokinetic studies were performed on days one and eight. Eight patients (average age 7.6 years; five primary HLH [pHLH] and three secondary HLH [sHLH]) completed the study; none experienced dose-limiting adverse events (AEs). All patients experienced a favorable response at one week, demonstrating clinical stabilization and improvement in serum ferritin levels. Further, all five patients (three pHLH, two sHLH) with newly diagnosed HLH achieved a complete response (CR) after eight weeks of treatment, and all were alive at one year. One patient with relapsed/refractory sHLH achieved a CR at eight weeks and was alive at one year, while two others with relapsed/refractory pHLH died. Our findings confirm the safety of this ruxolitinib-containing regimen for pediatric HLH, with the best results observed in patients with newly diagnosed disease. Further studies of ruxolitinib as frontline therapy for children with HLH are warranted.}, }
@article {pmid42242253, year = {2026}, author = {Fan, BE and Lam, BD}, title = {Artificial intelligence triage tool for bone marrow fibrosis in myeloproliferative neoplasms using complete blood counts.}, journal = {The Lancet. Haematology}, volume = {13}, number = {6}, pages = {e355-e357}, doi = {10.1016/S2352-3026(26)00129-8}, pmid = {42242253}, issn = {2352-3026}, }
@article {pmid42242398, year = {2026}, author = {Rivas-Nieto, AC and Alver, SK and Mooney, SJ and Mossavar-Rahmani, Y and Xue, X and Lash, JP and Kaplan, R}, title = {Physical Activity Patterns and Kidney Function Changes Among Hispanic/Latino Adults: The Hispanic Community Health Study/Study of Latinos.}, journal = {Journal of physical activity &amp; health}, volume = {}, number = {}, pages = {1-10}, doi = {10.1123/jpah.2025-0918}, pmid = {42242398}, issn = {1543-5474}, abstract = {BACKGROUND: Physical activity (PA) may be a modifiable factor for chronic kidney disease (CKD) prevention, but evidence specific to Hispanic/Latino populations is limited. Our objective was to examine associations between PA type/volume with changes in kidney function among Hispanic/Latino adults.<br><br>METHODS: We included participants (mean age: 41.6&#xa0;years, 55.2% women) in the Hispanic Community Health Study/Study of Latinos with complete data. PA was measured using both 7-day accelerometry and the Global Physical Activity Questionnaire. Primary outcomes were percent change in estimated glomerular filtration rate (eGFR) and percent change in urine albumin-to-creatinine ratio over a mean of 6.1&#xa0;years (N = 7071); incident CKD was the secondary outcome (N = 7177).<br><br>RESULTS: The mean eGFR change was -3.6&#xa0;mL/min/1.73&#xa0;m2, and mean urine albumin-to-creatinine ratio change was 4.0&#xa0;mg/g. In multivariable-adjusted models accounting for demographic, occupational, and clinical factors, neither accelerometer-measured light PA or moderate to vigorous PA (MVPA) nor self-reported MVPA were significantly associated with changes in eGFR, urine albumin-to-creatinine ratio, or incident CKD (P > .05). Diabetes status significantly modified associations between eGFR percent change and accelerometer-measured light PA (interaction P < .01), MVPA (interaction P = .02), and self-reported total MVPA (interaction P = .03). Among individuals with diabetes, higher self-reported total MVPA was associated with higher eGFR change (0.12% per 15&#xa0;min/d; 95% CI, 0.02-0.22), whereas greater accelerometer-measured MVPA was linked to higher CKD risk (incidence rate ratio: 1.12; 95% CI, 1.02-1.23). Among those without diabetes, associations were inverse with 95% CIs that overlapped the null.<br><br>CONCLUSIONS: PA types/volumes were not associated with kidney function decline or CKD incidence, though diabetes status may modify these relationships.}, }
@article {pmid42242424, year = {2026}, author = {Arnold, DE and Eissa, H and Dunn, E and Cuvelier, GDE and Wright, NAM and Marsh, RA and Parikh, S and Saldana, BD and Vander Lugt, MT and Bacchetta, R and Satter, LF and Chandrakasan, S and Kellner, E and Allenspach, EJ and Schmitt, EG and Logan, B and Burroughs, L and Cowan, MJ and Griffith, LM and Notarangelo, L and Pai, SY and Pulsipher, MA and Dvorak, CC and Haddad, E and Puck, JM and Torgerson, TR and Leiding, JW and Heimall, J and Chan, AY}, title = {IMPACT (Immune Monitoring and Phenotype Assessment of Clinical Trajectory) for Patients with Inborn Errors of Immunity from the Primary Immune Deficiency Treatment Consortium (PIDTC).}, journal = {The journal of allergy and clinical immunology. In practice}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaip.2026.05.025}, pmid = {42242424}, issn = {2213-2201}, abstract = {BACKGROUND: Evaluating natural history and outcomes of rare inborn errors of immunity (IEIs) has been challenging due to the diverse disease manifestations and lack of standardized data.<br><br>OBJECTIVE: We developed a set of standardized, quantitative, generalizable data collection modules to measure organ dysfunction in IEIs, modeled on the previously validated Common Terminology Criteria for Adverse Event (CTCAE) system for grading treatment toxicity.<br><br>METHODS: Disease conditions were organized by organ system. Experts from the Primary Immune Deficiency Treatment Consortium (PIDTC) identified essential features of severe combined immunodeficiency (SCID), chronic granulomatous disease (CGD), Wiskott-Aldrich syndrome (WAS), and primary immune regulatory disorders (PIRD) and compared these to CTCAE conditions, adding and refining features as needed. Dates of onset and resolution, disease-specific laboratory values, and therapeutic interventions were also incorporated. Modules were reviewed by protocol teams, key stakeholders, clinical coordinators and statisticians to improve feasibility and completeness.<br><br>RESULTS: We developed a tool called IMPACT (Immune Monitoring and Phenotype Assessment of Clinical Trajectory) containing 15 modules assessing 196 disease conditions. A grading system from 1 to 5 (mild, moderate, severe, life-threatening, fatal) permits longitudinal tracking of disease condition severity. Outcomes of interventions can be measured quantitatively by comparing scores before and after treatment.<br><br>CONCLUSION: Standardized, quantitative assessment tools for IEIs can yield uniform datasets to illuminate their natural history and evaluate outcomes of interventions, not only to understand specific diseases, but also to compare effects between disease entities. Tools, like IMPACT, are essential for therapeutic trials for rare, complex multisystem diseases like IEIs and other disorders with protean manifestations.}, }
@article {pmid42242633, year = {2026}, author = {Goldstein, CE and Armond, ACV and Cobey, KD and Voldal, EC and Chen, Y and Tingley, K and Shaw, JF and Heagerty, PJ and Hemming, K and Kenny, A and Li, F and Ouyang, Y and Xia, F and Moher, D and Hughes, JP and Taljaard, M}, title = {Data sharing in stepped-wedge cluster randomized trials: suboptimal data availability despite "data available upon request".}, journal = {Journal of clinical epidemiology}, volume = {}, number = {}, pages = {112353}, doi = {10.1016/j.jclinepi.2026.112353}, pmid = {42242633}, issn = {1878-5921}, abstract = {BACKGROUND: Data sharing enhances transparency, facilitates reproducibility, and promotes innovation in health research. For statisticians, access to data from real trials is essential to develop, validate, and refine statistical methods.<br><br>OBJECTIVES: Within a collection of published stepped-wedge cluster randomized trials (SW-CRTs), we aimed to describe the prevalence and types of data sharing statements; the actual availability of data after emailing authors; and factors associated with data obtainment.<br><br>METHODS: We identified SW-CRTs published between 2016-2022 from a previous systematic review and updated that search to include studies published through 31 December 2023. Data sharing statements, when provided, were classified as indicating data were publicly available, available upon request, or not available. Authors were emailed to request datasets. Associations between trial characteristics and data obtainment were explored using bivariable logistic regression and results reported as Odds Ratio (OR) with 95% Confidence Interval (CI).<br><br>RESULTS: Of 217 SW-CRTs identified, 98 (45%) had no clear data sharing statements, 89 (41%) indicated data were available upon request, 16 (7%) indicated data were not available, and 14 (7%) indicated data were publicly available. Datasets were ultimately obtained for 76 (35%) SW-CRTs. Data obtainment did not differ between studies with no data sharing statement and those indicating data were available upon request (both 34%). The odds of data obtainment were significantly higher among trials conducted in low- and middle-income countries (OR=2.9, 95% CI 1.5-5.4). The odds of data obtainment increased with years since publication (OR=1.13; 95% CI 0.99-1.29) and years since trial initiation (OR=1.11; 95% CI 1.00-1.23) although confidence intervals overlapped with the null. There was no clear evidence of an association with having positive primary trial results (OR=0.62; 95% CI 0.35-1.10), nor with journal impact factor, trial size, type of design, region of corresponding author, and funding source.<br><br>CONCLUSION: Data sharing practices in SW-CRTs are suboptimal. The presence of a data sharing statement is not predictive of actual data availability. There is significant regional variation in whether data were obtained but few other characteristics explain variation in data obtainment. Clear guidance and dedicated resources to facilitate data sharing in research are required.}, }
@article {pmid42242864, year = {2026}, author = {Jiang, F and Shen, Y and Li, B and Henry, M and Davidson, N and Huang, Y}, title = {Inhibition of histone demethylase LSD1 suppresses CD47 expression and enhances efficacy of CD47 blockade in breast cancer.}, journal = {Journal for immunotherapy of cancer}, volume = {14}, number = {6}, pages = {}, doi = {10.1136/jitc-2025-014681}, pmid = {42242864}, issn = {2051-1426}, abstract = {BACKGROUND: CD47 functions as a "don't eat me" checkpoint, inhibiting macrophage-mediated phagocytosis in triple-negative breast cancer (TNBC). While anti-CD47 therapies can restore immune surveillance, their efficacy in TNBC is often limited by immune evasion and drug development challenges.<br><br>METHODS: We investigated the crosstalk between the histone demethylase lysine-specific demethylase 1 (LSD1) and CD47 signaling in TNBC using in silico datasets, isogenic cell lines, conditional BRCA1 knockout models, and syngeneic mouse models. Techniques such as immunohistochemistry, multiplex immunofluorescence, immunoprecipitation, protein ubiquitination, chromatin immunoprecipitation, chemotaxis, flow cytometry, and phagocytosis assays were employed to examine the epigenetic regulation of CD47 by LSD1 and its impact on antitumor immunity. The efficacy of combining LSD1 inhibition with anti-CD47 therapy was evaluated in BALB/cJ mice bearing TNBC tumors.<br><br>RESULTS: In TNBC tumors, CD47 expression is positively correlated with elevated LSD1 levels, which are associated with increased infiltration of M2 macrophages and a concomitant decrease in M1 macrophages and CD8+T cells. Inhibition of LSD1 led to downregulation of CD47 by suppressing the expression and activity of its key transcriptional regulators, NF-&#x3ba;B (p65) and STAT3, through distinct mechanisms. Loss of LSD1 reduced p65 transcription, which was linked to an accumulation of the repressive histone mark H3K9me2 at the p65 promoter. Conversely, LSD1 inhibition promoted polyubiquitination and subsequent destabilization of STAT3. LSD1 inhibition also enhanced phagocytosis and promoted M1 polarization of macrophages. CD47 downregulation induced the production of interferon-&#x3b3; and Th1-type chemokines in TNBC cells, facilitating increased tumor infiltration of CD8+T cells. Furthermore, combining LSD1 inhibition with anti-CD47 therapy significantly improved antitumor efficacy compared with monotherapy in syngeneic tumor models, without inducing significant toxicity. This combination therapy also promoted a shift in macrophage polarization toward the M1 phenotype, further enhancing CD8+T&#x2009;cell infiltration within tumors. Depletion of CD8+T cells significantly diminished the antitumor efficacy of the combination therapy.<br><br>CONCLUSION: Targeting LSD1 enhances the efficacy of anti-CD47 therapy by overcoming immune evasion, offering a promising strategy to improve immunotherapy outcomes in TNBC.}, }
@article {pmid42233964, year = {2026}, author = {Del Vecchio, NJ and Doria-Rose, VP and Todd, KW and Rendle, KA and Chubak, J and Halm, EA and Alonge, OD and Issaka, RB and Neslund-Dudas, C and Honda, S and Ziebell, RA and Li, CI and Zheng, Y and Hughes, AE and Ritzwoller, DP and Corley, DA}, title = {Impacts of a Public Health Emergency on Cancer Testing Rates, Follow-up, and Cancer Diagnosis: an Evaluation of the COVID-19 Pandemic.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-26-0292}, pmid = {42233964}, issn = {1538-7755}, abstract = {BACKGROUND: Public health emergencies can substantially impact routine healthcare. Large cancer screening declines during the early months of the COVID-19 pandemic are well-documented; however, COVID-19's impact on follow-up of abnormal screening exams and cancer diagnoses is less reported. We examined the impacts of COVID-19 on the cervical, colorectal, and lung cancer screening processes, within 10 health systems in the Population-based Research to Optimize the Screening Process (PROSPR) consortium.<br><br>METHODS: PROSPR data were used to calculate: (1) monthly rates of cancer testing and, for pre-COVID and COVID time periods, (2) proportions of individuals receiving recommended follow-up within 6 months of an abnormal test, and (3) cancer incidence. Surveys were used to assess the healthcare systems' local context.<br><br>RESULTS: During the first two months of the pandemic, cancer testing decreased across all health systems and cancer types (range18-96%). Overall, decreases in monthly rates were followed by rapid recovery to pre-pandemic rates. The rates of 6-month follow-up of abnormal screening results trended down in the COVID vs. pre-COVID periods, as did the diagnosis of new cancers.<br><br>CONCLUSIONS: Declines in cancer testing in the early months of the COVID-19 pandemic were short-term, with at least short-term impacts on diagnostic follow-up and cancer diagnosis. The systems with the smallest decreases were those that both utilized remote screening outreach (e.g., mailed FIT kits) and did not pause that outreach at the start of the pandemic.<br><br>IMPACT: Strategies and policies implemented by healthcare systems during public health emergencies can help minimize disruptions in care.}, }
@article {pmid42234759, year = {2026}, author = {Naffeti, BS and Ayoub, HH and Johnston, C and Abu-Raddad, LJ}, title = {Projected public health benefits of a hypothetical HSV-1 vaccine in the United States: A mathematical modeling analysis.}, journal = {Science advances}, volume = {12}, number = {23}, pages = {eaee0698}, pmid = {42234759}, issn = {2375-2548}, mesh = {Humans ; *Herpesvirus 1, Human/immunology ; United States/epidemiology ; *Models, Theoretical ; *Herpes Simplex Virus Vaccines/immunology ; *Public Health ; *Herpes Simplex/prevention &amp; control/epidemiology/immunology ; Vaccination ; Female ; Adolescent ; Infant ; }, abstract = {Herpes simplex virus type 1 (HSV-1) infection is highly prevalent worldwide and causes oral, genital, and neonatal herpes. Several HSV vaccine candidates are currently in development. This study used mathematical modeling to estimate the potential population-level impact of HSV-1 vaccination strategies in the United States. Infant vaccination with 70% efficacy and lifelong protection introduced in 2030 reduced oral and genital incidence rate by 47.3 and 58.3% by 2075, respectively, with annual new infections declining by 41.2 and 53.5%, corresponding to 28.5 million cumulative infections averted. The number needed to vaccinate to prevent one infection, defined from program initiation to a specified year, declined from 35.8 by 2040 to 7.2 by 2070. Addition of adolescent catch-up vaccination further reduced oral and particularly genital incidence. Lifelong protection produced approximately threefold greater impact than 15-year protection. HSV-1 vaccination could substantially reduce oral and genital HSV-1 burden, supporting prioritization of vaccine development and integration into public health strategies.}, }
@article {pmid42234933, year = {2026}, author = {Doroshow, DB and Leal, TA and Waqar, SN and Borghaei, H and Camidge, DR and Dragnev, KH and Edelman, MJ and Gandara, DR and Gerber, DE and Gray, JE and Hirsch, FR and Husain, H and Kozono, DE and Leighl, NB and Li, BT and Mack, PC and Neal, JW and Paik, PK and Patel, SP and Riess, JW and Redman, MW and Reckamp, KL}, title = {Resistance to Immune Checkpoint Inhibitor Treatment in Non-Small Cell Lung Cancer Clinical Trials: A Perspective From Lung-MAP Investigators.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2501896}, doi = {10.1200/JCO-25-01896}, pmid = {42234933}, issn = {1527-7755}, }
@article {pmid42235031, year = {2026}, author = {Annamalay, A and Radich, J}, title = {Chronic Myeloid Leukemia in Low- and Middle-Income Countries. Reply.}, journal = {The New England journal of medicine}, volume = {394}, number = {21}, pages = {2175-2176}, doi = {10.1056/NEJMc2605636}, pmid = {42235031}, issn = {1533-4406}, }
@article {pmid42236300, year = {2026}, author = {Andrews, H and Agnihotram, R and Blumenthal, G and Bullock, J and Collins, G and Doherty, GJ and Farago, AF and Ishii, Y and Kasichayanula, S and LeBlanc, M and Levi-D'Ancona, E and Li, C and McCullough, K and Morrow, PK and Navarro, B and Sandhu, P and Shah, S and Sharon, E and Su, Z and Vallett, C and Villalobos, Y and Allen, JD and Stewart, MD}, title = {Assessing Contribution of Effect in Oncology Combination Therapies: Lessons Learned to Inform and Optimize Future Registrational Trial Designs.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyag222}, pmid = {42236300}, issn = {1549-490X}, abstract = {Combination therapies can be used to significantly improve clinical outcomes in patients undergoing treatment for cancer, however, they also present challenges when establishing the contribution of effect (COE) for each component. Although factorial trials remain the most rigorous approach for determining COE, they are often impractical, such as in settings with rare cancers, aggressive disease, evolving standards of care, or monotherapy components with limited activity. As more combination regimens are co-developed from the outset, alternative approaches to registrational trial designs are needed to balance scientific rigor with feasibility and patient acceptability. Thoughtfully designed alternative approaches can support an understanding of COE when grounded in prior evidence and mechanistic understanding. Four major categories of evidence emerge to support designing combination trials without factorial arms: (1) data from trials of the same combination in other tumor types; (2) data from trials of agents with similar mechanisms of action; (3) data from early-phase or parallel trials of the combination within the same disease setting; and (4) strong mechanistic or clinical evidence that a monotherapy component lacks activity and/or imposes harm, supporting omission of inactive arms. Early regulatory engagement, prespecified decision rules, and transparent justification of design choices are essential to ensure that combination regimens provide meaningful improvement in efficacy over monotherapies while minimizing unnecessary toxicity. Applying these principles to combination therapy development can maximize patient benefit while maintaining scientific rigor.}, }
@article {pmid42237020, year = {2026}, author = {Richards, AR and Gomez, MF and Dowling, BI and Bulka, CM and Gigic, B and Figueiredo, JC and Li, CI and Shibata, D and Toriola, AT and Byrd, DA and Ulrich, CM and Teng, M and Stewart, PA and Siegel, EM and Kresovich, JK}, title = {Abundance and balance of circulating leukocyte subsets and colorectal cancer survival.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {42237020}, issn = {1532-1827}, abstract = {BACKGROUND: Cancer immunology research has traditionally focused on tumor-infiltrating leukocytes, but the role of the peripheral leukocytes remains understudied. Since tumor-infiltrating leukocytes are recruited from the blood, circulating immune profiles may provide prognostic insights obtainable before surgery, reflecting overall immune competence.<br><br>METHODS: We analyzed treatment-na&#xef;ve blood samples from 134 stage I-III colorectal cancer (CRC) patients using a nested case-control design (33 recurrences, 45 deaths; median follow-up: 7.4 years). Circulating leukocyte subsets were estimated using methylation cytometry applied to genome-wide methylation profiles. Cox regression models estimated associations between leukocyte metrics and disease-free and overall survival, adjusting for clinical factors.<br><br>RESULTS: Higher counts of circulating neutrophils and T-regulatory cells were associated with worse disease-free and overall survival (neutrophil, disease-free HR: 1.32, 95% CI: 1.01, 1.72, P&#x2009;=&#x2009;0.04; overall HR: 1.39, 95% CI: 1.00, 1.94, P&#x2009;=&#x2009;0.05; T regulatory, disease-free HR: 1.32, 95% CI: 1.00, 1.74, P&#x2009;=&#x2009;0.05; overall HR: 1.38, 95% CI: 1.00, 1.90, P&#x2009;=&#x2009;0.05). Memory B cells were associated with worse disease-free survival (HR: 1.56, 95% CI: 1.31, 1.86, P&#x2009;<&#x2009;0.0001), particularly in those diagnosed with rectal cancer. Higher basophil counts and proportions were associated with worse overall survival (count HR: 1.44, 95% CI: 1.05, 1.99, P&#x2009;=&#x2009;0.02; proportion HR: 1.47, 95% CI: 1.06, 2.03, P&#x2009;=&#x2009;0.02), with stronger associations in those diagnosed at earlier stages or with rectal tumors.<br><br>CONCLUSIONS: Peripheral immune cell composition identifies CRC patients at higher risk for recurrence and death, providing insights into systemic immune contributions to CRC survival.}, }
@article {pmid42237094, year = {2026}, author = {Lim, MY and Gangaraju, R and Jafari, O and Yang, Z and Tiong, JWT and Chiang, ECL and Ma, S and Jiang, JY and Ryu, J and Lam, BD and Ranjan, M and Li, A}, title = {Clinically Relevant Bleeding in Individuals With Cancer: Insights From a Nationwide Cohort Study.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70394}, pmid = {42237094}, issn = {1096-8652}, support = {R01 HL180402/NH/NIH HHS/United States ; K23 HL159271/NH/NIH HHS/United States ; K08 HL159290/NH/NIH HHS/United States ; RR190104//Cancer Prevention and Research Institute of Texas/ ; ASH Scholar Award//American Society of Hematology/ ; Career Development Award//Conquer Cancer Foundation/ ; }, abstract = {Cancer care is often complicated by coagulopathy leading to thrombosis and bleeding. While venous thromboembolism (VTE) has been extensively studied, bleeding remains an underestimated threat. To address this knowledge gap, we leveraged the Epic Cosmos database to determine the impact of cancer-associated clinically relevant bleeding (CRB) in 2 455 332 individuals with incident cancer encounters from 215 US health systems between 2018 and 2024. In the 12 months leading up to the cancer diagnosis, the period prevalence of CRB was 5.3% in the overall cohort, highlighting CRB as a common early presentation preceding cancer diagnosis. In the 12-month window after cancer diagnosis, the cumulative incidence of CRB was 6.3% in the overall cohort, 7.0% in those receiving systemic antineoplastic therapy, and up to 15.0% among individuals on certain baseline anticoagulants. In addition to age, sex, and race, factors appreciably associated with CRB on multivariable analysis included cancer types, metastatic disease, systemic therapy, anticoagulant or antiplatelet use, higher comorbidity index, recent hospitalization, recent history of bleeding or VTE, and selective laboratory features (hemoglobin, platelets, albumin, eGFR). Furthermore, the onset of CRB as a time varying covariate was independently associated with mortality in multivariable adjusted analysis: intracranial hemorrhage (HR 4.17, 95% CI 4.11-4.24); gastrointestinal bleeding (HR 2.52, 95% CI 2.50-2.55); other bleeding (HR 2.46, 95% CI 2.44-2.49). Together, these findings reveal a substantial and overlooked risk of bleeding in cancer care and underscore a need for validated bleeding risk models that can be integrated alongside VTE prediction tools to guide personalized thromboprophylaxis decisions.}, }
@article {pmid42237652, year = {2026}, author = {Abramson, JS and Siddiqi, T and Gordon, LI and Lunning, MA and Wang, M and Arnason, JE and Kamdar, M and Maloney, DG and Shadman, M and Andreadis, CB and Sehgal, A and Solomon, SR and Ghosh, N and Hidalgo-López, JE and Wang, J and Ding, X and Ogasawara, K and Singh, A and Palomba, ML}, title = {Five-year survival outcomes from TRANSCEND NHL 001 of lisocabtagene maraleucel in R/R LBCL.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025032270}, pmid = {42237652}, issn = {1528-0020}, abstract = {We present 5-year survival results in patients with R/R LBCL from TRANSCEND NHL 001 (TRANSCEND), including data from the separate long-term follow-up (LTFU) study. Overall, 345 patients were leukapheresed, 270 received liso-cel, and 257 were efficacy evaluable. Among efficacy-evaluable patients, median overall survival (OS) was 27.5 months (95% confidence interval [CI], 16.2‒47.3; leukapheresed set, 15.2 months [95% CI, 11.5‒23.4]) with estimated 5-year OS rate of 38% (95% CI, 32‒45; leukapheresed set, 33% [95% CI, 28‒39]). Median disease-specific survival (DSS; excludes deaths unrelated to disease progression) was 67.8 months (95% CI, 23.5‒not reached [NR]; leukapheresed set, 27.4 months [95% CI, 14.4‒69.7]) with estimated 5-year DSS rate of 52% (95% CI, 45‒59; leukapheresed set, 47% [95% CI, 41‒52]). Among efficacy-evaluable patients from TRANSCEND who were alive at end-of-study and enrolled in the LTFU (n=84), median OS and DSS were NR (95% CI, NR‒NR) and estimated 5-year OS and DSS rates were 78% (95% CI, 67‒86) and 92% (95% CI, 84‒97), respectively. Most deaths occurred ≤2 years after infusion; no new safety signals were observed with low rates of late severe infections and second primary malignancies. These data support the curative potential of liso-cel in patients with R/R LBCL. Clinicaltrials.gov: NCT02631044, NCT03435796.}, }
@article {pmid42237892, year = {2026}, author = {Connerty, P and Colgan, JN and El-Najjar, F and Henry, E and Xie, J and Idais, D and Gentile, C and Mao, J and Dolman, MEM and Marshall, GM and Lock, RB}, title = {The myeloid cell leukaemia-1 inhibitor MIK665 is a potent therapy in preclinical models of paediatric acute myeloid leukaemia.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.70596}, pmid = {42237892}, issn = {1365-2141}, support = {RSP-655-FY2023//Tour de Cure/ ; RSP-023-2017//Tour de Cure/ ; RRE/0700:SZ//Anthony Rothe Memorial Trust/ ; 1157871//National Health and Medical Research Council/ ; //Heart Research Australia/ ; //Perpetual IMPACT/ ; //Catholic Archdiocese of Sydney/ ; //Heart Research Institute/ ; }, abstract = {Paediatric acute myeloid leukaemia (AML) remains a deadly disease, with survival rates reaching a plateau despite treatment with high-intensity chemotherapy. Recent advancements in therapeutic strategies, such as targeted therapies to inhibit AML dependencies, have aimed to improve outcomes. The evasion of apoptosis, regulated by the B-cell lymphoma 2 (BCL2) family of proteins, is a key feature of cancer progression and treatment resistance. Bcl-2 homology domain 3 (BH3) mimetics, such as venetoclax (ABT-199), which targets BCL2, have shown promising activity in AML. This study investigates for the first time the therapeutic potential of MIK665, a BH3 mimetic targeting myeloid cell leukaemia-1 (MCL1), in paediatric AML. We evaluated the efficacy of MIK665 against a diverse panel of AML cell lines and demonstrated its effectiveness as a single-agent treatment. Additionally, MIK665 showed significant activity against a subset of paediatric AML patient-derived xenografts (PDXs) in both ex vivo and in vivo experiments, with minimal impact on cardiac tissue pathophysiology. These findings strongly support the clinical advancement of MIK665 for paediatric AML treatment in a precision medicine approach.}, }
@article {pmid42238104, year = {2024}, author = {Hudson, A and Geng, EH and Odeny, TA and Bukusi, EA and Petersen, ML and van der Laan, MJ}, title = {An approach to nonparametric inference on the causal dose-response function.}, journal = {Journal of causal inference}, volume = {12}, number = {1}, pages = {}, pmid = {42238104}, issn = {2193-3677}, abstract = {The causal dose-response curve is commonly selected as the statistical parameter of interest in studies where the goal is to understand the effect of a continuous exposure on an outcome. Most of the available methodology for statistical inference on the dose-response function in the continuous exposure setting requires strong parametric assumptions on the probability distribution. Such parametric assumptions are typically untenable in practice and lead to invalid inference. It is often preferable to instead use nonparametric methods for inference, which only make mild assumptions about the data-generating mechanism. We propose a nonparametric test of the null hypothesis that the dose-response function is equal to a constant function. We argue that when the null hypothesis holds, the dose-response function has zero variance. Thus, one can test the null hypothesis by assessing whether there is sufficient evidence to claim that the variance is positive. We construct a novel estimator for the variance of the dose-response function, for which we can fully characterize the null limiting distribution and thus perform well-calibrated tests of the null hypothesis. We also present an approach for constructing simultaneous confidence bands for the dose-response function by inverting our proposed hypothesis test. We assess the validity of our proposal in a simulation study. In a data example, we study, in a population of patients who have initiated treatment for HIV, how the distance required to travel to an HIV clinic affects retention in care.}, }
@article {pmid42240813, year = {2026}, author = {Mandrik, O and Thomas, C and Bessey, A and Brennan, A and Carvalho, AL and Castilla-Rodríguez, I and Doroshenko, O and Hill, H and Kunst, N and Nagy, B and Payne, K and Pollard, D and Ramsey, SD and Roitberg, F and Shinkins, B and Smith, RA and Thom, H and Whyte, S}, title = {Correction: Ten Recommendations for Modelling Cost Effectiveness of Screening: Perspectives of an International Stakeholder Group.}, journal = {PharmacoEconomics}, volume = {}, number = {}, pages = {}, doi = {10.1007/s40273-026-01627-y}, pmid = {42240813}, issn = {1179-2027}, }
@article {pmid42240981, year = {2026}, author = {Quandt, Z and Othus, M and Sharon, E}, title = {Fluids for Immune Checkpoint Inhibitor Diabetic Ketoacidosis-Reply.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2026.1589}, pmid = {42240981}, issn = {2374-2445}, }
@article {pmid42241697, year = {2026}, author = {Sorror, ML and Artz, AS}, title = {Implementing CHARM in Transplant Practice.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026020708}, pmid = {42241697}, issn = {2473-9537}, }
@article {pmid42227161, year = {2026}, author = {Cardamone, LM and Prasad, P and Croix, M and Seidenfeld, A and Heldman, M and McConn, K and Mulanovich, V and Liakos, ADP and Koo, S and Chemaly, RF and Boeckh, M and Yoke, LH}, title = {Immunocompromised Host Infectious Diseases: A Recommended Educational Content Outline for Advanced Practice Providers.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70252}, doi = {10.1111/tid.70252}, pmid = {42227161}, issn = {1399-3062}, }
@article {pmid42227732, year = {2026}, author = {Deng, Y and Wang, R and Zhang, T and Zhan, X}, title = {Randomized Interventional Effects in Semicompeting Risks, With Application to a Hematopoietic Cell Transplantation Study.}, journal = {Statistics in medicine}, volume = {45}, number = {13-14}, pages = {e70628}, doi = {10.1002/sim.70628}, pmid = {42227732}, issn = {1097-0258}, abstract = {In clinical studies, the risk of the primary (terminal) event may be modified by intermediate events, resulting in semicompeting risks. To study the treatment effect on the terminal event mediated by the intermediate event, researchers wish to decompose the total effect into direct and indirect effects. In this article, we extend the randomized interventional approach to time-to-event outcomes, where both intermediate and terminal events are subject to right censoring. We envision a random draw for the intermediate event process from a reference distribution, either marginally over time-varying confounders or conditionally given the observed history. We present the identification formula for interventional effects. We also discuss some variants of the identification assumptions. We estimate the treatment effects using nonparametric maximum likelihood estimation and propose a sensitivity analysis that incorporates a latent frailty. As an illustration, we study the effect of matched unrelated donor versus haploidentical donor on death mediated by relapse in a hematopoietic cell transplantation study with graft-versus-host disease (GVHD) as the time-varying confounder. We find that matched unrelated donor transplantation is preferable in terms of survival rates under the use of post-transplant PTCy GVHD prophylaxis for lymphoma patients.}, }
@article {pmid42229584, year = {2026}, author = {Francis, PA and Pagani, O and Fleming, GF and Walley, BA and Colleoni, M and Rubovszky, G and Tondini, C and Ciruelos, EM and Gomez, HL and Bonnefoi, HR and Burstein, HJ and Chini, C and Puglisi, F and Spazzapan, S and Bernardo, A and Climent, MA and Bellet, M and Ruhstaller, T and Bermejo, B and Chia, SKL and Martino, S and Geyer, CE and Goetz, MP and Ingle, JN and Stearns, V and Davidson, NE and Le Du, F and Müller, B and Coleman, RE and Loibl, S and Winer, EP and Ruepp, B and Loi, S and Láng, I and Coates, AS and Gelber, RD and Goldhirsch, A and Regan, MM and ,  and , }, title = {Final outcomes of the SOFT and TEXT phase III trials in premenopausal hormone receptor-positive early breast cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2026.05.704}, pmid = {42229584}, issn = {1569-8041}, abstract = {BACKGROUND: The SOFT trial found adding ovarian function suppression (OFS) to tamoxifen (T) reduced breast cancer recurrence, and exemestane (E)+OFS further reduced recurrence. SOFT and TEXT combined analysis showed a significant reduction in distant recurrence with E+OFS versus T+OFS. We now report final 15-year outcomes.<br><br>PATIENTS AND METHODS: Premenopausal women with hormone receptor-positive early breast cancer were enrolled, with 3047 in SOFT and 2660 in TEXT intention-to-treat populations. SOFT randomized to 5 years of T versus T+OFS versus E+OFS. TEXT randomized to 5 years of T+OFS versus E+OFS. Chemotherapy was optional, prior to SOFT entry with subsequent premenopausal oestradiol, or concurrent with OFS in TEXT. Endpoints included disease-free survival, breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI) and overall survival. 15-year Kaplan-Meier estimates, hazard ratios (HR) and 95% confidence intervals (CI) are reported.<br><br>RESULTS: In SOFT, escalating endocrine therapy (ET) continued to reduce recurrence with 15-year BCFI 78.6% for E+OFS, 75.7% for T+OFS and 72.1% for T; T+OFS versus T, HR 0.82 (CI 0.69-0.98) P=0.03. In the SOFT no-chemotherapy cohort, OFS reduced breast cancer events at 15 years, while DRFI and overall survival remained high regardless of ET assignment. After prior chemotherapy for HER2-negative tumours (n=1257), SOFT 15-year overall survival was 81.0% with E+OFS versus 77.1% with T+OFS versus 76.8% with T. In women under age 35 with HER2-negative tumours (n=241), 15-year overall survival was 82.5% with E+OFS, 77.9% with T+OFS and 68.1% with T. In combined SOFT and TEXT analysis, among those with HER2-negative tumours (n=4035), E+OFS versus T+OFS reduced distant recurrence HR 0.75 (CI 0.63-0.90), with a smaller reduction in deaths HR 0.89 (CI 0.74-1.06), with absolute survival benefits largest with high-risk features, particularly young age or high-grade tumours.<br><br>CONCLUSION: Meaningful overall survival benefit in hormone receptor-positive, HER2-negative breast cancer from adjuvant exemestane and/or OFS compared with tamoxifen alone is limited to high-risk premenopausal subgroups. Tamoxifen-based ET may not result in optimal outcomes in premenopausal high-grade HER2-negative tumours.}, }
@article {pmid42229633, year = {2026}, author = {Dacic, S and Shenker, D and Redman, M and Brunner, L and Saqi, A and Cooper, WA and Borczuk, A and Chung, JH and Glass, C and Lopez, JM and Roden, AC and Sholl, L and Weissferdt, A and Brosnan-Cashman, J and Hennek, S and Grullon, S and Posadas, J and Fujimoto, J and Connolly, C and Wynes, MW and Sanchez-Espiridion, B and Lee, JJ and Berezowska, S and Chou, TY and Kerr, K and Nicholson, AG and Schalper, KA and Tsao, MS and Ready, N and Cascone, T and Heymach, J and Sepesi, B and Shu, C and Rizvi, N and Sonett, J and Altorki, N and Provencio, M and Bunn, PA and Kris, MG and Travis, W and Yu, L and Wistuba, I and , }, title = {Machine learning assessment of pathologic response in lung cancer resections after neoadjuvant therapy - IASLC MPR Project.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {103953}, doi = {10.1016/j.jtho.2026.103953}, pmid = {42229633}, issn = {1556-1380}, abstract = {INTRODUCTION: Machine learning algorithms may improve efficiency and accuracy of pathologic response (PR) assessment in surgically resected lung cancers following neoadjuvant therapy. The aim of this study was to develop digital models for quantifying tumor bed (TB) area and residual viable tumor (VT), and to compare these results to previously published assessments of PR by pathologists from the IASLC reproducibility study.<br><br>METHODS: Manual pathologist annotations (N=15,564) of regions including TB and VT were used to train convolutional neural network model (digital AI) and a Convex Hull algorithm (CHA). PR was determined by the percentage of VT in the TB area. The pathologist determined the average PR (APR) across slides (unweighted) which was compared to the weighted average for digital AI and CHA. The concordance between pathologist APR, digital AI and CHA was calculated, and correlated with outcomes.<br><br>RESULTS: There was a strong correlation between approaches: APR vs. Digital AI (0.97), APR vs. CHA (0.97), and Digital AI vs. CHA (0.99). Digital PR and CHA showed 100% agreement for MPR. The kappa concordance for MPR was 0.82 (95% CI: 0.69, 0.96) for APR versus Digital AI/CHA with 6 discordant cases. The concordance was higher for squamous cell carcinoma (Kappa 0.92, 95% CI: 0.76, 1.0) than for non-squamous carcinoma (Kappa 0.77, 95% CI: 0.59, 0.96). APR and digital AI showed similar relapse-free survival (RFS) and overall survival (OS).<br><br>CONCLUSION: The overall high level of agreement supports the utility of the machine learning approaches for evaluations of PR in patients with NSCLC.}, }
@article {pmid42230962, year = {2026}, author = {Arrieta-Bolaños, E and Lima, ACM and Andreani, M and De Santis, D and Malard, F and Mayor, NP and Mehta, RS and Meisel, R and Pagliuca, S and Petersdorf, E and Piemontese, S and Sacchi, N and Santoro, N and Sanz, J and Schetelig, J and Spellman, SR and Onida, F and Sánchez-Ortega, I and Mohty, M and Yakoub-Agha, I and Fleischhauer, K and Ruggeri, A}, title = {HLA matching in contemporary haematopoietic cell transplantation: Recommendations from the EBMT Practice Harmonisation and Guidelines Committee.}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {42230962}, issn = {1476-5365}, abstract = {HLA compatibility has been a cornerstone for safe and successful allogeneic haematopoietic cell transplantation (HCT), with human leukocyte antigen (HLA)-mismatched transplants consistently associated with inferior survival. However, recent advances in typing technologies, supportive care, and novel graft-versus-host disease (GvHD) prophylaxes have prompted the revisiting of HLA mismatch relevance in contemporary HCT. Within the framework of the 3[rd] Workshops of the Practice Harmonization &amp; Guidelines Committee, the EBMT convened a group of experts in histocompatibility &amp; immunogenetics, HCT immunobiology, and clinical HCT, to review the current state of the art and develop a set of consensus-based recommendations on the role of HLA in current HCT. The topics included technological aspects of HLA typing, the role of HLA mismatches in donor selection, and the detection and management of anti-HLA antibodies in HLA-mismatched transplantation. Moreover, the role of HLA matching relative to other non-HLA factors and in the context of novel GvHD prophylaxes, non-malignant disease, and pediatric populations was defined. Finally, the relevance of special models for HLA matching and of post-HCT monitoring of HLA-loss in malignant disease relapse was reviewed. The present document summarizes the expert consensus on these topics, to provide evidence-based recommendations for clinical decision-making.}, }
@article {pmid42232582, year = {2025}, author = {Mugwanya, KK and Matemo, D and Meisner, A and Schaafsma, T and Morton, J and Wandera, C and Kemunto, V and Cherotich, I and Odhiambo, S and Bii, M and Oduor, B and Achieng, E and Oyombra, T and Owaga, D and Beima-Sofie, KM and Baeten, JM and Kinuthia, J}, title = {Integrating oral pre-exposure prophylaxis delivery in primary care family planning clinics: a pragmatic, stepped-wedge, cluster-randomised trial.}, journal = {The Lancet. Primary care}, volume = {1}, number = {5}, pages = {}, pmid = {42232582}, issn = {3050-5143}, abstract = {BACKGROUND: Integrating pre-exposure prophylaxis (PrEP) delivery in family planning (FP) settings may offer an efficient platform to reach women at elevated risk for HIV.<br><br>METHODS: We conducted a stepped-wedge cluster randomized trial to integrate systematic screening for HIV risk and PrEP delivery in twelve public FP clinics in Kisumu County, Kenya. Clients were HIV-negative women 15-49 years accessing the participating clinics. Each clinic represented a cluster, and four clinics sequentially transitioned from usual care (control) to the intervention period in a randomized staged order every three-month interval. The intervention included provider training and technical support to build FP clinic staff capacity to deliver PrEP as part of the standard of care. There was no masking. Oral PrEP was free to clients. A subset of women assessed to be at elevated HIV risk including those who declined PrEP were enrolled in nested cohort and followed quarterly up to 24 months to measure HIV incidence. The primary outcomes were the proportion of women screened for oral PrEP among those attending FP clinics and PrEP initiation among women screened and assessed to be eligible for PrEP. Analysis was intention-to-treat, with all women not known to be living with HIV at the first clinic visit encounter included in the analysis for the HIV risk and PrEP screening outcome. This trial is registered with ClinicalTrials.gov., NCT04666792 and completed.<br><br>RESULTS: Between March 1, 2021 and December 31, 2022, 25457 HIV-negative women visited twelve FP clinics contributing 7386 woman-encounters during control period and 21343 woman-encounters during the intervention period. Median age was 27 (IQR 23-31) years. The proportion of woman-encounters screened for PrEP significantly increased from 2.9% (213/7386) to 91.6% (19560/21343) (relative risk: 20&#xb7;5, 95%CI 3&#xb7;5-120.4; p=0&#xb7;0008). Oral PrEP initiation among women assessed to be at elevated HIV risk increased from 3.9% (5/120) to 40.6% (985/2429) (relative risk: 50&#xb7;1, 95%CI 2&#xb7;8-913.4; p=0&#xb7;0082). Five HIV infections occurred during 833&#xb7;4 women-years of cohort follow-up (incidence 0.60 95%CI 0.19-1.40 per 100 woman-years). All infections were in women who either declined PrEP (n=3) or had undetectable tenofovir diphosphate in dried blood spots at multiple visits prior to seroconversion (n=2).<br><br>INTERPRETATION: An implementation intervention package to build capacity of public clinic FP healthcare providers successfully led to integration of oral PrEP delivery in real-world FP clinics in Kenya. These findings could help inform similar strategies in FP clinics in other African settings.}, }
@article {pmid42232894, year = {2026}, author = {Liu, Y and Carlson, C and Prajogi, GB and Jhingran, A and Holliday, E and Paly, J and Longo, J and Puckett, LL and Zaorsky, NG and Sarria, G and Castaneda, SA and Li, BC}, title = {A New Remote Classroom Approach to Contouring Training for Pelvic Malignancies in Low- to Middle-Income Asian Countries.}, journal = {Cureus}, volume = {18}, number = {4}, pages = {e108054}, pmid = {42232894}, issn = {2168-8184}, abstract = {BACKGROUND AND PURPOSE: The feasibility, learner interest, and educational impact of online contouring training in low- and middle-income countries (LMICs) in Asia have not been documented on a large participant scale; hence, we aimed to investigate these factors while conducting a training program in contouring pelvic malignancies.<br><br>MATERIALS AND METHODS: A 10-session contouring course was offered to primarily radiation oncologists in Southeast Asia (SEA) via Zoom (Zoom Communications, Inc., San Jose, USA). The curriculum included case-based learning and supplemental reading materials focusing on common contouring scenarios and errors. Participation and pre- and post-program surveys, including demographics, confidence scores, a 10-question contouring knowledge test, and anonymous feedback, were recorded and analyzed. Changes in pre- and post-program scores were evaluated using a paired t-test.<br><br>RESULTS: A total of 276&#xa0;physicians participated in the curriculum, with 144 participants completing pre- and post-confidence score surveys and knowledge tests. The attendance for each session averaged 140 (range 115-158). Among paired participants, mean confidence scores increased from 2.92 to 3.67 out of 5 (+26.28%, p<0.01) and were significantly improved across all disease sites (range +21.5% to +34.1%). Mean knowledge test scores increased from 4.47 to 6.53 out of 10 (+46.2%, p<0.01). The average likelihood of recommending this training program to another colleague was 9.63 out of 10.<br><br>CONCLUSIONS: &#xa0;The pelvic malignancies contouring training program, which focused on avoiding common errors, resulted in robust participation, significant improvements in confidence and knowledge scores, and excellent course recommendation scores. This strategy could potentially be replicated for continuous medical education, scaled to other countries, and applied to other cancer disease sites in the future.}, }
@article {pmid42233054, year = {2026}, author = {Srinivasan, P and Bechtel, M and Wyczechowska, D and Ochoa, AC and Fisch, MJ and Henry, NL and Unger, JM and Hamilton-Reeves, JM}, title = {Flow cytometry method to identify arginase-1 expressing MDSCs.}, journal = {MethodsX}, volume = {16}, number = {}, pages = {103957}, pmid = {42233054}, issn = {2215-0161}, abstract = {Myeloid-derived suppressor cells (MDSCs) contribute to immune suppression in cancer through arginase-1 (ARG1), which limits T-cell activation. Conventional assays such as ELISA or qPCR cannot determine the cellular source of ARG1 in blood. Recognizing the importance of ARG1 in immunosuppression, we developed and validated a standardized flow cytometry method using a commercially available ARG1 antibody to measure intracellular ARG1 in MDSC subsets. This method includes detailed instructions, including experimental optimization using positive and negative controls, to help other researchers perform flow cytometric measurement of ARG1 expressing cells. In this method, peripheral blood mononuclear cells were stained for lymphoid and myeloid markers (CD3, CD20, CD56, HLA-DR, CD33, CD11b, CD14, and CD15), fixed, and permeabilized before intracellular ARG1 staining. Antibody specificity was verified using neutrophils as positive and CD4[+] T cells as negative controls. The method was applied to blood samples from patients with bladder cancer (n = 23) and healthy volunteers (n = 10), demonstrating reliable detection of intracellular ARG1 in MDSC subpopulations. This accessible protocol provides an adaptable method for quantifying cell-specific ARG1 expression and studying MDSC-mediated immunosuppression.•The flow cytometry method described here was developed by validating the arginase1 antibody binding specificity using cells expressing high and very low levels of arginase-1.•Arginase-1-expressing cells of the peripheral blood monocytes were identified using this method.•This method can be adapted to any cell type and will be a valuable tool in future immunosuppression studies.}, }
@article {pmid42233504, year = {2026}, author = {Mamis, K and Bozic, I}, title = {Early-stage cancer results in a multiplicative increase in cell-free DNA originating from healthy tissue.}, journal = {Journal of the Royal Society, Interface}, volume = {23}, number = {239}, pages = {}, doi = {10.1098/rsif.2025.0349}, pmid = {42233504}, issn = {1742-5662}, support = {DMS-2045166//National Science Foundation/ ; //Pacific Institute for the Mathematical Sciences/ ; }, abstract = {Cell-free DNA (cfDNA) is a promising biomarker for cancer detection. However, the sources of elevated cfDNA in patients with early-stage cancer, and the mechanisms by which cfDNA is shed into, and subsequently cleared from the circulation are still poorly understood. Using a rich dataset of cfDNA in healthy individuals and early-stage cancer patients, we find a multiplicative increase in cfDNA concentration in the presence of cancer. This increase is cancer type-specific, ranging from an approximately 1.3-fold increase in lung cancer to an approximately 12-fold increase in liver cancer, and does not originate from the tumour, but from healthy tissue. Employing an additional dataset reporting the tissue of origin of cfDNA, we observe a significant increase in the correlation between cfDNA originating from leukocytes and from non-leukocyte sources in cancer patients. Introducing a mathematical model for cfDNA dynamics, we find that the observed correlation can be explained by a saturation mechanism in cfDNA clearance. Saturation in clearance implies that smaller increases in cfDNA shedding may lead to proportionally larger increases in cfDNA levels. Our findings quantify cfDNA dynamics in patients with cancer, with implications for improving the accuracy of liquid biopsies for early cancer detection.}, }
@article {pmid42233639, year = {2026}, author = {Stearns, K and Marcink, T and Pawlack, E and Sobolik, EB and Porotto, M and Greninger, AL and Nieweisk, S and Moscona, A}, title = {Human parainfluenza virus 3 fusion protein cleavage: a key determinant of infection and spread.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0212625}, doi = {10.1128/jvi.02126-25}, pmid = {42233639}, issn = {1098-5514}, abstract = {UNLABELLED: Human parainfluenza virus 3 (HPIV3) entry into target cells depends on a viral fusion complex composed of hemagglutinin-neuraminidase (HN) and fusion protein (F). In addition to attachment, HN activates F to mediate membrane fusion, while its neuraminidase activity promotes viral release. This creates a biological paradox: virions must repeatedly engage sialic acid-rich substrates in the airway without prematurely triggering F until they reach the target cell sialic acid receptor. Unlike the F proteins of laboratory strains that are cleaved intracellularly by furin to process F from its pro-protein to the active form that is essential for fusion, the F proteins of HPIV3 field strains lack a furin cleavage site and undergo partial cleavage mediated by extracellular serine proteases. We show that virions isolated directly from infected humans contain both cleaved and uncleaved F. In viral migration assays, reducing the proportion of cleaved F on virions increases the distance virions travel before infecting a cell. Even virions bearing only uncleaved F upon egress from infected cells can establish infection in vivo. These findings support a model in which uncleaved F on viral surfaces permits virions to engage and disengage sialylated substrates without undergoing premature fusion protein triggering, allowing virions to traverse the airway. Cleavage of F at the target cell then licenses membrane fusion, ensuring that virions initiate infection at the correct site. HPIV3 exploits host protease environments to produce virions with heterogeneity in F cleavage, equipped to either establish local infection or spread to distant target cells.<br><br>IMPORTANCE: Parainfluenza viruses employ their surface glycoproteins, the receptor-binding (hemagglutinin-neuraminidase) and fusion (F) proteins, to fuse with target cell membranes and infect the airway. F is made as an inactive precursor that is activated when host cell proteases cleave it to produce the fusion-competent form. Previous studies, utilizing laboratory-adapted viruses, assumed that F proteins are pre-cleaved on virus produced by infected people. We show that virions isolated directly from infected humans contain both cleaved and uncleaved F proteins. In viral migration assays, reducing the proportion of cleaved F on virions increases the distance virions travel before infecting a cell. The uncleaved F proteins enable virions to travel from their cell of origin without undergoing premature fusion protein activation, allowing virions to traverse the airway and infect the proper target cells. HPIV3 exploits host protease environments to produce a spectrum of virions suited to either local infection or intra-host spread.}, }
@article {pmid41860794, year = {2026}, author = {Cunningham, D and Liu, J and Cevher Zeytin, I and de la Cerda, DA and Ghatwai, N and Courtney, AN and Guo, L and Rathi, P and Yao, CQ and Zhang, N and An, Z and Heczey, A}, title = {Coexpression of IL15 Promotes Effector Differentiation and Sustained Proliferative Capacity in ALPPL2-Specific Human CAR T Cells.}, journal = {Cancer immunology research}, volume = {14}, number = {6}, pages = {933-943}, doi = {10.1158/2326-6066.CIR-25-0609}, pmid = {41860794}, issn = {2326-6074}, support = {RP190561 &amp; RP250465//Cancer Prevention and Research Institute of Texas (CPRIT)/ ; AU-0042-20030616//Welch Foundation (The Welch Foundation)/ ; //Texas Children's Hospital (TCH)/ ; //Seattle Children's Research Institute/ ; }, abstract = {Chimeric antigen receptor (CAR) T cells have robust antitumor activity against hematologic malignancies and have the potential to benefit patients with solid tumors. Immune recognition of murine proteins expressed in adoptively transferred T cells and the lack of homeostatic cytokines in the tumor microenvironment can limit the expansion and persistence of CAR T cells. CARs generated only from human sequences could reduce the risk of immune-mediated rejection, and interleukin 15 (IL15), which promotes T-cell survival and fitness, may improve the expansion and persistence of CAR T cells. In this study, we report a CAR construct (ABBz) assembled from human sequences including a single-chain variable fragment (scFv) specific to alkaline phosphatase, placental-like 2 (ALPPL2). This binder was selected through an unbiased, high-throughput screen of a human antibody-derived, phage-displayed scFv library based on binding specificity, stringency, and low dissociation constant. We demonstrated specificity to the antigen, effective cytolytic function, and cytokine production in ABBz T cells. We showed NK-like effector differentiation with sustained proliferative capacity specific to secreted IL15 coexpression in ABBz T cells. Lastly, we demonstrated that ABBz CAR T cells had robust antitumor activity, which was further enhanced through IL15 coexpression, resulting in NK-like effector differentiation with increased cytotoxicity and superior expansion capacity due to reduced apoptosis of CAR T cells. These results demonstrate that IL15 coexpression can promote effector differentiation while maintaining the proliferative capacity of huALPPL2-CAR T cells and provide a foundation for further clinical development of IL15-coexpressing huALPPL2-CAR T cells in patients.}, }
@article {pmid42218667, year = {2026}, author = {Vasavada, A and Triplette, M and Palazzo, L and Ralston, J and Carter-Bawa, L and Luce, C and Green, BB and Gao, H and Anderson, ML and Su, YR and Rogers, K and Wernli, KJ}, title = {Is Anybody Out There? Understanding the Reach of Lung Cancer Screening Health Communication Through EHR Patient Portal.}, journal = {Journal of health communication}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/10810730.2026.2679491}, pmid = {42218667}, issn = {1087-0415}, abstract = {Health communication addressing individuals eligible for lung cancer screening (LCS) can increase screening uptake and adherence, which remain low in the U.S. Digital Communication via EHR patient portals offers a scalable solution, but face barriers related to portal access and use. We conducted a secondary analysis of a pragmatic clinical trial (Kaiser Permanente Washington, Nov 2022-Apr 2024) to identify gaps in access and engagement with an LCS health communication intervention delivered via portal message. We assessed factors associated with 1) patient portal access (all participants, n = 1837); and 2) opening the intervention message (intervention arm only, n = 820) using multivariate log binomial regression to calculate prevalence ratios (PRs) and confidence intervals (CIs). Most participants (89.6%) had access to the portal. No access was associated with current tobacco use (PR 0.4), neighborhood income <$50K (PR 0.3), and <5 years of insurance (PR 0.5). Among the intervention group, 81.2% opened the message. Not opening was associated with older age (PR 0.7), current tobacco use (PR 0.5), >1 well-care visit in the past year (PR 0.6), and 5-10 years of insurance (PR 0.5). While patient portals can broadly deliver LCS interventions, disparities in access and engagement suggest the need for alternative communication strategies.}, }
@article {pmid42224345, year = {2026}, author = {Radtke, S and Laszlo, GS and Swing, K and Repele, A and Barton, JW and King, DJ and Pande, D and Enstrom, MR and Li, J and Wolf, CB and Reevey, L and Petty, NE and Kanestrom, G and Loeb, KR and Pettenger-Willey, CM and Othus, M and Kehret, AR and Cole, FM and Lunn-Halbert, MC and Hamlin, DK and Wilbur, DSS and Sandmaier, BM and Kiem, HP and Walter, RB}, title = {[211At]Astatine-Based Conditioning with a Humanized CD45 Antibody for Autologous Hematopoietic Stem Cell Gene Therapy.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2026033789}, pmid = {42224345}, issn = {1528-0020}, abstract = {Successful transplantation of autologous gene-modified hematopoietic stem/progenitor cells (HSPCs) requires efficient ablation of resident hematopoietic stem cells. Since conventional myeloablative conditioning regimens are associated with non-hematologic toxicities, we evaluated CD45-directed radioimmunotherapy (RIT) using the a-emitter astatine-211 (211At) before transplantation of ex vivo gene-edited autologous HSPCs as an alternative in nonhuman primates. We humanized the CD45 antibody, BC8 (HuBC8), and labeled it with 211At. As a model, mobilized CD34+ HSPCs were multiplex gene-edited using an adenine base editor, modifying the HBG promoter to reactivate fetal hemoglobin (HbF) and deleting CD33. Two animals each received 300 or 400 µCi/kg of 211At. In contrast to historic controls conditioned with total body irradiation, CD45-RIT animals did not show any noticeable non-hematopoietic toxicities and were almost entirely transfusion independent with rapid recovery of neutrophils and platelets. 211At enabled dose-dependent engraftment of gene-edited cells. A new single cell sequencing assay revealed up to 70% combined mono- and bi-allelic gene-editing efficiency in the blood, consistent with complete replacement of the bone marrow stem cell compartment. Assessment by bulk analysis underestimated the frequency of gene-edited cells, highlighting the importance of a single cell readout. Single cell sequencing further confirmed stable and unbiased contribution of multiplex-edited HSPCs to all mature lineages in the blood, providing high-resolution data assuring successful replacement upon autologous HSPC gene therapy. Levels of edited cells remained stable for the entire follow-up of >18 months. Together, these studies identify 211At-CD45 RIT as a targeted alternative for myeloablative conditioning for autologous gene therapy.}, }
@article {pmid42224351, year = {2026}, author = {Lin, Z and Gao, Y and Sun, W}, title = {Supervised deep learning with gene functional annotation for cell classification.}, journal = {PLoS computational biology}, volume = {22}, number = {6}, pages = {e1014327}, doi = {10.1371/journal.pcbi.1014327}, pmid = {42224351}, issn = {1553-7358}, abstract = {Gene-by-gene differential expression analysis is a widely used supervised approach for interpreting single-cell RNA-sequencing (scRNA-seq) data. However, modern scRNA-seq datasets often contain large numbers of cells, leading to the identification of many differentially expressed genes with extremely small p-values but negligible effect sizes, thus making biological interpretation difficult. To overcome this challenge, we developed Supervised Deep learning with gene functional ANnotation (SDAN), a method that integrates gene functional annotation information (e.g., protein-protein interaction) with gene-expression profiles through a graph neural network. SDAN identifies functionally coherent gene sets that optimally classify cells, and the resulting cell-level classification scores can be aggregated to make individual-level predictions. We evaluated SDAN alongside three representative existing methods in three real-data applications aimed at identifying gene sets associated with severe COVID-19, dementia, and cancer immunotherapy response. Across all applications, SDAN consistently outperformed the alternative approaches by achieving two objectives simultaneously: accurate outcome classification and clear assignment of genes to functionally related gene sets.}, }
@article {pmid42224356, year = {2026}, author = {Macleod, D and Floyd, S and Shanaube, K and Probert, W and Bwalya, J and Schaap, A and Skalland, T and Moore, A and Piwowar-Manning, E and Hoddinott, G and Bond, V and Simwinga, M and Mandla, N and Donnell, D and Bock, P and Ayles, H and Fidler, S and Hayes, R and , }, title = {Migration and its impact on universal HIV testing and treatment in the HPTN 071 (PopART) study communities.}, journal = {PLOS global public health}, volume = {6}, number = {6}, pages = {e0005357}, doi = {10.1371/journal.pgph.0005357}, pmid = {42224356}, issn = {2767-3375}, abstract = {Migrants have been identified as a population left behind by the AIDS (Acquired Immune Deficiency Syndrome) response, with evidence showing poorer HIV (Human Immunodeficiency Virus) outcomes and reduced intervention effectiveness in mobile populations. We used data from the HPTN 071 (PopART) trial (ClinicalTrials.gov number, NCT01900977) to investigate migration and HIV-related indicators, assessing whether community migration influenced PopART trial results and whether migration was associated with HIV status and position on the care continuum. The PopART trial, conducted in Zambia and South Africa (SA) from November 2013 to June 2018, evaluated a universal testing and treatment intervention using a three-arm design. A cohort of 18-44-year-olds was followed annually to estimate HIV incidence, with migration out of trial communities tracked using this cohort. migration into and within the community was tracked using intervention delivery data in community members aged 18 + . HIV-related indicators were HIV status, knowledge of HIV-positive status and ART use. Migration's influence on the trial HIV incidence results was analysed using a two-stage approach for cluster-randomised trials, adjusting for community-level migration. Associations between HIV-related indicators and both out-migration (Poisson regression using cohort data) and in-migration (logistic regression using cross-sectional data) were also estimated. While migration differed between trial arms, there was no evidence that it confounded the intervention effect on HIV incidence. There was evidence out-migration was higher among HIV-positive individuals who did not know (or did not disclose) their HIV-positive status compared to those HIV-negative (adjusted rate ratio: Zambia 1.28, 95%CI 1.17-1.39; SA 1.27, 95%CI 1.17-1.38). Residents who had moved into the community within the previous year were less likely to be aware of their HIV-positive status than longer-term residents (adjusted odds ratio: Zambia 0.18, 95%CI 0.16-0.19; SA 0.23, 95%CI 0.20-0.28) and contributed to approximately one in four of the newly identified HIV infections. Following intervention delivery the gap in knowledge of HIV status and ART treatment coverage between recent in-migrants and longer-term residents closed. Countries with high HIV burden should aim to ensure a sustained delivery of HIV services in areas with high levels of population mobility and in areas with moderate to high HIV prevalence.}, }
@article {pmid42225836, year = {2026}, author = {Chan, M and Ma, H and Subbiah, V and Gujral, TS}, title = {Mutation-centric kinase drug repurposing for rare cancers.}, journal = {Nature reviews. Cancer}, volume = {}, number = {}, pages = {}, pmid = {42225836}, issn = {1474-1768}, }
@article {pmid42124561, year = {2026}, author = {Talavera, IC and Graham, JB and Swarts, JL and Traxinger, BR and Peters, MQ and Warrier, L and Koehne, AL and Arkatkar, T and Jerome, KR and Prlic, M and Lund, JM}, title = {Regulatory T cells restrain IL-15-mediated cytotoxic and bystander T cell activity in mucosal tissue without compromising antigen-driven memory.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42124561}, issn = {2692-8205}, abstract = {Many pathogenic human infections enter the host via a mucosal surface. These nonlymphoid tissues are abundantly populated by polyclonal memory CD8 T cells that persist following infections to protect the host in the event of repeat exposure. Memory T cells can be triggered via T cell receptor (TCR) interaction with their cognate antigen upon re-infection to exert effector functions, including cytotoxicity and cytokine production, and assist in pathogen elimination. Alternatively, some T cells are 'bystander activated' by cytokines without antigenic signal. This layered approach boosts efficient pathogen clearance but also poses a threat to host tissues if this response is not properly controlled. Here we investigate the regulatory mechanisms modulating the tissue memory CD8 T cell response upon recall, leveraging mouse models to distinguish antigen-driven versus cytokine-activated memory tissue CD8 T cell immunity. We find that regulatory T cells (Treg) play a role in restricting cytotoxic and bystander activity in mucosal T cells without compromising the antigen-driven protective memory CD8 T cell response. Critically, Treg provide extrinsic regulation of tissue CD8 T cell cytotoxicity through restriction of available IL-2 and IL-15 trans-presentation. Our findings help to define the extrinsic environmental and cellular cues in mucosal tissues that direct tissue memory CD8 T cell cytotoxicity.}, }
@article {pmid42147192, year = {2026}, author = {Alexander, MW and Wood, B and See-Hwee Oh, H and Bot, VA and Borger, J and Galbiati, F and Walker, KA and Resnick, SM and Ochs-Balcom, HM and Wyss-Coray, T and Kooperberg, C and Reiner, AP and Jacobs, EG and Rabin, JS and Casaletto, KB and Saloner, R}, title = {Plasma proteomics link menopause timing to brain aging and dementia risk.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {42147192}, issn = {2693-5015}, abstract = {Earlier menopause is a risk factor for several age-related diseases, including dementia. The biological pathways linking menopause timing to later-life brain aging are not understood. Leveraging large-scale plasma proteomics in postmenopausal women from the UK Biobank (N=15,012), earlier menopause was associated with upregulation of pro-inflammatory and extracellular matrix degradation pathways, plus accelerated aging across proteomic clocks of organ and cellular aging, including brain and oligodendrocyte aging. Elevated GDF15, a canonical aging marker, was the top protein correlate of earlier menopause. We observed robust replication of menopause timing proteomic shifts in the Women's Health Initiative Long Life Study (N=1,210). In UKB, proteins associated with earlier menopause, including GDF15, exhibited concordant associations with incident dementia risk and brain atrophy, cerebral small vessel disease burden, and white matter microstructural integrity. Collectively, our findings identify proteomic signatures linking ovarian aging to brain aging, providing a framework to inform interventions to reduce dementia risk.}, }
@article {pmid42213891, year = {2026}, author = {Coghill, AE and Bender Ignacio, R}, title = {Further unraveling the association between HIV, immune suppression, and cancer survival.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciag334}, pmid = {42213891}, issn = {1537-6591}, }
@article {pmid42214050, year = {2026}, author = {Gunn, CM and Boyer, N and Sheikh, S and Lee, JM and Woloshin, S and Specht, JM and Hubbard, RA and Aiello Bowles, EJ and Tosteson, ANA}, title = {Patient- and Physician-Identified Considerations for Clinical Implementation of a New Risk-Based Prediction Tool to Guide Surveillance Mammography in Breast Cancer Survivors.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2501048}, doi = {10.1200/OP-25-01048}, pmid = {42214050}, issn = {2688-1535}, abstract = {PURPOSE: Patient, tumor, and treatment factors can help predict the chance that a woman with a history of breast cancer diagnosis will be diagnosed with a second breast cancer within a year of a negative mammogram. This qualitative study elucidates breast cancer survivor and multispecialty physician perspectives on barriers/facilitators to clinical implementation of a risk-prediction tool to support surveillance decisions.<br><br>MATERIALS AND METHODS: We enrolled women who completed primary breast cancer treatment and physicians from November 2023 to April 2024. Participants were recruited through Breast Cancer Surveillance Consortium's registries; patients participated in one of four focus groups and physicians participated in individual semistructured interviews. Participants were presented with information about an interval cancer risk prediction tool and were prompted to share perspectives on facilitators and barriers to using such a tool. To identify salient themes, thematic analysis was undertaken by three research team members.<br><br>RESULTS: Participants included 40 physicians and 23 patients. Three themes emerged: (1) evidence needed for tool acceptance, (2) tool features to facilitate usage, and (3) barriers to tool adoption. Both cancer survivor and physician groups were accepting of risk prediction tool use for surveillance imaging when tool development information was available; they perceived the tool would fit within workflows, and data integrity could be verified. Both groups anticipated structural (time) and technological barriers (magnetic resonance imaging availability) could impede adoption.<br><br>CONCLUSION: Qualitative findings from focus groups and interviews analyzed thematically suggest implementing a risk prediction tool for surveillance imaging requires evidence transparency, health record integration, data integrity protection, and system supports to promote ease of use in clinical settings while mitigating unintended consequences. All are important to consider during tool development and implementation planning.}, }
@article {pmid42217442, year = {2026}, author = {Brown, LG and Coleman, IM and Chu, TLH and Sayar, E and Patel, RA and Hanratty, B and Adil, M and Li, D and Li, Y and Nguyen, HM and Sessions, CJ and Sweeney, EL and Alumkal, JJ and da Costa, RMG and Wang, Y and Lin, DW and True, LD and Dumpit, R and Corey, E and Lee, JK and Nelson, PS and Xin, L and Haffner, MC and Morrissey, C}, title = {Systematic analysis of hippo pathway signaling identifies TEAD1 as a transcriptional regulator of neuroendocrine prostate cancer.}, journal = {Neoplasia (New York, N.Y.)}, volume = {78}, number = {}, pages = {101321}, doi = {10.1016/j.neo.2026.101321}, pmid = {42217442}, issn = {1476-5586}, abstract = {Treatment-induced neuroendocrine prostate cancer (NEPC) represents an aggressive form of castration-resistant prostate cancer (CRPC) associated with lineage plasticity and therapeutic resistance. In this study, we investigated the role of the Hippo signaling axis in the transdifferentiation from androgen receptor-positive prostate cancer (ARPC) to NEPC. RNA sequencing analyses of CRPC metastases revealed coordinated alterations in Hippo pathway components, with decreased expression of YAP1, LATS2, and TEAD2 and increased expression of LATS1, TEAD1, and the RNA splicing regulator RBFOX2 in NEPC. These transcriptional alterations were consistently observed across multiple model systems and patient samples. Epigenetic analyses demonstrated that reduced expression of YAP1, TEAD2, and LATS2 was associated with increased DNA methylation, whereas elevated TEAD1 expression correlated with DNA hypomethylation in NEPC. NEPC selectively retained TEAD1 expression, including a spliced isoform not detected in ARPC. Proteomic interactome analyses revealed that TEAD1 associated with RNA splicing factors and DNA repair proteins. Functional studies showed that TEAD1 knockdown led to the reversion of gene programs associated with epithelial differentiation. These findings indicate that the conversion of ARPC to NEPC involves coordinated loss of AR, YAP1, and REST activity alongside sustained TEAD1 expression and altered RNA processing. Our data identify TEAD1 as a transcriptional regulator associated with the NEPC state and suggest a role for TEAD1-linked transcriptional and post-transcriptional mechanisms in prostate cancer lineage plasticity.}, }
@article {pmid42218145, year = {2026}, author = {Ping, J and Jia, G and Cai, Q and Guo, X and Wang, J and Tao, R and Li, B and Bauer, JA and Xie, Y and Ambs, S and Barnard, ME and Chen, Y and Choi, JY and Gao, YT and Garcia-Closas, M and Gu, J and Hu, JJ and Iwasaki, M and John, EM and Kweon, SS and Li, CI and Matsuda, K and Matsuo, K and Nathanson, KL and Nemesure, B and Olopade, OI and Pal, T and Park, SK and Park, B and Press, MF and Sanderson, M and Sandler, DP and Yao, S and Zheng, Y and Ahearn, T and Brewster, AM and Falusi, A and Hennis, AJM and Ito, H and Kubo, M and Lee, ES and Makumbi, T and Mapoko, BSE and Noh, DY and O'Brien, KM and Ojengbede, O and Olshan, AF and Park, MH and Reid, S and Yamaji, T and Zirpoli, G and Butler, EN and Huang, M and Low, SK and Obafunwa, J and Weinberg, CR and Zhang, H and Zhao, H and Ambrosone, CB and Cote, ML and Huo, D and Haiman, CA and Kang, D and Palmer, JR and Troester, MA and Shu, XO and Long, J and Zheng, W}, title = {Multi-ancestry transcriptome-wide association studies uncover insights into breast cancer genetics and biology.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-73801-x}, pmid = {42218145}, issn = {2041-1723}, support = {R01CA235553//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01CA202981//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01CA148667//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01CA124558//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {Genome-wide association studies (GWAS) have identified over 200 genetic risk loci for breast cancer, yet their target genes remain largely unknown. We conduct multi-ancestry transcriptome-wide association studies (TWAS) to discover potential breast cancer susceptibility genes. We develop ancestry-specific genetic models to predict levels of gene expression, alternative splicing, and 3' UTR alternative polyadenylation using genomic and transcriptomic data from 652 normal female tissue samples and apply these models to GWAS data of 178,534 cases and 248,300 controls for association analyses. We identify 290 genes associated with breast cancer risk, including 103 previously unreported and 46 not located at known GWAS loci, and 39 genes show distinct associations with breast cancer risk by estrogen-receptor status. Single-cell RNA sequencing and in vitro experiment data provide additional functional evidence for 169 genes. These genes are enriched in pathways implicated in breast carcinogenesis. Our study uncovers insights into breast cancer genetics and biology.}, }
@article {pmid42211136, year = {2026}, author = {Rashidi, A and Minot, SS and Lee, SJ and Hill, GR and Podlesny, D}, title = {Cohesive modules of engraftment in fecal microbiota transplantation.}, journal = {iScience}, volume = {29}, number = {6}, pages = {116025}, pmid = {42211136}, issn = {2589-0042}, abstract = {While single-strain probiotics fail to address community-level microbiota injuries in dysbiosis-related conditions and fecal microbiota transplantation (FMT) produces unpredictable communities, a middle-ground approach has emerged. This approach involves using small consortia of species, combining the precision of single-strain probiotics and the holistic approach intrinsic to FMT. The species selection in this oligomicrobial strategy is typically proprietary or based on studies linking single species to disease or health. To advance this approach, we developed the concept of cohesive modules of engraftment (CME) and a workflow for their identification from FMT trials. CMEs represent small donor microbiota subsets that engraft as units (modularity), while maintaining their original composition (cohesiveness). In benchmarking, we identified >200 highly cohesive CMEs (2-5 species) in 5 FMT trials and found evidence for cross feeding as a mechanism for CME integrity. Due to their predictable post-treatment compositions, CMEs deserve investigation as potential ingredients of future therapeutic microbial consortia.}, }
@article {pmid42211393, year = {2026}, author = {Makranz, C and Huguely, C and Zhang, M and Davis, D and Anderson, B and Haynes, T and Spurgeon, J and Hara, A and Briceno, N and Song, H and Zhang, W and Okada, H and Watanabe, M and Gilbert, MR and Terabe, M}, title = {Inhibition of chemokine CXCL12 modulates the tumor microenvironment in glioblastoma and potentiates immune checkpoint inhibitor efficacy in a tissue-specific manner.}, journal = {Neuro-oncology advances}, volume = {8}, number = {1}, pages = {vdag118}, pmid = {42211393}, issn = {2632-2498}, abstract = {BACKGROUND: Immunotherapy, while effective for many extra-cranial solid tumors, has not shown benefits against glioblastoma. Limited T cell infiltration and an immunosuppressive tumor microenvironment (TME) are among the main barriers to successful immunotherapy. We hypothesized that blocking the chemokine CXCL12 would modulate the TME composition and reverse GBM resistance to immunotherapy.<br><br>METHODS: We used a syngeneic murine SB28 GBM model resistant to immune checkpoint inhibitor (ICI) and compared orthotopic and subcutaneous tumors to differentiate tumor-intrinsic factors from CNS-related barriers. We treated SB28 tumor-bearing mice with vehicle, ICI, CXCL12 inhibitor (NOX-A12), or a combination of NOX-A12 with ICI. We assessed treatment effects on immune cell populations in the blood and the TME, and on tumor growth and mouse survival.<br><br>RESULTS: ICI alone increased effector CD8[+]T cells in subcutaneous tumors but did not alter immune subsets in intracranial tumors. The combination of NOX-A12 and ICI increased effector CD8[+] and CD4[+] T cells in both models. In subcutaneous tumors, combination treatment also reduced MHC-II[low] tumor-associated macrophages (TAM) and slowed tumor growth. However, in orthotopic tumors, TAM populations remained unaffected, and survival was not extended, despite similar T-cell modulation, supporting the role of TAM in mediating GBM resistance to ICI.<br><br>CONCLUSION: CXCL12 inhibition demonstrates therapeutic potential in facilitating anti-tumor immune response by dual mechanism, including T cell expansion and TAM reduction. The inability to deplete TAMs and improve survival in intracranial GBM underscores the need to address brain-specific mechanisms underlying TAM persistence to advance immunotherapy in GBM.}, }
@article {pmid42213435, year = {2026}, author = {Bhatt, NS and Wang, F and Izumi, S and Chen, Y and Ohlsen, TJD and Armstrong, GT and Huang, IC and Kirchhoff, A and Park, ER and Snyder, C and Yabroff, KR and Yasui, Y and Nathan, PC}, title = {Financial Hardship and Nonadherence to Lifestyle and Surveillance in Childhood Cancer Survivors.}, journal = {JAMA network open}, volume = {9}, number = {5}, pages = {e2615527}, pmid = {42213435}, issn = {2574-3805}, mesh = {Humans ; Female ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Male ; Retrospective Studies ; Adult ; Child ; Young Adult ; *Patient Compliance/statistics &amp; numerical data/psychology ; *Neoplasms ; *Financial Stress/psychology/epidemiology ; Child, Preschool ; Adolescent ; *Healthy Lifestyle ; Life Style ; }, abstract = {IMPORTANCE: The association between medical financial hardship and nonadherence to healthy lifestyle and late-effects surveillance recommendations in long-term survivors of childhood cancer is unknown.<br><br>OBJECTIVE: To study the associations between medical financial hardship and nonadherence to healthy lifestyle and late-effects surveillance recommendations.<br><br>This retrospective cohort study was performed among participants in the multiinstitutional Childhood Cancer Survivor Study. Participants were 5-year cancer survivors diagnosed at age 21 years or younger between January 1, 1970, and December 31, 1999, and who completed both a medical financial hardship survey between 2017 and 2019 and a follow-up survey assessing lifestyle behaviors and adherence to risk-based surveillance between 2020 and 2022. Data were analyzed between September 29, 2023, and September 2, 2025.<br><br>EXPOSURE: Self-reported medical financial hardship determined by an affirmative response to at least 1 item in the material, behavioral, or psychological domains.<br><br>MAIN OUTCOMES AND MEASURES: Associations of non-guideline-concordant physical activity, problematic drinking, smoking, and abnormal body mass index with domains of medical hardship were examined using separate multivariable logistic regression models. Associations between a composite lifestyle score (unhealthy, moderately healthy, and healthy) and nonadherence to surveillance for cardiomyopathy or breast, colorectal, cervical, and/or skin cancer were examined using polytomous logistic regression models.<br><br>RESULTS: Among 3322 survivors who completed both surveys (median [range] age, 41 [20-69] years; 1751 female [52.7%]), the presence of material, behavioral, and psychological hardship was reported by 1401 (42.2%), 1003 (30.2%), and 1243 (37.4%), respectively. Material hardship was associated with a greater odds of non-guideline-concordant physical activity (odds ratio [OR], 1.67 [95% CI, 1.29-2.18]) and abnormal body mass index (OR, 1.47 [95% CI, 1.15-1.88]). Behavioral and psychological hardships were associated with a higher odds of smoking (OR, 2.29 [95% CI, 1.13-4.62] and 3.95 [95% CI, 2.42-6.44], respectively). Material and psychological hardship were associated with a composite unhealthy lifestyle score (OR, 1.52 [95% CI, 1.11-2.07] and 1.96 [95% CI, 1.31-2.93], respectively), and a higher risk was noted among survivors reporting hardship in at least 2 domains. Psychological hardship was associated with greater nonadherence to skin cancer surveillance (OR, 1.78 [95% CI, 1.05-3.02]) among survivors at high risk due to treatment exposures. Material hardship was associated with greater nonadherence to breast cancer screening (OR, 2.85 [95% CI, 1.27-6.38]) among survivors at average risk. Associations between multiple medical hardship domains and nonadherence to cervical cancer screening were also observed (material and behavioral hardship: OR, 3.20 [95% CI, 1.44-7.14]; material and psychological hardship: OR, 2.18 [95% CI, 1.10-4.35]; behavioral and psychological hardship: OR, 3.25 [95% CI, 1.50-7.04]).<br><br>CONCLUSIONS AND RELEVANCE: This cohort study of adult survivors of childhood cancer found that medical financial hardship was associated with nonadherence to healthy lifestyle behaviors and certain recommended surveillance tests for subsequent malignant neoplasms. These findings underscore the need to identify and address medical financial hardship as a potential risk factor of nonadherence to healthy lifestyle and guideline-concordant survivorship care.}, }
@article {pmid42204244, year = {2026}, author = {Lin, HY and Sarkar, I and Mazumder, H and Huang, PY and Muir, KR and Schleutker, J and Pashayan, N and Batra, J and Neal, DE and Grönberg, H and Nielsen, SF and Nordestgaard, BG and Tangen, CM and MacInnis, RJ and Wolk, A and Albanes, D and Travis, RC and Stanford, JL and Mucci, LA and Kibel, AS and Cussenot, O and Berndt, SI and Koutros, S and Sørensen, KD and Cybulski, C and Grindedal, EM and Hoegel, J and Maier, C and Hamilton, RJ and Rosenstein, BS and Vega, A and Kogevinas, M and Wiklund, F and Penney, KL and Teixeira, MR and Brenner, H and John, EM and Kaneva, R and Logothetis, CJ and Neuhausen, SL and De Ruyck, K and Ost, P and Gamulin, M and Usmani, N and Claessens, F and Castelao, JE and Townsend, PA and ,  and ,  and Kote-Jarai, Z and Haiman, CA and Eeles, RA and ,  and Park, JY}, title = {Polygenic risk score with KLK3 SNP-SNP interaction pairs for predicting prostate cancer aggressiveness.}, journal = {Communications medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43856-026-01645-z}, pmid = {42204244}, issn = {2730-664X}, support = {HT9425-23-1-0438//U.S. Department of Defense (United States Department of Defense)/ ; }, abstract = {BACKGROUND: Prostate cancer (PCa) is heterogeneous, making risk stratification essential for clinical care. Although polygenic risk scores (PRSs) with main effects of single-nucleotide polymorphisms (SNPs) can help identify individuals at high risk before biological and clinical onset, a PRS for predicting PCa aggressiveness remains underdeveloped. The KLK3, which encodes prostate-specific antigen (PSA), is linked to PCa aggressiveness. Recent findings on KLK3 SNP-SNP interactions show promise for predicting PCa aggressiveness. The objective of this study is to develop a PRS (PRS-KLK3int) by examining KLK3 SNP-SNP interaction pairs.<br><br>METHODS: The PRS-KLK3int was developed based on a discovery set (10,836 PCa patients) and two validation sets with 14,348 and 16,584 patients of European ancestry. A total of 3145 SNP pairs and two published PRSs were evaluated.<br><br>RESULTS: This study developed a PRS-KLK3int with 284 SNPs, combining an existing PRS with 270 SNPs and 12 SNP-SNP interaction pairs with 15 SNPs (one overlapped). All these 12 pairs were involved with at least one SNP from KLK3. The PRS-KLK3int outperformed two existing PRSs in predicting PCa aggressiveness (p-values: 3.5&#xd7;10[-18], 9&#xd7;10[-14], and 1.7&#xd7;10[-20] for the three sets). It effectively distinguished high-risk from low-risk groups across all datasets. The top 1% high-risk group had a higher prevalence of PCa aggressiveness than the middle 50% group (45.5% vs. 25.9%, OR&#x2009;=&#x2009;2.38, p&#x2009;=&#x2009;2.2&#xd7;10[-5]) in the discovery set, and similar results were observed in validation sets (OR&#x2009;=&#x2009;2.56, p&#x2009;=&#x2009;4.3&#xd7;10[-6]; OR&#x2009;=&#x2009;2.07, p&#x2009;=&#x2009;2.1&#xd7;10[-5]).<br><br>CONCLUSIONS: These findings support PRS-KLK3int as a valuable tool for PCa severity stratification, especially in identifying extremely high-risk PCa patients.}, }
@article {pmid42205853, year = {2026}, author = {McGee, LA and Rohit, A and Buras, M and Bajaj, G and Chang, JH and Kalman, NS and Grover, R and Akthar, A and Kole, AJ and McDonald, M and Katz, S and Lee, N and Tsai, H and Urbanic, J and Vargas, C and Zeng, J and Molitoris, J and Lester, S and Mohammadi, H and Holtzman, A}, title = {Proton Therapy for Head and Neck Adenoid Cystic Carcinoma: A Multi-institutional Review.}, journal = {International journal of particle therapy}, volume = {20}, number = {}, pages = {101320}, pmid = {42205853}, issn = {2331-5180}, abstract = {PURPOSE: To evaluate efficacy and toxicity (CTCAE v4.0) outcomes in patients with adenoid cystic carcinoma (ACC) treated with proton beam therapy (PBT).<br><br>PATIENTS AND METHODS: From 2012 through 2023, 79 patients with non-metastatic ACC were treated with PBT and enrolled on the Proton Collaborative Group (PCG) registry. Kaplan-Meier analyses quantified locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). ACC patients receiving reirradiation with PBT were excluded from this analysis.<br><br>RESULTS: Median follow-up was 3 years (0.01-6.72). Twenty-six patients were unable to undergo surgery and received definitive PBT versus postoperative PBT (n=53). Median postoperative PBT dose was 66 GyE and 70 GyE for definitive patients treated with conventional fractionation. Most patients had localized disease (n=75); few had nodal metastases (n=4). 62% were locally advanced (T3-T4) at the time of PBT treatment. 3-year Locoregional control (LRC) for all patients was 98% [95% CI (94.3, 100)]. Advanced T-staging, positive margins and definitive-intent PBT were not associated with worsened LRC. 3-year Progression free survival (PFS) was 80.5% (70.6, 91.7). Patients receiving definitive intent PBT had lower but nonsignificant PFS (73.3% vs. 83.8%, p-0.075). Advanced T-staging and positive margins did not have worsened PFS. Overall survival at 3 years was 89.2% (81.4, 97.8). Acute grade 3 toxicities occurred in 16 patients, the most common included the following: mucositis (n=5), oral pain (n=3), and dermatitis (n=5). Late grade 3 toxicity (n=2) included middle ear inflammation (n=1) and skin ulceration (n=1). There were no grade 4+ toxicities.<br><br>CONCLUSION: PBT appears to be highly efficacious in providing LRC for patients with ACC including those patients treated with definitive intent. PBT toxicity was acceptable. Longer follow-up is needed.}, }
@article {pmid42206435, year = {2026}, author = {Tettero, JM and Zhang, MJ and Liu, W and Nawas, MT and Milano, F and Bejanyan, N and Bachanova, V and Broglie, L and Saber, W and Gui, G and Dillon, LW and Walter, RB and Page, KM and Hourigan, CS and El Chaer, F}, title = {Real-world heterogeneity in the prognostic value of pre-transplant flow cytometry measurable residual disease in acute myeloid leukemia in first complete remission: CIBMTR analysis.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2026.300764}, pmid = {42206435}, issn = {1592-8721}, abstract = {In this real-world, large, observational study from the Center for International Blood and Marrow Transplant Research (CIBMTR), we examined the association between pre-transplant measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) test results and outcomes after allogeneic hematopoietic cell transplantation (alloHCT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1). We included 2,544 patients who underwent transplant during 2013-2019; 11% had detectable MRD prior to alloHCT. Patients' median age was 58 years. Among MRD-negative and MRD-positive groups, 48% vs 52% received myeloablative conditioning, and 37% vs 29% had matched unrelated donors, respectively. The 1-year cumulative incidence of relapse was 35% in the MRD-positive group and 25% in the MRD-negative group (P < .001). MRD positivity was associated with inferior overall survival (hazard ratio [HR], 1.27; 95% CI, 1.06-1.51; P = .009) and disease-free survival (HR, 1.31; 95% CI, 1.11-1.53; P = .001), and increased relapse risk (HR, 1.42; 95% CI, 1.17-1.72; P < .001), but not with non-relapse mortality. Notably, patients with pre-alloHCT MRD negativity remained at high risk of relapse, underscoring the limited prognostic utility of registryreported MFC-MRD testing due to variability in methods and thresholds. Survival analyses across the 12 largest centers demonstrated substantial variability in the prognostic impact of MRD. These findings underscore that although pre-alloHCT MRD by MFC remains a clinically relevant prognostic biomarker, its reliability is contingent upon methodological standardization across centers. These findings highlight the need for standardized MRD assessment to improve risk stratification in AML.}, }
@article {pmid42207168, year = {2026}, author = {Zeng, J and Cui, S and Hippe, DS and Fu, J and Yaseen, F and He, Y and Kang, J and Grassberger, C and Vesselle, HJ and Kinahan, PE and Eaton, KD and Baik, CS and Santana-Davila, R and Lee, S and Rengan, R and Bowen, SR}, title = {Mature Outcomes and Patterns of Failure in the Phase II FLARE-RT Trial of Biological Image-guided and Risk-Adaptive Chemoradiation for Unresectable NSCLC.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-2626}, pmid = {42207168}, issn = {1557-3265}, abstract = {PURPOSE: FLARE-RT tested personalized functional-lung-avoidance and response-adaptive radiotherapy intensification for unresectable non-small cell lung cancer (NSCLC) using FDG-PET/CT and SPECT/CT. We report mature outcomes and failure patterns.<br><br>METHODS: 49 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on FLARE-RT (NCT02773238) from 2016-2021 and initiated chemoradiation. Patients with Week 3 FDG-PET response received 60Gy in 30 fractions. Patients with non-response received concomitant boosts Weeks 4-6 to residual metabolic disease of 74-90Gy total guided by FDG uptake. Overall survival (OS, primary endpoint) and progression free survival (PFS) were estimated via Kaplan-Meier. Locoregional progression (LRP) and distant metastasis (DM) cumulative incidence were estimated via Aalen-Johansen, with death and alternative progression pattern as competing risks. Predictors of treatment failure modes were identified through Fine-Gray regression.<br><br>RESULTS: At 52.3 months median follow-up, 1-year and 2-year OS were 81.6% (95%CI:71.5-93.2%) and 54.2% (CI:41.8-70.4%), respectively; 1-year and 2-year PFS were 53.1% (CI:40.9-69.0%) and 40.5% (CI:28.8-57.0%), respectively. Cumulative incidence for 1-year and 2-year LRP was 12.2% (CI:4.9-23.2%) and 18.5% (CI:9.0-30.6%), respectively; 1-year and 2-year DM were 34.7% (CI:21.7-48.1%) and 43.1% (CI:28.9-56.5%), respectively. Higher pre-RT FDG-PET total lesion glycolysis (TLG) correlated with increased LRP (HR=1.87 [CI:1.41-2.49], p<0.001), whereas higher mid-RT TLG correlated with DM (HR=1.52 [CI:1.05-2.21], p=0.03). 25 of 49 patients received durvalumab and exhibited lower 1-year DM (20.0% vs. 54.2%, p=0.04) with equivocal 1-year LRP (20.0% vs. 4.2%, p=0.27).<br><br>CONCLUSION: Biological image-guided FLARE-RT achieved durable locoregional control with consistent survival outcomes relative to RTOG0616 (60Gy arm) and RTOG1106 (adaptive arm). This informs biomarker-guided and risk-adaptive therapy for unresectable NSCLC.}, }
@article {pmid42207534, year = {2026}, author = {Schlam, I and Tolaney, SM and Lin, NU and Parsons, H and Morganti, S}, title = {Circulating Tumor DNA in Early Breast Cancer: A Review.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2026.1465}, pmid = {42207534}, issn = {2374-2445}, abstract = {IMPORTANCE: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker with the potential to detect minimal residual disease (MRD), monitor treatment response, and identify recurrence (eg, molecular relapse) earlier than conventional clinical or imaging approaches. Although ctDNA-based MRD assays have demonstrated prognostic value in early breast cancer, their optimal clinical utility remains uncertain.<br><br>OBSERVATIONS: This review summarizes the current data on ctDNA MRD assays in early breast cancer. Although these assays have established analytical and clinical validity, their clinical utility remains uncertain. Dynamics of ctDNA during neoadjuvant therapy are associated with pathologic complete response and long-term outcomes. Following completion of curative-intent therapy, ctDNA positivity (eg, presence of MRD) is strongly associated with future distant recurrence. Similarly, the emergence of ctDNA during surveillance precedes the clinical diagnosis of overt metastatic disease. Although observational studies and meta-analyses have supported ctDNA as a complementary biomarker for established risk-stratification tools, evidence that demonstrates improved outcomes with ctDNA-guided management remains limited. Furthermore, the optimal timing and frequency of testing remain unknown, and studies comparing assays are lacking. Multiple ongoing prospective interventional trials are evaluating whether ctDNA-guided treatment escalation or de-escalation can improve patient outcomes and support the routine implementation of ctDNA assays in clinical practice.<br><br>CONCLUSIONS AND RELEVANCE: ctDNA-based MRD assays hold promise for refining risk stratification, enabling earlier detection of recurrence, and informing treatment decisions in patients with early breast cancer, but clinical utility has not yet been demonstrated. Prospective trials are essential to determine whether ctDNA-guided interventions improve outcomes beyond standard management. Clinicians should understand the strengths, limitations, and evolving evidence base of ctDNA assays, as well as patient preferences, prior to incorporating them into patient care.}, }
@article {pmid42207938, year = {2026}, author = {Bear Don't Walk Iv, OJ and Yowelunh McLester-Davis, LW and Pete, D and Peter, D and Hernandez-Hernandez, K and Calac, AJ and de la Sierra, VQ and Dhein, K and Henare, K and Tsosie, KS}, title = {Reclaiming Data, Restoring Health: The Indigenous Biomedical Data Science Renaissance.}, journal = {Annual review of biomedical data science}, volume = {}, number = {}, pages = {}, doi = {10.1146/annurev-biodatasci-092524-121351}, pmid = {42207938}, issn = {2574-3414}, abstract = {Indigenous Peoples are leading a renaissance in biomedical data science. Throughout this narrative review, we highlight advancements from leaders in this renaissance across four phases of biomedical data science: ethics and values that inform research, data harmonization, model development and assessment, and commercialization. In addition, we synthesize five teachings that advance biomedical data science: Indigenous sovereignty, ethical stewardship, relationality and trust, community prioritization, and Indigenous worldviews. We conclude with considerations for all biomedical data scientists, Indigenous People in biomedical data science, and Indigenous leaders leveraging biomedical data science to advance Indigenous health and well-being. This renaissance offers a road map for global biomedical systems to evolve beyond colonial legacies toward practices that uphold self-determination, restore balance, embody relationality, and promote the well-being of human and nonhuman kin.}, }
@article {pmid42209122, year = {2026}, author = {Osborne, D and Cutler, CS and Chaple, IF and Ribeiro Pereira, PM and Peterson, TE and Solingapuram Sai, KK and Wang, J and Scott, PJH and Chen, DL}, title = {Industry-Academic Collaboration in Nuclear Medicine: Proceedings from the 2024 CMIIT Industry Partners Circle.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.126.272619}, pmid = {42209122}, issn = {1535-5667}, abstract = {Advancing and streamlining the development pipeline and translation of theranostic radiopharmaceuticals for application in nuclear medicine necessitates continued cross-sector collaboration among key stakeholders from the Society of Nuclear Medicine and Molecular Imaging (SNMMI), industry partners, and academics to ensure continued growth and innovation and clinical translation. One mechanism the SNMMI has for such dialogue is its biennial Industry Partners Circle (IPC). After the success of prior IPCs, the Center for Molecular Imaging, Innovation, and Translation (CMIIT) hosted the latest IPC in January 2024. The goals of the 2024 CMIIT IPC were to address 4 key priorities that have emerged for the translational community: grow the workforce pipeline, improve academia/industry collaborations to support career development, facilitate radiopharmaceutical clinical trials, and overcome barriers in developing α-therapies. The IPC was attended by SNMMI staff and leadership, members of the CMIIT board of directors, key stakeholders from academia, and industry representatives from a broad range of biopharmaceutical companies and equipment manufacturers. This article summarizes the discussions that were conveyed at the 2024 CMIIT IPC.}, }
@article {pmid42201779, year = {2026}, author = {Banda, K and Davies, HR and Kumar, Y and Memari, Y and Degasperi, A and Radke, M and Rodriguez, I and Gooley, TA and Katz, R and Menghi, F and Harding, T and Lin, K and Liu, ET and Nik-Zainal, S and Swisher, EM}, title = {HRDetect in Tubo-ovarian Carcinoma: Stratification and Therapeutic Implications.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-1629}, pmid = {42201779}, issn = {1557-3265}, abstract = {PURPOSE: To evaluate HRDetect, a mutational-signature-based algorithm, for prognostic utility in tubo-ovarian carcinoma (OC), and to determine if whole-genome sequencing (WGS) with rearrangement signature (RS) analysis can refine genomic classification beyond the traditional homologous recombination deficient (HRD) versus proficient (HRP) framework.<br><br>EXPERIMENTAL DESIGN: WGS was performed on matched tumor-normal pairs from 185 patients with advanced-stage OC from the University of Washington (UW) cohort. HRDetect scores were calculated using substitution signatures, rearrangement signatures, microhomology-mediated deletions, and global loss of heterozygosity. An independent validation cohort (ARIEL2, n&#x202f;=&#x202f;77) of platinum-sensitive OC treated with rucaparib, was analyzed to correlate HRDetect with PARP inhibitor (PARPi) response. RS analysis and unsupervised hierarchical clustering were employed to delineate genomic subgroups.<br><br>RESULTS: In the UW cohort, 51.4% of cases were classified as HRDetect-high and had significantly prolonged median overall survival versus others (6.2 vs 4.1 years; HR=0.6; 95% CI=0.41-0.87; p=0.007). 48.4% of HRDetect-high tumors harbored BRCA1/2 mutations or BRCA1 promoter methylation, while 22.1% lacked BRCA1/2 alterations. A substantial fraction (23.2%) fell into an HRDetect-intermediate category, highlighting greater genomic heterogeneity than currently appreciated. RS profiling uncovered eleven genomic clusters, with specific RS profiles (RS1, RS14, RS18) correlating with poor survival. In ARIEL2, HRDetect-high tumors showed better PARPi responses, with improved progression-free survival (11.1 vs 7.1 months; HR=0.44; 95% CI=0.26-0.74; p=0.03) and response rates (54% vs 22.5%).<br><br>CONCLUSIONS: HRDetect predicts survival and sensitivity to PARPi in OC. Combined with RS-based clustering, it reveals unappreciated genomic heterogeneity, and supports a nuanced stratification framework to improve precision oncology in OC.}, }
@article {pmid42203177, year = {2026}, author = {Olbrich, P and Fischer, M and Deyà-Martinez, A and Campos-Asensio, C and Neth, O and Hadjadj, J and Forbes Satter, LR and Leiding, JW and Torgerson, TR and Bakhtiar, S and Baris, S and Badolato, R and Bloomfield, M and Buddingh, EP and Burroughs, LM and Burns, S and Cooper, MA and Crickx, E and Ehl, S and Farmand, S and Freeman, AF and Gonzalez-Granado, LI and Hagin, D and Hanitsch, LG and Hanzlikova, J and Hauck, F and Ivorra-Cortés, J and Körholz, J and Lankester, AC and Leahy, TR and Meyts, I and Milner, JD and Nademi, Z and Pachlopnik Schmid, J and Pergent, M and Prévot, J and Rivière, JG and Roxo-Junior, P and Schuetz, C and Slatter, MA and Soler Palacín, P and Warnatz, K and Vítovcová, P and Vastert, SJ and Neven, B and Albert, MH and Speckmann, C and , }, title = {Guidance on JAK inhibitor treatment for inborn errors of JAK-STAT signaling (2026). An international consensus statement on behalf of the ESID/EBMT-IEWP and ERN-RITA.}, journal = {The Journal of allergy and clinical immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaci.2026.05.005}, pmid = {42203177}, issn = {1097-6825}, abstract = {BACKGROUND: Inborn errors of immunity (IEI) associated with gain-of-function (GOF) in the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathways (JAK-STAT GOF IEI) are rare disorders characterized by immune dysregulation, autoimmunity, malignancy and increased infection susceptibility. To date, no JAK inhibitors (JAKi) are licensed for these conditions, but they are frequently prescribed off-label, even though high-quality evidence and treatment guidelines remain limited.<br><br>OBJECTIVE: To develop evidence- and consensus-based recommendations for JAKi treatment in JAK-STAT GOF IEI across all age groups based on a systematic literature review and expert consensus.<br><br>METHODS: An international expert group conducted a systematic literature review and developed recommendations on JAKi treatment in JAK-STAT GOF IEI using a modified Delphi approach. Recommendations were developed based on published evidence, data from an international retrospective cohort study, and patient representative input. These statements were then tested for consensus in a two round Delphi survey procedure in a larger, interdisciplinary expert panel.<br><br>RESULTS: Consensus- and evidence-based guidance is presented across five thematic areas: (I) JAKi indications/contraindications, (II) pre-treatment assessment, (III) pharmacology/dosing, (IV) monitoring, and (V) use in the context of hematopoietic stem cell transplantation. A total of 51 statements were established and contextualized with the available evidence.<br><br>CONCLUSION: This consensus provides structured guidance for clinicians managing JAK-STAT GOF IEI with JAKi. While prospective trials will further refine these strategies, this guidance represents the current international standard of care, reflecting the synthesis of clinical experience and the best available evidence.}, }
@article {pmid42203568, year = {2026}, author = {Maitra, A and Chari, ST and Wu, B and Van Den Eeden, SK and Fisher, W and Vege, SS and Rinaudo, JA and Feng, Z and , }, title = {Towards early detection of pancreatic cancer: The current status of cohort studies by the Diabetes-Pancreatic Ductal AdenoCarcinoma Working Group.}, journal = {Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.pan.2026.04.020}, pmid = {42203568}, issn = {1424-3911}, abstract = {The Diabetes-Pancreatic Ductal Adenocarcinoma Working Group (DM-PDAC WG) was formed within the Consortium for Study of Chronic Pancreatitis Diabetes and Pancreatic Cancer (CPDPC) to study the link between new-onset diabetes and pancreatic cancer. Its goals were to i) estimate the risk of PDAC in a prospectively assembled cohort of individuals with NOD identified at its glycemic onset (GNOD), ii) Establish a biobank of clinically annotated bio-specimens from GNOD subjects with pre-symptomatic PDAC and control new-onset type 2 DM, iii) Conduct Phase 3 validation studies of promising biomarkers for identification of occult PDAC in GNOD; iv) Provide a platform for development of a future interventional screening protocol for early detection of PDAC in NOD patients that incorporates imaging studies and clinical algorithms. The study identified >20,000 subjects with GNOD and assembled a biobank of serial blood samples in 2270 GNOD subjects. The risk of PDAC in GNOD and the distribution of lead time from GNOD to PDAC clinical diagnosis have been definitively defined in a cohort of 18,838 GNOD subjects identified during the course of the study. Ongoing biomarker and metabolomics studies will not only provide data on performance of tested biomarkers, but also an unprecedented repository of data on a large number of type 2 DM subjects. There are also ongoing studies on the "science of NOD" to understand its pathogenesis. Overall, the DM-PDAC Working Group has been successful in its mission to further our understanding of the link between diabetes pancreatic cancer.}, }
@article {pmid42203843, year = {2026}, author = {Antwi, SO and Coombes, BJ and Carlson, EE and Larson, NB and Rabe, KG and Atkinson, HJ and Majumder, S and Bamlet, WR and Schaid, DJ and Zhong, J and McKean, D and Arslan, AA and Beane Freeman, LE and Bracci, PM and Canzian, F and Truong, T and Atkins, J and Du, M and Gallinger, S and Goodman, PJ and Katzke, V and Campa, D and Kooperberg, C and Le Marchand, L and Neale, RE and Patel, AV and Wactawski-Wende, J and Perdomo, S and Shu, XO and Visvanathan, K and Van Den Eeden, SK and White, E and Zheng, W and Albanes, D and Andreotti, G and Brennan, P and Chanock, SJ and Chen, Y and Darst, B and Ferrari, P and Giovannucci, EL and Goggins, M and Haiman, C and Hassan, M and Hung, RJ and Jones, MR and Kraft, P and Malats, N and Moore, SC and Ng, K and Peters, U and Porta, M and Rothman, N and Sánchez, MJ and Sesso, HD and Silverman, DT and Southey, MC and Milne, RL and Um, CY and Yu, H and Yuan, C and ,  and ,  and Risch, HA and Wolpin, BM and Stolzenberg-Solomon, RZ and Klein, AP and Amundadottir, LT and Oberg, AL}, title = {Polygenic scores for risk of pancreatic ductal adenocarcinoma: evaluation of novel and published models.}, journal = {NPJ precision oncology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41698-026-01479-x}, pmid = {42203843}, issn = {2397-768X}, support = {K01CA23787/CA/NCI NIH HHS/United States ; U01CA210138/CA/NCI NIH HHS/United States ; R01CA272668/CA/NCI NIH HHS/United States ; }, abstract = {Polygenic risk scores (PRSs) may enhance risk stratification for pancreatic ductal adenocarcinoma (PDAC), but existing models vary widely in design, predictive performance, and cross-ancestry transferability. We developed genome-wide PRSs using Bayesian methods (LDpred2 and PRS-CS) and p value thresholding (PRSice-2) and systematically evaluated these alongside 13 published PRSs to identify models with robust predictive performance across ancestries. Using GWAS summary statistics from 7531 cases and 10,631 controls, we derived the PRSs and tested associations in an independent sample of 4508 PDAC cases and 46,189 controls, with adjustment for well-established PDAC risk factors. Among all models, the genome-wide LDpred2-based PRS showed the strongest association with PDAC (OR = 1.57 per standard deviation increase; 95% CI: 1.51-1.62) and significantly improved discrimination beyond established risk factors alone (AUC = 0.74-0.76; p < 0.0001). Importantly, the genome-wide LDpred2 PRS demonstrated consistent associations across African, Admixed American, and European ancestry groups, whereas the best-performing published PRS was associated with PDAC risk only in individuals of European ancestry. These findings support genome-wide PRSs as a promising framework for multi-ancestry risk stratification for PDAC and to inform targeted early detection strategies.}, }
@article {pmid42189191, year = {2026}, author = {Sayar, E and Richards, HM and Gulati, R and Patel, RA and Hanratty, B and Lee, HJ and Coleman, I and Mustafi, P and Ding, CC and Chen, WS and Quigley, D and Setty, M and Lang, JM and True, LD and Kollath, L and Lin, DW and Luo, J and Lee, JK and Ha, G and Yu, EY and Cheng, HH and Montgomery, B and Corey, E and Morrissey, C and Schweizer, MT and Nelson, PS and Raychaudhuri, R and Haffner, MC}, title = {Integrative Surface Antigen Profiling of KLK2 and STEAP1 in Advanced Prostate Cancer.}, journal = {Molecular cancer research : MCR}, volume = {}, number = {}, pages = {}, doi = {10.1158/1541-7786.MCR-26-0052}, pmid = {42189191}, issn = {1557-3125}, abstract = {KLK2 and STEAP1 are two cell surface targets with relevance for prostate cancer therapy. The objective of this study was to characterize the expression landscape of KLK2 and STEAP1 in metastatic castration-resistant prostate cancer (mCRPC) and to define associated transcriptomic, genomic, and epigenomic features. We analyzed a total of 1095 patient samples from three mCRPC cohorts, including in situ studies of rapid autopsy cases and patient derived xenograft models. We found that KLK2 and STEAP1 expression is strongly enriched in AR-positive tumors and largely absent in neuroendocrine and double-negative phenotypes. Within AR+ tumors, pairwise comparisons revealed co-expression and high combined positivity rates for STEAP1, KLK2, and PSMA, suggesting that co-targeting any two of these antigens increases overall tumor coverage. Analysis of samples from a rapid autopsy cohort, which enabled assessment of intra- and inter-tumoral diversity, showed comparable degrees of expression heterogeneity for KLK2 and STEAP1. Antigen expression correlated positively with AR genomic alterations and serum PSA levels, and negatively with RB1 and PTEN loss. Transcriptomic and epigenome analyses demonstrated distinct mechanisms governing antigen expression: KLK2 showed a strict AR dependence with coordinated AR/FOXA1/HOXB13 binding and enhancer activation, whereas STEAP1 was only partially AR-dependent and additionally regulated by locus-specific DNA methylation changes. Further, KLK2 and STEAP1 expression states were associated with distinct transcriptional programs and immune microenvironmental features. Implications: These findings establish KLK2 and STEAP1 as key prostate adenocarcinoma-lineage antigens and provide critical insights to inform the rational design and clinical development of cell-surface antigen-directed therapies in prostate cancer.}, }
@article {pmid42189487, year = {2026}, author = {Jeon, JJ and Chun, H and Lee, J and Son, H and Lee, C and Lee, K and Oh, SS and Hwang, S and Hyun, CS and Kim, MH and Cho, E and Lee, S and Shin, JI}, title = {Evaluating the Performance of Artificial Intelligence in Accurately Detecting Skin Cancer: An Umbrella Review of Systematic Reviews and Meta-analyses.}, journal = {American journal of clinical dermatology}, volume = {}, number = {}, pages = {}, pmid = {42189487}, issn = {1179-1888}, abstract = {BACKGROUND: Artificial intelligence technology is being widely developed in dermatology. However, there remains a lack of comprehensive data analyzing the diagnostic performance of artificial intelligence in skin cancer.<br><br>OBJECTIVE: We aimed to evaluate the diagnostic accuracy of artificial intelligence in skin cancer detection.<br><br>METHODS: MEDLINE, Embase, Cochrane library, Web of Science, and Scopus were searched from database inception to 9 April, 2025. Studies were included if they exclusively assessed the diagnostic accuracy of artificial intelligence for primary cutaneous malignancies. The artificial intelligence performance in skin cancer diagnosis was evaluated using accuracy, area under the curve value, sensitivity, and specificity.<br><br>RESULTS: Twenty-eight systematic reviews and meta-analyses were included. Across the studies, reported sensitivity ranged from 83.7 to 94.4% for basal cell carcinoma, 57.0-90.1% for squamous cell carcinoma, and 48-100% for melanoma. Specificity ranged from 77.9 to 96% for basal cell carcinoma, 92.6-98% for squamous cell carcinoma, and 36-100% for melanoma. Area under the curve values extracted from the reviews varied widely, generally ranged from 0.61 to 0.99. Narrative comparisons within the included studies suggested that deep learning models frequently demonstrated diagnostic performance non-inferior or superior to human clinicians, although prospective validation in real-world clinical workflows remains limited.<br><br>CONCLUSIONS: Current evidence suggests that artificial intelligence technologies have demonstrated potential for skin cancer diagnosis, but with important limitations. Variability in diagnostic metrics, driven largely by data heterogeneity and differing validation strategies, poses significant challenges. Emerging evidence suggests future research should transition toward multimodal artificial intelligence systems that integrate structured clinical metadata with image analysis. This will require methodological standardization and validation in real-world settings.}, }
@article {pmid42191051, year = {2026}, author = {Oshiro, CE and Cushing-Haugen, KL and Vecchio, NJD and Alonge, OD and Ghai, NR and Green, BB and Honda, SA and Neslund-Dudas, C and Ritzwoller, DP and Skinner, CS and Tao, M and Vachani, A and Chubak, J and Corley, DA and Haas, JS and Li, CI and Tiro, JA and Rendle, KA}, title = {Body Mass Index and Initiation of Cancer Screening: A Closer Look at Differences by Race, Ethnicity, and Sex in a Multi-Center Population.}, journal = {American journal of preventive medicine}, volume = {}, number = {}, pages = {108434}, doi = {10.1016/j.amepre.2026.108434}, pmid = {42191051}, issn = {1873-2607}, abstract = {INTRODUCTION: Obesity is associated with risk for several screen-detectable cancers, yet cancer screening rates are lower among adults with obesity. It is unclear whether associations between BMI and screening initiation differ by race, ethnicity, or sex.<br><br>METHODS: A retrospective cohort study was conducted among adults initiating cervical, colorectal, or lung cancer screening using electronic health record data from 10 US health systems (2010-2020 for the cervical/colorectal cohorts; 2014-2021 for lung). Associations between screening initiation (within 15 months of becoming age-eligible) and BMI categories were analyzed using separate logistic regression models. Effect modification by race/ethnicity and sex was assessed. Data were analyzed from 2023-2025.<br><br>RESULTS: Among 23,849 adults eligible for cervical cancer screening, overweight (BMI 25 to <30 kg/m[2]), class 1 obesity (BMI 30 to <35), class 2 obesity (BMI 35 to <40) and class 3 obesity (BMI 40 or greater), patients had lower odds of screening initiation than adults with healthy weight (BMI 18.5 to <25). Similarly, among 561,132 adults eligible for colorectal cancer screening, overweight and class 1 - 3 obesity were associated with lower odds of screening. Race and ethnicity moderated associations between BMI and cervical (p=0.0013) and colorectal screening (p<0.0001), and sex moderated associations for BMI and colorectal screening (p<0.0001). Stratified analysis was not conducted for the lung cohort (49,199) due to smaller sample size.<br><br>CONCLUSION: Adults with obesity have lower odds of timely screening initiation. Given the increased risk of cancers in adults with obesity, effective interventions to target suboptimal cancer screening are critically important.}, }
@article {pmid42191663, year = {2026}, author = {Kharaji, M and Safwat, AA and Cheng, D and Firoozeh, N and Hassan, MHD and Zhu, C and Orouskhani, M and Guo, Y and Medverd, JR and Cross, NM and Mossa-Basha, M}, title = {Artificial Intelligence in Neuroradiology: A Review of FDA-regulated Algorithms.}, journal = {The British journal of radiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/bjr/tqag120}, pmid = {42191663}, issn = {1748-880X}, abstract = {Artificial intelligence (AI) is increasingly integrated into neuroradiology practice, with a growing number of FDA-cleared algorithms now supporting tasks ranging from acute triage to volumetric analysis. This review provides a structured overview of commercially available, FDA-regulated AI tools in neuroradiology, organized by clinical application. These include detection and prioritization of intracranial hemorrhage and large vessel occlusion, aneurysm identification on CTA, automated ASPECTS scoring, and brain tumor segmentation, as well as tools for image enhancement and quantitative analysis in neurodegenerative and demyelinating diseases. For each application, we describe the algorithm's intended function, summarize available performance data, and highlight areas where AI can add clinical value, such as reducing time to diagnosis, improving detection of subtle findings, or standardizing measurements. We also discuss key limitations, including reduced performance outside intended-use parameters and the need for broader validation. As AI tools continue to evolve, understanding their strengths, limitations, and optimal use cases is essential to their safe and effective deployment in neuroradiology.}, }
@article {pmid42196715, year = {2026}, author = {Nash, SH and Adcock, R and Wang, C and Hebert-DeRouen, MC and Joe, NS and Pete, D and Kratzer, TB and Wiggins, CL and Liu, L and McDowell, BD}, title = {Area-Level Sociodemographic Differences Between Indian Health Service Purchased/Referred and Non-Purchased/Referred Care Delivery Areas.}, journal = {International journal of environmental research and public health}, volume = {23}, number = {5}, pages = {}, doi = {10.3390/ijerph23050622}, pmid = {42196715}, issn = {1660-4601}, support = {1R21MD018641/MD/NIMHD NIH HHS/United States ; P30 CA086862-25S2/CA/NCI NIH HHS/United States ; P30CA118100/CA/NCI NIH HHS/United States ; Contract HHSN261201800014I, Task Order HHSN26100001/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; NIH K00CA253685/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *United States Indian Health Service/statistics &amp; numerical data ; *Indians, North American/statistics &amp; numerical data ; *Health Services Accessibility/statistics &amp; numerical data ; Socioeconomic Factors ; Female ; Socioeconomic Disparities in Health ; Alaska Natives/statistics &amp; numerical data ; Sociodemographic Factors ; Adult ; Male ; Middle Aged ; }, abstract = {PURPOSE: Purchased/Referred Care Delivery Area (PRCDA) counties are those where resident American Indian and Alaska Native (AIAN) people are eligible for Indian Health Service care. Due to concerns about racial misclassification, cancer statistics for AIAN people are often restricted to PRCDA counties. Differences in sociodemographic characteristics may exist between PRCDA and non-PRCDA counties, but have not been described; therefore, the potential selection bias associated with the restriction to PRCDA counties remains unknown.<br><br>METHODS: We used data from the University of California, San Francisco Health Atlas to explore ecological differences in county-level demographic, socioeconomic, healthcare access, and health outcomes data between PRCDA and non-PRCDA counties (n = 3152 counties). We tested for statistical differences in mean levels of demographics between PRCDA and non-PRCDA counties using Pooled or Welch t-tests.<br><br>RESULTS: We observed small, but statistically significant differences between PRCDA and non-PRCDA counties in county-level demographic and socioeconomic characteristics (age, poverty, utility services threat, unemployment, educational attainment, computer access, and median income), neighborhood and environment characteristics (overcrowding, severe mortgage/rent burden), healthcare access and utilization (uninsured, annual checkup, annual dental visit, mammography, binge drinking, smoking, physical inactivity, social isolation), and health outcomes (poor mental health, arthritis, poor self-rated health, high blood pressure, diabetes, high cholesterol, and obesity).<br><br>CONCLUSIONS: These results indicate variability in county-level measures between PRCDA and non-PRCDA counties. While these data do not speak specifically to AIAN peoples' experiences, they provide critical contextual information to understand how exclusion of AIAN people residing in non-PRCDA counties from cancer statistics may bias risk estimates.}, }
@article {pmid42200639, year = {2026}, author = {Loes, AN and Tarabi, RAL and Li, SH and Atkinson, RK and Huddleston, J and Kikawa, C and Griffiths, T and Drapeau, EM and Wong, S-S and Cheng, SMS and Leung, NHL and Cobey, S and Cowling, BJ and Bedford, T and Hensley, SE and Bloom, JD}, title = {Strain-specific differences in the response to egg-derived versus recombinant protein influenza vaccines.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0031726}, doi = {10.1128/jvi.00317-26}, pmid = {42200639}, issn = {1098-5514}, abstract = {UNLABELLED: The 2023/2024 influenza vaccine included an updated H1N1 component designed to better match a new clade of H1N1 that had multiple mutations in antigenic epitopes of hemagglutinin. Despite this update, the vaccine trended toward being less effective against the vaccine-matched H1N1 clade than the parental H1N1 clade lacking the new antigenic mutations. Here, we measure neutralization titers of serum antibodies from individuals who had received either a recombinant protein or an egg-derived vaccine against a set of viruses with hemagglutinins from 58 H1N1 strains representative of the diversity during the 2023/2024 season. We find that egg-derived vaccine recipients, but not recombinant protein vaccine recipients, had a relatively lower boost in neutralizing titers to the new clade that the updated vaccine was designed to target. We suggest that the difference in the extent that the egg-derived vs recombinant protein vaccines boosted neutralizing titers to the new H1N1 clade is because the seed strain for the egg-derived vaccine strain had acquired a reversion of a key antigenic mutation (K142R) present in that clade. Our results show how egg-derived vs recombinant protein vaccines can elicit different relative titer boosts against different subsets of viral strains, a phenomenon that could impact vaccine effectiveness.<br><br>IMPORTANCE: Influenza vaccines can be produced from virus grown in eggs or grown in cells or made with recombinant protein. Egg-derived influenza vaccines often contain egg-adaptive mutations in the viral antigen hemagglutinin (HA) which can impact the antigenicity or immunogenicity of the HA. In this study, we compare neutralization titers from egg-derived and recombinant protein vaccine recipients against recently circulating influenza A(H1N1) strains. We find that the egg-derived vaccine induces less of a boost in titers than the recombinant protein vaccine to the new clade of viral strains that the vaccine was designed to target.}, }
@article {pmid42200680, year = {2026}, author = {Wolf, AMD and Hoffman, RM and Walter, LC and Zeigler-Johnson, C and Church, TR and Guerra, CE and Elkin, EB and Etzioni, R and Herzig, A and Oeffinger, KC and Perkins, RB and Raoof, S and Tina Shih, YC and Skates, SJ and Kratzer, TB and Manassaram-Baptiste, D and Smith, RA}, title = {Colorectal cancer screening: An update to the American Cancer Society guideline, 2026.}, journal = {CA: a cancer journal for clinicians}, volume = {76}, number = {3}, pages = {e70083}, doi = {10.3322/caac.70083}, pmid = {42200680}, issn = {1542-4863}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/epidemiology ; *Early Detection of Cancer/methods/standards ; United States/epidemiology ; American Cancer Society ; Feces/chemistry ; Middle Aged ; Mass Screening/standards/methods ; Occult Blood ; Aged ; Biomarkers, Tumor ; Practice Guidelines as Topic ; }, abstract = {Colorectal cancer (CRC) is a leading cause of cancer incidence and mortality in the United States, with rates recently increasing among adults younger than 65 years. In 2018, the American Cancer Society (ACS) lowered the recommended age to initiate screening for average-risk adults to age 45 years. Since then, new molecular-based screening tests-a multitarget stool RNA test (mt-sRNA), a next-generation mt-sDNA test, and a blood-based cell-free DNA assay-have received regulatory approval for CRC screening. For this update, the ACS Guideline Development Group commissioned a targeted, systematic evidence review evaluating diagnostic performance and published modeling studies to judge the potential impact of these tests on CRC incidence and mortality. The ACS reaffirms the recommendation that average-risk adults should initiate CRC screening at age 45 years and continue through age 75 years for those with a life expectancy greater than 10 years. Consistent with prior guidelines, the ACS emphasizes that offering multiple, recommended screening options supports informed patient choice and may improve participation, because the most effective screening test is the one that the patient completes. The next-generation mt-sDNA test, which is an updated version of an already recommended mt-sDNA test, and the mt-sRNA test demonstrated high sensitivity for CRC and moderate sensitivity for advanced precancerous lesions and are recommended, along with annual high-sensitivity fecal immunochemical and high-sensitivity guaiac-based fecal occult blood tests, as preferred stool-based screening options at 3-year intervals. Compared with established stool-based tests, blood-based tests demonstrated lower sensitivity for both advanced precancerous lesions and stage I cancers, with modeling studies predicting less effectiveness in reducing CRC incidence and mortality. At this time, blood-based tests should be recommended only to individuals who decline or do not complete preferred screening tests. Ongoing evaluation of adherence, real-world implementation, and clinical outcomes will inform future updates for these new tests. For screening to be effective, a positive result on any noncolonoscopy screening test requires timely follow-up with colonoscopy, preferably within 6 months, to complete the screening process.}, }
@article {pmid42201458, year = {2026}, author = {Weiss, NS and Kessler, L and Etzioni, R}, title = {The analysis of cancer screening trials in which the outcome is the incidence of late-stage disease.}, journal = {European journal of epidemiology}, volume = {}, number = {}, pages = {}, pmid = {42201458}, issn = {1573-7284}, support = {R35 CA274442/CA/NCI NIH HHS/United States ; }, abstract = {The National Health Service-Galleri randomized trial seeks to determine the extent to which a blood-based multi-cancer screening test can lead to a reduced incidence of a variety of cancers that are at a late stage as of the time of initial diagnosis. In February 2026, the investigators of this trial issued a news release indicating that after several years of follow-up, for a group of 12 pre-specified forms of cancer there was a lower incidence of stage IV cancer among patients in the intervention arm of the trial than in the control arm. The release stated that a group of participants whose stage IV cancer could not have been influenced by the screening - those with stage IV disease already present as of the initial screening exam - had been excluded from this analysis. We argue that while it is appropriate to restrict such an analysis to persons without prevalent stage IV cancer at the start of the trial, a valid result will be obtained only after accounting for the counterparts of these cases that are present in the trial's control arm. We describe how this can be accomplished, and the assumptions needed for such a strategy to succeed.}, }
@article {pmid42185298, year = {2026}, author = {Mullins, JI and Deng, W and Giorgi, EE and Magaret, CA and Rolland, M and Bhattacharya, T and Westfall, DH and Yssel, AEJ and Bumgarner, RE and Murrell, B and Ndung'u, T and Robb, ML and Rossenkhan, R and Edlefsen, PT and Dong, KL and Chen, L and Gwashu-Nyangiwe, A and Zhao, H and Thebus, R and Ndabambi, N and Galvao, B and Sawe, F and Nitayaphan, S and York, T and Matten, D and Murrell, H and Pankow, AP and Juraska, M and Ludwig, J and Hural, J and Cohen, MS and Corey, L and McElrath, MJ and Gilbert, PB and Williamson, C}, title = {Long-read deep sequencing reveals high rates of multilineage transmission and rapid viral population changes in acute HIV infection.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-73496-0}, pmid = {42185298}, issn = {2041-1723}, support = {INV-016189/GATES/Gates Foundation/United States ; INV-033558/GATES/Gates Foundation/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; P30 AI060354/AI/NIAID NIH HHS/United States ; UKZNRSA1001//International AIDS Vaccine Initiative (International AIDS Vaccine Initiative, Inc.)/ ; 19275//Gilead Sciences (Gilead)/ ; W81XWH-11-2-0174//Henry M. Jackson Foundation (Henry M. Jackson Foundation for the Advancement of Military Medicine)/ ; }, abstract = {Understanding the selective forces acting upon HIV early in infection is crucial to design prevention strategies. By leveraging deep sequencing and the short diagnostic intervals of the FRESH and RV217 cohorts between the last-negative and first-positive RNA tests (median 4 days), we captured a precise and early snapshot of acute HIV infection. The frequency of multiple transmitted viruses of 37% in these as well as placebo recipients from the AMP trials (NCT02716675 and NCT02568215) was higher than previously published, with the true frequency likely to be higher. The relative abundance of lineages fluctuated substantially over time in two-thirds of the multilineage infections, generating uncertainty in identifying the specific viruses that were transmitted and founding the infection. At the population level, viral populations exhibited limited diversity and selection on the Gag and Env proteins at the earliest times examined, with sites inferred to be undergoing negative selection most evident. These data may help explain vaccination failures and provide new targets for prevention.}, }
@article {pmid42185494, year = {2026}, author = {Xie, Y and Lin, J and Liu, H and Xiong, Y and Han, J and Huang, Z and Weng, J and Wan, Z and Li, P and Wang, P and Liu, X and Wu, L and Cai, Q and Huang, M and Luo, Y and Wang, X and Yu, H}, title = {ICIsAtlas reveals a suppressive NK cell niche in pan-cancer immunotherapy profiles.}, journal = {Communications biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s42003-026-10336-3}, pmid = {42185494}, issn = {2399-3642}, support = {82272965, 82473456//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82372715//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2025A04J5297//Guangzhou Municipal Science and Technology Project/ ; 2025A04J4447//Guangzhou Municipal Science and Technology Project/ ; 2025A1515011921, 2024A1515030054//Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)/ ; }, abstract = {Immune checkpoint inhibitors (ICIs) have reshaped the treatment in multiple tumors. However, a substantial proportion of patients exhibit limited responses. The lack of harmonized, large-scale pan-cancer ICI datasets coupled with accessible analysis tools hinders the systematic discovery of response biomarkers and resistance mechanisms. Therefore, we developed a comprehensive resource named ICIsAtlas, which encompassed curated transcriptomic and clinical data from 1,268 ICI-treated patients across eight tumor types, with an accompanying R package implementing a complete workflow for deconvolution and biomarker evaluation. Applying the ICIsAtlas framework, a systematic pan-cancer analysis was performed. We identified the universal signatures that were specific for ICI response, including cooperative interactions among favorable immune cells. In addition, we discovered a competitive cell community and SERPING1 + VEGFA+ Natural Killer (NK) cell-mediated immunosuppressive niche in non-responders, which were further validated with single-cell and multiplex immunohistochemistry data. The ICIsAtlas resource and R package represent a powerful, publicly available platform for hypothesis generation and biomarker discovery, which could be used to develop the next-generation biomarkers and therapeutic targets to improve tumor immunotherapy.}, }
@article {pmid42185525, year = {2026}, author = {Ayoub, HH and Jerome, KR and Chemaitelly, H and Wald, A and Abu-Raddad, LJ}, title = {Mathematical modeling of the population-level impact of hypothetical herpes simplex virus type 2 curative therapy.}, journal = {Communications medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43856-026-01677-5}, pmid = {42185525}, issn = {2730-664X}, abstract = {BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection is a prevalent lifelong infection and the leading cause of genital ulcer disease (GUD), yet no vaccines or curative interventions are currently available. Emerging curative approaches have demonstrated proof-of-concept efficacy in preclinical studies, but their potential population-level impact remains unknown. This study assessed the potential impact of curative therapy on HSV-2 disease burden and transmission.<br><br>METHODS: A dynamic HSV-2 transmission model was developed for the United States and calibrated to prevalence estimates from the National Health and Nutrition Examination Surveys. Curative therapy was assumed to be introduced in 2030 and scaled to 20%, 50%, or 80% coverage by 2040 under two scenarios: (i) treatment of symptomatic individuals only and (ii) treatment of all individuals with HSV-2 infection.<br><br>RESULTS: Here we show that, by 2050, at 80% coverage, curative therapy for symptomatic individuals reduces the number of 15-49-year-olds with GUD and GUD days by 86.7% and 86.2%, respectively, and decreases the incidence rate and annual new infections by 54.0% and 51.7%, averting 5.4 million cumulative infections. The numbers needed to treat to avert one prevalent or incident symptomatic HSV-2 infection, one incident HSV-2 infection, and one year of GUD days are 0.90, 3.4, and 0.61, respectively.<br><br>CONCLUSIONS: Curative therapy could substantially reduce HSV-2 incidence and recurrent GUD, yielding population-level benefits beyond individual cure.}, }
@article {pmid42185641, year = {2026}, author = {Vaz, JM and Zhu, S and Useche, M and Shih, L and Marchiano, E and Beronja, S and Clurman, BE and Rodriguez, C and Barber, B and Chan, M and Gujral, TS}, title = {Transcriptional states define dependencies and therapeutic vulnerabilities in head and neck cancer.}, journal = {NPJ precision oncology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41698-026-01509-8}, pmid = {42185641}, issn = {2397-768X}, support = {R01CA273081/CA/NCI NIH HHS/United States ; }, abstract = {Molecular heterogeneity in head and neck squamous cell carcinoma (HNSCC) is well recognized, yet existing subtype frameworks remain largely descriptive and have not translated into therapeutic decision-making. Here, we establish a mechanistic platform that converts transcriptomic diversity into drug-actionable tumor states. Integrating multi-cohort RNA-seq from 727 tumors across five independent datasets, genome-scale CRISPR dependency maps, and pharmacologic screening, we define distinct tumor survival circuits across HPV-negative HNSCC and nominate subtype-matched therapeutic strategies. These circuits encompass a proliferative axis (MYC, MET/FAK, inflammatory and translational programs), an epithelial-differentiated/adhesion program, an EMT-like state with stromal activation, and mitochondrial/oxidative metabolic states, each mapping to selective liabilities (e.g., mitotic/autophagy control, ERBB/PI3K and cadherin signaling, OXPHOS/mitochondrial translation, and G2/M-integrin-Notch pathways, respectively). We then develop a transcriptomic predictor of EGFR-inhibitor response using machine learning and validate it in prospectively collected, fresh patient-derived 3D microtumors. The resulting 13-gene signature identifies erlotinib-responsive tumors (R = 0.93) and maps biologically to an epithelial-differentiated state, outperforming EGFR expression alone. Our study establishes a subtype-to-dependency-to-therapy framework, enabling precision stratification and providing a clinically feasible path for prospective biomarker deployment.}, }
@article {pmid42187338, year = {2026}, author = {Lee, Y and Yang, Q and Kay, M and Bailey, DE and Gigic, B and Hardikar, S and Toriola, AT and Shibata, D and Li, CI and Byrd, DA and Figueiredo, JC and Strehli, I and Mclaws, M and Florou, V and Ilozumba, M and Erickson, P and Medhe, A and Ulrich, CM and Gonzalez-Guarda, RM}, title = {Distinct Symptom Occurrence Subgroups Among Patients With Colorectal Cancer: Differences in Social Determinants of Health and Diet Quality.}, journal = {Research in nursing &amp; health}, volume = {}, number = {}, pages = {}, doi = {10.1002/nur.70083}, pmid = {42187338}, issn = {1098-240X}, support = {20427//Sigma Theta Tau International/ ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 AG083580/AG/NIA NIH HHS/United States ; T32DK110966/DK/NIDDK NIH HHS/United States ; R01NR018762/NR/NINR NIH HHS/United States ; }, abstract = {Colorectal cancer (CRC) is a leading cause of cancer mortality in the United States. Many patients with CRC experience physical and psychological symptoms that diminish quality of life and are shaped by social determinants of health (SDOH) and diet quality. This study aimed to (a) identify distinct symptom occurrence subgroups among patients with CRC, and (b) examine differences in SDOH characteristics and diet quality across these symptom occurrence subgroups. We conducted a secondary analysis of the ColoCare Study dataset from the Huntsman Cancer Institute, including CRC patients 6 months postdiagnosis. Latent class analysis identified subgroups based on the presence of symptoms. Chi-square tests and ANOVA examined subgroup differences in SDOH and diet quality, measured by the Healthy Eating Index (HEI)-2020. Logistic regression adjusted for cancer stage, comorbidity status, neoadjuvant or adjuvant therapy. Among 256 patients, three subgroups emerged: low (n = 84), moderate (n = 123), and high symptom occurrence (n = 49). Patients with high symptom occurrence were younger (F = 4.48, p = 0.01), more often Hispanic (χ[2] = 9.10, p = 0.01), had lower income (χ[2] = 12.92, p = 0.01), and more frequently received neoadjuvant therapy (χ[2] = 10.30, p = 0.006). They reported lower total social support (F = 5.60, p = 0.004) and poorer diet quality (F = 9.58, p = 0.0001). After adjustment, high symptom occurrence group had lower odds of adequate income (OR = 0.28, p = 0.0312), social support (OR = 0.886, p = 0.0100), and diet quality (OR = 0.94, p = 0.0156). Distinct CRC symptom profiles highlight the need for personalized dietary interventions and enhanced social support to improve symptom management. PATIENT OR PUBLIC CONTRIBUTION: Findings emphasize care strategies that address SDOH to optimize outcomes and quality of life for patients with CRC.}, }
@article {pmid42188820, year = {2026}, author = {Bhushan, NL and Gonzalez, R and Southwell, BG}, title = {Social Context Considerations for Future HIV Vaccine Introduction and Implementation.}, journal = {Vaccines}, volume = {14}, number = {5}, pages = {}, doi = {10.3390/vaccines14050450}, pmid = {42188820}, issn = {2076-393X}, abstract = {Background: The development of an efficacious preventive human immunodeficiency virus (HIV) vaccine remains a central goal of global HIV elimination efforts, yet biological performance alone will not determine a future vaccine's public health impact. Method: This review draws on behavioral science, communication research, vaccine implementation, and HIV prevention literature to identify cognitive, social, and structural challenges that are likely to shape public acceptance and uptake of a future HIV vaccine, as well as to outline evidence-based opportunities for addressing them. Results: Based on the available literature, mental models of both HIV and vaccination will be a critical determinant of how communities consider a future vaccine, particularly given that emerging mRNA and adjuvanted platforms may generate side effects that could be easily misinterpreted and that highly effective long-acting pre-exposure prophylaxis (PrEP) options already exist and will shape how individuals evaluate a vaccine's relative value. HIV-related stigma further complicates this landscape by making vaccination a socially interpreted behavior, unlike some other vaccination efforts. Together, these factors suggest that hesitancy and misalignment between public understanding and scientific evidence are predictable and should be anticipated rather than addressed reactively. At the same time, decades of HIV prevention implementation research have established an evidence base for vaccine communication, and existing community engagement infrastructure offers a foundation upon which future rollout efforts can build. We highlight three evidence-based strategies as particularly promising levers for encouraging acceptance and adoption. Conclusions: We conclude with recommendations for HIV vaccine researchers and healthcare professionals to invest in formative research, build community partnerships in advance of vaccine availability, and pilot integrated delivery models within existing HIV prevention services.}, }
@article {pmid42189090, year = {2026}, author = {Olivas-Martinez, A and Gao, F and Janes, H}, title = {A General Framework for Designing and Evaluating Active-Controlled Trials with Non-Inferiority Objectives.}, journal = {Statistics in medicine}, volume = {45}, number = {13-14}, pages = {e70618}, doi = {10.1002/sim.70618}, pmid = {42189090}, issn = {1097-0258}, support = {UM1AI068635/NH/NIH HHS/United States ; }, mesh = {Humans ; HIV Infections/prevention &amp; control ; *Research Design ; *Equivalence Trials as Topic ; *Randomized Controlled Trials as Topic/methods ; Anti-HIV Agents/therapeutic use ; Models, Statistical ; }, abstract = {Active-controlled trials with non-inferiority objectives are often used when effective interventions are available, but new options may offer advantages or meet public health needs. In these trials, participants are randomized to an experimental intervention or an active control. The traditional non-inferiority criterion requires that the new intervention preserve a substantial proportion of the active control effect. A key challenge is the absence of a placebo arm, which necessitates reliance on historical data to estimate the active control effect and assumptions about how well this effect applies to the target population. Another challenge arises when the active control is highly effective, as the new intervention may still be valuable even if it does not meet the traditional criterion. This has motivated alternative criteria based on sufficient efficacy relative to a hypothetical placebo. In this work, we propose a general framework for designing and evaluating non-inferiority trials that integrates all existing analytical methods and accommodates both traditional and alternative success criteria. The framework enables the systematic comparison of methods in terms of type I error, power, and robustness to misspecification of the active control effect. We illustrate its applicability in the design of a future HIV prevention trial with a highly effective active control. In this application, our framework identifies methods that provide greater efficiency and robustness than commonly used approaches and demonstrates practical advantages of the alternative non-inferiority criterion. Overall, this framework offers a comprehensive toolkit for rigorous non-inferiority trial design, supporting method selection and the evaluation of new interventions.}, }
@article {pmid42094153, year = {2026}, author = {Xu, H and Yu, G and Lu, Y and Fuller, H and Song, S and Shen, Y and Chiang, CWK and Darst, BF and Ye, K}, title = {Polygenic predisposition modifies the associations of fish oil supplementation with circulating omega-3 fatty acids: a cross-sectional gene-diet interaction study in UK Biobank.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42094153}, support = {R35 GM143060/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND: Several genetic variants have been identified to modify the effects of fish oil supplementation (FOS) on increasing circulating omega-3 fatty acids, but it remains unexplored whether polygenic predisposition to low circulating omega-3 fatty acids modifies these effects.<br><br>OBJECTIVE: To test if polygenic scores (PGS) for circulating omega-3 fatty acids modify the associations of FOS with corresponding circulating concentrations.<br><br>METHODS: We developed PGS models for absolute circulating concentrations of total omega-3 fatty acids (Omega-3), docosahexaenoic acid (DHA), and their relative percentages in total fatty acids (Omega-3% and DHA%), using a multi-ethnic genome-wide association study (N=136,016). PGS models were validated in 437,803 UK Biobank participants of European (EUR), Central/South Asian (CSA), African, and East Asian genetic ancestries. Linear models tested PGS-by-FOS interactions on corresponding observed circulating concentrations. Discovery analysis was performed separately in 237,380 EUR participants and each non-EUR group. Replication analyses were performed using oily fish intake and in another 178,935 EUR participants.<br><br>RESULTS: In EUR participants, PGS explained 5.3-11.1% of the phenotypic variance, and significant PGS-by-FOS interactions were detected across all four circulating omega-3 traits. Among participants in the bottom 5% of the PGS distribution, FOS was significantly associated with a 0.40 SD (95% CI: 0.39-0.44) increase in Omega-3. This association effect was 11.1% larger than the population average (&#x3b2; = 0.36; 95% CI: 0.35-0.37; PInt = 0.016) and 42.8% larger than that in participants in the top 5% of the PGS distribution (&#x3b2; = 0.28 SD; 95% CI: 0.25-0.32; PInt = 4.03&#xd7;10[-10]). These interaction patterns were consistently observed in CSA ancestry and confirmed in replication and sensitivity analyses.<br><br>CONCLUSIONS: PGS modify the associations of FOS with circulating omega-3 fatty acids in EUR and CSA populations, with larger FOS effects in participants with lower PGS. These findings support the development of genome-informed precision nutrition.}, }
@article {pmid42094349, year = {2026}, author = {Taber, A and Frutoso, M and Potchen, N and Koehne, AL and Schmitz, C and Morrell, ED and Prlic, M and Wright, SW}, title = {Human lung γδ T cells maintain functionality during inflammatory lung disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42094349}, issn = {2692-8205}, abstract = {γδ T cells provide mucosal defense against infection while also contributing to tissue repair. However, data regarding the effect of the human lung environment on γδ T cell functionality remains limited. To address whether lung inflammation impacts γδ T cell functionality, we analyzed lung and matched hilar lymph node (LN) tissue from deceased donors and patients with interstitial lung disease (ILD). We performed high-parameter spectral flow cytometry to examine the expression pattern of phenotypic biomarkers and assess ex vivo function. We identified lung-specific enrichment of γδ T cells with an effector memory phenotype relative to matched regional LN. We then used an ex vivo stimulation approach to interrogate the capacity to protect against infection (granzyme B [GzmB], interferon-γ [IFNγ] and tumor necrosis factor [TNFα]) and promote epithelial cell proliferation (amphiregulin [AREG]). We found that γδ T cells in lung and LN from deceased donors had similar functional properties. While γδ T cell populations from ILD lungs largely maintained cytokine production capacity, expression was diminished relative to LN counterparts. Importantly, lung γδ T cells maintained polyfunctional GzmB, IFNγ and TNFα expression across cohorts. Overall, we report human lung γδ T cells are regionally distinct with conserved functionality in a fibrotic environment.}, }
@article {pmid42177030, year = {2026}, author = {Boutin, CA and Callegari, M and Florescu, D and Nguyen, MH and Kaul, D and Avery, R and Chong, P and Fisher, C and Limaye, AP and Clough, L and Pergam, SA and Green, M and Michaels, MG and Danziger-Isakov, L and Angarone, M and Keefer, L and Daud, A and Lorenzo-Redondo, R and Tan, M and Ison, MG}, title = {A Phase 2 Multi-Center, Prospective, Randomized, Double-Blind Study to Assess the Clinical and Antiviral Efficacy and Safety of Nitazoxanide for the Treatment of Norovirus in Hematopoietic Stem Cell and Solid Organ Transplant Recipients.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ajt.2026.04.010}, pmid = {42177030}, issn = {1600-6143}, abstract = {Norovirus (NoV) may cause or contribute to chronic diarrhea among immunocompromised hosts. Neither vaccines nor antiviral therapies are available to prevent or treat NoV. We conducted an NIH-sponsored multi-center, prospective, randomized, double-blind study of nitazoxanide for the treatment of NoV infected adult transplant patients between 2018 and 2021. Subjects with a positive stool NoV PCR within 14 days of enrollment and active gastrointestinal symptoms were randomly assigned (1:1) to nitazoxanide or placebo for 56 consecutive doses and followed for 6 months. Primary endpoint was time to symptom resolution. Secondary endpoints included virologic efficacy and frequency of adverse events. 31 subjects (16 nitazoxanide,15 placebo) were enrolled. Most had chronic (≥14 days) symptoms (77%) and were solid organ transplant recipients (30/31). In the intention-to-treat population, the median time to symptom resolution was 19.0 days (95% CI: 1.0, 31.0) versus 11.0 days (95% CI: 2.0, 14.0) for the nitazoxanide and placebo groups respectively (p=0.459). Time to first negative stool NoV PCR was not significantly different between treatment arms (p=0.873). There were no serious adverse events related to nitazoxanide. Nitazoxanide did not shorten time to symptom resolution or viral shedding. Although safe, nitazoxanide likely contributes little to the management of chronic NoV. ClinicalTrials.gov: NCT03395405 (registration date 2018-01-04).}, }
@article {pmid42177092, year = {2026}, author = {Kogut, S and Padilla-Gálvez, M and Blanco-Melo, D}, title = {Transcriptional regulation of human endogenous retroviruses in cancer.}, journal = {Advances in virus research}, volume = {124}, number = {}, pages = {61-95}, doi = {10.1016/bs.aivir.2026.03.002}, pmid = {42177092}, issn = {1557-8399}, mesh = {Humans ; *Endogenous Retroviruses/genetics ; *Neoplasms/virology/genetics/therapy ; *Gene Expression Regulation, Viral ; *Transcription, Genetic ; *Gene Expression Regulation, Neoplastic ; Neoplastic Stem Cells/virology ; }, abstract = {Human endogenous retroviruses (HERVs) provide a direct record of the millions of years of co-evolution between humans and viruses. Yet, due to their repetitive nature and former reputation as "junk DNA," a full characterization of the functional roles and transcriptional regulation of HERVs remains to be achieved. As sequencing technologies improve, better resolution data regarding HERV expression and regulation has become attainable, and there is mounting evidence of aberrant HERV expression in various human diseases, particularly cancer. However, the perturbations to the transcriptional regulatory processes that govern these endogenized retroviral elements in cancer remain unclear. In this review, we will summarize the state of our understanding of the various mechanisms that control HERV expression in cancer, focusing primarily on aberrant methylation and KRAB-domain containing zinc finger proteins (KZFPs), among others. Many of these regulatory mechanisms are employed in stem cells to regulate pluripotency and differentiation and are also deployed in a subpopulation of cancer cells with high self-renewal and proliferation capacity, called cancer stem cells. While the expression of specific HERVs in cancer could be beneficial, deleterious, or neutral, the potential to use HERVs as biomarkers or immune adjuvants to enhance immunotherapies against cancer is promising. The implications of shared transcriptional mechanisms across cancer and stem cells will expose new areas to intervene with cancer treatments, ushering in a new era of HERV-based cancer therapeutics and diagnostics.}, }
@article {pmid42177172, year = {2026}, author = {Peters, BA and Qi, Q and Xue, X and Moon, JY and Yu, B and Thomas, SN and Cordero, C and Daviglus, ML and Burk, RD and Kaplan, RC and Isasi, CR}, title = {Association of gut microbiome with mobility impairment in the Hispanic Community Health Study/Study of Latinos.}, journal = {NPJ biofilms and microbiomes}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41522-026-01019-2}, pmid = {42177172}, issn = {2055-5008}, support = {R03HL182350/HL/NHLBI NIH HHS/United States ; R01DK134672/DK/NIDDK NIH HHS/United States ; R01AG085320/AG/NIA NIH HHS/United States ; }, abstract = {Aging-related declines in mobility are more common in women than men. The gut microbiome may play a role in physical function, but sex-specific roles are unknown. In adults ≥50 years old (n = 1187 women, 585 men), we examined associations of self-reported mobility impairment with gut microbiome assessed by stool shotgun sequencing, and examined heterogeneity by sex. Gut microbiome α-diversity was lower and overall composition (β-diversity) altered in women with mobility impairment compared to without, but this was not the case in men. Fifteen microbiome species were associated with mobility impairment in both women and men, including enrichment of Streptococcus and Lactobacillus and depletion of Eubacterium species. An additional 84 species were associated with mobility impairment in women only, including enrichment of Gammaproteobacteria species, but none were associated with mobility impairment in men only. Correlations of impaired mobility-related microbiome scores, derived from universal and women-specific microbiome species, with serum metabolites (n = 385) suggested that impaired mobility-related species may be involved in synthesis of imidazole propionate and deoxycholic acid metabolites, while species depleted with mobility impairment may be involved in sex hormone metabolism and guanidinoacetate production, the latter in women only. Gut microbiota may play a role in physical function and sex differences therein.}, }
@article {pmid42177198, year = {2026}, author = {Gianopulos, JE and Schutter, A and Dobersch, S and Wallace-Povirk, A and Kogut, SE and Doak, A and Chanana, P and Ge, S and Mangino, L and Yamamoto, N and Boila, LD and Padilla-Galvez, M and Hui, J and Rhoads, N and Gifford, RJ and Cheung, KJ and Blanco-Melo, D and Notta, F and Kugel, S}, title = {ZNF274 constrains lineage plasticity and drives intrinsic resistance to CDK7 inhibitors in pancreatic cancer.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-73380-x}, pmid = {42177198}, issn = {2041-1723}, abstract = {Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by two distinct transcriptional subtypes: classical and basal, which may interconvert. We show the KRAB-ZNF protein, ZNF274, correlates with PDAC subtype and regulates sensitivity to CDK7 inhibition by facilitating heterochromatin maintenance and gene suppression. We find ZNF274 loss drives a classical to basal transition, induces invasive protrusions and facilitates invasion capacity. We define two mechanistic arms to this regulation. ZNF274 directly suppresses ZEB1 expression. When ZNF274 is lost, ZEB1 facilitates acquisition of mesenchymal features, keratin gene expression, and susceptibility to CDK7 inhibition. Second, ZNF274 dampens expression of repetitive elements including human endogenous retroviruses (HERVs). HERV expression following ZNF274 loss induces a double stranded RNA response that reinforces the classical to basal subtype transition. Here, we show ZNF274 is an important epigenetic regulator of cellular plasticity and sensitivity to CDK7 inhibition, presenting a therapeutic liability of PDAC subtype transition that is actionable in the clinic.}, }
@article {pmid42178683, year = {2026}, author = {Huang, S and Mishima, Y and Bailey, SL and Chauhan, A and Quesada, J and Klotz, P and Morrow, T and Provencher, K and Chen, J and López, JA and Tsai, TL and Panch, S and Stolla, M}, title = {Factors associated with aggregate formation in cold-stored platelets.}, journal = {Vox sanguinis}, volume = {}, number = {}, pages = {}, doi = {10.1111/vox.70294}, pmid = {42178683}, issn = {1423-0410}, support = {W81XWH-12-1-0441//U.S. Department of Defense/ ; EDMS 5570//U.S. Department of Defense/ ; }, abstract = {BACKGROUND AND OBJECTIVES: Cold-stored platelets (CSPs) can form aggregates, ultimately rendering them unusable. The causes of these aggregates and how to prevent them are poorly understood. This study aimed to identify potential factors associated with aggregate formation in CSPs stored in plasma for up to 14 days.<br><br>MATERIALS AND METHODS: We obtained CSPs from 79 unique donors during a clinical trial. We retrospectively analysed aggregate rates among donors of different sexes, ages and blood groups. In a subgroup, samples were also tested by enzyme-linked immunosorbent assay&#xa0;for markers of thrombosis and inflammation. Platelets from mice lacking von Willebrand factor (VWF) and human apheresis platelets treated with VWF and caplacizumab were stored and assessed for platelet count and aggregate formation by visual inspection and flow cytometry.<br><br>RESULTS: Forty-five (57%) units developed aggregates, and 34 (43%) did not. Units with aggregates had significantly lower soluble thrombomodulin levels and higher VWF levels approaching significance. In a multivariate analysis, platelets from female donors and donors with ABO type A were significantly more likely to form aggregates than those from male donors and donors with ABO type O, respectively. In the oldest donor cohort, units with aggregates were significantly less common than those without. Interfering with VWF levels and VWF function during storage did not reliably cause or prevent aggregates.<br><br>CONCLUSION: Donor sex, age, ABO type and thrombomodulin were significantly associated with aggregate formation or prevention.}, }
@article {pmid42178982, year = {2026}, author = {Daniele, C and Wacks, R and Hills, S and Garcia, L and LeBlanc, E and Rillamas-Sun, E and Wallace, R and Waring, M and Sturgeon, SR and Ryckman, KK and Spracklen, CN}, title = {Association of self-reported birth weight and preterm birth with blood pressure measures and risk for hypertension in older women from the women's health initiative.}, journal = {Journal of developmental origins of health and disease}, volume = {17}, number = {}, pages = {e22}, doi = {10.1017/S2040174426100579}, pmid = {42178982}, issn = {2040-1752}, mesh = {Humans ; Female ; *Premature Birth/epidemiology/physiopathology ; *Hypertension/epidemiology/etiology/diagnosis ; *Blood Pressure/physiology ; Self Report ; *Birth Weight/physiology ; Middle Aged ; Pregnancy ; Risk Factors ; Women's Health ; Infant, Newborn ; }, abstract = {Prenatal and early-life exposures may contribute to lifelong hypertension risk. We examined the relationships between an individual's birth weight or preterm birth status with their 1) risk for hypertension and 2) related quantitative blood pressure measures [mean systolic blood pressure (SBP), diastolic blood pressure (DBP), and 30-second pulse] among post-menopausal women from the Women's Health Initiative observational cohort. At study entry, birth weight and preterm birth status were self-reported by category (<6 lbs., 6-7 lbs. 15 oz., 8-9 lbs. 15 oz., or ≥10 lbs.; ≥4 weeks premature or full term). Prevalent and incident hypertension status were self-reported; baseline SBP, DBP, and 30-second pulse were measured by trained study staff. Linear, logistic, and Cox-proportional hazards regression models were used to estimate associations between birth weight and preterm birth and blood pressure outcomes. After adjustments, participants born weighing <6 lbs. had a higher mean SBP and were at increased risk for prevalent and incident hypertension compared to participants born at a normal birth weight (6-7 lbs. 15 oz.). Women born weighing ≥10 lbs. had a lower mean SBP and were at lower risk for prevalent and incident hypertension when compared to participants born at a normal birth weight. Compared to participants born full term, those born preterm were at increased risk for prevalent and incident hypertension; however, this relationship was weaker when stratifying by birth weight. Long-term follow-up or targeted counseling may be required for individuals born prematurely or at lower birth weights to prevent hypertension and associated cardiovascular outcomes.}, }
@article {pmid42179247, year = {2026}, author = {Ma, W and Kim, RS and Isasi, CR and Gallo, LC and Perreira, KM and Trifan, G and Daviglus, ML and Pirzada, A and Sotres-Alvarez, D and Cordero, C and Penedo, FJ and Kaplan, RC}, title = {Favorable Cardiovascular Health Among Hispanic and Non-Hispanic Adults in the United States: Results From the Hispanic Community Health Study/Study of Latinos and National Health and Nutrition Examination Survey, 2008 to 2024.}, journal = {Journal of the American Heart Association}, volume = {}, number = {}, pages = {e047791}, doi = {10.1161/JAHA.125.047791}, pmid = {42179247}, issn = {2047-9980}, abstract = {BACKGROUND: The long-term trends of favorable cardiovascular health among US Hispanic and Latino adults are not well understood. Using recent data spanning 2008 to 2024, this study examines contemporary changes in cardiovascular health within a diverse Hispanic and Latino population and compares them with national patterns.<br><br>METHODS: We applied the American Heart Association's Life's Essential 8 metrics of cardiovascular risk factor status to HCHS/SOL (Hispanic Community Health Study/Study of Latinos) participants aged 28 to 74&#x2009;years who were free of cardiovascular disease. Across 3 study visits (2008-2024), we examined the prevalence of achieving favorable metrics (Life's Essential 8 score &#x2265;80) for nicotine exposure, body mass index, blood lipids, blood glucose, and blood pressure. Comparisons were made with Hispanic and Latino and non-Hispanic White adults in the NHANES (National Health and Nutrition Examination Survey).<br><br>RESULTS: Over time, Hispanic and Latino adults had increasing prevalence of meeting the favorable Life's Essential 8 metric for blood lipids (HCHS/SOL, 29.4%-45.3%; NHANES, 30.6%-38.9%) and nicotine exposure (HCHS/SOL, 56.3%-63.4%; NHANES, 60.8%-67.1%), along with declining prevalence of meeting the favorable blood glucose metric (HCHS/SOL, 44.6%-37.5%; NHANES, 33.6%-30.0%). When comparing the Hispanic and Latino populations versus NHANES non-Hispanic White adults, the most marked and persistent differences were more favorable nicotine exposure and less favorable body mass index and glucose levels among the Hispanic and Latino groups.<br><br>CONCLUSIONS: Hispanic and Latino adults exhibit both advantages and disadvantages in cardiovascular health compared with non-Hispanic White adults. These findings underscore the need for targeted interventions and culturally tailored policies to address cardiovascular health disparities.}, }
@article {pmid42182038, year = {2025}, author = {Doty, RT and Munday, AD and Cottnair, H and Funk, SE and Young, DJ and Dunbar, CE and Wu, M and Abkowitz, JL}, title = {Restricting glycine uptake with bitopertin improves erythropoiesis in preclinical models of Diamond-Blackfan anemia.}, journal = {Blood. Red cells &amp; iron}, volume = {1}, number = {2}, pages = {}, pmid = {42182038}, issn = {3050-5984}, abstract = {Diamond-Blackfan anemia (DBA) results from germ line haploinsufficiency of 1 of at least 26 distinct ribosomal proteins. Although patients with DBA have hematopoietic stem and progenitor cell defects, the dominant clinical phenotype is severe anemia. In ~60% of patients with DBA, the anemia responds to corticosteroids. However, these responses are often time limited, and steroid-related complications are common, leaving an unmet need for an effective and safe oral therapy. In DBA, ribosomal haploinsufficiency leads to slowed translation and impaired protein synthesis. Globin synthesis is significantly slowed, whereas the production of heme, which requires a small amount of protein because it is synthesized enzymatically, proceeds at a near normal rate. This results in an excess of intracellular heme in early erythroblasts, elevated reactive oxygen species, and other heme-induced toxicity. Bitopertin, an oral competitive inhibitor of glycine import, has been shown to reduce heme synthesis and to have an excellent safety profile in unrelated phase 2 and 3 studies. We reasoned that bitopertin might help balance heme synthesis with globin synthesis and improve erythropoiesis in patients with DBA. Our observations in samples from patients with DBA, CD34[+] cells engineered to downregulate RPS19, and a murine DBA model support this concept, justify ongoing clinical studies, and provide insight into optimal trial design.}, }
@article {pmid42183754, year = {2026}, author = {Olives, EV and Crump, A and Ransome, Y and Castillo, WC and Kawachi, I and Jones, S and Reeve, B}, title = {Toward the Development of a Multilevel Measure of Structural Racism: Theory and Methods.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwag112}, pmid = {42183754}, issn = {1476-6256}, abstract = {Structural racism adversely affects the health and well-being of many Black and Hispanic/Latino Americans. This study sought to establish a theoretical foundation for developing a novel multilevel structural racism measure for use within Black and Hispanic/Latino communities in the United States (US). Based on a framework developed by the National Institute on Minority Health and Health Disparities (NIMHD), a content development team (n = 4 social epidemiologists) pre-selected 68 candidate indicators to be included in the ecological level index based on published literature. Subsequently, an expert panel consisting of leaders of community organizations (n = 3), health equity researchers (n = 5), and social stratification researchers (n = 2) participated in a modified three-phase Delphi panel process. This process yielded thirty-eight ecological-level indicators earmarked for inclusion, 30 for elimination, and 76 newly proposed. After revision of the newly proposed indicators, the final list included 71 indicators for structural racism measurement and spanned various domains of the NIMHD framework. This study sets the stage for a practical tool that can help researchers, clinicians, and policymakers identify structural racism's effects and guide efforts toward equity and justice in healthcare and beyond.}, }
@article {pmid42184910, year = {2026}, author = {Julceus, EF and Mendoza, JA and Flory, K and Frongillo, EA and Merchant, AT and Malik, FS and Cooper, DK and Reboussin, BA and Sauder, KA and Bellatorre, A and Liese, AD}, title = {Association of resilience with hemoglobin A1c among youth and young adults with youth-onset diabetes.}, journal = {Annals of epidemiology}, volume = {}, number = {}, pages = {110125}, doi = {10.1016/j.annepidem.2026.110125}, pmid = {42184910}, issn = {1873-2585}, abstract = {PURPOSE: We assessed whether resilience is associated with hemoglobin A1c (HbA1c) in youth and young adults (YYA) with youth-onset type 1 (T1D) and type 2 diabetes (T2D).<br><br>METHODS: A cross-sectional analysis of data from the multicenter SEARCH Food Security Cohort study (2019-2022) was conducted including 574 and 82 YYA with youth-onset T1D and T2D, respectively. Resilience, assessed with the 10-item Connor-Davidson Resilience scale, was analyzed in categories determined through tertiles (low &#x2264;25, moderate 26-32, and high &#x2265;33). Multivariable logistic regression models adjusted for sociodemographic and clinical factors, perceived social support, and symptoms of depression, anxiety, and eating problems.<br><br>RESULTS: Regardless of diabetes type, compared to participants with high resilience, those with low resilience had higher odds of HbA1c >9% (OR 1.90, 95% CI 1.06-3.41); the OR was 1.62 (95% CI 0.97-2.70) for those with intermediate resilience. Among YYA with T1D, those with low and intermediate resilience had elevated odds of HbA1c >9% (OR 1.96, 95% CI 1.02-3.79; OR 2.01, 95% CI 1.13-3.59, respectively) compared to those with high resilience.<br><br>CONCLUSIONS: Findings were consistent with the hypothesis that resilience was protective of elevated HbA1c in YYA with diabetes. Strategies to enhance resilience in these populations might be beneficial.}, }
@article {pmid42171881, year = {2026}, author = {Yan, F and Cruz-Correa, M and Specht, J and Wang, EW and Lu, J and Soliman, H and Jackson-Fisher, A and Tang, SY and Jiang, S and Le Corre, C and Li, M and Sommerhalder, D}, title = {A phase 1 study of PF-07260437, a B7-H4 × CD3 bispecific T-cell engager, in patients with advanced or metastatic breast, ovarian, and endometrial cancer.}, journal = {Investigational new drugs}, volume = {}, number = {}, pages = {}, pmid = {42171881}, issn = {1573-0646}, abstract = {B7-H4 is overexpressed in various cancers, making it a promising target for cancer immunotherapy. This phase 1, open-label, first-in-human study in patients with advanced/metastatic breast, ovarian and endometrial cancer evaluates the safety, pharmacokinetics (PK), and anti-tumour activity of PF-07260437, a novel B7-H4xCD3 bispecific T-cell engager. Enrolled patients received escalating doses of PF-07260437 (with/without priming dose) subcutaneously every two weeks, with a starting dose of 100 µg. Primary objectives included determination of maximum tolerated dose (MTD)/recommended dose for expansion (RDE), safety and tolerability. Secondary objectives included PK parameters and immunogenicity. Bayesian logistic regression model (BLRM) was used to guide dose escalation. Thirty patients with advanced/metastatic breast, ovarian and endometrial cancer received the study treatment during dose escalation; all were female (median age, 61.0 [41-75] years). Four patients (13.3%) experienced DLTs (alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, cytokine release syndrome). Overall, 29 (96.7%) patients experienced 202 treatment-related TEAEs (no grade 4/5 TEAEs); no TEAE resulted in study discontinuation. No objective response was observed. Disease control rate (DCR) was 33.3% (95% CI: 17.3%, 52.8%). PF-07260437 ≥ 300 μg resulted in exposures in the theoretic efficacious range, with a transient increase in serum cytokines levels following the first dose. The study was terminated by the Sponsor based on the overall assessment of the observed clinical safety, preliminary efficacy, pharmacokinetic and pharmacodynamic data. The MTD was not reached. PF-07260437 was tolerable in patients with breast, ovarian, and endometrial cancers with manageable TEAEs. TRIAL REGISTRATION NUMBER: NCT05067972. REGISTRATION DATE: 5 October, 2021.}, }
@article {pmid42173164, year = {2026}, author = {Schaefer, DA and Longley, RM and Wolfe, ED and Keane, EP and Larizza, IS and Boardman, AC and Rosenberg, J and Mate-Kole, M and Waldman, LP and Majhail, N and Lee, SJ and Khera, N and Amonoo, HL}, title = {Corrigendum to 'Financial Toxicity, Psychological Well-Being, and Quality of Life in Hematopoietic Stem Cell Transplantation' [Transplantation and Cellular Therapy 31 (2025) 936.e1-936.e10].}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.04.033}, pmid = {42173164}, issn = {2666-6367}, }
@article {pmid42173253, year = {2026}, author = {Al-Juhaishi, T and Ahn, KW and Chen, T and Patel, KK and Patel, J and Herrera, AF and Turtle, CJ and Rizzo, JD and Khimani, F and Awan, FT and Gibran-Nunes, F and Ahmed, G and Baird, J and Lekakis, LJ and Shadman, M and Shafey, M and Reidell, PA and Merryman, RW and Hamadani, M and Ahmed, S}, title = {Outcomes of Hematopoietic Cell Transplantation in Patients with Plasmablastic Lymphoma.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.05.030}, pmid = {42173253}, issn = {2666-6367}, abstract = {Plasmablastic lymphoma (PBL) is a rare and aggressive type of non-Hodgkin lymphoma with biological features that overlap between B-cell lymphoma and plasma cell neoplasm. There is currently no established standard treatment, however intensive combination regimens such as EPOCH are recommended. There is a paucity of data regarding outcomes of hematopoietic cell transplantation (HCT) in this disease. Herein, we analyze data of patients with PBL who received autologous (autoHCT) or allogeneic (alloHCT) transplants using the Center for International Marrow and Transplant Research (CIBMTR) Registry. Between 2015-2024, a total of 186 and 31 patients underwent autoHCT and alloHCT respectively and met eligibility for the study. In the autoHCT group, 3-year OS was 75.5% [95% CI: 68.3%-82.1%] and 3-year PFS was 60.6% [95% CI: 52.4%-68.5%], while 3-year NRM was 6.2% [95% CI: 2.9%-10.6%]. Outcomes of patients who received autoHCT after only 1 line of therapy were significantly better with 3-year PFS at 74.7% [95% CI: 61%-85.7%] compared to 54% [95% CI: 39.9%-67.8%] in patients who received more than one line of therapy prior to transplant (p=0.046). In the alloHCT group, 3-year OS was 37.2% [95% CI: 19%-57.5%], 3-year PFS was 33.3% [95% CI: 16.3%-53.3%], and 3-year GRFS was 20.8% [95% CI: 7.9%-37.8%], while 3-year NRM of 23.3% [95% CI: 8%-43.5%], and 3-year relapse risk of 43.3% [95% CI: 26%-61.6%]. Relapse risk appears to plateau at approximately one year, suggesting the potential for curative outcomes in this disease. Overall, both autoHCT and alloHCT have demonstrated the potential to achieve prolonged survival in this aggressive lymphoma; however, early implementation of autoHCT following first-line therapy was associated with the most favorable outcomes.}, }
@article {pmid42173832, year = {2026}, author = {Sinnott-Armstrong, N and Strausz, S and Urpa, L and Abner, E and Johnson, JP and Valliere, J and Palumaa, T and ,  and ,  and ,  and Palta, P and Dashti, HS and Chang, KM and Vujkovic, M and Daly, M and Pritchard, JK and Saxena, R and Jones, SE and Ollila, HM}, title = {Genetic variants affect diurnal glucose levels throughout the day.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-72432-6}, pmid = {42173832}, issn = {2041-1723}, abstract = {Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. The genetic variants that contribute to the temporal control of glucose levels have not been previously examined. Using genome-wide data from ~420,000 individuals from the UK Biobank and replication in ~100,000 individuals from the Estonian Biobank, ~500,000 from FinnGen, ~160,000 from the VA Million Veteran Program, and ~52,000 from the MGB Biobank, we show that glucose levels are under diurnal genetic control. We discover a robust temporal association of glucose levels at the Melatonin receptor 1B (MTNR1B, rs10830963, P = 1×10[-22]) and a canonical circadian pacemaker gene Cryptochrome 2 (CRY2) loci (rs12419690, P = 1×10[-16]). Furthermore, we show that sleep modulates glucose levels, and the genetic variants have an independent role in diurnal glucose control. Finally, we show that these variants independently modulate risk of type 2 diabetes and that sleep medications including melatonin associate with type 2 diabetes. Our findings, together with earlier genetic and epidemiological evidence, show a clear connection between sleep and metabolism and highlight genetic variation at MTNR1B and CRY2 in the control of diurnal glucose levels.}, }
@article {pmid42176311, year = {2026}, author = {Schwengfelder, J and Peters, N and Wohlfahrt, P and Richter, C}, title = {Dual-energy CT for proton therapy: Impact of advanced slice-wise patient-thickness estimation methods for improved stopping-power prediction.}, journal = {Journal of applied clinical medical physics}, volume = {27}, number = {5}, pages = {e70630}, doi = {10.1002/acm2.70630}, pmid = {42176311}, issn = {1526-9914}, mesh = {Humans ; *Proton Therapy/methods ; *Radiotherapy Planning, Computer-Assisted/methods ; *Tomography, X-Ray Computed/methods ; *Phantoms, Imaging ; Radiotherapy Dosage ; Radiotherapy, Intensity-Modulated/methods ; *Image Processing, Computer-Assisted/methods ; Algorithms ; *Neoplasms/radiotherapy/diagnostic imaging ; }, abstract = {BACKGROUND: The direct prediction of stopping-power ratio (SPR) from dual-energy CT (DECT) has become gold-standard in proton therapy. Remaining uncertainties due to patient-size-specific CT number variations are mitigated by calibration factors based on patient size defined as water-equivalent thickness.<br><br>PURPOSE: To improve SPR prediction, two slice-wise thickness estimation methods (TEM-B1 and -B2) were compared with the previously used one (TEM-A).<br><br>METHODS: TEM-A is using the maximum attenuation projections in x- and y-direction, while TEM-B1 and -B2 incorporate all voxels of the object to better describe non-elliptical geometries. Simplified geometries were used to investigate TEM dependencies on several parameters (e.g., object shape, rotation). TEMs were then applied to DECT scans of cylindrical acrylic phantoms with varying diameters and to patient data. Clinical treatment plans were recalculated on generated TEM-specific SPR datasets, and the impact of different estimated thicknesses on SPR was assessed.<br><br>RESULTS: In contrast to TEM-A, TEM-B1 and -B2 demonstrated robustness to object shape and rotation. Couch attenuation affected all evaluated TEMs with TEM-A being most affected. For patient scans, TEM-B1 and B2 agreed closely but differed from TEM-A, especially in high diameters. In obese patients, this leads to relative proton range deviations up to 0.3% when comparing TEM-B1 and TEM-A. In the sensitivity analysis, TEM-B1 and -B2 maintained SPR uncertainties below &#xb1;3% even for cortical bone.<br><br>CONCLUSIONS: TEM-B1 and -B2 reduced deviations in thickness estimation and increased robustness to object shape, overcoming the limitations of TEM-A and improving SPR prediction accuracy.}, }
@article {pmid42176867, year = {2026}, author = {Thonglert, K and Greer, MD and Schaub, SK and Bowen, SR and Nyflot, MJ and Grassberger, C and Menghini, AM and Kim, EY and Wong, T and Apisarnthanarax, S}, title = {Proton beam therapy for large localized hepatocellular carcinomas in western patients.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2026.05.013}, pmid = {42176867}, issn = {1879-355X}, abstract = {PURPOSE/OBJECTIVES: Optimal management of large, unresectable hepatocellular carcinoma (HCC) remains uncertain. Proton beam therapy (PBT) offers dosimetric advantages for sparing normal liver. Clinical outcomes for these patients in Western populations are limited. This study evaluated clinical outcomes, toxicity, and patterns of failure among Western patients with large localized HCC treated with PBT.<br><br>MATERIALS/METHODS: A retrospective single-institution cohort of patients with HCC tumor &#x2265; 5 cm, ineligible for surgery or other liver-directed therapies, and treated with PBT was analyzed. Patients with uncontrolled extrahepatic metastases, concurrent systemic therapy, or mixed histology were excluded. All patients received 45.0-67.5 Gy(RBE) in 15 fractions. Competing risk and Kaplan-Meier methods were used to assess local failure (LF), overall survival (OS), progression-free survival (PFS), and radiation-induced liver disease (RILD). Univariate Cox regression evaluated predictors of OS, LF, and non-classic radiation-induced liver disease (ncRILD).<br><br>RESULTS: Fifty-one patients met criteria and had the following high-risk features: Barcelona Clinic Liver Cancer (BCLC) stage C (45%), Child-Pugh (CP)-B/C cirrhosis (26%), vascular invasion (39%), and a median tumor size of 9.2 cm. Median follow-up for survivors was 51 months. The 1-, 2-, and 3-year cumulative incidences of LF were 4%, 13% and 13%, respectively. Most failures were out-of-field intrahepatic (50%) or distant (21%); only 4% developed isolated LF. One-, 2- and 3-year OS rates were 65%, 46%, and 30%, respectively. Tumor size independently predicted OS (HR 1.18; p<0.01). ncRILD occurred in 15% and was 6% in CP-A and 43% in CP-B+ patients.<br><br>CONCLUSIONS: Dose-escalated PBT achieves excellent local control with acceptable toxicity for large HCC in Western patients, including tumors > 10 cm. Patients with preserved liver function derive the greatest benefit, whereas those with CP-B cirrhosis have higher hepatotoxicity risks. Out-of-field intrahepatic and distant progression remain dominant failure patterns, highlighting opportunities to integrate systemic therapy with definitive PBT.}, }
@article {pmid42176868, year = {2026}, author = {Petit, C and Phan, J and Ng, SP and Filion, E and Lee, N and Poon, I and Palma, DA and Yom, SS and Lee, J and Heron, DE and Siddiqui, F and Liem, X and Yamazaki, H and Foote, RL and Lo, SS and Caudell, J and Biau, J and Karam, I and Nguyen-Tan, PF and Bahig, H}, title = {Defining the Role of SABR in Head and Neck Cancer: Results from a Multi-institutional Delphi Consensus.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2026.05.019}, pmid = {42176868}, issn = {1879-355X}, abstract = {BACKGROUND: The role of stereotactic ablative radiotherapy (SABR) in head and neck cancer remains uncertain. Historically used mainly for re-irradiation, its application in other clinical scenarios has expanded with recent advances.<br><br>OBJECTIVE: To develop international expert consensus on indications, technical parameters and clinical application of head and neck SABR using a modified Delphi process.<br><br>METHODS: A three-round modified Delphi process was conducted between 07/2021 and 01/2023. Radiation oncologists with experience in head and neck SABR were invited to participate. Round 1 consisted of open-ended questions; Rounds 2 and 3 involved rating agreement with 103 statements addressing indications, contraindications, planning, dose and fractionation, toxicity mitigation, systemic therapy integration and follow-up. Consensus was defined as &#x2265;75 percent agreement and major agreement as 65-74 percent.<br><br>RESULTS: Seventeen of 26 invited experts (65.4%) completed all rounds, with representation from North America, Europe and Asia-Oceania. Of the 103 statements, 56 (54.3%) reached consensus and 12 (11.7%) achieved major agreement. Consensus supported SABR for re-irradiation of small isolated recurrences, unresectable tumors or second primaries in previously irradiated fields and oligometastatic lesions in untreated patients. Use in local palliation and in patients unfit for standard fractionation within a clinical trial also met consensus. No consensus was reached for postoperative SABR, including its use for positive margins or extranodal extension, nor for SABR boost in first-course treatment. Technically, consensus favored VMAT, tight PTV margins of 2-3 mm, multimodality imaging (thin-slice CT, MRI and PET/CT) and daily volumetric imaging with physician verification. CTV expansion was discouraged, and elective nodal irradiation was not recommended. Every-other-day fractionation and dose reduction near critical structures were endorsed. Consensus emphasized counselling on key toxicities and supported imaging at 2-3 months post-SABR. No consensus was reached on systemic therapy integration.<br><br>CONCLUSION: This multi-institutional Delphi study provides expert-derived recommendations reflecting the current state of head and neck SABR practice and identifies priorities for future research.}, }
@article {pmid42168198, year = {2026}, author = {Barnao, KM and Hubbard, AK and Chan, ICC and Zhou, W and Jakubek, YA and Genovese, G and Wong, WSW and Kelly, RL and Young, CD and Brown, DW and Huang, WY and Freedman, ND and Jones, K and Hutchinson, A and Hicks, B and Tran, D and Arnett, D and Barnes, KC and Bis, JC and Boerwinkle, E and Brody, JA and Carson, AP and Chasman, DI and Cho, MH and Desai, P and Doyle, MF and Fornage, M and Guo, X and Heard-Costa, N and Irvin, MR and Johnson, AD and Kardia, SLR and Kooperberg, C and Levy, D and Lewis, JP and Li, Y and Loos, RJF and Mack, TM and Mathias, RA and Mitchell, BD and North, KE and Pankratz, N and Peyser, PA and Preuss, MH and Psaty, BM and Raffield, LM and Redline, S and Rich, SS and Rotter, JI and Silverman, EK and Smith, AV and Smith, JA and Stilp, A and Cao, Y and Scheet, P and Reiner, AP and Bick, AG and Chanock, SJ and Auer, PL and Bolton, KL and Machiela, MJ}, title = {Co-occurring clonal hematopoiesis exhibits strong selection and high leukemia risk.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-73302-x}, pmid = {42168198}, issn = {2041-1723}, abstract = {Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are two types of clonal hematopoiesis (CH) associated with hematological parameters and malignancy risk. Here we show, in genomic data from 546,090 biobank participants, that co-occurring CH (≥2 CH mutations detected) is present in 1.6% of cancer-free individuals and shows strong evidence for selection (up to 804x enrichment). Co-occurrence is more frequent in those with a prior cancer (3.6%), suggesting treatment-induced selection. Acquisition of CHIP usually precedes mCAs with co-occurrences manifesting stronger phenotypic disruptions in telomere attrition and hematologic parameters than component CH events. Individuals with co-occurring CH have pronounced elevations in risk of myeloid and lymphoid malignancies (HRs>40), particularly when CHIP and mCAs overlap genomically. Our findings indicate CH co-occurrences are selected for in the aging population and identify CH clones with notable implications for future malignancy risk.}, }
@article {pmid42169668, year = {2026}, author = {Lewis, FM and Griffith, KA and Ganschow, P and Gadi, VK and Tercyak, KP and Oxford, M and Fukui, J and Derry-Vick, H and Manst, D and Zahlis, EH and Shands, ME}, title = {Promoting Adjustment Among Families Impacted by Non-Curable, Advanced Stage Parental Cancer: A Randomized Controlled Trial of the Enhancing Connections Palliative Care Program.}, journal = {Journal of palliative medicine}, volume = {29}, number = {4}, pages = {443-452}, doi = {10.1177/10966218251408290}, pmid = {42169668}, issn = {1557-7740}, mesh = {Humans ; Female ; Male ; *Palliative Care ; *Neoplasms/psychology ; *Adaptation, Psychological ; Adult ; Middle Aged ; *Parents/psychology/education ; Child ; *Parenting/psychology ; United States ; Adolescent ; }, abstract = {BACKGROUND: Annually hundreds of thousands of children are impacted by a parent with cancer, and an estimated 25% have advanced stage disease. Programs to assist these families lag far behind the need.<br><br>OBJECTIVES: To test the short-term efficacy of a telephone-delivered cancer parenting program for child-rearing parents with non-curable, advanced-stage cancer, the Enhancing Connections Palliative Care (EC-PC) Program.<br><br>DESIGN: Two-group randomized controlled trial with assessment at three months. Experimental group parents received five educational counseling sessions by telephone at two-week intervals; participants in the alternative treatment control group were mailed a booklet about ways to communicate and support children's coping with parental cancer.<br><br>SETTING: The program was delivered centrally from the study center.<br><br>SUBJECTS: Fifty-six child-rearing parents with non-curable advanced cancer were enrolled from medical providers, service agencies, and cancer centers in the United States.<br><br>MEASUREMENTS: Outcomes were parents' and children's depressed mood and anxiety, parenting skills, parenting self-efficacy, and children's behavioral-emotional adjustment.<br><br>RESULTS: Between-group analysis using Mixed Models showed a significant effect that benefitted the experimental group: parenting skills significantly improved compared with controls. Results were clinically significant in both the intent to treat (d = 0.54, p = 0.34) and per-protocol analysis (d = 0.64, p = 0.018). Effect sizes were larger in the experimental group compared with controls. Within-group analysis reflected additional improvements in parents' self-efficacy, depressed mood, and children's behavioral-emotional adjustment.<br><br>CONCLUSIONS: EC-PC is a telephone-delivered intervention that significantly improved parenting skills and offers a scalable approach to support families coping with advanced cancer. Larger trials are warranted.}, }
@article {pmid42169882, year = {2026}, author = {King, G and Sahai, V}, title = {Clearing the bar: adding anti-VEGF therapy to chemoimmunotherapy for biliary tract cancer.}, journal = {Journal of gastrointestinal oncology}, volume = {17}, number = {2}, pages = {116}, pmid = {42169882}, issn = {2078-6891}, }
@article {pmid42094409, year = {2026}, author = {Montague, Z and Grover, RM and Baumgartner, A and Trofimov, A and Hadlock, J and Nourmohammad, A}, title = {T-cell repertoire response in individuals with post-acute sequelae of COVID-19.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42094409}, issn = {2692-8205}, support = {R03 AI175977/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {T-cells are central to SARS-CoV-2 clearance and immunological memory, yet their contribution to the persistence of post-acute sequelae of COVID-19 (PASC) remains poorly understood. The immunological features that distinguish individuals who develop PASC from those who recover fully are unresolved, in part due to the phenotypic heterogeneity of the condition and the likely multiplicity of its underlying mechanisms. Here, we profiled longitudinal bulk TCRβ repertoires from 120 individuals in the INCOV cohort-71 with PASC and 49 without-sampled at two to three time points spanning the acute and post-acute phases of infection. Using robust statistical modeling of repertoire composition and clonal dynamics, we found that global statistics such as V, J gene usage and CDR3 length do not differ between groups, but that locally enriched sequence motifs and differentially dynamic clones reveal distinct T-cell signatures associated with PASC status. Clones contracting following the peak of the acute response were significantly enriched for SARS-CoV-2 specificity in both groups. Interestingly, Influenza A-specific TCRs were disproportionately enriched among contracting clones in PASC[+] repertoires, implicating viral co-infection as a potential contributor to early disease severity and, possibly, PASC pathogenesis. Rare public TCR clones were markedly enriched for SARS-CoV-2 specificity, with PASC[+] individuals harboring a modestly but significantly higher proportion than PASC[-] individuals. Together, we identified over 1,000 candidate TCRβ receptors potentially discriminating PASC[+] from PASC[-] immune responses, opening a path toward the identification of disease-relevant T-cell specificities and the development of T-cell-based immunological biomarkers for long COVID.}, }
@article {pmid42166356, year = {2026}, author = {Creamer, JP and Ray, S and Stewart, S and Gulsuner, S and Saliba, AN and Wu, J and Huang, FY and Leppä, AM and Wang, B and Abbas, HA and Abkowitz, JL and Appelbaum, JS and Kaufmann, SH and Becker, PS and Trumpp, A and Jobanputra, V and Fang, M and Swisher, EM and Doulatov, S}, title = {Chromosome 5q deletion drives evolution of aneuploidy in myeloid neoplasms with complex karyotype.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025031996}, pmid = {42166356}, issn = {1528-0020}, abstract = {Clonal acquisition of multiple chromosomal abnormalities in hematopoietic stem and progenitor cells (HSPCs) is a hallmark of high-risk acute myeloid leukemias with complex karyotype (AML-CK). AML-CK is associated with TP53 mutations and chromosome 5q deletions (del5q); however, the drivers and clonal trajectories of aneuploid evolution in HSPCs remain unknown. We have developed a patient-derived induced pluripotent stem cell (iPSC) model in which preleukemic HSPCs clonally evolve to distinct, highly aneuploid states following transient mitotic inhibition. By tracking chromosome evolution at single cell resolution, we show that TP53-mutant HSPCs with del5q, but not TP53- mutation alone, evolved complex chromosomal changes. Clonal evolution was marked by stepwise acquisition of numerical and structural chromosome changes seen in AML-CK patients, with individual abnormalities conferring fitness advantage. iPSC-derived aneuploid HSPCs and primary AML-CK patient samples exhibited a conserved gene expression signature marked by upregulation of PTEN, cohesins, and anti-apoptotic factor BCL2, indicative of a shared aneuploid cell state in HSPCs. Clinical BCL2 inhibitor venetoclax eradicated BCL2-dependent aneuploid clones, with resistant clones undergoing a lineage switch to upregulate alternative BCL2 factors. In summary, we demonstrate that mutant TP53 and del5q drive chromosome evolution marked by stepwise acquisition of individual abnormalities. Moreover, aneuploid HSPCs exhibit a shared gene expression state which confers unique targetable therapeutic vulnerabilities in AML-CK.}, }
@article {pmid42166746, year = {2026}, author = {Major, A and Ma, E and Masaquel, A and Tsang, M and Di, M and Kaur, S and Pophali, P and Werner, S and Bungay, R and Latrémouille-Viau, D and Guerin, A and Reyes, C and Wu, M and Cassoli, L and Torka, P}, title = {Patient-reported time toxicity with bispecific antibody therapies in relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyag202}, pmid = {42166746}, issn = {1549-490X}, abstract = {BACKGROUND: Several bispecific antibodies (BsAbs), including mosunetuzumab, glofitamab, and epcoritamab, are approved for non-Hodgkin lymphoma (NHL). However, real-world patient-centered data evaluating treatment-related time burden and preferences are lacking.<br><br>METHODS: We conducted an online survey of 120 patients with relapsed/refractory follicular lymphoma (FL; N&#x2009;=&#x2009;60) and diffuse large B-cell lymphoma (DLBCL; N&#x2009;=&#x2009;60) receiving BsAbs. Participants reported all-cause healthcare visits and time spent on cancer-related healthcare resource utilization over the past 30&#x2009;days, including travel, treatment administration, recovery, and impact on daily activities. Participants also evaluated two hypothetical treatment profiles to assess preference for fixed-duration versus treat-to-progression therapy.<br><br>RESULTS: Participants with FL reported a mean of 2.5 healthcare visits in the past 30&#x2009;days, with significantly fewer visits for mosunetuzumab versus epcoritamab (1.7 vs 3.3, respectively; P&#x2009;<&#x2009;0.01). In DLBCL, the mean was 2.6 visits, with fewer visits for glofitamab versus epcoritamab (2.2 vs 3.0; P&#x2009;=&#x2009;0.01). Although epcoritamab visits were shorter in FL, more frequent visits and longer recovery time resulted in significantly lower monthly time burden with mosunetuzumab versus epcoritamab (31.2 vs 61.9&#x2009;hours; P&#x2009;<&#x2009;0.05). Similarly, monthly time burden was also lower with glofitamab than epcoritamab in DLBCL (43.0 vs 87.7&#x2009;hours; P&#x2009;<&#x2009;0.05). Most participants reported little to moderate impact on daily activities. Across treatment groups, &#x2265;92% preferred a hypothetical fixed-duration regimen over a treat-to-progression therapy.<br><br>CONCLUSION: Our real-world data, including novel aspects of time toxicity, demonstrate clinically meaningful differences in time burden associated with BsAbs and emphasize the importance of incorporating patient convenience and preference into shared decision-making in NHL.}, }
@article {pmid42167833, year = {2026}, author = {Blosser, CD and Barbir, EB and Shaikhouni, S and Murakami, N}, title = {Malignancy and Kidney Transplant: Core Curriculum 2026.}, journal = {American journal of kidney diseases : the official journal of the National Kidney Foundation}, volume = {87}, number = {6}, pages = {852-866}, doi = {10.1053/j.ajkd.2026.01.011}, pmid = {42167833}, issn = {1523-6838}, mesh = {Humans ; *Kidney Transplantation/adverse effects ; *Neoplasms/therapy/diagnosis/etiology/epidemiology ; Curriculum ; *Kidney Failure, Chronic/surgery ; Male ; *Postoperative Complications/therapy/diagnosis ; Middle Aged ; Female ; }, abstract = {Kidney transplant recipients are at least twice as likely to develop cancer compared with immunocompetent people. Cancer is now the second leading cause of death in kidney transplant recipients. Candidates and recipients are living longer with chronic conditions and immunosuppression, which increases the risk of cancers, especially skin and kidney cancers, lymphoma, and plasma cell dyscrasias. Given the complexities associated with the care of transplant patients with cancer, along with the advent of novel cancer therapies that include targeted and immunotherapies (ie, immune checkpoint inhibitors and CAR-T cells), there is a growing need for nephrologists to understand and manage the associated risks and optimize diagnosis and treatment. The screening and management of cancer in the setting of kidney transplantation is best accomplished by a multidisciplinary team, involving knowledgeable nephrologists, oncologists, and patients. In this Core Curriculum, we review common pretransplant and posttransplant cancers and management strategies through a series of clinical cases.}, }
@article {pmid42078334, year = {2026}, author = {Alexander, MW and Wood, B and Oh, HS and Bot, VA and Borger, J and Galbiati, F and Walker, KA and Resnick, SM and Ochs-Balcom, HM and Wyss-Coray, T and Kooperberg, C and Reiner, AP and Jacobs, EG and Rabin, JS and Casaletto, KB and Saloner, R}, title = {Plasma proteomics link menopause timing to brain aging and dementia risk.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42078334}, abstract = {Earlier menopause is a risk factor for several age-related diseases, including dementia. The biological pathways linking menopause timing to later-life brain aging are not understood. Leveraging large-scale plasma proteomics in postmenopausal women from the UK Biobank (N=15,012), earlier menopause was associated with upregulation of pro-inflammatory and extracellular matrix degradation pathways, plus accelerated aging across proteomic clocks of organ and cellular aging, including brain and oligodendrocyte aging. Elevated GDF15, a canonical aging marker, was the top protein correlate of earlier menopause. We observed robust replication of menopause timing proteomic shifts in the Women's Health Initiative Long Life Study (N=1,210). In UKB, proteins associated with earlier menopause, including GDF15, exhibited concordant associations with incident dementia risk and brain atrophy, cerebral small vessel disease burden, and white matter microstructural integrity. Collectively, our findings identify proteomic signatures linking ovarian aging to brain aging, providing a framework to inform interventions to reduce dementia risk.}, }
@article {pmid42159492, year = {2026}, author = {Portuguese, AJ and Inocencio, TJ and Quon, P and Harnett, J and Zhou, ZY and Hazra, NC and Xu, MK and Eales, J and Chen, H and Little, M and Ma, Q}, title = {Comparative economic analysis of B-cell maturation antigen-targeted bispecific antibodies in triple-class exposed relapsed/refractory multiple myeloma: linvoseltamab versus teclistamab and elranatamab.}, journal = {Current medical research and opinion}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/03007995.2026.2665022}, pmid = {42159492}, issn = {1473-4877}, abstract = {OBJECTIVE: To evaluate the total cost of care, average monthly treatment cost, and cost per outcome of linvoseltamab versus teclistamab and elranatamab in triple-class-exposed relapsed/refractory multiple myeloma (RRMM) using matching-adjusted indirect comparisons (MAICs).<br><br>METHODS: Total cost per patient and cost per outcome were estimated over 1- and 2-year time horizons from a United States commercial payer perspective. Cost components included drug acquisition, administration, monitoring, adverse events, progression, and death. Dosing schedules were applied per prescribing information, aligning with pivotal trial-based MAIC-adjusted clinical inputs. Costs were sourced from databases and published literature.<br><br>RESULTS: The 1- and 2-year cumulative costs were $387,773 and $488,088 with linvoseltamab versus $500,670 and $639,013 with teclistamab; costs per progression-free (PF) month were $40,904 and $29,036 versus $63,057 and $50,877; costs per overall response were $538,573 and $677,901 versus $794,714 and $1,014,307. The 1- and 2-year cumulative costs were $383,368 and $472,907 with linvoseltamab versus $416,359 and $475,918 with elranatamab, for adjusted median treatment durations of 11.3 versus 5.6&#x2009;months; 1- and 2-year costs per PF month were $43,417 and $29,912 versus $50,529 and $33,304, while costs per overall response were $539,955 and $666,066 versus $682,556 and $780,193.<br><br>CONCLUSION: Linvoseltamab had lower total costs and cost per outcome than teclistamab at 1- and 2-year timepoints. Linvoseltamab had comparable total costs to elranatamab despite longer treatment duration, and consistently lower costs per outcome. Within this exploratory MAIC model, linvoseltamab was associated with lower economic burden in heavily pretreated RRMM. These results should be interpreted considering study assumptions and limitations.}, }
@article {pmid42160714, year = {2026}, author = {Banerjee, R and Cheung, MC and Derman, B and Messersmith, H and Al Hadidi, S and Bhella, S and Chmielewski, C and Ebraheem, MS and Kennedy, CT and Kumar, S and Langerak, A and Lipe, B and Mian, H and Riva, E and Seth, R and Subramanian, L and Usmani, SZ and Wildes, TM and Zanwar, S and Zhuo, Y and Hicks, LK}, title = {Treatment of Multiple Myeloma: ASCO Living Guideline, Version 2026.1.1.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {101200JCO2601139}, doi = {10.1200/JCO-26-01139}, pmid = {42160714}, issn = {1527-7755}, abstract = {Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website.}, }
@article {pmid42160761, year = {2026}, author = {Aljawai, YM and Nawas, MT and McCurdy, SR and Kanakry, CG and Kanakry, JA and Rimando, JC and Saultz, JN and Al-Juhaishi, T and Lazaryan, A and Milano, F and Mehta, RS}, title = {Absolute Risk Trade-offs of Donor Age, Sex, and Graft Source in PTCy-Based Transplantation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026020359}, pmid = {42160761}, issn = {2473-9537}, }
@article {pmid42160762, year = {2026}, author = {Iovino, L and Shadman, M and Milano, F and Gopal, AK}, title = {"Immunologic Dream Team": BiTEs peri-allotransplant to redirect donor lymphocytes towards GVL.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026020530}, pmid = {42160762}, issn = {2473-9537}, abstract = {Bispecific T cell engagers (BiTEs) provide high rates of responses in patients with relapsed and refractory B cell lymphomas and multiple myeloma otherwise resistant to other therapies, but unfortunately the duration of response to these treatments is limited in time. Allogeneic stem cell transplantation is a potentially curative approach for those disorders, although its indication is limited to patients who achieve remission. While no established strategies to improve the "graft versus tumor effect" are available, relapses still account for the majority of the post-transplant failures. Herein, we report the first case in literature of a successful treatment with glofitamab, a CD20X2/CD3 BiTE, in a post-transplant relapse of mantle cell lymphoma with central nervous disease involvement. We propose the combination of BiTEs and allogeneic transplant as an integrated and sequential immunological approach to be tested in clinical trials.}, }
@article {pmid42161461, year = {2026}, author = {Radich, J}, title = {Portrait of a Pioneer: Fred Appelbaum.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {5}, pages = {509-512}, doi = {10.1016/j.jtct.2026.04.015}, pmid = {42161461}, issn = {2666-6367}, }
@article {pmid42161522, year = {2026}, author = {Yamazaki, T and Kumagai, Y and Maeda, K and Aizawa, T and Maekawa, K and Enomoto, A and Ishihara, S and Haga, H}, title = {CCL5 enhances invasion of squamous cell carcinoma via syndecan-1-dependent ERK signaling.}, journal = {Cell structure and function}, volume = {}, number = {}, pages = {}, doi = {10.1247/csf.26030}, pmid = {42161522}, issn = {1347-3700}, abstract = {Cancer cells form clusters and invade the surrounding stroma. This phenomenon is associated with metastasis and poor prognosis in patients with cancer. Therefore, prevention of invasion may improve cancer therapy. A previous study suggested that the C-C motif chemokine ligand 5 (CCL5) is more highly expressed in the highly invasive subclone than in the less invasive subclone derived from A431 cell line, a model of human skin squamous cell carcinoma. However, the role of CCL5 and the mechanisms through which it regulates invasion in A431 cell clusters remain unclear. Herein, we investigated the molecular mechanisms underlying CCL5-induced invasion in A431 cell clusters. Knockdown of CCL5 suppressed invasion on A431 cell clusters, whereas treatment with recombinant CCL5 promoted invasion of them. Mechanistically, CCL5 increased the phosphorylation levels of Src and ERK, leading to the invasion of A431 cell clusters. Furthermore, the knockdown of syndecan-1 (SDC1), a transmembrane protein known to interact to CCL5, suppressed CCL5-induced invasion in A431 cell clusters. Consistently, knockdown of SDC1 reduced the level of phosphorylated ERK. These findings demonstrate that the CCL5 promotes the invasion of A431 cells clusters through SDC1-dependent ERK signaling and Src phosphorylation.Key words: Invasion, CCL5, syndecan-1, ERK signaling, Src.}, }
@article {pmid42165780, year = {2026}, author = {Flores, MN and Zhao, Y and Li, L and Spacht, WA and Kooperberg, C and Manson, JE and Eaton, CB and Reiner, AP and Honigberg, MC and Lau, ES}, title = {Protein Biomarkers of Infertility Implicate Inflammation and Cell Growth/Remodeling Pathways.}, journal = {JACC. Advances}, volume = {}, number = {}, pages = {102788}, doi = {10.1016/j.jacadv.2026.102788}, pmid = {42165780}, issn = {2772-963X}, }
@article {pmid42166213, year = {2026}, author = {Heffner, JL and Baker, K and Fan, X and Kelly, MM and Orzechowski, M and Ruiz, RA and Nfn, S and Serfozo, E and Stimatze, T and Karekla, M}, title = {Avatar-led Digital Health Intervention for Sexual and Gender Minority Young Adult Smoking Cessation: Randomized Controlled Pilot Trial.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntag113}, pmid = {42166213}, issn = {1469-994X}, abstract = {INTRODUCTION: Accessible, culturally-tailored interventions are needed to address the high prevalence of cigarette smoking and the challenges to cessation experienced by sexual and gender minority (SGM) young adults. This study evaluated, in a randomized, controlled pilot trial, the acceptability, preliminary cessation-related outcomes, and impact on theory-based change processes of the SGM-tailored, Acceptance and Commitment Therapy (ACT)-based Empowered, Queer, Quitting, and Living (EQQUAL) digital program relative to the National Cancer Institute's Smokefree.gov program.<br><br>METHODS: Participants were SGM young adults, aged 18-30, who smoked at least weekly. Participants were randomized 1:1 to either EQQUAL or Smokefree.gov, both of which included a web app and text messaging. Outcomes were assessed at 3 months post-randomization, and smoking abstinence was biochemically-verified.<br><br>RESULTS: The sample included 124 participants (n=63 in EQQUAL, n=61 in Smokefree.gov). On the primary acceptability outcomes, overall satisfaction was descriptively higher in the EQQUAL arm (68.8% vs. 60.0%; OR=1.17, 95% CI=0.50-2.78), and EQQUAL usability ratings exceeded the acceptable benchmark score of 68. The average number of EQQUAL digital sessions completed was 1.4 (of 6). On the primary cessation outcomes, biochemically-verified 7-day point prevalence abstinence was higher in EQQUAL than Smokefree.gov (11.1% vs. 4.9%; OR=1.89, 95% CI=0.45-9.66). Change in readiness to quit and cigarettes per day were similar between arms, as were outcomes of theory-based change processes.<br><br>CONCLUSIONS: EQQUAL demonstrated potential benefits over Smokefree.gov on acceptability and cessation, albeit with a lack of robust effect on theory-based change processes. Increased engagement with the web-based portion of the program may be needed to improve outcomes.}, }
@article {pmid42151133, year = {2026}, author = {Hanna, S and Salveson, PJ and Wicky, B and Kennedy, MA and Hicks, DR and Moller, C and Cheng, S and Li, X and Abedi, M and Coventry, B and Said, MY and Bera, AK and Kang, A and Stoddard, BL and Baker, D}, title = {De novo design of a macrocycle-induced dimerization system for cellular control.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71345-8}, pmid = {42151133}, issn = {2041-1723}, support = {INV-043758/GATES/Gates Foundation/United States ; INV-043758/GATES/Gates Foundation/United States ; }, abstract = {Investigating and manipulating cellular events requires precise control of protein function. To enable control over cellular processes, we set out to design a chemically induced dimerization (CID) system consisting of a de novo-designed ligand and protein pair. Here, we describe the design of a C2 symmetric membrane-permeable macrocyclic peptide and a cognate protein homodimer which binds the macrocycle through a large interface with both chains. The designed homodimer binds the macrocycle with a KD of 36 nM, and the x-ray crystal structure of the protein homodimer-macrocycle complex is very close to the computational design model, with the C2 axis of the macrocycle aligned with the homodimer C2 axis. Transcriptional and split luciferase assays in mammalian cells demonstrate conditional control over both a reporter gene expression and luciferase reconstitution.}, }
@article {pmid42152147, year = {2026}, author = {He, Z and Konigshofer, Y and Garlick, R and Ramprakash, J and Ramesh, M and Hall, E and Corner, A and Clarissa, M and Wright, JH and Cannon, VK and Yu, M and Grady, WM and Yeung, CCS and Heimer, Z and Wang, Z and Zou, S and Jia, S and Liu, F and Bonora, G and Bomsztyk, K and Mar, D and Cole, KD and He, HJ}, title = {Development, characterization, and inter-laboratory validation of methylated human cell free DNA candidate reference materials.}, journal = {Clinical epigenetics}, volume = {}, number = {}, pages = {}, doi = {10.1186/s13148-026-02156-3}, pmid = {42152147}, issn = {1868-7083}, support = {ACN20006/CA/NCI NIH HHS/United States ; R50CA233042/CA/NCI NIH HHS/United States ; R50CA233042/CA/NCI NIH HHS/United States ; ACN20006/CA/NCI NIH HHS/United States ; ACN20006/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Aberrant DNA methylation biomarkers have demonstrated potential for early cancer detection, multicancer detection, and determining the tissue of origin. Due to their stability, frequency, and accessibility in bodily fluids, circulating cell-free DNA (cfDNA) methylation is a promising biomarker in liquid biopsy. A reliable and quantifiable analysis of cfDNA methylation status is critical to its application. However, there are current challenges and a lack of consensus on measurement methods. To address this, we developed two candidate methylated cfDNA reference materials (RMs).<br><br>METHODS: The National Institute of Standards and Technology (NIST) RM consists of five components, formulated by mixing in vitro methylated cfDNA simulant at fractions of 0%, 5%, 25%, 50%, and 100% with native-state cfDNA simulant derived from the GM24385 cell line. The LGC Clinical Diagnostics (LGC) RM consists of two components: non-methylated cfDNA simulant derived from GM24385 genomic DNA and whole genome amplification and methylated cfDNA produced by in vitro methylation of amplified material. The candidate RMs were characterized, and the methylation status of three targets was confirmed by droplet digital PCR (ddPCR) assays. To test the utility of these RMs, six laboratories participated in an interlaboratory study, each using their own lab-developed assays and methods, which included methylation-specific qPCR, nanoplate digital PCR (dPCR), ddPCR, matrix methylated DNA immunoprecipitation-based assays, and whole-genome bisulfite sequencing.<br><br>RESULTS: The interlaboratory study results showed that the designed percentage of methylation was well correlated with the observed values across all participating labs, and good reproducibility was found for each individual method. However, slightly different methylation proportions associated with assay-specific biases were observed.<br><br>CONCLUSIONS: This study clearly demonstrates the value of candidate RMs as standards for evaluating assay performance, as well as for increasing confidence in reporting cfDNA methylation status for clinical applications.}, }
@article {pmid42155643, year = {2026}, author = {DeFilipp, Z and Alousi, A and Levine, JE and Holtan, SG and Abedin, S and Gooptu, M and Harris, AC and Magenau, JM and Pusic, I and Schroeder, MA and Chen, YB and MacMillan, ML and Malki, MMA and Hamadani, M and Carpenter, PA and Hamilton, BK}, title = {Clinical Management of Acute Graft-Versus-Host Disease: An Evidence-Based Review from the ASTCT Committee on Practice Guidelines.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.04.053}, pmid = {42155643}, issn = {2666-6367}, abstract = {Acute graft-versus-host disease (GVHD) is a well-established complication of allogeneic hematopoietic cell transplantation. Although the incidence of severe acute GVHD is decreasing with advances in prophylactic approaches, many clinical questions remain. Herein, acute GVHD diagnosis, grading, and treatment are reviewed and critically evaluated. Specific criteria were used for searching the published literature, grading the quality and strength of evidence, and grading the strength of recommendations. A panel of experts developed consensus recommendations for the clinical management of acute GVHD, providing guidance on behalf of the American Society for Transplantation and Cellular Therapy. Key recommendations include: 1) The MAGIC grading scheme is supported as the consensus grading scheme for acute GVHD; 2) Clinical tools and non-invasive blood-based biomarkers can aid in risk stratification of patients with newly diagnosed acute GVHD; 3) Corticosteroids remain the recommended first-line systemic therapy for acute GVHD, despite innovative approaches to improve front-line treatment; 4) Ruxolitinib is supported as the second-line therapy standard, while acknowledging remestemcel-L-rknd is a recognized alternative standard for pediatric patients. Finally, no consensus treatment exists for third-line therapy. Ongoing and future studies will seek to improve upon the current treatment paradigm through risk-adapted strategies. Innovative investigative approaches will be needed to address the unmet needs in acute GVHD.}, }
@article {pmid42155724, year = {2026}, author = {Dai, J and Qi, Q and Nianogo, R and Wong, ND and Moin, T and McClain, AC and Alver, SK and Cordero, C and Mossavar-Rahmani, Y and Daviglus, ML and Sotres-Alvarez, D and Chen, L}, title = {Meal Timing in Relation to Glycemic Control and Cardiovascular Disease Risk Factors in Adults with Diabetes: A Prospective Cohort Study.}, journal = {Clinical nutrition ESPEN}, volume = {}, number = {}, pages = {103345}, doi = {10.1016/j.clnesp.2026.103345}, pmid = {42155724}, issn = {2405-4577}, abstract = {BACKGROUND AND AIMS: The favorable meal timing for glycemic control in individuals with diabetes remains unclear. The primary aim of this study was to evaluate the prospective association of meal timing with hemoglobin A1C (HbA1c) in individuals with diabetes. The secondary aim was to evaluate associations of meal timing with other cardiovascular disease (CVD) risk factors, including triglycerides, low-density and high-density lipoprotein cholesterol (LDL-C, HDL-C), and systolic and diastolic blood pressure (SBP, DBP).<br><br>METHODS: This cohort study included participants with diabetes at baseline (2008-2011) and attending visit 2 examination (2014-2017). Baseline dietary intakes were assessed using two 24-hour dietary recalls. Linear regression was performed to estimate prospective associations of energy intake (EI) and glycemic load (GL) at each meal timing with HbA1c and other CVD risk factors at visit 2.<br><br>RESULTS: This study included 1,740 participants (mean age: 52.8 years; 59.2% female). Meal timings were associated with HbA1c and CVD risk factors, but in different directions and varied by sex and antidiabetic medication use. For HbA1c, there were generally inverse associations with morning meals, particular early-morning meal (6:00-8:59 AM) in males [EI: percent change, -2.86 (95% CI, -5.48 to -0.17)] and late-morning meal (9:00-11:59 AM) in individuals without antidiabetic medication use [EI: -2.83 (-5.49 to -0.09); GL: -3.31 (-6.46 to -0.05)]. For triglyceride, inverse associations were found for early-morning meals, whereas positive associations were found for afternoon meals (12:00-5:59 PM) in females and individuals without antidiabetic medication use. For LDL-C, positive associations were found for evening meals (6:00-11:59 PM) in individuals without antidiabetic medication use. There were overall positive associations of afternoon meal with SBP and DBP.<br><br>CONCLUSION: A greater proportion of daily energy intake or glycemic load consumed during morning meals was associated with lower HbA1c levels and more favorable cardiovascular risk factor profiles in individuals with diabetes. Medication use and sex should be considered when discussing potential meal-timing recommendations.}, }
@article {pmid42157490, year = {2026}, author = {Ockerman, F and Chen, BD and Sun, Q and Kharitonova, EV and Chen, C and Zhou, LY and Loos, RJF and Kooperberg, C and Peters, U and Haessler, J and Reiner, AP and Jung, SY and Manson, JE and Nassir, R and North, KE and Buyske, S and Haiman, CA and Conti, DV and Wilkens, LR and Lange, EM and Cox, NJ and Cao, H and Raffield, LM and Li, Y and Tao, R}, title = {An Efficient Lasso Framework for Admixture-Aware Polygenic Scores.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100628}, doi = {10.1016/j.xhgg.2026.100628}, pmid = {42157490}, issn = {2666-2477}, abstract = {Polygenic scores (PGSs) have promising clinical applications for risk stratification, disease screening, and personalized medicine. However, most PGSs are trained on predominantly European ancestry cohorts and have limited portability to external populations. While cross-population PGSs have demonstrated greater generalizability than single-ancestry PGSs, they fail to properly account for individuals with recent admixture between continental ancestry groups. GAUDI, a recently proposed PGS method, overcomes this gap by leveraging local ancestry to estimate ancestry-specific effects, penalizing but allowing ancestry-differential effects. However, the modified fused LASSO approach used by GAUDI is computationally expensive and does not readily accommodate more than two-way admixture. To address these limitations, we introduce HAUDI, an efficient LASSO framework for admixed PGS construction. HAUDI reparametrizes the GAUDI model as a standard LASSO problem, allowing for extension to multi-way admixture settings and far superior computational speed than GAUDI. In extensive simulations, HAUDI compares favorably to GAUDI while dramatically reducing computation time. In real data applications, HAUDI uniformly outperforms GAUDI across 18 clinical phenotypes, including total triglycerides (TG), C-reactive protein (CRP), and mean corpuscular hemoglobin concentration (MCHC), and shows substantial benefits over ancestry-agnostic PGSs for white blood cell count (WBC) and chronic kidney disease (CKD). It is also substantially faster and more accurate than the recently proposed SDPR_admix method.}, }
@article {pmid42157919, year = {2026}, author = {Yousefiasl, M and Abadifard, E and Khanmohammadi, S and Hashemi, M and Habibzadeh, A and Meymanatabadi, Z and Esmailsorkh, F and Momtazi, H}, title = {Association of Body Roundness Index, Lipid Accumulation Product, and Triglyceride-Glucose Index With Psoriasis: A Systematic Review of Observational Studies.}, journal = {Health science reports}, volume = {9}, number = {}, pages = {e72542}, pmid = {42157919}, issn = {2398-8835}, abstract = {BACKGROUND AND AIMS: Lipid dysregulation plays a crucial role in psoriasis pathogenesis and its cardiometabolic comorbidities. Novel anthropometric indices such as Body Roundness Index (BRI), Lipid Accumulation Product (LAP), and Triglyceride-Glucose (TyG) index have been proposed to better reflect underlying metabolic dysfunction and may be associated with psoriasis risk, severity, and related complications. This systematic review evaluates the current evidence on the associations of BRI, LAP, and the TyG index with psoriasis and related clinical outcomes.<br><br>METHODS: A comprehensive literature search was conducted from inception up to September 2025. Observational studies examining the relationship between BRI, LAP, or TyG index and psoriasis or its clinical outcomes were included. Data synthesis comprised qualitative and descriptive statistical analyses.<br><br>RESULTS: Fifteen studies comprising 65,130 participants from diverse countries met the inclusion criteria. Higher LAP was consistently associated with increased psoriasis risk but showed weak or no correlation with disease severity (PASI). All BRI studies, primarily using US National Health and Nutrition Examination Survey data, demonstrated a positive association between BRI and psoriasis risk, with modest predictive ability (AUC 0.56-0.58). TyG index was linked to adverse metabolic and cardiovascular outcomes, fatty liver disease, and all-cause mortality in psoriasis patients, although correlations with PASI were generally non-significant.<br><br>CONCLUSIONS: BRI, LAP, and TyG index are consistently associated with psoriasis risk and related metabolic and cardiovascular complications, highlighting their potential utility for early risk stratification and holistic management of psoriasis patients. Further prospective studies are warranted to clarify their predictive value for disease severity and long-term outcomes.}, }
@article {pmid42158038, year = {2026}, author = {Kung, E and Deo, R and Choudhary, MC and Chew, KW and Evering, TH and Ignacio, RB and Jagannathan, P and Flynn, JP and Regan, J and Moser, C and Giganti, MJ and Hughes, MD and Ritz, J and Javan, AC and Greninger, AL and Singh, U and Fischer, W and Daar, ES and Wohl, DA and Eron, JJ and Currier, JS and Coombs, RW and Smith, DM and Li, JZ and , }, title = {Impact of Sex on Viral Shedding and Symptom Severity During Acute COVID-19.}, journal = {Pathogens &amp; immunity}, volume = {11}, number = {1}, pages = {142-153}, pmid = {42158038}, issn = {2469-2964}, abstract = {BACKGROUND: To evaluate the impact of sex on acute SARS-CoV-2 infection, 668 participants from the ACTIV-2/A5401 study were followed over a 28-day period.<br><br>METHODS: A primary analysis was performed on 469 participants with quantifiable viral loads at baseline.<br><br>RESULTS: Male and female participants had comparable nasal SARS-CoV-2 RNA levels at study entry and throughout follow-up. However, sex-specific differences in viral shedding emerged when stratified by symptom duration. In the first 3 days after symptom onset, female participants exhibited higher nasal SARS-CoV-2 RNA levels than males, but lower viral RNA levels thereafter. The higher viral RNA levels in females during the earliest phase of acute COVID-19 were observed even after adjusting for age, race, and region of enrollment. Female participants also tended to have higher symptom scores across days since symptom onset, but no significant correlation was observed between nasal SARS-CoV-2 RNA levels and symptom score regardless of sex.<br><br>CONCLUSION: These findings highlight the impact of sex on both viral shedding and symptom dynamics and underscore the importance of considering time since symptom onset when evaluating antiviral therapies for respiratory viruses in clinical trials.}, }
@article {pmid42149699, year = {2026}, author = {Zahed, H and Feng, X and Alcala, K and Smith-Byrne, K and Moez, E and Guida, F and Albanes, D and Weinstein, SJ and Arslan, AA and Cai, Q and Shu, XO and Zheng, W and Chen, C and Triplette, M and Tinker, LF and Langhammer, A and Nøst, TH and Hveem, K and Milne, RL and Bassett, JK and Sheikh, M and Malekzadeh, R and Wang, Y and Patel, AV and Visvanathan, K and Yuan, JM and Wang, R and Koh, WP and Sesso, HD and Zhang, X and Johansson, MB and Amos, C and Hung, RJ and Muller, D and Robbins, HA and Johansson, M}, title = {Biomarker-Based Eligibility for Lung Cancer Screening: Validation of the Protein-Based INTEGRAL-Risk Model.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2026.8044}, pmid = {42149699}, issn = {1538-3598}, abstract = {IMPORTANCE: Screening by low-dose computed tomography can reduce lung cancer mortality among high-risk individuals, but many lung cancers occur among individuals with a smoking history who are not eligible for screening.<br><br>OBJECTIVE: To develop and validate the protein-based Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL)-Risk model in individuals with a smoking history from the general population.<br><br>Cohorts in the Lung Cancer Cohort Consortium recruited research participants in the US, Europe, Asia, and Australia between 1985 and 2009, who were followed up for lung cancer and other health outcomes until 2021. Fourteen case cohorts of 3695 participants with a smoking history within the Lung Cancer Cohort Consortium, including 2305 randomly sampled participants and 1390 patients diagnosed with lung cancer within 3 years after blood sample collection, were designed. Plasma or serum samples from each participant were assayed using the INTEGRAL protein panel in 2022. The INTEGRAL-Risk model was trained using 7 predefined case cohorts (training set; n&#x2009;=&#x2009;1951) to estimate absolute risk of being diagnosed with lung cancer based on age, smoking history, and 13 proteins. The validity of the INTEGRAL-Risk model was assessed in 7 independent case cohorts (testing set; n&#x2009;=&#x2009;1744) at 1, 2, and 3 years after blood collection.<br><br>EXPOSURE: Absolute risk estimates from the protein-based INTEGRAL-Risk model.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was the validity of the INTEGRAL-Risk model in the testing set with respect to discrimination (area under the curve [AUC]) and calibration (ratio of expected-to-observed cases [E/O]).<br><br>RESULTS: A total of 3695 participants were included, with 1951 participants (including 807 with lung cancer) in the training set and 1744 participants (including 583 with lung cancer) in the testing set. In the combined 14 training and testing sets, after application of statistical weights, 323 570 participants were represented (185 016 [57%] female; median [IQR] age, 60 [51-67] years). In the independent testing set, discrimination of the INTEGRAL-Risk model was highest at 1 year of follow-up and exceeded that of the questionnaire-based PLCOm2012 (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) model (INTEGRAL-Risk AUC of 0.88 [95% CI, 0.85-0.91] vs PLCOm2012 AUC of 0.79 [95% CI, 0.75-0.83]; P value for difference <.001). Using a risk threshold to achieve the same specificity as US Preventive Services Task Force (USPSTF) 2021 criteria, the INTEGRAL-Risk model captured 85% of lung cancer cases compared with 63% by USPSTF 2021 and 70% by PLCOm2012. Discrimination of the INTEGRAL-Risk model decreased with longer prediction horizons, with a 2-year AUC of 0.84 (95% CI, 0.81-0.86) and 3-year AUC of 0.81 (95% CI, 0.79-0.83). The model was well calibrated (E/O over 3 years, 0.87 [95% CI, 0.69-1.14]).<br><br>CONCLUSIONS AND RELEVANCE: Compared with questionnaire-based approaches, the protein-based INTEGRAL-Risk model improved short-term prediction of lung cancer in people with a smoking history. This model has potential to improve selection of high-risk individuals who are most likely to benefit from lung cancer screening.}, }
@article {pmid42150149, year = {2026}, author = {Gogebakan, KC and Lange, J and Gulati, R and Dubard-Gault, ME and Drescher, CW and Malone, KE and Etzioni, R}, title = {Impact of Multicancer Screening on Late-Stage Cancer at Diagnosis in Breast Cancer Survivors: A Modeling Study.}, journal = {JCO precision oncology}, volume = {10}, number = {5}, pages = {e2600305}, doi = {10.1200/PO-26-00305}, pmid = {42150149}, issn = {2473-4284}, mesh = {Humans ; Female ; Middle Aged ; *Cancer Survivors ; *Breast Neoplasms/diagnosis ; Aged ; *Early Detection of Cancer/methods ; Neoplasms, Second Primary/diagnosis ; Neoplasm Staging ; }, abstract = {PURPOSE: Breast cancer survivors are at elevated risk of multiple new primary cancers compared with the general population. The impact of multicancer screening on late-stage cancer diagnosis is under clinical investigation in average-risk individuals, but it is unclear whether findings will generalize to breast cancer survivors.<br><br>METHODS: We adapted an existing multicancer natural history model for the average-risk US population to reflect increased risks of second primary cancers and all-cause mortality among female breast cancer survivors. We modeled 16 cancer types other than breast cancer and specified a range of natural history parameters and screening test sensitivities to reflect uncertainty in disease onset, progression, and detectability of target cancers. We evaluated annual multicancer screening over a lifetime horizon in simulated hormone receptor-positive (HR-positive) and hormone receptor-negative (HR-negative) cohorts of survivors age 50-74 years and in age-matched women without prior cancer (average-risk women). Outcomes included absolute and relative reductions in late-stage diagnoses compared with no multicancer screening.<br><br>RESULTS: Across a range of natural histories and test sensitivities, multicancer screening was projected to reduce 35-99 late-stage diagnoses per 100,000 person-years (PY; 9%-25% reduction) among HR-positive survivors and 39-111 per 100,000 PY (9%-26% reduction) among HR-negative survivors, compared with 30-84 per 100,000 PY (7%-20% reduction) among average-risk women. Lung cancer contributed most to the reduction in late-stage diagnoses (34%-38%), followed by colorectal cancer (14%-16%) in all populations. Ovarian cancer accounted for greater reduction in HR-negative than HR-positive survivors (10%-11% v 6%).<br><br>CONCLUSION: Model-based projections suggest that multicancer screening may reduce late-stage diagnoses among breast cancer survivors more than among average-risk women. This suggests a potential role in long-term surveillance for second primary cancers in this high-risk population.}, }
@article {pmid42150685, year = {2026}, author = {Wechkin, HA and Loggers, ET}, title = {Voluntarily Stopping Eating and Drinking (VSED) with Hospice Support in America: A Case Series.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2026.05.006}, pmid = {42150685}, issn = {1873-6513}, abstract = {CONTEXT: Despite increasing public awareness of voluntary stopping of eating and drinking (VSED), there are no descriptions of the clinical course of US patients who pursue VSED, with or without hospice support.<br><br>OBJECTIVES: We report on the socio-demographics and clinical experiences of US patients pursuing VSED with hospice support.<br><br>METHODS: We employed retrospective chart review methodology to review a consecutive case series of 20 patients who requested and received hospice support for VSED.<br><br>RESULTS: Average age was 80 years (standard deviation [SD] 14, range 50-95), 55% female, 85% white, 60% divorced or widowed, 100% spoke English as their primary language, 75% were living in a private residence, and 55% had a daughter as their informal caregiver. 100% of patients who started VSED with hospice support died, an average of 9.6 days (SD 4.1, median 9.0, range 4-23). Eleven (55%) had documentation of thirst, 3 (15%) had documentation of hunger, 19 (95%) had documentation of taking pain medication at least once and 17 (85%) had documentation of anxiety, agitation and/or delirium at least once, for which they received lorazepam (88%), haloperidol (47%) and/or quetiapine (29%). No patients required hospitalization or sedation.<br><br>CONCLUSIONS: While this study has significant limitations, VSED was completed by all who initiated the process and death generally occurred within 10 days. Therefore, those initiating VSED should be considered eligible for hospice care, with care initiated quickly. Symptoms during VSED were typical of hospice patients and can be managed using common hospice techniques and medications.}, }
@article {pmid42079111, year = {2026}, author = {Miao, Z and Qu, Y and Huang, S and Laux, L and Peters, S and Aristel, A and Zhang, Z and Niedernhofer, L and McMahon, A and Kim, J and Zhang, NR}, title = {Dissecting the coordinated progression of cell states in spatial transcriptomics with CoPro.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42079111}, issn = {2692-8205}, abstract = {Spatial transcriptomics enables the study of how cells coordinate their molecular states within tissue, providing insight into both normal function and disease processes. A key challenge is to identify gene expression programs that vary continuously across space and are coordinated between cell types. We present CoPro, a computational framework for detecting the spatially coordinated progression of cellular states. CoPro can operate in both supervised and unsupervised modes to identify gene programs that co-vary within or between cell types, and to disentangle multiple overlapping spatial patterns. CoPro can be applied to single-cell-level spatial transcriptomics datasets, including MERFISH, SeqFISH+, Xenium, and histology-imputed transcriptomic data. We demonstrate the utility of CoPro with data collected from colon, brain, liver, and kidney tissues. In the colon, CoPro separates epithelial differentiation along the crypt axis from spatially localized inflammatory signals. In the aging liver, it identifies multiple aging-associated cellular programs superimposed on anatomical zonation. In the brain, the flexible kernel design enables the decoupling of the gene expression gradient along the dorsal-ventral and medial-lateral axes. In the kidney, CoPro identifies tubule-vasculature coordination that is essential in nephron function. These results demonstrate CoPro's utility for analyzing spatial coordination of gene expression in complex tissues and disentangling overlapping biological processes, such as anatomical organization and disease-associated variation.}, }
@article {pmid42079119, year = {2026}, author = {Hanna, S and Salveson, PJ and Wicky, B and Kennedy, MA and Hicks, DR and Moller, C and Cheng, S and Li, X and Abedi, M and Coventry, B and Said, MY and Bera, AK and Kang, A and Stoddard, BL and Baker, D}, title = {De novo design of a macrocycle induced dimerization system for cellular control.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42079119}, issn = {2692-8205}, abstract = {Investigating and manipulating cellular events requires precise control of protein function. To enable control over cellular processes, we set out to design a chemically induced dimerization (CID) system consisting of a de novo designed ligand and protein pair. Here we describe the design of a C2 symmetric membrane permeable macrocyclic peptide and a cognate protein homodimer which binds the macrocycle through a large interface with both chains. The designed homodimer binds the macrocycle with a K D of 36 nM, and the x-ray crystal structure of the protein homodimer-macrocycle complex is very close to the computational design model, with the C2 axis of the macrocycle aligned with the homodimer C2 axis. Transcriptional and split luciferase assays in mammalian cells demonstrates conditional control over both a reporter gene expression and luciferase reconstitution.}, }
@article {pmid42079185, year = {2026}, author = {Tanis, S and Lixandrão, M and Ivich, A and Grieshober, L and Lawson-Michod, KA and Collin, LJ and Peres, LC and Salas, LA and Marks, JR and Bitler, BG and Greene, CS and Schildkraut, JM and Doherty, JA and Davidson, NR}, title = {Transcriptomic subtypes in high-grade serous ovarian cancer are driven by tumor cellular composition.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42079185}, issn = {2692-8205}, abstract = {High-grade serous ovarian carcinoma (HGSC) is an aggressive malignancy for which bulk transcriptomic subtypes are used to stratify tumors, interpret biology, and guide biomarker development. The four TCGA-derived subtypes, mesenchymal (C1.MES), immunoreactive (C2.IMM), proliferative (C5.PRO), and differentiated (C4.DIF), are consistently observed across cohorts. However, despite their prominence, these subtypes have not translated into therapeutic utility, and their biological basis remains unresolved. Here, we show that HGSC transcriptomic subtypes are largely determined by tumor cellular composition rather than intrinsic malignant transcriptional programs. By integrating controlled single-cell-derived pseudobulk simulations with deconvolution-based analysis of 1,834 primary HGSC tumors across RNA-seq and microarray cohorts, we demonstrate that subtype probabilities align along a composition-driven axis of stromal and immune variation. Cellular composition alone predicted subtype labels with high accuracy (ROC-AUC = 0.81-0.95) and explained a substantial fraction of subtype-associated transcriptomic variation, with the mesenchymal (C1.MES) subtype representing the most robust and reproducible example of composition-driven signal. Although a secondary, composition-independent expression signal is detectable, it does not define the dominant structure of subtype classification. These findings redefine HGSC transcriptomic subtypes as features of the tumor ecosystem rather than discrete malignant states. This reinterpretation has immediate implications for studies that use subtype labels to infer tumor-intrinsic biology and provides a generalizable framework for separating composition-driven and intrinsic signals in bulk tumor data.}, }
@article {pmid42142354, year = {2026}, author = {Cheng, GS and Bergeron, A}, title = {Reply to Couderc et al.: Non-invasive management of bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation.}, journal = {American journal of respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajrccm/aamag189}, pmid = {42142354}, issn = {1535-4970}, }
@article {pmid42143731, year = {2026}, author = {Sood, N and Sullivan, JK and Hampshire, K and Fox, J and Kuczmarski, T and Ndovu, A and Sirias, T and Armand, W and Furie, G and Laney, E and Philipsborn, R and Whelan, H and Wheat, S and Erny, B and Sorensen, C}, title = {The Climate Resources for Health Education Initiative: Accelerating Professional Education in Climate and Health.}, journal = {Academic medicine : journal of the Association of American Medical Colleges}, volume = {}, number = {}, pages = {}, doi = {10.1093/acamed/wvag152}, pmid = {42143731}, issn = {1938-808X}, abstract = {Multiple international reports, peer-reviewed studies, and medical organizations have documented that climate change-defined as the rapid, long-term shifts in global temperatures and weather patterns driven primarily by human activities, such as the burning of fossil fuels-is already affecting human health and well-being. Recently, many health professional organizations have called upon current and future health professionals to acquire the knowledge, skills, and agency to address this public health threat. The Climate Resources for Health Education (CRHE) project was created by students, trainees, and faculty through the Global Consortium on Climate and Health Education to address this gap. The CRHE program provides organized, comprehensive, evidenced-based, peer-reviewed, and freely accessible climate health learning resources that can be delivered in standalone sessions or integrated into existing curricula. This manuscript details the innovative, grassroots, and trainee-led approach to developing this educational resource, designed to support educators and learners to incorporate climate change and planetary health information into health curricula. To date, there have been over 400 unique individuals consisting of trainees and faculty that have contributed to the CRHE project. A survey of a small subset of CRHE volunteers (34 respondents of 95 invited volunteers) demonstrated that CRHE participation had positive impact on reciprocal mentorship, knowledge gained in climate and health, and experience in curriculum development. In summary, the CRHE program is a comprehensive, free online resource that aims to help close the gap between the documented health impacts of climate change and the extent of its integration into medical education.}, }
@article {pmid42144191, year = {2026}, author = {Blumenberg, V and Diorio, C and Gauthier, J and Agrusa, JE and Dreyzin, A and Hänel, G and Espinoza-Gutarra, MR and Geer, M and Perales, MA and Ramakrishna, S and Jain, MD and Gill, S and Locke, FL and Shouval, R and Subklewe, M and Komanduri, KV and Chapuis, AG and Paczesny, S and Rejeski, K and Shah, NN}, title = {Expert Panel Review and Practical Guidance on Biomarker Testing With Engineered Immune Effector Cells.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.05.005}, pmid = {42144191}, issn = {2666-6367}, abstract = {BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape across several hematologic malignancies. However, variability in biomarker assays, timing, and interpretation across clinical centers hampers the comparability of results, limits translational insight, and constrains evidence-based decision-making. As immune effector cells expand into emergent platforms and new indications, standardized biomarker frameworks are increasingly critical for optimizing patient outcomes and prospectively advancing the field.<br><br>OBJECTIVES: These expert panel recommendations, developed by the American Society for Transplantation and Cellular Therapy (ASTCT) Committee on Cellular Therapy, aim to harmonize biomarker testing practices in CAR T-cell therapy. It provides evidence-based recommendations on the selection, timing, and clinical application of laboratory-based, cytokine, and CAR T-cell monitoring assays to inform toxicity management, guide treatment decisions, and support future research.<br><br>STUDY DESIGN: A multidisciplinary expert panel reviewed current literature, clinical practices, and available evidence on biomarker use in CAR T-cell recipients. Through iterative consensus, the group established recommendations for routine laboratory assessments, cytokine profiling, and CAR T-cell pharmacokinetic monitoring. Biomarkers were stratified by clinical utility into "must-have," "can-have," and "nice-to-have" tiers based on clinical relevance, reproducibility, intent, and biological significance.<br><br>RESULTS: The panel recommends comprehensive baseline laboratory testing-including metabolic panels, complete blood counts, inflammatory markers, and disease-specific biomarkers-prior to lymphodepletion. Serial measurements of inflammatory markers and targeted cytokines (e.g., IL-6, IFN-&#x3b3;, TNF-&#x3b1;, CXCL9) are advised during acute toxicity phases. CAR T-cell monitoring by flow cytometry or ddPCR should occur at defined intervals to assess expansion, persistence, and therapeutic response. Both cytokines and CAR-T kinetics carry great promise as potential dynamic predictors of toxicity or non-response. Harmonized timing, fold-change calculations, and standardized reporting are critical for enabling cross-study comparability and advancing biomarker-driven care.<br><br>CONCLUSIONS: Standardized biomarker testing is essential to improve patient outcomes, enable precision toxicity management, and accelerate CAR T-cell therapy innovation. These ASTCT consensus recommendations provide a practical framework for clinical implementation and future research, bridging routine practice with next-generation biomarker-driven strategies.}, }
@article {pmid42144948, year = {2026}, author = {Garza, R and Marchioni, JM and Honeycutt, JD and Hurlburt, NK and Torres, C and Garcia, A and Neog, S and Loranc, E and Yemington, E and Towers, D and Ssewanyana, I and Pancera, M and Lavinder, JJ and Jagannathan, P and Greenhouse, B and Bol, S and Bunnik, EM}, title = {The N-terminal region of malaria vaccine candidate Plasmodium falciparum asparagine-rich merozoite antigen is immunodominant and targeted by polyreactive antibodies.}, journal = {Disease models &amp; mechanisms}, volume = {}, number = {}, pages = {}, doi = {10.1242/dmm.052979}, pmid = {42144948}, issn = {1754-8411}, abstract = {The development of malaria blood-stage vaccines has been hampered by sequence variation in many Plasmodium falciparum proteins involved in erythrocyte invasion. In the past few years, asparagine-rich merozoite antigen (PfARMA) has emerged as a potential vaccine candidate due to its low amino acid sequence diversity and the association between anti-PfARMA antibody levels and protection to malaria. Here, we used samples from P. falciparum-exposed individuals to study naturally acquired B cell and antibody responses to PfARMA. B cell responses to PfARMA were dominated by IgM+ B cells that recognized the N-terminal intrinsically disordered region 1 (IDR1) of PfARMA. A human monoclonal antibody (hmAb) to IDR1 was non-neutralizing, while a second hmAb binding to the folded domain showed weak neutralizing activity. Both PfARMA-specific plasma IgM and IgG responses predominately targeted IDR1 and their levels increased with P. falciparum exposure. However, in contrast to previous reports, these antibody responses did not correlate with protection in age and exposure-matched children. Interestingly, approximately 30% of unexposed individuals had IgG that also targeted IDR1 and was polyreactive, binding to regions with high asparagine content. Finally, we determined that PfARMA is located in or near micronemes that contain erythrocyte binding antigen 175 (PfEBA-175). These data suggest that while IgG to the folded domain of PfARMA may inhibit parasite growth, antibody responses to PfARMA are primarily directed to IDR1. Consequently, these responses may reflect recent exposure rather than contributing to functional immunity to malaria.}, }
@article {pmid42149601, year = {2026}, author = {Ross, J and Trejo, MJ and Kaplan, RC and Perreira, KM and Poteat, TC and Gallo, LC and Shook-Sa, BE and Hinerman, AS and Hanna, DB}, title = {Self-Reported HIV Testing and Diagnosis Prevalence Among US Hispanic or Latino Adults.}, journal = {JAMA internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamainternmed.2026.0623}, pmid = {42149601}, issn = {2168-6114}, }
@article {pmid42138341, year = {2026}, author = {Moore, PL and Stamatatos, L and Trkola, A}, title = {How Vaccinating People Living With HIV May Guide bNAb‑Based Vaccines.}, journal = {Journal of the International AIDS Society}, volume = {29}, number = {5}, pages = {e70119}, pmid = {42138341}, issn = {1758-2652}, support = {//South African Research Chairs Initiative of the Department of Science and Innovation/ ; }, }
@article {pmid42139062, year = {2026}, author = {Kim, JH and Long, AN and Xie, Y and Carter, KT and Noehl-Tekorius, SR and Elz, AE and Yu, M}, title = {Protocol optimization to process mouse colon samples for single-nuclei RNA sequencing using FLEX library preparation.}, journal = {STAR protocols}, volume = {7}, number = {2}, pages = {104581}, doi = {10.1016/j.xpro.2026.104581}, pmid = {42139062}, issn = {2666-1667}, abstract = {Single-nuclei RNA sequencing enables the interrogation of tissue microenvironments in clinical samples preserved by snap-freezing, where cell membrane damage precludes single-cell isolation, but nuclei remain intact for high-quality molecular profiling. Here, we present an optimized protocol to process mouse colon samples for single-nuclei RNA sequencing using FLEX library preparation. We describe steps for preparing and dissociating colon tissue, nuclei filtration, and fixation. We then detail procedures for Chromium Fixed RNA Profiling (Gene Expression Flex).}, }
@article {pmid42140607, year = {2026}, author = {Hernandez-Lopez, V and Hall, E and Stacey, A}, title = {Sporadic retinal capillary hemangioma regresses with belzutifan.}, journal = {Canadian journal of ophthalmology. Journal canadien d'ophtalmologie}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jcjo.2026.04.025}, pmid = {42140607}, issn = {1715-3360}, }
@article {pmid42078392, year = {2026}, author = {Vergara, C and Ni, Z and Zhong, J and McKean, D and Connelly, KE and Antwi, SO and Arslan, AA and Bracci, PM and Du, M and Gallinger, S and Genkinger, J and Haiman, CA and Hassan, M and Hung, RJ and Huff, C and Kooperberg, C and Kastrinos, F and LeMarchand, L and Lee, W and Lynch, SM and Moore, SC and Oberg, AL and Park, MA and Permuth, JB and Risch, HA and Scheet, P and Schwartz, A and Shu, XO and Stolzenberg-Solomon, RZ and Wolpin, BM and Zheng, W and Albanes, D and Andreotti, G and Bamlet, WR and Beane-Freeman, L and Berndt, SI and Brennan, P and Buring, JE and Cabrera-Castro, N and Campa, D and Canzian, F and Chanock, SJ and Chen, Y and Chung, CC and Eliassen, AH and Gaziano, JM and Giles, GG and Giovannucci, EL and Goggins, M and Goodman, PJ and Hicks, B and Hutchinson, A and Jones, MR and Katzke, V and Kogevinas, M and Kurtz, RC and Laheru, D and Lee, IM and Malats, N and Milne, R and Mucci, L and Neale, RE and Orlow, I and Patel, AV and Peruchet, L and Peters, U and Porta, M and Rabe, KG and Real, FX and Ricceri, F and Rothman, N and Sesso, HD and Setiawan, VW and Silverman, D and Southey, MC and Stampfer, MJ and Tobias, GS and Um, C and Visvanathan, K and Wactawski-Wende, J and Wentzensen, N and Willett, WC and Yu, H and Kraft, P and Duggal, P and Amundadottir, LT and Klein, AP}, title = {Novel Genetic Risk Loci for Pancreatic Ductal Adenocarcinoma Identified in a Genome-wide Study of African Ancestry Individuals.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42078392}, support = {U01 CA247283/CA/NCI NIH HHS/United States ; }, abstract = {UNLABELLED: Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 (CLPTM1L, rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10[-8]), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors.<br><br>STATEMENT OF SIGNIFICANCE: To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.}, }
@article {pmid42079148, year = {2026}, author = {Harel, N and Sung, K and Dumm, W and Johnson, MM and Rich, D and Fukuyama, J and Haddox, HK and Matsen, FA}, title = {Entrenchment of germline amino-acid differences in antibody affinity maturation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42079148}, issn = {2692-8205}, abstract = {Entrenchment - epistasis that locks in amino acid differences between homologous proteins, so each disfavors substitutions toward the other's state - has been demonstrated along individual protein lineages over deep evolutionary time. Antibodies offer a unique system for studying entrenchment: multiple homologous germline V gene paralogs provide diverse starting points, and the rapid somatic evolution of affinity maturation generates dense phylogenies from which selection on germlineencoded residues can be inferred. Using DASM, a deep learning model that separates selection from mutation in antibody repertoire data, we test for entrenchment across immunoglobulin heavy chain variable (IGHV) genes. We detect entrenchment at two levels of germline divergence, driven by different sources of epistasis. Within V gene families (up to ~20% amino acid divergence), entrenched sites cluster at the borders of the complementarity-determining regions (CDRs, the antigen-binding loops) and show high germline diversity. These sites contact antigen, light chain, and the heavy chain CDR3 loop, all of which are encoded independently of the IGHV germline. This pattern is consistent with epistasis from genetically uncoupled partners. Between V gene families, at deeper levels of divergence (25-40%), entrenchment additionally includes positions in the framework scaffold distant from binding interfaces, suggesting a larger contribution from intra-heavy-chain structural constraints. Observed mutation frequencies in human repertoires corroborate these predictions where data are sufficient. Together, these results demonstrate that the rapid somatic evolution of antibodies can serve as a lens for revealing epistatic constraints acting on germline-encoded residues, including constraints imposed by genetically uncoupled partners assembled during B cell development.}, }
@article {pmid42133238, year = {2026}, author = {Ghia, P and Brown, JR and Shadman, M and Wendtner, CM}, title = {A Comprehensive Review of the Role of Zanubrutinib for Patients with Chronic Lymphocytic Leukemia.}, journal = {Oncology and therapy}, volume = {}, number = {}, pages = {}, pmid = {42133238}, issn = {2366-1089}, abstract = {The approval of ibrutinib over a decade ago introduced Bruton tyrosine kinase (BTK) inhibition as a foundational, chemotherapy-free treatment approach for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). A continuous single-agent BTK inhibitor (BTKi) or a time-limited B cell lymphoma 2 inhibitor (BCL2i)-based regimen plus an anti-CD20 monoclonal antibody or BTKi is now standard of care for CLL/SLL. Although ibrutinib offers durable remission for many patients, its use is limited by side effects associated with inhibition of kinases other than BTK (off-target effects). The second-generation BTKi zanubrutinib was developed to provide sustained BTK inhibition with greater selectivity for BTK in order to improve clinical efficacy and tolerability with minimized off-target effects. The head-to-head ALPINE study of patients with relapsed/refractory (R/R) CLL/SLL demonstrated superior efficacy with zanubrutinib versus ibrutinib, with superior overall response rates and prolonged progression-free survival (PFS), while acalabrutinib demonstrated non-inferior PFS outcomes versus ibrutinib in patients with high-risk R/R CLL/SLL. Data also showed improved safety outcomes with zanubrutinib versus ibrutinib with significantly lower rates of atrial fibrillation/flutter, and infection, and a trend toward lower rates of other adverse events associated with ibrutinib, with the exception of neutropenia. This is reflected in treatment guidelines for CLL, where zanubrutinib and the other approved second-generation BTKi, acalabrutinib, are recommended over ibrutinib owing to their superior safety profiles (particularly reduced cardiotoxicity). In this review, we consider the pharmacologic properties of zanubrutinib that differentiate it from ibrutinib and acalabrutinib, and provide a comprehensive overview of the efficacy and safety data that led to zanubrutinib monotherapy becoming a preferred therapy for a significant subgroup of patients with CLL/SLL. We also highlight trials in CLL/SLL and Richter's transformation with zanubrutinib in targeted therapy combinations that offer the potential for time-limited treatment courses.}, }
@article {pmid42134328, year = {2026}, author = {Batra, J and Rutkowska, M and Zhou, Y and Ye, C and Adavikolanu, R and Young, JM and Anand, D and Verma, S and Parthasarathy, H and Gordon, M and Malpotra, S and Cupic, A and Kehrer, T and Dos Santos, M and Benjamin, R and Moen, JM and Winters, DM and Caval, V and Rojc, A and Mena, I and Aslam, S and Martinez-Romero, C and Viñas, IC and Khalil, Z and Farrugia, K and Villalón-Letelier, F and Banerjee, A and Tussia-Cohen, D and Diallo, A and Maji, S and Muralidharan, M and Foussard, H and Chen, IP and Fuchs, R and San Felipe, CJ and Zuliani-Alvarez, L and Choudhury, P and Obernier, K and Gracias, S and Suryawanshi, RK and Bonaventure, B and Ibáñez, C and Johnson, JR and Juste, J and Pache, L and Stroud, RM and Verba, KA and Fraser, JS and van Bakel, H and Taha, TY and Ott, M and Hagai, T and Jouvenet, N and Demeret, C and Polacco, BJ and Swaney, DL and Echeverria, I and Bouhaddou, M and Eckhardt, M and Malik, HS and Martinez-Sobrido, L and Miorin, L and García-Sastre, A and Krogan, NJ}, title = {Coronavirus protein interaction mapping in bat and human cells reveals network rewiring governing immune evasion and zoonotic potential.}, journal = {Cell host &amp; microbe}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.chom.2026.04.015}, pmid = {42134328}, issn = {1934-6069}, abstract = {Coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can cause severe disease in humans, whereas reservoir hosts such as horseshoe bats remain asymptomatic. To investigate how host-specific protein-protein interactions (PPIs) influence infection, we generated comparative PPI maps for SARS-CoV-2 and its bat progenitor RaTG13, using affinity purification mass spectrometry (AP-MS) in human and greater horseshoe bat cells. We identify both conserved and virus- and host-specific interactions that regulate infection dynamics. Notably, SARS-CoV-2 requires a nonsynonymous mutation in the nucleocapsid to replicate in bat cells expressing human ACE2 and TMPRSS2. Strikingly, a single amino acid difference in Orf9b between viruses acts as a molecular switch that reprograms mitochondrial targeting: in human cells, enhanced translocase of outer mitochondrial membrane 70 (Tom70) binding promotes immune evasion, whereas in bat cells, strengthened interaction with the bat-enriched restriction factor mitochondrial amidoxime reducing component 2 (MTARC2) limits infection. These findings establish a general principle by which minimal sequence variation can reshape virus-host interactions and contribute to immune antagonism, host adaptation, and species barriers.}, }
@article {pmid42137282, year = {2026}, author = {Hill, TF and Helmers, AE and Yu-Hong Cheng, R and Singh, S and Homad, LJ and Narvekar, P and Asher, GD and Camp, ND and Suchland, ER and Ott, AR and Hale, M and Thouvenel, CD and Stoffers, CM and Lachkar, S and McGuire, AT and Rawlings, DJ and James, RG}, title = {Humanized mice enable in vivo evaluation of engineered plasma cell biology and therapeutic function.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {1}, pages = {201666}, pmid = {42137282}, issn = {3117-387X}, abstract = {Engineered plasma cells (ePCs) offer a durable strategy for in vivo delivery of therapeutic antibodies, but standard immunodeficient mouse models lack human immune factors critical for PC survival and function. We utilized a humanized mouse model in which NOD.Cg-Prkdc [scid] Il2rg [tm1Wjl] /SzJ (NSG) mice were engrafted with human CD34[+] stem cells as recipients for infusions with autologous ePCs. In this setting, ePCs localized to PC niches and stably secreted antibodies for over 3 months. To improve the selection of antibodies for secretion, we developed a B cell receptor surface display screen that identified candidate antibody sequences with high secretion potential. An anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody (clone 297) selected by this method showed robust secretion both in vitro and in vivo, and serum from ePC-engrafted mice potently neutralized SARS-CoV-2 pseudovirus. Together, these findings establish a physiologically relevant model for testing human ePCs, and offer a generalizable strategy for optimizing antibody selection to support long-term therapeutic delivery.}, }
@article {pmid42137286, year = {2026}, author = {Hordeaux, J and Keeler, AM and Stone, D}, title = {Advancing AAV technology-From promise to product.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {1}, pages = {201672}, pmid = {42137286}, issn = {3117-387X}, }
@article {pmid42137296, year = {2026}, author = {Li, C and Anderson, AK and Kuhlmann, AS and Nelson, V and Germond, A and Wang, H and Georgakopoulou, A and Gil, S and Martinez-Reyes, J and Riker, A and Raman, SS and Kim, J and Ng, P and Palmer, D and Alpert, MD and Skamangas, N and Bailey, C and Ou, T and Fennessey, CM and Farzan, M and Jerome, KR and Keele, BF and Kiem, HP and Lieber, A and Bui, JK}, title = {In vivo HSC gene therapy enables sustained eCD4-Ig expression for SIV prevention.}, journal = {Molecular therapy. Advances}, volume = {34}, number = {1}, pages = {201683}, pmid = {42137296}, issn = {3117-387X}, abstract = {We aim to develop an in vivo hematopoietic stem cell (HSC) gene therapy approach for the prevention and control of HIV-1 infection. Toward this goal, we engineered helper-dependent adenovirus (HDAd) 6/3+ vectors to directly transduce HSCs in vivo, enabling progeny cells to secrete eCD4-Ig, a decoy protein that broadly neutralizes HIV/simian immunodeficiency virus (SIV) isolates by mimicking the primary viral receptor CD4 and coreceptors such as CCR5. In rhesus macaques, the HDAd 6/3+ platform achieved long-term expression of an enhanced eCD4-Ig variant ("eCD4-Ig-Emm06") that retained potent neutralization efficacy in vivo. Transduced HSCs differentiated into lymphoid and myeloid lineages and trafficked to systemic tissues, with B cells emerging as a major source of eCD4Ig-Emm06. HDAd-eCD4Ig-Emm06-treated animals had significantly reduced splenic viral reservoirs, and the animal with the highest circulating levels of eCD4Ig-Emm06 exhibited fewer founder viruses, delayed onset to viremia, and lower plasma viral loads, demonstrating promise within this proof-of-concept study. Further improvements in protective efficacy may be achieved through approaches identified in this study, including lineage-specific expression, reduced immunogenicity, and efficient selection. These findings validate HDAd 6/3+ as a promising platform for durable gene-based delivery of biologic therapeutics and guide advancement of HSC gene therapy for HIV and other chronic infections.}, }
@article {pmid42128867, year = {2026}, author = {Atsuta, Y and Ohbiki, M and Sakaida, E and Asano-Mori, Y and Yamaguchi, M and Takita, J and Lee, SJ}, title = {[Mentorship to support career development among women physicians].}, journal = {[Rinsho ketsueki] The Japanese journal of clinical hematology}, volume = {67}, number = {4}, pages = {349-354}, doi = {10.11406/rinketsu.67.349}, pmid = {42128867}, issn = {0485-1439}, mesh = {*Physicians, Women ; Female ; Humans ; *Mentors ; *Mentoring ; *Career Mobility ; Leadership ; Career Choice ; }, abstract = {Mentorship is a critical mechanism for the growth and career development of young physicians and plays an especially decisive role in addressing the "leaky pipeline" faced by women in medicine. In this article, we first clarify the distinctions between four forms of support-mentor, sponsor, ally, and coach-and review initiatives at the levels of professional societies, institutions, and individuals. We then present concrete examples from Japan: the Japanese Data Center for Hematopoietic Cell Transplantation, which combines a registry scientist training program with flexible work arrangements; Chiba University, where a formal mentoring system for medical students and a team-based clinical structure provide embedded, structural mentorship; and a small survey of women physicians in general hospitals, which reveals limited formal mentoring systems and diverse needs regarding mentor characteristics. Drawing on these experiences, we describe key attributes of effective mentors, including accessibility, reliability, and respect for mentees' values and goals, and we highlight three central mentoring roles: supporting academic success, promoting sustainable work-life balance, and fostering leadership development. To create an environment in which women physicians can fully realize their potential, high-quality mentorship must be strengthened across academic societies, healthcare institutions, and individual practitioners.}, }
@article {pmid42129165, year = {2026}, author = {Lewnard, JA and Paredes, MI and Yechezkel, M and Davis, GS and Hong, V and Skela, J and Pandey, U and Parker, NT and Granskog, LC and Pomichowski, ME and Reyes, IAC and Rodriguez-Barraquer, I and Müller, NF and Tartof, SY}, title = {Extensive cryptic circulation sustains mpox among men who have sex with men.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42129165}, issn = {2041-1723}, support = {CDC-RFA-FT-23-0069//U.S. Department of Health &amp; Human Services | Centers for Disease Control and Prevention (CDC)/ ; CDC-RFA-FT-23-0069//U.S. Department of Health &amp; Human Services | Centers for Disease Control and Prevention (CDC)/ ; }, mesh = {Male ; Humans ; *Homosexuality, Male/statistics &amp; numerical data ; *Mpox, Monkeypox/epidemiology/transmission/virology/diagnosis ; Phylogeny ; *Monkeypox virus/genetics/classification/isolation &amp; purification ; Adult ; Los Angeles/epidemiology ; Middle Aged ; Prospective Studies ; Young Adult ; }, abstract = {Sporadic cases of clade IIb mpox continue to be notified among men who have sex with men, with most lacking identifiable transmission links. To resolve underlying dynamics, we tested prospectively for evidence of monkeypox virus infection in anorectal swabs from a cohort of men who have sex with men in Los Angeles, whom we monitored concurrently for clinical mpox diagnoses during summer, 2024. Here we estimate that infections exceeded reported mpox cases by a 33-fold margin (95% confidence interval: 16-68). Independent estimates derived from phylogenetic reconstruction and a meta-analysis of surveillance studies corroborated this extensive under-reporting. We estimate that undiagnosed infections must cause at least 31-44% of all transmission to explain observed monkeypox virus phylogenies; under realistic modeling assumptions, this proportion rises to 61-97%. Contrary to current guidance, our findings suggest a substantial proportion of monkeypox virus circulation may be associated with subclinical infections, challenging the feasibility of current mpox elimination targets.}, }
@article {pmid42129592, year = {2026}, author = {Useche, M and Gomez-Castillo, L and Cushing-Haugen, K and Ferrandino, R and Futran, N and Marchiano, E and Rodriguez, CP and Harris, HR and Barber, B}, title = {Poor Diet and Oral Cavity Cancer Risk in Smoking and Non-Smoking Men and Women: An Analysis of Three US Cohorts.}, journal = {Head &amp; neck}, volume = {}, number = {}, pages = {}, doi = {10.1002/hed.70317}, pmid = {42129592}, issn = {1097-0347}, support = {UM1 CA186107/NH/NIH HHS/United States ; P01 CA87969/NH/NIH HHS/United States ; UM1 CA176726/NH/NIH HHS/United States ; }, abstract = {INTRODUCTION: Oral cavity cancer (OCC) incidence is rising among non-smokers and younger individuals without traditional risk factors. While carcinogenic exposures such as tobacco and alcohol are well studied, the association between unhealthy dietary patterns and OCC has been minimally explored. This study evaluated the association between dietary patterns and OCC risk in men and women.<br><br>METHODS: This prospective cohort study used data from three large U.S. longitudinal cohorts: the Nurses' Health Study (n&#x2009;=&#x2009;68&#x2009;715, 1986-2016), Nurses' Health Study II (n&#x2009;=&#x2009;93&#x2009;887, 1991-2017), and the Health Professionals Follow-up Study (n&#x2009;=&#x2009;47&#x2009;923, 1986-2016). Participants included 162&#x2009;602 women and 47&#x2009;923 men without cancer at baseline. Dietary intake was assessed every 4&#x2009;years using validated food frequency questionnaires. Three dietary patterns were evaluated: Western, Prudent, and the Alternative Healthy Eating Index-2010 (AHEI). Cox proportional hazard models estimated hazard ratios and 95% confidence intervals (CIs).<br><br>RESULTS: Over 30&#x2009;years of follow-up, 226 incident OCC cases were identified (124 in women and 102 in men). Among women, lower adherence to the Prudent and AHEI dietary patterns had higher OCC risk (HR for lowest vs. highest quartile, HR 1.86, 95% CI 1.03-3.35, and HR 2.17, 95% CI 1.24-3.77, respectively). Among non- or light-smoking and non- or light-drinking women, low adherence to the Prudent diet significantly increased OCC risk (HR for lowest vs. highest quartile 2.94, 95% CI 1.06-8.10). No associations were observed in men. Formal tests for interaction by sex were not statistically significant.<br><br>CONCLUSIONS: Low adherence to Prudent and AHEI dietary patterns was associated with a higher risk of OCC in women but not men that warrants further investigation in larger pooled studies.}, }
@article {pmid42064962, year = {2026}, author = {Valliere, J and Strausz, S and Tchio, C and Risse-Adams, OS and Sinnott-Armstrong, N and Ollila, HM and Saxena, R}, title = {Meta-analysis of Cannabis Use Identifies Shared Genetic Loci with Sleep and Circadian Rhythms.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42064962}, abstract = {Cannabis use is an increasingly common therapeutic for a variety of chronic diseases. In addition, people with sleep problems may self-medicate using cannabis products. However, genetic architecture of cannabis use and its shared genetic predispositions with sleep traits has not been systematically examined. We performed a meta-analysis of cannabis use within the All of Us and UK Biobank cohorts, consisting of 152,807 cases and 220,272 controls. Our meta-analysis identified 39 independent loci, including the previously reported CADM2 locus associated with cannabis use and replicating previous work. Additionally our associations include neuronal and sleep-regulating genes such as HTR1A, RAI1, SLC39A8, and NCAM1. Moreover, tissue-specific analyses revealed that the genetic architecture of cannabis use is heavily enriched within the central nervous system and specific brain cell types. In addition, we observed significant positive genetic correlations with clinical insomnia, insomnia-related medication usage, and objectively measured nighttime physical activity, alongside negative correlations with morningness chronotype and daytime activity. Fine-mapping and colocalization analyses identified shared genetic signals between cannabis use and clinical insomnia including a near-perfect colocalization at SLC39A8 and CADM2. Together, these results highlight the shared genetic risk between cannabis use and sleep disorders. Additionally, our findings indicate the importance of investigating the genetic effects of cannabis use as its use becomes more widespread, both recreationally and medicinally.}, }
@article {pmid42119783, year = {2026}, author = {Federico, V and Avenoso, D and Raj, K and De Lavallade, H and Wilson, W and Matera, R and Salvatore, D and Canale, FA and Merla, M and Contento, C and Campagna, G and Renzo, GD and Vaddinelli, D and Natale, A and Seripa, D and Grassi, T and Saraceni, F and Santarone, S and Carella, AM and Russo, D and Milano, F and Martino, M and Renzo, ND}, title = {Fludarabine-Treosulfan (FT10) Conditioning in Older AML Patients Undergoing Haploidentical Transplantation: A Prospective Italian Study with External Comparison to the Haplo-UK Reduced-Intensity Conditioning Cohort.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.05.006}, pmid = {42119783}, issn = {2666-6367}, abstract = {BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) remains the only curative strategy for high-risk acute myeloid leukemia (AML), but its applicability in elderly and comorbid patients is limited by conditioning-related toxicity. Haploidentical HSCT (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) has expanded access to transplantation, yet the optimal reduced-intensity conditioning (RIC) regimen in this setting remains undefined. Treosulfan-based conditioning combined with fludarabine (FT10) has demonstrated a favourable toxicity profile in matched donor transplantation, but prospective data in the haploidentical platform are scarce.<br><br>METHODS: We conducted a prospective, multicentre feasibility study across eight transplant centres, enrolling patients with intermediate- or high-risk AML (ELN-2017), aged &#x2265;65 years, with haematopoietic cell transplantation-comorbidity index (HCT-CI) &#x2265;2, lacking an HLA-identical donor and undergoing FT10-based haplo-HSCT between June 2019 and December 2023. Conditioning consisted of treosulfan (30 g/m&#xb2;) and fludarabine (150 mg/m&#xb2;), followed by GVHD prophylaxis with PTCy, cyclosporine and mycophenolate mofetil. Primary endpoint was cumulative incidence of non-relapse mortality (NRM). Transplant outcomes were descriptively compared with an external reduced-intensity conditioning cohort from the prospective phase II Haplo-UK study.<br><br>RESULTS: Thirty-five AML patients were included in the FT10 cohort (median age 69 years); 58% were transplanted in complete remission (CR) with negative MRD, 22% in CR with positive MRD and 20% with active disease. Median neutrophil and platelet engraftment occurred at days +14 and +22, respectively, with full donor chimerism achieved in 94% of evaluable patients and one case of graft failure (2.8%). Cumulative incidence of NRM was 18% at day +100 and 28% at 1 year, with infections representing the leading cause of non-relapse death. Outcomes were strongly influenced by disease status at transplant: 1-year OS and LFS were 79% and 70% in patients transplanted in CR/MRD-negative, compared with 42% and 38% in those transplanted with active disease. Acute grade II-IV and chronic GVHD occurred in 13% and 40% of patients, respectively. When restricted to patients transplanted in CR, survival and relapse outcomes were broadly comparable to those observed in the Haplo-UK cohort, despite the substantially older age and higher comorbidity burden of FT10 patients.<br><br>CONCLUSIONS: In this prospective, real-world multicentre study, FT10-based haploidentical HSCT with PTCy proved feasible and effective in elderly, comorbid AML patients. These findings suggest that FT10 represents a viable conditioning option for a highly vulnerable population traditionally excluded from transplant and support further validation in larger comparative studies.}, }
@article {pmid42120368, year = {2026}, author = {Zhang, R and Qi, J and McKasson, M and Choi, J and Gutierrez, V and Brennan, C and Hong, S and Chour, W and Ng, RH and Xie, J and Yuan, D and Webster, A and Sidhu, SK and Anderson, A and Chen, D and Edmark, R and Murray, KM and Li, S and McDonald, C and Rowen, L and Wang, S and Rasheed, Y and Su, Y and Wagner, JR and Chen, JM and Nawaly, K and Fu, J and Duven, A and Forman, SJ and Song, M and Priceman, SJ and Brown, CE and Ribas, A and Wong, DJ and Paulson, KG and Drescher, CW and Puig-Saus, C and Goldman, JD and Trimble, CL and Heath, JR}, title = {Whole-protein screening and multi-modal profiling of antigen-specific CD4[+] T cells at single-cell resolution.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {42120368}, issn = {2041-1723}, support = {CA264090-01//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *CD4-Positive T-Lymphocytes/immunology/metabolism ; SARS-CoV-2/immunology ; *Single-Cell Analysis/methods ; Papillomavirus E7 Proteins/immunology ; COVID-19/immunology/virology ; Oncogene Proteins, Viral/immunology ; Spike Glycoprotein, Coronavirus/immunology/metabolism/genetics ; Female ; Antigens, Viral/immunology ; Male ; Human papillomavirus 16/immunology ; Repressor Proteins/immunology ; Receptors, Antigen, T-Cell/immunology ; High-Throughput Screening Assays/methods ; Papillomavirus Infections/immunology/virology ; Longitudinal Studies ; Adult ; }, abstract = {Systematic whole-protein screening and comprehensive profiling of antigen-specific CD4[+] T cells are crucial for advancing vaccine design and cancer immunotherapies, yet remain technically challenging. Here, we present a high-throughput platform that utilizes large-scale class II single-chain trimer libraries to detect antigen-specific CD4[+] T cells, while simultaneously profiling their antigen specificity, TCRα/β sequences, MHC restriction, whole transcriptomes, and patient/timepoint origins at single-cell resolution. Upon rigorous platform validation, we screened the full SARS-CoV-2 spike receptor binding domain in a longitudinal cohort of 22 participants, identifying 2,188 antigen-specific CD4[+] T cells and showing key metrics defining the immunogenicity of class II-restricted viral antigens. We further extended the platform to whole-protein screening of HPV-16 E6/E7 in a cohort of precancerous patients, indicating HPV-specific CD4 TCRs that, upon extensive characterization, demonstrate strong therapeutic potential. By integrating high-throughput antigen screening with high-dimensional, multi-modal cellular characterization, our approach provides detailed insight into CD4[+] T cell immunity, potentially guiding vaccine design and next-generation TCR-based cancer immunotherapies.}, }
@article {pmid42127031, year = {2026}, author = {Petersen, GL and Edlefsen, PT and Li, X and Morrison, R and Kabyemela, E and Nelson, JL and Duffy, PE and Fried, M and Harrington, WE}, title = {Maternal microchimerism at birth associates with reduced odds of non-malarial fever and respiratory tract infections in Tanzanian children.}, journal = {PLOS global public health}, volume = {6}, number = {5}, pages = {e0006439}, doi = {10.1371/journal.pgph.0006439}, pmid = {42127031}, issn = {2767-3375}, abstract = {The presence of maternal cells in the offspring at birth, a phenomenon known as maternal microchimerism, has been previously associated with decreased odds of malaria and respiratory infections in early childhood suggesting a role in immunological responses to infections. Here, we assess the effect of cord blood maternal microchimerism on symptomatic non-malarial infections in Tanzanian children. We conducted a secondary analysis using a nested birth cohort of 52 children from Muheza, Tanzania, with previously measured cord blood maternal microchimerism and longitudinal records on infections in the first four years of life. The associations between maternal microchimerism and symptomatic lower and upper respiratory tract infections, diarrhea, and non-malarial fever were estimated using generalized estimating equation models. In total, 29% of the 52 children in the study screened positive for cord blood maternal microchimerism. Detected versus non-detected maternal microchimerism was associated with 58% lower odds of non-malarial fever (fully adjusted odds ratio (OR): 0.42 [95% CI: 0.18-0.98]) and 28% lower odds of respiratory tract infection (OR: 0.72 [95% CI: 0.53-0.96]). Lower and upper respiratory tract infections contributed equally to the observed association with any symptomatic respiratory tract infections (ORs respectively: 0.81 [95% CI: 0.50-1.31] and 0.71 [95% CI: 0.50-1.01]). We did not find any association between maternal microchimerism and odds of diarrhea (OR: 1.63 [95% CI: 0.85-3.13]). Detectable cord blood maternal microchimerism was associated with lower odds of non-malarial fever and symptomatic respiratory infections in Tanzanian infants. These findings emphasize that MMc may play an underrecognized role in protection from infection during early childhood.}, }
@article {pmid42127995, year = {2026}, author = {Yadav, H and White, B and Soto, F and Zhang, Z and Pennington, K and Adarsh, S and Smilnak, G and Sturek, J and Cheng, GS and Sheshadri, A}, title = {FEV1Q: A Race-Neutral Approach to Risk Assessment in Allogeneic Hematopoietic Cell Transplantation.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1093/annalsats/aaoag127}, pmid = {42127995}, issn = {2325-6621}, }
@article {pmid42115165, year = {2026}, author = {Barnabas, RV and Brown, ER and Bukusi, EA and Njoroge, B and Winer, RL and Galloway, DA and Wakhungu, IN and Biwott, C and Kimanthi, S and Heller, KB and Krows, M and Morrison, S and Rechkina, EA and Cherne, SL and McClelland, RS and Mugo, NR and Onono, MA}, title = {Efficacy and durability of immediate versus delayed single-dose HPV vaccination for persistent infection among young women in Kenya: a randomized, blinded, cross-over clinical trial.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-72654-8}, pmid = {42115165}, issn = {2041-1723}, support = {Inv-062781//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; }, abstract = {Evidence is needed for single-dose human papillomavirus (HPV) vaccine efficacy (VE) durability to support vaccination guidelines. In this randomized crossover trial (NCT03675256), healthy young women aged 15-20 years, recruited through community-based screening in Kenya, were randomly allocated to immediate nonavalent or bivalent HPV vaccination and delayed control at month 30/36 (age 17-23 years), or immediate control and delayed nonavalent HPV vaccination. Cervical swabs collected every six months were tested for HPV DNA to determine incident persistent HPV infection. The primary outcome was VE at 54 months, estimated among participants who were HPV naive at enrollment vaccination using Cox proportional hazards models with time-varying covariates for HPV vaccine status and time; negative coefficients for time since vaccination indicate durability. For incident persistent HPV 16/18 infections, 104 were detected: 93 pre-crossover and 11 post-crossover; HPV 16/18 VE was 99.3% (95% CI: 96.2,99.9%). For incident persistent HPV 16/18/31/33/45/52/58, 117 infections occurred: 103 pre-crossover and 14 post-crossover; HPV 16/18/31/33/45/52/58 VE was 98.9% (95% CI: 94.9,99.8%). Coefficients for time since vaccination were -0.0014 (95% CI: -0.0027,-0.0002) for HPV 16/18 and -0.0016 (95% CI: -0.0028,-0.0004) for HPV 16/18/31/33/45/52/58. Single-dose HPV vaccination is highly efficacious (> 98%) and durable over 54 months in young women.}, }
@article {pmid42115634, year = {2026}, author = {Abdou, Y and Rozenblit, M and Trapani, D and Zerdes, I and Boudreau, E and Zhou, Y and Adam, V and Barrios, C and Bousrih, C and Branch, V and Carey, LA and Cameron, D and Chen, S and Chua, BH and Davidson, NE and Domchek, SM and El-Abed, S and El-Ashry, D and Flowers, M and Foldi, J and Garber, J and Goulioti, T and Hodgdon, C and Hung, JL and Klar, N and Norton, L and Parajuli, R and Piccart, M and Pollastro, T and Santa-Maria, CA and Schumacher-Wulf, E and Stecklein, SR and Thulin, A and Tovey, H and Winer, E and Wolff, AC and Lin, NU and O'Reilly, S}, title = {Invest where impact begins: recommendations from Breast Cancer Research Foundation Early Career Investigator Working Group (Part 1 of 2).}, journal = {NPJ breast cancer}, volume = {12}, number = {1}, pages = {}, pmid = {42115634}, issn = {2374-4677}, }
@article {pmid42115681, year = {2026}, author = {Courville, EL and Grant, M and Mason, E and Chen, X and d'Onofrio, G and Hedley, B and Frater, JL and Ouseph, MM and Zini, G and McFadden, S and Han, JY and Shirai, C and Obstfeld, A and Yaeger, LH and Pozdnyakova, O}, title = {Performance of Automated Hematology Analyzer Criteria in Detecting Peripheral Blood Smear Abnormalities: A Systematic Literature Review.}, journal = {International journal of laboratory hematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ijlh.70139}, pmid = {42115681}, issn = {1751-553X}, abstract = {OBJECTIVES: Criteria for visual examination of stained peripheral blood smear (PBS) differ among institutions in the United States and internationally. In an effort to standardize review criteria, the International Consensus Group for Hematology Review (ICGHR) proposed in 2005 a consensus list of rules for CBC findings that should trigger a review of automated cell counter results and potentially lead to further testing or blood smear review. The primary aim of this paper is to report on the published literature in the past 20 years regarding PBS review criteria and their ability to identify relevant peripheral blood abnormalities.<br><br>METHODS: We performed a systematic review of the published literature from 2005 to 2025 to investigate and summarize PBS review criteria and performance in the context of automated hematology analyzers in clinical laboratories.<br><br>RESULTS: Of 5351 citations, 68 studies met our search criteria. These studies included 22 countries and all major hematology analyzer manufacturers. Marked variability was observed in study populations, analyzer flagging criteria, details of PBS visual review, definitions of a "positive" smear, and approaches to statistical data analysis. Across studies, the blast flag sensitivity ranged from 18% to 100% while the blast flag specificity ranged from 17% to 100%. Wide ranges in sensitivity/specificity were also seen for atypical and/or abnormal lymphocyte flags across studies. For studies analyzing the same patient population, less striking variation was seen across instruments.<br><br>CONCLUSIONS: This systematic review provides a 20-year overview of the literature, highlighting significant variability in PBS review criteria, dependence on study design and hematology analyzer, and the importance of developing harmonized evidence-based guidelines.}, }
@article {pmid42116597, year = {2026}, author = {Garduno, AC and Viswanath, V and Smarr, B and McEvoy, L and Xiao, Q and Full, K and Gallo, L and Parada, H and Crandall, C and Cauley, J and Tinker, LF and LaCroix, AZ}, title = {Sleep Pattern Clusters, Physical Function and Fall Risk: Geriatric Syndromes among Older Ambulatory Women.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {}, number = {}, pages = {}, doi = {10.1093/gerona/glag115}, pmid = {42116597}, issn = {1758-535X}, abstract = {BACKGROUND: Poor sleep is a suspected risk factor for lower physical functioning and frequent falling at older ages. We evaluated the relationship of multiple sleep and rest-activity rhythm (RAR) metrics with fall risk and physical functioning.<br><br>METHODS: Older women (N&#x2009;=&#x2009;4,543) wore hip-worn accelerometers, recording their falls daily for 13&#x2009;months following accelerometry. Uniform manifold approximation projection identified sleep-circadian clusters; K-Means clustering further distinguished healthy and unhealthy sleep patterns. After cross-validation, we examined associations between sleep clusters and fall risk using adjusted, negative binomial models. Linear regression models estimated associations of sleep clusters with Short Physical Performance Battery (SPPB) score and its sub-scores. We evaluated whether SPPB status modified associations of sleep and RAR with fall risk.<br><br>RESULTS: Five sleep clusters were identified including C1 ("sleep disturbed", n&#x2009;=&#x2009;1051), C2 ("healthy", n&#x2009;=&#x2009;1043), C3 ("mild RAR, active", n&#x2009;=&#x2009;1446), C4 ("earlier sleepers, n&#x2009;=&#x2009;105), and C5 ("shorter, mildly disrupted, later sleeper", n&#x2009;=&#x2009;898). Unhealthy sleep clusters C1 and C4 were associated with a higher fall risk compared to healthy cluster C2 after adjustment (C4, IRR: 1.76 (95%CI : 1.15-2.69)). These same clusters were also associated with lower balance scores (score: 0-4) after adjustment (C1, beta: -0.11 (95% CI:-0.21 to -0.01); C4, beta: -0.30 (95%CI: -0.55 to -0.05)).<br><br>CONCLUSIONS: Older women with unhealthier sleep-RAR patterns are more at risk for falling, which may be partially explained by the role of sleep on balance and physical functioning.}, }
@article {pmid42118466, year = {2026}, author = {Jennings-Shaffer, C and Chen, ZC and Palacios, JA and Matsen, FA}, title = {Generalizing Matrix Representations to Fully Heterochronous Ranked Tree Shapes.}, journal = {Bulletin of mathematical biology}, volume = {88}, number = {5}, pages = {}, pmid = {42118466}, issn = {1522-9602}, support = {2143242//National Science Foundation/ ; R35GM148338/NH/NIH HHS/United States ; R01-AI146028//National Institute of Allergy and Infectious Diseases/ ; S10OD028685//Office of Research Infrastructure Programs, National Institutes of Health/ ; }, mesh = {*Phylogeny ; Mathematical Concepts ; Humans ; *Models, Genetic ; Likelihood Functions ; *Biological Evolution ; }, abstract = {Phylogenetic tree shapes capture fundamental signatures of evolution. We consider "ranked" tree shapes, which are equipped with a total order on the internal nodes compatible with the tree graph. Recent work has established an elegant bijection between ranked tree shapes and a class of integer matrices, called F-matrices, defined by simple inequalities. This formulation is for isochronous ranked tree shapes, where all leaves share the same sampling time, such as in the study of ancient human demography from present-day individuals. However, branch lengths of phylogenetic trees can represent units other than calendar time, such as evolutionary distance. A tree equipped with branch lengths quantifying evolutionary distance, called a rooted phylogram, is output by popular maximum-likelihood methods. These trees are broadly relevant, such as to study the affinity maturation of B cells in the immune system. Discretizing time in a rooted phylogram gives a fully heterochronous ranked tree shape, where leaves are part of the total order. Here we extend the F-matrix framework to such fully heterochronous ranked tree shapes. We establish an explicit bijection between a class of F-matrices and the space of such tree shapes. The matrix representation has the key feature that the value at any entry is highly constrained by four previous entries, enabling straightforward enumeration of all valid tree shapes. We also use this framework to develop probabilistic models on ranked tree shapes. Our work extends understanding of combinatorial objects that have a rich history in the literature.}, }
@article {pmid42118692, year = {2026}, author = {Rejeski, K and Banerjee, R and Hill, JA}, title = {How we prevent infections in adults receiving bispecific antibody therapies for advanced B-cell malignancies.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025032298}, pmid = {42118692}, issn = {1528-0020}, abstract = {T-cell engaging bispecific antibodies (BsAbs) have transformed the treatment landscape for multiple hematologic malignancies and are under investigation in the frontline setting, within combination regimens, and for non-malignant diseases. However, their increasing use has revealed new patterns of immune suppression and infectious complications that differ from other treatment modalities including chimeric antigen receptor T-cell therapy. Notably, infections are frequent and represent the principal cause of non-relapse mortality. These risks with repeated BsAb dosing arise from multifactorial mechanisms, including B-cell or plasma-cell aplasia, hypogammaglobulinemia, and early cytopenias. Additional contributors such as T-cell exhaustion, cytokine-directed immune modulation, and disease-related immunodeficiency further compound infection risk. The result is a dynamic and cumulative impairment of host immunity that evolves over the course of therapy. In this "How I Treat" article, we provide a practical, phase-based framework for preventing and managing infections in patients receiving BsAbs for non-Hodgkin lymphoma or multiple myeloma. Our review includes pre-treatment evaluation, the period of active therapy, and long-term follow-up. Using representative cases, we highlight strategies for infectious disease screening, antimicrobial prophylaxis, immunoglobulin supplementation, vaccination, and other supportive care practices. Our aim is to equip clinicians with an evidence-informed and pragmatic framework for mitigating BsAb-related infection risks.}, }
@article {pmid42118698, year = {2026}, author = {Kastritis, E and Palladini, G and Minnema, MC and Wechalekar, AD and Jaccard, A and Lee, HC and Sanchorawala, V and Mollee, P and Lu, J and Schönland, SO and Gatt, ME and Suzuki, K and Kim, K and Cibeira, MT and Bhutani, M and Beksac, M and Libby, EN and Valent, J and Hungria, V and Rosenzweig, MA and Bumma, N and Huart, A and Dimopoulos, MA and Bhutani, D and Waxman, A and Goodman, S and Zonder, JA and Lam, S and Song, KW and Hansen, T and Manier, S and Roeloffzen, WWH and Jamroziak, K and Kwok, F and Shimazaki, C and Kim, JS and Crusoé, EQ and Tran, N and Wang, J and Chen, Y and Vasey, SY and Schecter, JM and Vermeulen, J and Comenzo, R and Merlini, G}, title = {Daratumumab-Bortezomib-Cyclophosphamide-Dexamethasone in Newly Diagnosed Amyloidosis: ANDROMEDA Final Survival Analysis.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025032099}, pmid = {42118698}, issn = {1528-0020}, abstract = {In the primary analysis of ANDROMEDA, addition of subcutaneous daratumumab to bortezomib/cyclophosphamide/dexamethasone (D-VCd) significantly improved hematologic complete response (CR) rate versus VCd, establishing D-VCd as the only approved therapy for light-chain (AL) amyloidosis. We present results from the preplanned final analysis. In this phase 3 trial, we randomly assigned 388 patients with newly diagnosed AL amyloidosis to six cycles of VCd alone (control group) or with subcutaneous daratumumab (D-VCd) followed by single-agent daratumumab every 4 weeks for up to 24 total cycles. The primary endpoint was hematologic CR. The updated hematologic CR rate was 59.5% for D-VCd versus 19.2% for VCd (odds ratio, 6.03; 95% confidence interval [CI], 3.80-9.58; P<0.0001). Median time to hematologic CR was shorter with D-VCd (67.5 days [range, 8.0-879.0]) versus VCd (85.0 days [range, 14.0-617.0]). With a median follow-up of 61.4 months, significant improvement was observed with D-VCd versus VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P=0.0121). Cardiac and renal response rates were 2-3 times higher with D-VCd versus VCd. Achieving hematologic or cardiac CR was associated with improved major organ deterioration-progression-free survival and overall survival. Adverse events were consistent with the known safety profiles for VCd and daratumumab. Adding daratumumab to VCd resulted in deeper and more rapid hematologic responses and recovery of organ function, translating to statistically significant improvement in both overall survival and major organ deterioration-progression-free survival in newly diagnosed AL amyloidosis. ClinicalTrials.gov NCT03201965.}, }
@article {pmid42118855, year = {2026}, author = {Colgan, JN and Peplinski, JH and Wang, YC and Kirkey, DC and Wallace, L and Feng, Y and Fan, L and Connerty, P and Ries, RE and Lamble, AJ and Huang, BJ and Alonzo, TA and Ma, X and Tarlock, K and Meshinchi, S}, title = {Clinical implications of RAS mutations in AML: Prognostic significance is based upon involved gene and mutation complexity.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018699}, pmid = {42118855}, issn = {2473-9537}, abstract = {Acute myeloid leukemia (AML) is a heterogeneous disease with complex mutational profiles that lead to variable clinical outcomes. NRAS and KRAS are among the most frequently mutated genes in AML, but their clinical impact has not been well-characterized. In this cohort of over 2000 children and young adults with AML, we evaluated the role of mutations in RAS genes and mutation complexity in outcome determination. Given enrichment in KMT2A-rearranged AML (KMT2A-r), we specifically studied the significance of RAS mutations in KMT2A-r AML. Using variant calls from next generation sequencing (NGS) platforms, we identified RAS mutations in 35.1% (N=669) (NRAS, N=518; KRAS, N=216). We demonstrated that NRAS mutations were not associated with outcome in AML or in KMT2A-r AML. In contrast, KRAS mutations demonstrated inferior outcomes in AML, with enrichment of prevalence and enhancement of prognostic implications in KMT2A-r AML, including non-high risk KMT2A fusions. Additionally, we describe a complex RAS mutation cohort (Comp-RAS) characterized by two distinct RAS mutations or high variant allele frequency (VAF) RAS mutations that collectively account for 13.5% (n=90) of patients with RAS mutations. Patients with complex KRAS mutations, and those with complex RAS mutations in the KMT2A-r cohort, had a distinctly adverse outcome, and data demonstrates that Comp-RAS status drives adverse outcomes for those with KRAS mutations in the whole AML cohort.}, }
@article {pmid41809001, year = {2026}, author = {Loes, AN and Tarabi, RAL and Li, SH and Atkinson, RK and Huddleston, J and Kikawa, C and Griffiths, T and Drapeau, EM and Wong, SS and Cheng, SMS and Leung, NHL and Cobey, S and Cowling, BJ and Bedford, T and Hensley, SE and Bloom, JD}, title = {Strain-specific differences in the response to egg-derived versus recombinant protein influenza vaccines.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, doi = {10.64898/2026.02.23.707528}, pmid = {41809001}, issn = {2692-8205}, abstract = {The 2023/2024 influenza vaccine included an updated H1N1 component designed to better match a new clade of H1N1 that had multiple mutations in antigenic epitopes of hemagglutinin. Despite this update, the vaccine trended towards being less effective against the vaccine-matched H1N1 clade than the parental H1N1 clade lacking the new antigenic mutations. Here we measure neutralization titers of serum antibodies from individuals who had received either a recombinant protein or an egg-derived vaccine against a set of viruses with hemagglutinins from 58 H1N1 strains representative of the diversity during the 2023/2024 season. We find that egg-derived vaccine recipients, but not recombinant protein vaccine recipients, had a relatively lower boost in neutralizing titers to the new clade that the updated vaccine was designed to target. We suggest that the difference in the extent that the egg-derived versus recombinant protein vaccines boosted neutralizing titers to the new H1N1 clade is because the seed strain for the egg-derived vaccine strain had acquired a reversion of a key antigenic mutation (K142R) present in that clade. Our results show how egg-derived versus recombinant protein vaccines can elicit different relative titer boosts against different subsets of viral strains, a phenomenon that could impact vaccine effectiveness.}, }
@article {pmid42039454, year = {2026}, author = {Potchen, NB and MacMillan, HR and Domenjo-Vila, E and Konecny, AJ and Taber, AK and DeJong, CS and Daggupati, G and Shree, S and McCartney, SA and Wright, SW and Newell, EW and Dixon, DR and Prlic, M}, title = {Tissue-specific adaptation of human T cells is preserved during tissue inflammation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42039454}, issn = {2692-8205}, abstract = {T cells play an essential role in protecting tissues against pathogens and regulating tissue homeostasis. Previous studies highlight that T cells display tissue-specific phenotypic and functional properties, suggesting that T cells adapt to their local environment. Whether inflammation disrupts tissue-specific T cell adaptation remains poorly understood. To address this open question, we examined the T cell compartment - including conventional CD4 and CD8 T cells, regulatory T cells, γδ T cells, and MAIT cells - from healthy and inflamed human mucosal tissues. Using high-parameter spectral flow cytometry, we examined phenotype ex vivo and the functional capacity following stimulation, utilizing conventional gating and unsupervised clustering analysis approaches. Overall, we analyzed 65 tissue samples including mild, moderate, and severely inflamed oral gingiva, healthy and inflamed lung, along with healthy and inflamed tissue from the decidual-placental interface. Across these mucosal barrier tissues, we find that tissue location plays a dominant role in shaping the composition, phenotype, and functional capacity of the T cell compartment. Importantly, these tissue-specific adaptations were largely maintained during states of tissue inflammation. This included the ability to exert tissue repair functions, which was preserved across T cell subsets, even in severely inflamed tissues.}, }
@article {pmid42039529, year = {2026}, author = {Valkiers, S and Mayer-Blackwell, K and Yeh, AC and Van Deuren, V and Fiore-Gartland, A and Hill, GR and Laukens, K and Meysman, P and Bradley, P}, title = {Deciphering antigen-driven T cell responses through vectorized TCRdist sequence neighborhood quantification.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42039529}, issn = {2692-8205}, abstract = {T cells provide precise mechanisms to defend the body against infection and malignancies, mediated through the expression of their hypervariable T cell receptors (TCRs). Interpreting similarity between TCRs, however, remains a significant challenge. While performant clustering methods exist, these often fail to distinguish between antigen-driven convergent selection and patterns arising stochastically from biases in the V(D)J recombination mechanism. Moreover, defining enrichment in sequence similarity among large repertoires is computationally taxing. To address these limitations, we present an efficient computational framework for rapid approximation of TCRdist distances using fixed-length vector embeddings and highly optimized nearest neighbor search, allowing sequence similarity enrichment testing at a multi-repertoire-wide scale. This framework leverages a novel shuffling-based background model that preserves important repertoire characteristics such as V gene frequency, CDR3 sequence length and generation probability more accurately than synthetic models. Together, these tools enable the efficient and robust identification of significantly neighbor enriched (SNE) TCR sequences at scale. We validate this approach by showing a significant enrichment of SNE clones in memory T cell fractions and further demonstrate its utility in identifying convergent T cell signatures of response to vaccination and viral infections, providing a scalable approach for antigen-agnostic T cell response profiling.}, }
@article {pmid42051576, year = {2026}, author = {Shalhout, SZ and Fragano, A and Chefitz, G and Andrew, TW and Lachance, K and Kulikauskas, R and Nghiem, P and Brownell, I}, title = {Immunotherapy Significantly Improves Merkel Cell Carcinoma-Specific Survival: A Single-Cohort Propensity Score-Matched Analysis.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42051576}, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICI) have improved outcomes in Merkel cell carcinoma (MCC). Population analyses suggest improved survival following the 2017 approval of ICI, but registry data lack treatment-level information including type of systemic therapy and initiation timepoint to directly estimate the benefit attributable to immunotherapy. This study compared Merkel Cell Carcinoma-specific survival between patients treated with first-line ICI versus cytotoxic chemotherapy.<br><br>METHODS: Patients were identified from the Seattle Merkel Cell Carcinoma Registry. Among 1,517 patients with MCC, 463 received first-line systemic therapy with either ICI or chemotherapy. Propensity scores were estimated using logistic regression including AJCC 8th stage, age, sex, MCPyV status, and immunosuppression. One-to-one nearest-neighbor matching produced balanced cohorts of 133 ICI-treated and 133 chemotherapy-treated patients. Merkel Cell Carcinoma-specific survival from therapy initiation was analyzed using Kaplan-Meier and Cox proportional hazards models with follow-up administratively censored at five years.<br><br>RESULTS: Baseline clinical characteristics were comparable between matched cohorts. ICI therapy was associated with significantly improved Merkel Cell Carcinoma-specific survival compared with chemotherapy (log-rank p<0.0001). Five-year Merkel Cell Carcinoma-specific survival was 56.8% (95% CI 46.8-65.6) for ICI versus 23.9% (95% CI 16.9-31.6) for chemotherapy. In multivariable stage-stratified Cox analysis, ICI remained independently associated with improved Merkel Cell Carcinoma-specific survival (HR 0.32, 95% CI 0.21-0.50; p<0.0001), while immunosuppression was associated with worse Merkel Cell Carcinoma-specific survival (HR 2.03, 95% CI 1.10-3.74; p=0.0228).<br><br>CONCLUSIONS: ICI therapy was associated with substantially improved MCC-specific survival compared with chemotherapy.}, }
@article {pmid42078349, year = {2026}, author = {Moon, JY and Filigrana, P and Gallo, LC and Perreira, KM and Cai, J and Daviglus, M and Fernández-Rhodes, LE and Garcia-Bedoya, O and Qi, Q and Thyagarajan, B and Tarraf, W and Wang, T and Kaplan, R and Isasi, CR}, title = {Non-genetic component of height as a surrogate marker for childhood socioeconomic position and its association with cardiovascular and brain health: results from HCHS/SOL.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {42078349}, abstract = {Childhood socioeconomic position (SEP) can have lifelong effects on health. Many studies have used adult height as a surrogate marker for early-life conditions. In this study, we derived the non-genetic component of height, calculated as the residual from sex-specific standardized height regressed on genetically predicted height, as a surrogate for childhood SEP, using data from the Hispanic Community Healthy Study/Study of Latinos (2008-2011). A positive residual would indicate favorable early-life conditions promoting growth, while a negative residual indicates early-life adversity that may stunt the development. The height residual was associated with early-life variables such as parental education, year of birth, US nativity and age at first migration to the US (50 states/DC), supporting the validity of height residual as a surrogate for early-life conditions. Furthermore, a height residual was positively associated with better cardiovascular health (CVH) and cognitive function among middle-aged and older adults. Interestingly, among <35 years old, the height residual was negatively associated with the "Life's Essential 8" clinical CVH scores. These results suggest the non-genetic component of height as a surrogate for childhood environment, with predictive value for CVH and cognitive function.}, }
@article {pmid42105088, year = {2026}, author = {Nassereddine, S and Feng, Y and Selep, J and El Chaer, F and Wells, L and Elsarrag, R and Doucette, K and Aggarwal, V and Williams, L and Tabbara, I and Liu, S and Diao, G and Percival, MM and Lai, C}, title = {Impact of diagnosis-to-treatment interval on the outcome of patients with acute myeloid leukemia.}, journal = {Annals of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1007/s00277-026-07052-7}, pmid = {42105088}, issn = {1432-0584}, abstract = {Acute myeloid leukemia (AML) is considered an oncologic emergency, yet the optimal timing for treatment initiation remains uncertain. We conducted a multi-institutional retrospective study of 698 adults with newly diagnosed AML presenting to four academic centers across the United States. Diagnosis-to-treatment intervals (DTI) were categorized as < 5 days, 5-10 days, and > 10 days. Outcomes were analyzed using multivariable models adjusting for age, treatment intensity, ELN 2017 risk classification, and white blood cell count. Among younger patients, DTI was not associated with differences in survival outcomes. In contrast, older patients demonstrated improved survival with delayed treatment (DTI > 10 days), particularly those with lower white blood cell counts. No adverse effects from treatment delay were observed in younger cohorts. This retrospective study showed that prolonged DTI is associated with improved survival in older adults with newly diagnosed AML, challenging the traditional assumption that immediate therapy universally improves outcomes. These findings underscore the importance of individualized treatment timing in the era of precision oncology.}, }
@article {pmid42106837, year = {2026}, author = {Lotan, Y and Anai, S and Kim, H and Gin, G and Akhavein, A and Miyake, M and Luu, M and Ahdoot, M and Messing, E and Peers, G and Chen, A and Moradzadeh, A and Chin, AI and Liu, M and Tanaka, S and Tikhonekov, S and Pagano, I and Zheng, Y and Zhang, Z and Furuya, H and Rosser, CJ}, title = {Detection of bladder cancer in patients with microscopic hematuria using Oncuria-Detect: results of a prospective, multicenter international study.}, journal = {Journal of translational medicine}, volume = {}, number = {}, pages = {}, doi = {10.1186/s12967-026-08245-4}, pmid = {42106837}, issn = {1479-5876}, abstract = {BACKGROUND: Microscopic hematuria occurs in up to 10% of the general population and initiates costly evaluation to ensure no bladder cancer exists. Oncuria-Detect is a 10-plex immunoassay that detects de novo bladder cancer by generating a protein biomarker signature from a single voided urine sample. This report details the analysis of our prospective study that compares the diagnostic performance of the multiplex Oncuria-Detect assay to that of the single-analyte (i.e., NMP22) BladderChek™ urine assay and urine cytology for identifying bladder/urothelial cancer in patients with microscopic hematuria.<br><br>METHODS: From September 2018 through July 2025, 9 medical facilities in the US and Japan prospectively enrolled 321 participants of whom 292 were deemed eligible. The bladder cancer diagnostic reference standard was cystoscopy with biopsy. Pre-cystoscopy, patients provided a urine sample for analysis by Oncuria-Detect and BladderChek&#x2122; (analyzed in a blinded manner) as well as urine cytology.<br><br>RESULTS: Bladder cancer was diagnosed in 22 patients (7.5%). The Oncuria-Detect assay had the following performance characteristics 82.0% sensitivity and 97.5% negative predictive value (NPV) compared to BladderChek&#x2122; (9.3% sensitivity and 95.4% NPV) and cytology (44.8% sensitivity and 97.2% NPV). Oncuria-Detect displayed favorable sensitivity for identifying early- and late-stage cancer. Oncuria-Detect had a favourable performance in detecting high-grade and MIBC (i.e., aggressive cancers); high-grade sensitivity was 93.5% (95%CI: 0.783-1.000) and MIBC sensitivity was 100.0% (95%CI: 1.000-1.000) compared to BladderChek&#x2122; high-grade sensitivity of 13.8% (95%CI: 0.000-0.370) and MIBC sensitivity was 0.0% (95%CI: 0.000-0.000) and cytology high-grade sensitivity was 60.1% (95%CI: 0.333-0.852) and MIBC sensitivity was 73.9% (95%CI: 0.000-1.000).<br><br>CONCLUSIONS: In this analysis of an international prospective trial, Oncuria-Detect performed favorably in the non-invasive evaluation of bladder cancer presence in patients presenting with microscopic hematuria.<br><br>CLINICAL TRIAL NUMBER: Clinicaltrials.gov NCT03193541.}, }
@article {pmid42107553, year = {2026}, author = {Gomez, SE and Larson, J and Hlatky, MA and Kooperberg, C and LaMonte, M and Tinker, L and Greenland, P and Albert, C and Froelicher, V and Wheeler, M and Stefanick, ML and Perez, MV}, title = {Women's Health Initiative Strong and Healthy Silent Atrial Fibrillation Recording Study: Rationale, Study Design and Baseline Data.}, journal = {American heart journal}, volume = {}, number = {}, pages = {107478}, doi = {10.1016/j.ahj.2026.107478}, pmid = {42107553}, issn = {1097-6744}, abstract = {RATIONALE: Atrial fibrillation (AF) has roughly tripled in prevalence over the last 50 years. This disease disproportionately affects morbidity and mortality among older women. Increased physical activity has been associated with lower incidence of new AF in some studies, but higher incidence in others, especially among elite athletes.<br><br>PRIMARY HYPOTHESIS: We designed a randomized trial within the Women's Health Initiative (WHI) Strong and Healthy (WHISH) trial to test the hypothesis that a pragmatic intervention consisting of multimodal messaging recommending physical activity levels consistent with national guidelines would decrease the incidence of AF among a cohort of older women.<br><br>DESIGN: The present WHISH Silent Atrial Fibrillation Recording (WHISH STAR) trial randomized 29,758 postmenopausal women without baseline AF who were enrolled in Medicare Fee-for-Service to the aforementioned intervention or comparison group, with planned 7-year follow-up to assess the primary outcome of incident clinical AF, namely those identified in Medicare claims. We also designed a sub-study of 1,257 women at high risk for AF (with a CHARGE-AF score &#x2265; 5%) to undergo serial, 7-day ECG patch monitoring to detect screened AF. We will use Cox proportional hazards models to compare the incidence of clinical AF in the participants assigned to physical activity intervention and the participants assigned to usual care groups. We will also compare the incidence of screened AF in the intervention and comparison groups detected on patch ECG monitors in the sub-study of women who underwent serial ECG patch monitoring. The WHISH STAR trial will rigorously evaluate of the effect of a pragmatic physical activity intervention on the development of AF in a large, diverse, well-characterized cohort of older women.<br><br>SITES: The WHISH trial is embedded within the nationwide WHI study, enrolling postmenopausal women from 40 US clinical centers.<br><br>ENROLLMENT DATES: Participants were enrolled in 2015 per the parent WHISH trial.<br><br>CURRENT STATUS: WHISH STAR is in the analysis phase.<br><br>TRIAL REGISTRATION: WHISH STAR has been registered on www.<br><br>CLINICALTRIALS: gov (NCT05366803).}, }
@article {pmid42108644, year = {2026}, author = {Shore, ND and Fizazi, K and Schweizer, MT and Castro, E and Azad, AA and George, DJ and da Trindade, KM and Zeng, H and Shrivastava, N and Tonkovyd, S and Bock, A and Nekkalapudi, S and Tang, Y and Lin, S and Agarwal, N}, title = {Phase III randomized studies of mevrometostat and enzalutamide in metastatic prostate cancer (MEVPRO-1 and MEVPRO-2): trial protocols.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {1-12}, doi = {10.1080/14796694.2026.2667441}, pmid = {42108644}, issn = {1744-8301}, abstract = {Phase I investigation of the enhancer of zeste homolog 2 inhibitor, mevrometostat, plus enzalutamide showed promising antitumor activity versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT03460977). MEVPRO-1 (open label) and MEVPRO-2 (double blind) are ongoing, global, phase III, randomized studies evaluating efficacy and safety of mevrometostat plus enzalutamide in patients with mCRPC. MEVPRO-1 will include ~600 patients with ≥12 weeks of prior abiraterone treatment, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, testosterone ≤50 ng/dL, and life expectancy ≥6 months. MEVPRO-2 will include ~900 androgen receptor pathway inhibitor-naïve patients, with ECOG PS 0-1, testosterone ≤50 ng/dL, and life expectancy ≥12 months. Patients are randomized 1:1 to mevrometostat (875 mg twice daily with food) plus enzalutamide (160 mg once daily), or physician's choice of enzalutamide or docetaxel (MEVPRO-1) or enzalutamide (MEVPRO-2). Primary endpoint is radiographic progression-free survival (rPFS) per Response Evaluation Criteria in Solid Tumors 1.1 (soft tissue) and Prostate Cancer Working Group 3 criteria (bone) assessed by blinded independent central review. Overall survival is a secondary objective. Kaplan-Meier analysis will summarize time-to-event endpoints. Safety will be assessed. Results will evaluate whether mevrometostat plus enzalutamide can provide clinical benefit in patients with mCRPC.Clinical trial registration: www.clinicaltrials.gov identifiers are NCT06551324 (MEVPRO-1) and NCT06629779 (MEVPRO-2).}, }
@article {pmid42109048, year = {2026}, author = {Zhuo, K and Banerjee, R}, title = {Withstanding the test of time for patients in oncology clinical trials.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyag176}, pmid = {42109048}, issn = {1549-490X}, }
@article {pmid42110835, year = {2026}, author = {Lim, MA and Murakami, N and Blosser, CD and Shaikhouni, S and Dadhania, DM and Hall, ET and Havlin, K and Basu, A}, title = {Practical Guide to Address Common Myths in the Pre- and Post-kidney Transplant Management of the Elderly Patient with Cancer: An Opinion Paper.}, journal = {Transplantation direct}, volume = {12}, number = {6}, pages = {e1934}, pmid = {42110835}, issn = {2373-8731}, abstract = {Two areas of overlap between kidney transplantation and oncology that remain fraught with uncertainty and bias are (1) transplant candidacy for elderly patients with historic or active cancers or premalignant conditions, and (2) managing cancer in elderly kidney transplant recipients. These have led to inadvertent inequities in the care of elderly kidney transplant candidates with historic or active malignancies. Incorporating a patient's viewpoint and an oncologist's perspective, we present a nuanced, multidisciplinary approach to management that goes beyond mere consideration of chronological age and focuses on the individual patient and his/her goals.}, }
@article {pmid42112409, year = {2026}, author = {Chen, C and Qian, Z and Zhang, B}, title = {Matching with Multiple Criteria and Its Application to Health Disparities Research.}, journal = {Observational studies}, volume = {12}, number = {1}, pages = {43-66}, pmid = {42112409}, issn = {2767-3324}, abstract = {Matching is a popular nonparametric covariate adjustment strategy in empirical health services research. Matching helps construct two groups comparable in many baseline covariates but different in some key aspects under investigation. The Institute of Medicine (IOM) defines a health services disparity as the difference in accessing health services between members of racial or ethnic minorities not justified by the difference in health status or patients' preference. To estimate a disparity measure consistent with the IOM definition, we propose a statistical matching methodology that constructs matched comparison groups from, for instance, white men, that resemble the target group, for instance, black men, in some selected covariates while remaining identical to the white men population before matching in the remaining covariates. Using the proposed method, we investigated the disparity gaps between white men and black men in the US in prostate-specific antigen (PSA) screening based on the 2020 Behavioral Risk Factor Surveillance System (BFRSS) database. We found a widening PSA screening rate as the white matched comparison group increasingly resembles the black men group. Finally, we provide code that replicates the case study and a tutorial that enables users to design customized matched comparison groups satisfying multiple criteria.}, }
@article {pmid42112456, year = {2026}, author = {Kelnhofer-Millevolte, LE and Nguyen, DH and Wilson, LS and Avgousti, DC}, title = {A comprehensive method for quantifying human cytomegalovirus plaque assays.}, journal = {Frontiers in cellular and infection microbiology}, volume = {16}, number = {}, pages = {1818664}, pmid = {42112456}, issn = {2235-2988}, mesh = {*Cytomegalovirus/growth &amp; development/physiology ; Humans ; *Viral Plaque Assay/methods ; Cytomegalovirus Infections/virology ; Staining and Labeling/methods ; Gentian Violet ; Image Processing, Computer-Assisted/methods ; Cell Line ; }, abstract = {Human cytomegalovirus (hCMV) is an important human pathogen accounting for significant morbidity in immunocompromised individuals from neonates to cancer patients. To effectively produce progeny and establish a new infection, hCMV produces dozens of proteins and manipulates the expression of thousands of host genes. When studying the effect of these viral or host genes on the production of new infective progeny, the plaque assay is the gold standard method employed. This assay is carried out by incubating serial dilutions of the supernatant to be investigated on a monolayer of permissive cells. The experimental setup includes covering the monolayer with an overlay, thereby allowing the virus to spread only through cell-to-cell contact. Subsequently, the areas of cell death, or plaques, are quantified by fixing and staining with crystal violet. Here we take advantage of the fluorescent nature of crystal violet and image hCMV plaques in a variety of modalities. Following the acquisition of these images, we developed a broadly applicable pipeline to use open access software ImageJ to quantify the number and size of the hCMV plaques. The use of this method can provide a standardized way to objectively count and quantify the infectious progeny produced, allowing researchers to better understand hCMV.}, }
@article {pmid42112614, year = {2026}, author = {Graff, JN and Smith, CEP and Sokolova, AO and Qian, DZ and Beer, TM and Latour, E and Bailey, S and Kreitner, D and Grivas, P and Schweizer, MT and Higano, CS and Alumkal, JJ and Vuky, J and Yu, EY and Cheng, HH}, title = {A Phase I/II Trial of Concurrent Chemo-hormonal Enzalutamide and Cabazitaxel in Patients with Metastatic Castration-Resistant Prostate Cancer.}, journal = {The oncologist}, volume = {}, number = {}, pages = {}, doi = {10.1093/oncolo/oyag180}, pmid = {42112614}, issn = {1549-490X}, abstract = {BACKGROUND AND OBJECTIVE: Despite treatment advances, treatment resistance for metastatic castration resistant prostate cancer (mCRPC) is nearly universal. We studied the efficacy, safety, and pharmacokinetic properties of the combination of enzalutamide and cabazitaxel in patients with mCRPC. For phase 1, we examined the safety of combination therapy and determined the recommended Phase 2 dose. Phase 2 primary endpoint included the percentage of patients achieving a ≥ 90% PSA decline (PSA90) as a measure of response to therapy.<br><br>METHODS: A phase 1/2 single-arm, multi-institutional clinical trial enrolled adults with histologically confirmed progressive mCRPC without prior docetaxel or cabazitaxel chemotherapy for mCRPC. Co-administration of enzalutamide 160&#x2009;mg orally once daily, cabazitaxel 25&#x2009;mg/m2 IV once every 21&#x2009;days, and prednisone 5&#x2009;mg orally twice daily in mCRPC. Descriptive statistical analysis was used for all primary and secondary endpoints. Estimated proportions are with 95% confidence interval using exact method.<br><br>KEY FINDINGS: The study met its primary endpoint with 61.1% (95% CI: 43.5% to 76.9%) of patients achieving PSA90. Observed toxicities were similar to those seen with either agent alone.<br><br>CONCLUSIONS: The combination of enzalutamide and cabazitaxel exhibited robust activity with a tolerable side effects. Chemo-hormonal therapies warrant further study in mCRPC.<br><br>WHAT DOES THE STUDY ADD: This study of enzalutamide and cabazitaxel combination therapy in patients with advanced, pre-treated mCRPC showed promising efficacy, indicating strong rationale for further investigation.<br><br>PATIENT SUMMARY: In this report we looked at outcomes for patients with metastatic prostate cancer treated at multiple institutions with enzalutamide and cabazitaxel at the same time after castration therapy alone had stopped working. We found the combination was safe and had anti-cancer effect, warranting further investigation.}, }
@article {pmid42113488, year = {2026}, author = {Hladik, F and Hughes, SM and Levy, CN and Creighton, RL and Mackelprang, R and Gornalusse, GG}, title = {Tenofovir, Interferon Pathways, and Mucosal Immunity: Implications for People Living With HIV.}, journal = {American journal of reproductive immunology (New York, N.Y. : 1989)}, volume = {95}, number = {5}, pages = {e70255}, doi = {10.1111/aji.70255}, pmid = {42113488}, issn = {1600-0897}, support = {R01 AI172111/NH/NIH HHS/United States ; R01 AI184122/NH/NIH HHS/United States ; R01 AI116292/NH/NIH HHS/United States ; R01 AI134293/NH/NIH HHS/United States ; R21 AI174903/NH/NIH HHS/United States ; KL2 TR002317/NH/NIH HHS/United States ; P30 AI027757/NH/NIH HHS/United States ; }, mesh = {Humans ; *Tenofovir/therapeutic use ; *HIV Infections/drug therapy/immunology ; *Immunity, Mucosal/drug effects ; *Interferons/metabolism ; Signal Transduction/drug effects ; *Anti-HIV Agents/therapeutic use ; }, abstract = {BACKGROUND: Antiretroviral therapy (ART) suppresses HIV replication and protects people living with HIV (PLWH) from progressing to AIDS. However, despite ART, many PLWH experience chronic immune activation, which contributes to premature aging and non-AIDS-related comorbidities. One reason for this chronic immune activation (CIA) is HIV and its reservoir. There is, however, accumulating evidence for an unexpected contributor: the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) class of drugs, particularly tenofovir, which can independently induce interferon (IFN) signaling in mucosal tissues. This CIA-driving effect of tenofovir and other NRTIs warrants further study, as these therapies are taken lifelong and PLWH suffer disproportionately from inflammation-related comorbidities.<br><br>OBJECTIVE: This review synthesizes evidence demonstrating that tenofovir contributes to CIA across multiple mucosal compartments (rectum, duodenum, and vagina) in both HIV-uninfected and infected individuals. We detail the known mechanisms that likely underlie NRTI-induced CIA: (1) Suppression of interleukin 10 (IL-10), and induction of interleukin 12 (IL-12) and interferon-stimulated genes (ISGs), through inhibition of the protein kinase AKT, and (2) interferon response-enhancing interactions with endogenous retroelements. Tenofovir also increases the number of specialized ISG[high] epithelial cells in the gut. We further discuss the hypothesis that the chronic interferon signaling driven by NRTIs exacerbates HIV reservoir persistence and T-cell exhaustion. Finally, we propose emerging therapeutic strategies, including NRTI-sparing antiretroviral regimens and targeted immunomodulatory treatments, to reduce CIA and improve clinical outcomes for PLWH.}, }
@article {pmid42114530, year = {2026}, author = {Mahomed, S and Paez, CA and Huang, Y and Seaton, KE and Yu, C and Gillespie, K and Miner, MD and Karuna, ST and Gamble, T and Heptinstall, J and Domin, E and Tang, H and Zhang, L and Gao, F and Yacovone, M and Spiegel, HML and Dumond, J and Anderson, MA and Piwowar-Manning, E and Dye, BJ and Tindale, I and Proulx-Burns, L and Trahey, M and Takuva, S and Takalani, A and Bailey, VC and Kalams, SA and Scott, H and Kosgei, J and Delany-Moretlwe, S and Kassim, S and Laher, F and Chirenje, ZM and Musodza, Y and Mhlanga, F and Mkhize, N and Weiner, JA and Ackerman, ME and McElrath, MJ and Pensiero, MN and Gama, L and Barouch, DH and Corey, L and Cohen, MS and Montefiori, DC and Tomaras, GD and Siegel, M and Kelley, CF and , }, title = {Safety, pharmacokinetics, and neutralisation activity of PGDM1400LS, VRC07-523LS, and PGT121.414.LS infused intravenously or subcutaneously (HVTN 140/HPTN 101 part B): a phase 1, randomised trial.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(25)00356-X}, pmid = {42114530}, issn = {2352-3018}, abstract = {BACKGROUND: Passive immunisation with a combination of broadly neutralising monoclonal antibodies (mAbs) presents a potential HIV-1 prevention modality. This study (HVTN 140/HPTN 101) sought to evaluate PGDM1400LS (targeting V3-glycan) administered alone (part A, previously reported), and in combination (part B) with VRC07-523LS (targeting CD4 binding site) and PGT121.414.LS (targeting V2-apex) in healthy adults without HIV-1.<br><br>METHODS: The study was a phase 1, multicentre, randomised, open-label trial done across the USA (five sites), Kenya (one site), South Africa (four sites), and Zimbabwe (three sites). Part B participants were randomly assigned to five groups (n=16 each), all receiving the three mAbs at months 0 and 4: infusion group T6 (20 mg/kg each mAb intravenously), T7 (20 mg/kg each mAb subcutaneously), T8 (1&#xb7;4 g each mAb intravenously), T9 (1&#xb7;4 g each mAb subcutaneously), and T10 (40 mg/kg each mAb intravenously). Primary endpoints were safety and tolerability throughout the study, and pharmacokinetics and neutralising activity on days 0, 3, 6, 28, 56, 112, 168, 224, and 280. Serum mAb concentrations over time were assessed via a validated anti-idiotype binding assay and analysed with two-compartment population pharmacokinetics models. Serum neutralisation titres were assessed by a validated TZM-bl assay. The study is registered at ClinicalTrials.gov (NCT05184452) and is complete.<br><br>FINDINGS: For the 80 part B participants enrolled from March 21 to Oct 5, 2022, the median age was 27&#xb7;0 years, with 47&#xb7;5% females. Most participants had mild-to-moderate solicited local and systemic symptoms. No serious adverse events were reported. On the basis of pharmacokinetics data from part A and part B combined, the estimated elimination half-life of PGDM1400LS was 53 days (51&#xb7;4-55&#xb7;3). Subcutaneous administration of PGDM1400LS exhibited bioavailability of 73&#xb7;0% (67&#xb7;5-78&#xb7;5%) relative to intravenous administration of the same dose. PGT121.414.LS had an estimated elimination half-life of 65 days (61&#xb7;8-68&#xb7;1) with subcutaneous bioavailability of 77&#xb7;7% (71&#xb7;2-84&#xb7;1), and VRC07-523LS had an estimated elimination half-life of 44 days (41&#xb7;6-45&#xb7;7) with a subcutaneous bioavailability of 80&#xb7;1% (71&#xb7;4-88&#xb7;8). Both weight-based and fixed-dose regimens showed similar pharmacokinetic profiles. Observed neutralisation titres were consistent with those predicted on the basis of concentrations and in vitro neutralisation. No treatment-induced anti-drug antibody responses were detected.<br><br>INTERPRETATION: The mAb combination of PGDM1400LS, PGT121.414.LS, and VRC07-523LS was safe and well tolerated, with no antagonistic pharmacokinetic interactions or loss of neutralisation activity. These findings support further evaluation of this combination in future efficacy trials.<br><br>FUNDING: National Institute of Allergy and Infectious Diseases-National Institutes of Health.}, }
@article {pmid42114785, year = {2026}, author = {Wright, JL and Moughan, J and Woodward, WA and Rahbar, H and Shah, AB and Comstock, C and Jarvis, LA and Tjoe, JA and Germain, I and Badve, SS and Strom, E and Recht, A and Ling, DC and Vallow, LA and Stephenson, JJ and Currey, A and Walker, EM and Reiter, H and Steinberg, ML and Pierce, LJ and Winter, K and Sparano, J and Davidson, NE and Wolff, A and Mamounas, EP and White, JR and McCormick, B}, title = {Impact of Tamoxifen Only after Lumpectomy for "Good Risk" Duct Carcinoma in Situ: Combined Analysis of the NRG Oncology/RTOG 9804 and ECOG-ACRIN E5194 Trials.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2026.04.103}, pmid = {42114785}, issn = {1879-355X}, abstract = {PURPOSE: The NRG/RTOG 9804 trial randomized patients with "good risk" ductal carcinoma in situ (DCIS) to radiation (RT) or none following lumpectomy. The ECOG-ACRIN E5194 trial had a comparable cohort observed without RT. Tamoxifen use was optional in both trials. This ancillary exploratory analysis combining both datasets assesses the effect of tamoxifen on ipsilateral breast recurrence (IBR) in "good risk" DCIS treated with lumpectomy alone.<br><br>METHODS AND MATERIALS: A combined database from the non-RT arm of NRG/RTOG 9804 and the "good risk" cohort from E5194 (low- or intermediate grade, &#x2264;2.5cm, excision margins &#x2265;3mm) was created and distributions of patient and DCIS characteristics by tamoxifen use were compared by Chi-square. IBR, invasive-IBR, DCIS-IBR, contralateral breast event, and overall survival were estimated and distributions between tamoxifen use were compared. Univariate and multivariable Fine-Gray regression was used to analyze factors that may be associated with endpoints.<br><br>RESULTS: 878 patients were analyzed (317 from NRG/RTOG 9804, 561 from E5194). The use of tamoxifen overall was 43.1% (65.6% in NRG/RTOG 9804, 30.3% in E5194). At median follow-up of 14.85 years, there were 117 IBR (65 invasive, 52 DCIS). There was a significant association for reduced IBR with tamoxifen use (p=0.001); estimated 15-year IBR (95% CI) with tamoxifen is 11.4% (7.9%, 15.5%) and without is 19.0% (15.3%, 22.9%). Tamoxifen use was significantly associated with reduced invasive-IBR (p=0.0048) but not DCIS-IBR (p=0.089). On multivariable analysis, patients who received tamoxifen were 46% less likely to have any IBR (HR=0.54, 95% CI: 0.35, 0.83; p=0.0045), and 57% less likely to have invasive-IBR (HR=0.43, 95% CI: 0.24, 0.77; p=0.0042).<br><br>CONCLUSION: For patients with "good risk" DCIS treated with lumpectomy without RT, tamoxifen use was significantly associated with a reduction in IBR overall and invasive-IBR, not DCIS-IBR.}, }
@article {pmid42101917, year = {2026}, author = {Gorsline, CA and Kumar, RN and McCulloch, DJ and Abidi, MZ and Limaye, AP and Harris, CE}, title = {Making the Most of a Transplant ID Conference: A Practical Guide for Trainees and Early-Career Faculty.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70228}, doi = {10.1111/tid.70228}, pmid = {42101917}, issn = {1399-3062}, abstract = {Attending conferences is a foundational component of professional growth in transplant infectious diseases (TIDs), yet trainees and early-career faculty often face an overwhelming array of meeting options and limited guidance on how to maximize the experience. This report outlines practical strategies for selecting the most impactful conferences, preparing effectively, engaging with poster sessions, cultivating meaningful professional connections, and incorporating rest and reflection into conference travel. Unlike previous discussions hosted by the TID Early Career Network (TxIDECN), which typically occurred over social media, this was a live expert panel with audience participation at the 2025 Fred Hutch Symposium on Infectious Diseases in the Immunocompromised Host on May 13, 2025, in Seattle, Washington. Here, we summarize that discussion with actionable tools to navigate conferences intentionally and translate these experiences into sustained academic and career development for emerging TID professionals.}, }
@article {pmid42103082, year = {2026}, author = {Lust, H and Williams, O and Schneiderman, J and Duerst, R and Jacobsohn, D and Rivera, A and Fuleihan, R and Tse, WT and Kletzel, M and Chaudhury, S}, title = {Excellent long-term survival and immune recovery with reduced-intensity conditioning HCT in inborn errors of immunity.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.05.002}, pmid = {42103082}, issn = {2666-6367}, abstract = {BACKGROUND: Reduced intensity conditioning (RIC) for pediatric patients with inborn errors of immunity (IEI) receiving allogeneic stem cell transplant (HCT) has improved outcomes, though the ideal regimen to minimize toxicity and optimize immune reconstitution (IR) remains unclear. RIC regimens with strong immune-ablation and low-dose alkylating agents offer an alternative that may reduce conditioning-related toxicity and lead to durable immune reconstitution.<br><br>OBJECTIVES: We aimed to determine the outcomes including overall survival, event free survival, rates of toxicity, and IR outcomes for patients with IEI receiving RIC HCT at our institution.<br><br>STUDY DESIGN: We reviewed survival, toxicity, and IR outcomes for patients with IEI receiving RIC HCT with targeted busulfan (2 days), fludarabine 180mg/m2, and rATG 8mg/kg (Bu2/Flu/rATG). Prior to 2007, busulfan target cumulative AUC was 32mg/L*h (cohort 1). Given high observed rates of graft failure, busulfan target was increased to 40mg/L*h and thiotepa was added in cord blood (UCB) transplants from 2008-2023 (cohort 2).<br><br>RESULTS: Between 2000-2023, 73 patients received Bu2/Flu/rATG conditioning. 5-year OS was 80%, 83% for SCID, and 77% for other IEI. For SCID, 5-year OS was lower for UCB recipients compared to PBSC - 58% vs 96% (P=0.002). Patients in cohort 1 experienced lower 5-year EFS - 44% vs 77% in cohort 2 (P=0.02). Graft failure was seen in 11 patients (15%). Incidence of &#x2265;grade 2 acute GVHD was 12%. At 1-year post-HCT, 87% of patients with evaluable data maintained full T-cell chimerism, with 80% demonstrating myeloid chimerism >50%. CD4[+] IR by day +100 was seen in 89% of patients.<br><br>CONCLUSIONS: We demonstrate excellent overall and graft-failure free survival in patients with IEI receiving a busulfan (cumulative 40mg*h/L)/fludarabine/rATG RIC regimen with high rates of early IR and sustained donor chimerism in both SCID and non-SCID IEI populations while maintaining low rates of GVHD and conditioning-related toxicity.}, }
@article {pmid42104007, year = {2026}, author = {Li, Y and Lee, DR and Allgeyer, ES and Schroeder, LK and Tu, S and Bewersdorf, J and Hao, X}, title = {Implementation of an adaptive-optics assisted isoSTED nanoscope.}, journal = {Nature protocols}, volume = {}, number = {}, pages = {}, pmid = {42104007}, issn = {1750-2799}, support = {U54 DK106857/DK/NIDDK NIH HHS/United States ; U54 DK106857/DK/NIDDK NIH HHS/United States ; LR25F050002//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; LR25F050002//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; RS-2023-00211106//National Research Foundation of Korea (NRF)/ ; }, abstract = {In stimulated emission depletion (STED) nanoscopy, high 3D resolution requires harnessing a 4Pi architecture using two opposing objectives. Here, we provide the step-by-step process for the construction and alignment of a 4Pi-STED nanoscope, commonly referred to as an 'isoSTED nanoscope'. The procedure guides interested researchers through the assembly of the optomechanical components, the configuration of the electronic and control devices, the alignment of the optical beam path and the assessment of the instrument's performance. The protocol offers a detailed roadmap for constructing an isoSTED nanoscope with adaptive optics in about 12 months and is designed for users with expertise in optical instrumentation builds. Once the instrument is finely calibrated, researchers can expect to achieve 3D biological images with isotropic sub-50-nm resolution in thick samples ≤35 µm in depth.}, }
@article {pmid42039413, year = {2026}, author = {Glass, DR and Dornisch, E and Yin, H and Ludmann, SA and Samudre, A and Kuhl, S and Malone, J and Chander, A and Kaul, SN and Phalen, CG and Parthasarathy, V and Dillon, MA and Genge, P and Stuckey, TJ and Anover-Sombke, S and Wittig, PJ and Pebworth, MP and He, Z and Henderson, KE and Ravisankar, P and Hernandez, V and Musgrove, B and Mishra, S and Krishnan, U and Thomson, Z and Weiss, M and Estep, N and Graybuck, L and Angus-Hill, M and Gustafson, CE and Kopp, M and Reading, J and Li, XJ and Viana, MP and Bumol, TF and Goldrath, AW and Sigvardsson, M and Bendall, SC and Skene, PJ and Green, DJ and Newell, EW and Torgerson, T and Glass, MC}, title = {Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {42039413}, issn = {2692-8205}, abstract = {Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults and by immature HLA-DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs.}, }
@article {pmid42095282, year = {2026}, author = {Rajasekhara, S and Bitar, HN and Loggers, ET and Norton, K and Sam, C and Case, AA and Tulsky, JA and Chwistek, M and Epstein, AS and Grossman, SR and Nelson, JE and Nortjé, N and Papio, J and Phung, P and Kolosky, J and McNiff Landrum, K}, title = {Implementation of Structured Oncologist Communication Skills Training within the Improving Goal Concordant Care Initiative: Lessons Learned and Future Progress.}, journal = {Journal of palliative medicine}, volume = {}, number = {}, pages = {10966218261449540}, doi = {10.1177/10966218261449540}, pmid = {42095282}, issn = {1557-7740}, abstract = {PURPOSE: Effective communication about goals of care is critical in oncology but limited by insufficient training and system barriers. As part of a multicomponent intervention, the Improving Goal Concordant Care (IGCC) initiative aimed to implement structured communication skills training (CST) for oncology clinicians. This study reports on the implementation and evaluation of CST across 10 dedicated cancer centers.<br><br>PATIENTS AND METHODS: IGCC was a collaborative improvement project led by the Alliance of Dedicated Cancer Centers between 2020 and 2023. Centers selected or developed CST programs meeting IGCC criteria and adapted local implementation and enabling strategies. The primary measure was the percentage of eligible oncology clinicians completing CST (target &#x2265;65%). Post-training evaluation and training impact surveys assessed clinicians' experience and perceived benefit of CST.<br><br>RESULTS: Nine centers completed CST implementation, training 2271 of 2841 eligible clinicians (80%). CST completion rates at all but one site exceeded the target, as did rates for medical oncologists, hematological oncologists, and advanced practice providers. CST completion was higher when incentives or mandates were used. Post-training evaluations showed high satisfaction with aggregated top-box scores of 93% for training quality, 94% for recommending to colleagues, and 94% for likelihood to use skills. Training impact surveys administered 6-12 months after training suggested improved self-efficacy and reduced distress, with a strong correlation between self-efficacy improvement and distress reduction.<br><br>CONCLUSIONS: IGCC demonstrated that CST can be effectively scaled across cancer centers and positively impact trained clinicians. Successful uptake was supported by leadership engagement, incentives, and mandates, while barriers included leadership transitions, time and resource constraints, and competing priorities. CST is a core component for advancing goal-concordant care.}, }
@article {pmid42095655, year = {2026}, author = {Weis, AM and Matthews, OJ and Bell, R and Pershing, NL and Dankwardt, A and Fleming, BA and Gigic, B and Schneider, M and Hardikar, S and Toriola, AT and Shibata, D and Li, CI and Byrd, DA and Stephens, WZ and Ulrich, CM and Mulvey, MA and Round, JL}, title = {Isolation of a highly virulent colibactin-positive tumor-promoting strain of Escherichia coli from the gut microbiota of an adult.}, journal = {mSphere}, volume = {}, number = {}, pages = {e0021926}, doi = {10.1128/msphere.00219-26}, pmid = {42095655}, issn = {2379-5042}, abstract = {Recent studies have pointed to critical roles for microbes in both exacerbation of and protection from the development of colon cancer. While much has been learned, the field remains understudied, with functional studies available for only a handful of bacteria. To identify novel microbes associated with colorectal cancer (CRC) development, we employed a preclinical chemical carcinogenesis CRC mouse model using germ-free mice that were colonized with human microbiotas. During the course of these studies, we identified a microbiota that exacerbated CRC, from which we isolated an Escherichia coli strain that had disseminated to the mouse kidneys. This strain, which we designated as AW001, was genetically similar to the reference adherent-invasive E. coli (AIEC) strain NC101 and encoded the DNA-damaging toxin colibactin. In relevant animal models, AW001 worsened both colitis and sepsis, making it a colitogenic AIEC-like strain with the capacity to cause invasive systemic infections similar to extraintestinal pathogenic E. coli (ExPEC). This strain will be a relevant tool to study human-associated intestinal E. coli strains capable of causing disease in mice.IMPORTANCEColorectal cancer (CRC) is a significant burden on human health. A growing body of work has pointed to critical roles for microbes in the exacerbation of and protection from the development of CRC. Specific Escherichia coli strains can produce colibactin, a genotoxin that has been implicated in exacerbating CRC. In this study, we tested human microbiotas in a mouse model of CRC and isolated a colibactin-positive Escherichia coli strain that led to tumorigenesis, disseminated from the gut to the mouse kidneys, caused death, and worsened both colitis and sepsis in murine models. Identification of this strain enhances our collective knowledge and adds an important tool for future studies on the role of microbes and CRC tumorigenesis.}, }
@article {pmid42098093, year = {2026}, author = {Pigazzi, M and Merlini, S and Da Ros, A and Marini, O and Faggin, G and Fortuna, N and Mattera, R and Buldini, B and Rizzardi, P and Meshinchi, S and Basso, G and Locatelli, F and Biffi, A}, title = {CD84 is a specific target for acute myeloid leukemia CAR-T cell therapy.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-72361-4}, pmid = {42098093}, issn = {2041-1723}, support = {IRP-synergy grant//Fondazione Citt&#xe0; della Speranza (City of Hope Foundation)/ ; IRP-synergy//Fondazione Citt&#xe0; della Speranza (City of Hope Foundation)/ ; IG-20562//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; PNRR CN3-National Center for Gene Therapy and Drugs Based on RNA Technology//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; PNRR CN3-National Center for Gene Therapy and Drugs Based on RNA Technology//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; }, abstract = {Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematologic malignancies, yet its application to acute myeloid leukemia (AML) remains challenging due to the scarcity of disease-specific antigens. The identification of a highly selective target is crucial to enhance efficacy while minimizing off-tumor toxicity. Here, we identify CD84 as a promising target for AML immunotherapy, displaying a unique expression profile: it is robustly and stably expressed by blasts, particularly in relapsed disease, and negligible on normal hematopoietic stem/progenitor cells. This profile renders CD84 an ideal target, with potential for improved therapeutic precision and potency, and with reduced risk of off-target effects and toxicity. To assess its potential, we generate CD84-directed CAR-T cells and test them in vitro and in vivo on clinically relevant models. The engineered cells exhibit potent cytotoxicity against CD84-expressing AML cell lines and patient-derived xenograft (PDX) cells, eliminating leukemic blasts even with low CD84 expression. In AML-PDX models, CAR-T treatment leads to sustained reduction of leukemia burden, doubling the survival of the treated animals compared to controls. No downregulation of CD84 expression on the blasts in the treated models is seen. Importantly, CD84 CAR-T cells spare normal hematopoietic stem/progenitor cells that after treatment retain their repopulation potential in humanized models. These findings establish CD84 as a target for AML immunotherapy and provide a compelling rationale for clinical development of CD84-directed approaches that may address an urgent need for treatment in aggressive and refractory AML.}, }
@article {pmid42100396, year = {2026}, author = {Smith, NL and Summers, C and Gooley, T and Shustov, A and Salit, R and Gardner, RA and Dahlberg, A and Bleakley, M and Sorror, ML and Holmberg, L and Carpenter, PA and Sandmaier, BM and Maloney, D and Thakar, MS}, title = {Autologous and allogeneic hematopoietic cell transplantation in children and adults with high-risk anaplastic large cell lymphoma.}, journal = {Frontiers in oncology}, volume = {16}, number = {}, pages = {1785566}, pmid = {42100396}, issn = {2234-943X}, abstract = {INTRODUCTION: Both autologous and allogeneic hematopoietic cell transplantation (HCT) have been used to treat high-risk anaplastic large cell lymphoma (ALCL) that has failed conventional chemotherapy. However, many patients are not able to fully eradicate disease prior to HCT, making the role of either form of HCT unclear. The aim of this study was to collect characteristics and outcomes of patients who underwent either autologous and/or allogeneic HCT and determine the role that disease status at HCT plays in overall survival (OS).<br><br>METHODS: To address this, we collected data on 41 patients with ALCL that underwent autologous (n=24) and/or allogeneic (n=17) HCT at our center between 1997-2020.<br><br>RESULTS: The 5-year estimated progression-free survival (PFS) and OS for the autologous HCT group was 40% (95% confidence interval, 20-59%) and 53% (31-71%), while for the allogeneic HCT group it was 65% (38-92%) and 65% (38-82%), respectively. For transplants performed in 2009 or later, 5-year OS was 91% (51-99%) in the allogeneic HCT group, and 51% (23-73%) in the autologous HCT group. Notable was that for those who entered transplant with detectable disease, 5-year OS was 50% (15-77%) with allogeneic HCT whereas it was 27% (7-54%) for autologous HCT.<br><br>DISCUSSION: These data confirm that HCT is a potentially curative therapy, and allogeneic HCT may have a survival advantage over autologous HCT when there is detectable disease prior to HCT.}, }
@article {pmid41564438, year = {2026}, author = {Davidson-Swinton, HR and Iyer, S and Kolchinski, A and Salem, JA and DeBoy, EA and Kilada, AG and Hwang, JS and Jain, T and Keel, SB and Gocke, CD and Zou, YS and Schratz, KE and Armanios, M}, title = {Lymphoid malignancy and clonality in the POT1-mediated long telomere syndrome.}, journal = {Blood}, volume = {147}, number = {19}, pages = {2226-2237}, doi = {10.1182/blood.2025031287}, pmid = {41564438}, issn = {1528-0020}, mesh = {Humans ; Middle Aged ; Shelterin Complex ; Adult ; Aged ; *Telomere-Binding Proteins/genetics ; Male ; Female ; Adolescent ; Child ; Aged, 80 and over ; Child, Preschool ; Young Adult ; *Lymphoma/genetics/pathology ; *Telomere/genetics ; Mutation ; Hematologic Neoplasms/genetics ; }, abstract = {Long telomere length (TL) extends replicative capacity in vitro and predisposes to clonal hematopoiesis. We characterized the cancer phenotype in 51 individuals from 24 families with mutant POT1, a negative regulator of telomerase elongation (median age, 51 years [range, 5-94]). Hematologic malignancies were second in prevalence after melanoma (27%), and lymphoid subsets were more common. They clustered with history of sarcoma, thyroid cancer, and chronic myeloproliferative neoplasms. UK Biobank participants with pathogenic POT1 variants had long TL and higher lymphoid malignancy rates (45% by the age of 80 years; hazard ratio, 8.28; 95% confidence interval, 5.29-13.0). Across cohorts, diagnoses encompassed acute lymphoblastic leukemia and Hodgkin lymphoma in children/young adults and chronic lymphocytic leukemia/multiple myeloma in adults. They clustered in families manifesting as autosomal dominant pan-lymphoma with genetic anticipation at times. Lymphocyte TL was longer than granulocytes at baseline (age-adjusted mean +1 kilobase; P< .0001) and was preserved longitudinally with aging. Ultralong lymphocyte TL >99th percentile was more sensitive for identifying pathogenic variants (58% vs 38% for granulocytes). Among asymptomatic POT1 variant carriers, 12 of 20 (60%) had immunophenotype-detected B- and/or T-cell clonality, with complete penetrance after the age of 65 years (7/7). IGH CDR3 sequencing supported age-dependent pruning of the B-cell repertoire, and cytogenetic and next-generation analyses uncovered preclinical clonal lymphoma-associated changes in nearly all POT1 variant carriers aged >60 years (9/10). Our data identify extended cellular longevity due to long TL as an inherited risk factor for lymphoma, explaining its syndromic association with solid tumors and, in some cases, myeloproliferative neoplasms.}, }
@article {pmid42085931, year = {2026}, author = {Wang, Z and Wang, Y and Peters, BA and Post, WS and Brown, TT and Palella, FJ and Rinaldo, CR and Witt, MD and Gange, SJ and Kuniholm, MH and Sha, BE and Chichetto, NE and Clish, CB and Gerszten, RE and Hodis, HN and Sharma, A and Anastos, K and Burk, RD and Kaplan, RC and Qi, Q and Hanna, DB}, title = {Multi-omics analysis of the gut microbiome and carotid artery atherosclerosis in men with and without HIV.}, journal = {EBioMedicine}, volume = {127}, number = {}, pages = {106281}, doi = {10.1016/j.ebiom.2026.106281}, pmid = {42085931}, issn = {2352-3964}, abstract = {BACKGROUND: How gut microbiota alterations may contribute to host inflammation and metabolomic profiles affecting atherosclerosis is not fully elucidated, especially in the context of HIV.<br><br>METHODS: We examined associations between gut microbial features (measured by shotgun metagenomics) and subclinical carotid atherosclerosis, as assessed by high-resolution B-mode ultrasound, in 359 men from the MACS/WIHS Combined Cohort Study. We measured 822 plasma metabolites using LC-MS/MS, and up to 2866 circulating proteins by the Olink Explore 3072/384 platform (with a primary focus on 617 proteins related to inflammation and immune function).<br><br>FINDINGS: Carotid artery plaque was detected in 115/359 men (32%). Adlercreutzia equolifaciens and Eubacterium sp3131 were associated with lower odds of plaque (OR [95% CI] = 0.57 [0.43, 0.77], 0.84 [0.76, 0.93], respectively), while Coprococcus sp13142 was associated with higher odds of plaque (OR [95% CI] = 1.14 [1.06, 1.23]). Results were consistent in men both with and without HIV. A. equolifaciens was positively correlated with HDL cholesterol and inversely correlated with systolic blood pressure. These plaque-associated microbial species were also associated with a range of circulating metabolites and inflammatory proteins. For example, A. equolifaciens positively correlated with the metabolites palmitoyl-EA and mesobilirubinogen, and inversely correlated with the pro-inflammatory chemokine CXCL9, the immune regulator CD160, and IL-24.<br><br>INTERPRETATION: We identified gut microbial features associated with carotid artery atherosclerosis, consistent across HIV status; these associations were partially explained by specific microbiota-related metabolites and inflammatory markers. If validated, these findings suggest gut microbiota-related targets for CVD prevention.<br><br>FUNDING: The study was funded by the National Heart, Lung, and Blood Institute (U01HL146204-04S1, K01HL169019).}, }
@article {pmid42088762, year = {2026}, author = {Cunningham, RA and Gottimukkala, KSV and Lane, DD and Poljakov, K and Lipson, P and Enstrom, MR and Rizzi, A and Chapuis, AG and Adair, JE}, title = {Nonviral Gold Nanoparticle-Mediated Delivery of CRISPR-Cas9 Ribonucleoprotein and Long DNA Transgenes Into Primary Blood Cells.}, journal = {Advanced nanobiomed research}, volume = {}, number = {}, pages = {}, pmid = {42088762}, issn = {2699-9307}, support = {R01 AI158728/AI/NIAID NIH HHS/United States ; R01 AI167009/AI/NIAID NIH HHS/United States ; }, abstract = {Gene editing using CRISPR systems has gained traction for its potential to treat various diseases, but delivery remains a major challenge. We have previously reported an entirely synthetic gold nanoparticle formulation which can safely and effectively deliver multiple different CRISPR systems as ribonucleoprotein (RNP) into hematopoietic stem cells and immune cells. Here, we describe a modified version of this nanoparticle to simultaneously deliver CRISPR Cas9 RNP and transgene-encoding DNA templates (HDT) as long as ~2.1 kb. We evaluate this HDT-CRISPR-AuNP for gene editing at two loci of interest with different transgene cargo. These nanoparticles successfully deliver gene editing into primary human T cells and hematopoietic stem and progenitor cells with insertion of an antigen-specific T cell receptor transgene. This proof-of-concept immune engineering study demonstrates a simple, synthetic nanoformulation for co-delivery of all cargo required for CRISPR-mediated delivery of transgene cassettes with potential for efficacy in vivo.}, }
@article {pmid42089518, year = {2026}, author = {Schopf, C and Domchek, SM and Tice, JA and Eby, PR and Mann, R and Lehman, CD and Cozzi, A and Trivedi, H and Lee, JM}, title = {Risk Stratification for Breast Cancer Screening: AJR Expert Panel Narrative Review.}, journal = {AJR. American journal of roentgenology}, volume = {}, number = {}, pages = {}, doi = {10.2214/AJR.26.34641}, pmid = {42089518}, issn = {1546-3141}, abstract = {Early detection of breast cancer reduces mortality and is influenced by screening strategies. The balance of benefits and harms within any screening program improves when screening is aligned with an individual patient's cancer risk profile, and specialized risk prediction tools can support this assessment. Although professional societies provide guidance on breast cancer risk evaluation, their recommendations vary. This variability creates uncertainty regarding standardized approaches to risk assessment, particularly with respect to the use of risk prediction tools, the optimal timing of risk assessment, and the translation of calculated risk into actionable screening decisions. This AJR Expert Panel Narrative Review provides an overview of breast cancer risk stratification, commonly used risk prediction models in current clinical practice, existing societal guidelines related to model use, and considerations for implementing these tools. The article applies such insights to propose a practical approach to incorporating risk assessment into clinical practice. Finally, the article highlights ongoing research aimed at improving breast cancer risk stratification and explores the potential role of deep learning-based prediction models in informing future screening strategies.}, }
@article {pmid42094234, year = {2026}, author = {Webster, R and Chambers, EO and Qiu, W and Dhaduk, R and Wang, L and Yasui, Y and Yuan, Y and Nathan, PC and Leisenring, W and Armstrong, GT and Howell, R and Schulte, T and Yalch, M and Cordova, M and Krull, KR and Brinkman, TM and Edelstein, K}, title = {Neurocognitive impairment and substance use in adult survivors of childhood cancer: a cross-sectional analysis from the Childhood Cancer Survivor Study.}, journal = {EClinicalMedicine}, volume = {95}, number = {}, pages = {103924}, pmid = {42094234}, issn = {2589-5370}, abstract = {BACKGROUND: Adult survivors of childhood cancer are at risk for neurocognitive impairment, emotional distress, and chronic pain, factors independently associated with substance use. However, interrelationships among these factors and their association with substance use remain poorly understood.<br><br>METHODS: Participants from the Childhood Cancer Survivor Study (CCSS) who reported symptoms of neurocognitive problems, distress, pain, and substance use were included. Data for these cross-sectional analyses were drawn from CCSS follow up questionnaires administered between 2003 and 2007. Polytomous regressions examined associations between neurocognitive impairment and substance use (alcohol: occasional, risky, heavy; smoking: current) and whether these associations were moderated by psychosomatic symptoms. The CCSS cohort study is registered with ClinicalTrials.gov, NCT01120353.<br><br>FINDINGS: 11,151 participants were included (53.2% female; mean age 31.4 years, SD 7.5). Survivors reported risky (40.9%; n = 4059/9894), or heavy (11%; n = 1096/9894) alcohol use and more than 25% reported previous (14.6%; n = 1482/10,182) or current (13.7%; n = 1395/10,182) cigarette use. Impaired emotional regulation was associated with smoking (odds ratio 1.81, 95% CI 1.53-2.14) and risky drinking (1.59, 1.25-2.03). Impaired emotion regulation with somatisation was associated with decreased occasional (0.54, 0.0-0.95) and heavy drinking (0.54, 0.0-0.95). Organisation impairment with somatisation was associated with decreased heavy drinking (0.34, 0.15-0.73), whereas pain with organisation impairment was associated with increased occasional (1.81, 1.03-3.19) and risky drinking (2.18, 1.24-3.85). Memory impairment was associated with risky (1.38, 1.10-1.73) and occasional drinking (1.37, 1.09-1.71).<br><br>INTERPRETATION: Neurocognitive impairment was associated with substance use and modified by psychosomatic symptoms. Findings support integrated screening to inform targeted interventions.<br><br>FUNDING: National Cancer Institute, Princess Margaret Cancer Centre Foundation, Ontario Ministry of Health and Long-Term Care, National Cancer Institute Cancer Center, and American Lebanese Syrian Associated Charities.}, }
@article {pmid42094603, year = {2026}, author = {Morgans, AK and Pieczonka, CM and Yu, EYW and Nagar, H and Gomella, LG and Osman, MM and Koo, PJ and Finkelstein, SE}, title = {Future opportunities and nuances with the use of PSMA PET in prostate cancer (MD PET 1).}, journal = {Theranostics}, volume = {16}, number = {11}, pages = {5816-5829}, pmid = {42094603}, issn = {1838-7640}, mesh = {Humans ; *Prostatic Neoplasms/diagnostic imaging/pathology ; Male ; *Glutamate Carboxypeptidase II/metabolism ; *Antigens, Surface/metabolism ; *Positron-Emission Tomography/methods ; }, abstract = {Imaging with prostate-specific membrane antigen (PSMA) PET has significantly improved prostate cancer staging with superior diagnostic performance compared to conventional methods. Although it is increasingly adopted in clinical practice, several barriers hinder its full integration into routine workflows. This review highlights the existing knowledge gaps, infrastructure limitations, and inconsistencies in interpretation that affect the utility of PSMA PET across healthcare settings. We examine the potential reasons behind variability in scan performance, including scanner design, detector technology, sensitivity, and resolution, as well as the accreditation status of the facilities and reader expertise. We also highlight the inconsistent understanding of PSMA PET ordering practices, particularly among urologists, and the influence of ownership-driven utilization, both of which contribute to underuse and overuse. Radiology reporting that lacks sufficient detail and a shortage of trained nuclear medicine specialists may present additional challenges to effective treatment planning, although diagnostic radiologists also contribute to PET scan interpretation. This review highlights the potential role of standardized reporting protocols, accreditation, expanded education, and integration of AI tools in enhancing diagnostic accuracy and consistency. Additionally, we examine the impact of PSMA PET on clinical decision-making in unfavorable intermediate-, high risk-, and biochemically recurrent prostate cancer, as well as the emerging role of PSMA PET-derived metrics in staging, biopsy guidance, and treatment planning. While PSMA PET has shown value in modifying management strategies, its clinical benefit requires validation through future, prospective, outcome-driven studies. In addition, emerging applications of PSMA PET in non-prostate malignancies hold the potential to transform diagnostic and therapeutic approaches beyond prostate cancer.}, }
@article {pmid42085603, year = {2026}, author = {Scheidegger, NK and Schneider, C and Alexe, G and Wang, YC and Alonzo, TA and Basanthakumar, A and Bourgeois, WA and Dudkiewicz-Garbicz, J and Khalid, D and Merickel, LA and Perry, JA and Ries, RE and Salhotra, S and Taillon, A and Gamis, AS and Aplenc, R and Harris, MH and Wunderlich, M and Armstrong, SA and Pollard, JA and Meshinchi, S and Pikman, Y and Stegmaier, K}, title = {Combining Menin and MEK inhibition to target poor prognosis KMT2A-rearranged RAS pathway-mutant acute myeloid leukemia.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025016208}, pmid = {42085603}, issn = {2473-9537}, abstract = {KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified RAS pathway mutations in 43% of AML cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with a lower complete remission (CR) rate, poor event-free (EFS) and overall survival (OS), and early relapses. Given the inferior outcome observed for children with dual mutations, we next sought to identify efficacious targeted drug combinations for this subset of childhood leukemia. We evaluated RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Treatment of AML cell lines and cultured leukemia cells from patient-derived xenograft (PDX) models resulted in a synergistic decrease in viability and promoted cell cycle arrest, apoptosis and downregulation of Myc targets in the combination compared to each drug alone. In vivo, the combination treatment of AML pediatric PDX models harboring KMT2A-r and RAS mutations reduced leukemia burden compared to single drug treatments, but without improving overall survival compared to menin inhibition alone. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and RAS pathway mutant leukemia, but one which will require further optimization. COG completed clinical trials AAML03P1, AAML0531, AAML1031 and C2961.}, }
@article {pmid42085744, year = {2026}, author = {Zhang, Y and Nguyen, NQH and Hanson, PA and Sevilla-Gonzalez, M and Haessler, J and Sarnowski, C and Yao, J and Yu, B and Jamshidi, A and Boerwinkle, E and Brown, MR and Chen, ZZ and Ida Chen, YD and Clish, C and DiCorpo, D and Durda, P and Gerszten, R and Goodarzi, MO and Guo, X and Heard-Costa, NL and Johnson, WC and Kooperberg, C and Pankow, JS and Post, WS and Reiner, AP and Rich, SS and Rotter, JI and de Vries, PS and Wood, AC and Taylor, KD and Manning, AK and Dupuis, J and Meigs, JB and Liu, CT}, title = {Plasma metabolomic profiles associated with cardiovascular disease in type 2 diabetes from the Trans-Omics for Precision Medicine (TOPMed) program.}, journal = {Atherosclerosis}, volume = {417}, number = {}, pages = {120758}, doi = {10.1016/j.atherosclerosis.2026.120758}, pmid = {42085744}, issn = {1879-1484}, abstract = {BACKGROUND AND AIMS: People with Type 2 diabetes (T2D) are twice as likely to develop cardiovascular disease (CVD), though not all excess risk has been fully elucidated. Plasma metabolomics profiles shared between these conditions may uncover molecular mechanisms linking T2D to CVD.<br><br>METHODS: We conducted a cross-sectional case-control analysis, comparing T2D individuals who had prevalent CVD to those without CVD at the time of metabolite measurement. Using untargeted liquid chromatography-mass spectrometry (LC-MS), we collected 522 metabolite abundances measured in 1374 participants with T2D (224 CVD cases) from the Trans-Omics for Precision Medicine (TOPMed) program. We used a mixed effects linear model to assess the association of CVD events with each metabolite abundance, adjusting for key covariates. Metabolites meeting a suggestive significance threshold were examined using metabolite set enrichment analysis and evaluated for replication in an independent cohort Atherosclerosis Risk in Communities (ARIC) (n&#xa0;=&#xa0;1891; 214 CVD cases). We performed meta-analysis to combine both the discovery and replication associations, and assessed overall significance using an experiment-wide Bonferroni-corrected threshold.<br><br>RESULTS: Metabolites meeting a suggestive threshold were enriched in metabolite sets linked to obesity and kidney disease. Meta-analysis identified eight metabolites reaching experiment-wide significance, confirming previously established associations of asymmetric dimethylarginine, phosphatidylcholines, and gluconic acid, while additionally identifying specific phosphatidylethanolamine species, N-acetyl-L-methionine, and allantoin associated with prevalent CVD among individuals with T2D.<br><br>CONCLUSIONS: Our results established and replicated metabolite associations with prevalent CVD in people with T2D. These metabolites may help characterize metabolic alterations underlying cardiovascular complications that arise in T2D.}, }
@article {pmid42080772, year = {2026}, author = {Huang, K and Wang, K and Schrum, A and Kusmaul, E and Fisler, E and Guerrero, M}, title = {Development and clinical deployment of an automated planning tool for prostate only and male whole pelvis plans based on multi-criteria optimization.}, journal = {Journal of applied clinical medical physics}, volume = {27}, number = {5}, pages = {e70598}, doi = {10.1002/acm2.70598}, pmid = {42080772}, issn = {1526-9914}, mesh = {Humans ; *Radiotherapy Planning, Computer-Assisted/methods/standards ; *Prostatic Neoplasms/radiotherapy ; Male ; Radiotherapy Dosage ; *Radiotherapy, Intensity-Modulated/methods ; Organs at Risk/radiation effects ; Retrospective Studies ; *Algorithms ; Prospective Studies ; *Pelvis/radiation effects ; Automation ; Pilot Projects ; }, abstract = {BACKGROUND: Multi-criteria optimization (MCO) is an advanced optimization technique that can be applied to any problem with multiple objectives that may be conflicting. MCO has been available in commercial treatment planning systems (TPS) for several years now and has been applied to treatment planning of many anatomical locations in a variety of ways. The MCO optimization method is based on the Pareto plans generation and is very powerful, but there are significant hurdles in terms of clinical implementation due to long computing times, lack of dosimetrists training and plan degradation after the optimized fluence is converted to deliverable. While some authors have studied the use of MCO in automation, no clinical implementation of an MCO-based auto-planning technique has been reported.<br><br>PURPOSE: This study aims to develop and clinically deploy an automated planning tool based on MCO for prostate and whole-pelvis radiotherapy.<br><br>MATERIALS AND METHODS: A Python script based on a commercial treatment planning system was developed to automate MCO, including Pareto plan generation, fluence plan selection, dose conversion, and post-processing. The tool underwent retrospective validation on 10 prostate patients with the input of four dosimetrists and a 10-month prospective pilot involving another three senior dosimetrists across different community sites. Dosimetrists evaluated plan quality and provided quantitative and qualitative feedback for iterative improvements of the tool. The study reports on the plan comparisons between the clinical and the MCO generated plans for retrospective patients. The study also reports the prospective use cases and the qualitative and quantitative evaluations from dosimetrists.<br><br>RESULTS: Retrospective evaluations showed 82.5% of MCO prostate plans were clinically acceptable. The tool generated prostate plans in approximately 10.1 min and whole pelvis plans in 27.2 min. Dosimetric analysis revealed comparable plan quality to clinical plans, with MCO plans achieving lower organ-at-risk doses. In the pilot phase, the MCO tool was used for 41 prospective patients, producing plans that dosimetrists could refine to achieve clinical acceptability within a median of 10 min.<br><br>CONCLUSIONS: This study demonstrates the successful development and clinical implementation of an MCO-based automated planning tool for generating acceptable VMAT plans for prostate and whole pelvis radiotherapy. The extensive pilot phase showcases an effective strategy for integrating automated planning solutions into routine clinical practice.}, }
@article {pmid42080933, year = {2026}, author = {Beauplet, B and Semple, C and Dornan, M and Verdonck-de Leeuw, I and Amano, K and Choi, A and Moore, E and Ninfa, A and Jansen, F and Dean, DR and Kouri, M and Del Fabbro, E and Elad, S and Koczwara, B}, title = {A Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology Clinical Practice Statement: Management of social eating and drinking challenges in adults with cancer.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {34}, number = {5}, pages = {}, pmid = {42080933}, issn = {1433-7339}, }
@article {pmid42082831, year = {2026}, author = {Hart, ML and Sokolov, D and Danquah, S and Zheng, E and Doan, AD and Davidsen, K and MacPherson, D and Sullivan, LB}, title = {Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.}, journal = {Nature metabolism}, volume = {}, number = {}, pages = {}, pmid = {42082831}, issn = {2522-5812}, support = {R35GM147118//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32GM007270//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; P30CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, abstract = {Decreased availability of the amino acid aspartate constrains cell function across diverse biological contexts, but the temporal interplay between aspartate abundance, downstream metabolic changes and functional effects remains poorly understood. Here we show that succinate dehydrogenase (SDH) inhibition suppresses pyrimidine synthesis via dual effects of cellular aspartate depletion and succinate accumulation. Using an aspartate biosensor and live-cell imaging, we monitor aspartate levels and cell proliferation across several models of aspartate limitation. While complex I inhibition or knockout of aspartate biosynthetic enzymes lead to a strict decrease in aspartate levels and impair proliferation, SDH inhibition produces a unique aspartate rebound, yet fails to restore proliferation. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis via succinate accumulation, which competitively inhibits aspartate utilization by mammalian aspartate transcarbamylase (ATCase), a key step in pyrimidine biosynthesis. This metabolic interaction occurs in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress and sensitivity to ATR kinase inhibition. Taken together, these findings define an unexpected role for succinate in modulating cellular nucleotide homeostasis and demonstrate how cascading metabolic interactions can unfold to impact cell function.}, }
@article {pmid42085243, year = {2026}, author = {Saw, WY and Kim, K and Huang, Y and Yun, JH and Ma, X and Bacon, J and Pershad, Y and Levy, D and O'Connor, GT and Boerwinkle, E and Barr, RG and Rich, SS and Rotter, JI and Carson, AP and Raffield, LM and Gharib, SA and Bartz, TM and Psaty, BM and Sofer, T and North, KE and Kaplan, R and Oelsner, EC and Manichaikul, A and Bick, AG and Scheet, P and Reiner, AP and ,  and Jakubek, YA and Auer, PL and Cho, MH and DeMeo, DL}, title = {Mosaic Loss of Y chromosome associates with lung function, emphysema and epigenetic aging.}, journal = {American journal of respiratory and critical care medicine}, volume = {}, number = {}, pages = {}, doi = {10.1093/ajrccm/aamag120}, pmid = {42085243}, issn = {1535-4970}, abstract = {RATIONALE: As the global population ages, identifying risk factors for age-related diseases, such as COPD, is crucial for public health. Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mosaicism event, but its relationship with pulmonary health remains undercharacterized.<br><br>OBJECTIVES: To examine the association between mLOY and pulmonary outcomes in men.<br><br>METHODS: Leveraging mLOY assessment (cell fraction&#x2009;&#x2265;&#x2009;5%) in over 12,000 men, including 5,097 from the COPDGene Study and 7,235 from six additional cohorts in the Trans-Omics for Precision Medicine program, we investigated mLOY associations with respiratory outcomes and epigenetic aging using multivariable cross-sectional, longitudinal, and prospective models. Primary outcomes included spirometry, CT-based emphysema, and epigenetic pace of aging.<br><br>RESULTS: The prevalence of mLOY increased with age. Cross-sectionally, mLOY was associated with airflow obstruction, with reduced FEV1/FVC of 0.018 [95% CI -0.030, -0.006] in COPDGene and 0.020 [95% CI -0.027, -0.013] in TOPMed. mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Longitudinally, mLOY was associated with faster FEV1 decline (&#x223c;55mL/year vs &#x223c;38mL/year). Prospectively, mLOY was associated with higher odds of developing COPD [OR&#x2009;=&#x2009;1.84, 95% CI 1.10, 3.07] and PRISm [OR&#x2009;=&#x2009;2.87, 95% CI 1.09, 7.56] among participants with normal lung function at baseline. Associations remained robust after adjusting for clonal hematopoiesis and telomere length.<br><br>CONCLUSIONS: mLOY is associated with lower lung function, accelerated lung function decline, higher emphysema, and faster pace of aging, positioning mLOY as a potential biomarker of respiratory aging in men.}, }
@article {pmid41993275, year = {2026}, author = {Zhao, Y and Finkbeiner, C and Setty, M and Lin, KZ}, title = {SCOPE: Localizing fate-decision states and their regulatory drivers in single-cell differentiation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41993275}, issn = {2692-8205}, abstract = {Identifying the precise transcriptomic states at which cells commit to a lineage (branchpoints) and the temporal lag in which chromatin accessibility foreshadows gene expression (epigenetic priming) remain fundamental challenges in developmental biology. While current methods for single-cell sequencing data effectively capture developmental flow, they often lack a principled mechanism for delineating the discrete boundaries, a crucial aspect required to map the molecular logic of lineage commitment. We present SCOPE (Semi-supervised Conformal Prediction), a framework that transforms high-dimensional single-cell measurements into rigorous, discrete prediction sets of all plausible future fates. By formalizing fate uncertainty via conformal inference, SCOPE localizes the precise biological windows during which multipotent progenitors specify their fate. In multi-omic data, SCOPE uncovers epigenetic priming and identifies its driving transcription factors by detecting regimes where chromatin-derived prediction sets resolve toward terminal fates significantly before their transcriptomic counterparts. We apply SCOPE across simulations, lineage-traced mouse hematopoiesis, multiple human hematopoietic datasets, and human retinogenesis to demonstrate its broad applicability and ability to recapitulate known fate specification drivers. Ultimately, SCOPE provides a statistically grounded foundation for localizing fate decisions across biological replicates and modalities, offering a robust tool for identifying the onset of lineage specification in complex developmental systems.}, }
@article {pmid42070993, year = {2026}, author = {Pozdnyakova, O and Yaeger, LH and Shirai, CL and McFadden, S and Chen, X and Obstfeld, A and Mason, EF and Ouseph, MM and Han, JY and Zini, G and Hedley, B and Grant, M and D'Onofrio, G and Frater, JL and Courville, EL}, title = {Practical Considerations in the Implementation of Peripheral Smear Review in the Clinical Laboratory.}, journal = {International journal of laboratory hematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ijlh.70131}, pmid = {42070993}, issn = {1751-553X}, abstract = {Even in the era of modern automated hematology analyzers, visual peripheral blood smear (PBS) review remains an important component of peripheral blood evaluation in a subset of specimens. Despite published PBS review guidelines, including those issued 20 years ago by the International Consensus Group for Hematology Review (ICGHR), knowledge gaps remain regarding selection and implementation of PBS visual review criteria in clinical laboratories. The purpose of this article, developed by an international working group (the Peripheral Smear Review Working Group [PSRWG]), is to help bridge knowledge gaps by providing practical guidance and items for consideration. PBS review may be indicated for automated analyzer system flags, suspect flags, numerical/definitive flags, or as a component of delta checks. Examples, explanations, and suggestions for each of these categories are provided as are examples of flag modification. Validation of PBS review criteria is a multistep process that includes defining criteria for a positive finding, selecting specimens for study, choosing the slide review method, and determining the statistical approach. Pragmatic approaches and important items to consider are provided for each of these validation steps. PBS visual review workflow must be tailored to the needs of the clinical laboratory/institution. These needs may differ depending on the accrediting agency, laboratory/institutional infrastructure, and population served. A discussion of these variables is provided. In this article, we expand on the proposed ICGHR rules with a discussion of practical considerations in the implementation of PBS review.}, }
@article {pmid42071009, year = {2026}, author = {Brasel, T and Brangel, P and Adetifa, I and Baize, S and Benkeser, D and Bertoletti, A and Bukreyev, A and Charlton, S and Cramer, J and Cross, RW and Davenport, MP and Emperador, D and Formenty, P and Follmann, D and Garry, RF and Gilbert, PB and Gilbert, SC and Gollihar, JD and Grassly, NC and Gruber, M and Gupta, SB and Günther, S and Hacker, A and Hoath, C and Holbrook, MR and Killip, M and King, D and Mandi, H and Munster, VJ and Mukandavire, C and Oestereich, L and Okogbenin, S and Oloo, P and Paessler, S and Plotkin, S and Richert, L and Safronetz, D and Saphire, EO and Sette, A and Shurtleff, A and Granerod, J and Wohl, D and Zaric, M and Ramsauer, K and Dahlke, C}, title = {Searching for immune correlates in Lassa vaccine development - workshop report.}, journal = {NPJ vaccines}, volume = {11}, number = {1}, pages = {}, pmid = {42071009}, issn = {2059-0105}, }
@article {pmid42080645, year = {2026}, author = {Dai, JY and Luebeck, EG and Hazelton, WD and Clarke, CA and Hubbell, E and Patel, AV}, title = {Modeled sojourn time and sensitivity for detecting preclinical cancers retrospectively by a multi-cancer early detection test.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-1925}, pmid = {42080645}, issn = {1538-7755}, abstract = {BACKGROUND: Blood-based multi-cancer early detection tests have potential for clinical benefit, but key performance metrics for cancer screening, such as sojourn time and sensitivity of these tests for detecting pre-clinical disease, are not yet known.<br><br>METHODS: In a retrospective analysis of stored plasma samples in the American Cancer Society Cancer Prevention Study-3 (CPS-3), GRAIL's MCED test was evaluated for detectability prior to cancer diagnosis. Classical state-transition models for cancer screening were modified to characterize the natural history of ctDNA-shedding cancers. The sensitivity estimand for detecting preclinical cancers by the MCED test was proposed in the context of retrospective testing, and a Bayesian likelihood method was developed to estimate preclinical detectable duration and sensitivity.<br><br>RESULTS: Analysis of CPS-3 data showed that for the twelve prespecified cancers that represent two-thirds of cancer deaths in the United States, the test had 64% estimated overall sensitivity across all stages, 43% sensitivity during an average 1.36-years preclinical detectable window before metastasis. Untestable assumptions on state transition and sensitivity are discussed, along with limitations related to using stored plasma samples.<br><br>CONCLUSIONS: State-transition models were developed for retrospective analysis of plasma samples from the CPS-3 study. Estimates for the length of the preclinical detectable window and the sensitivity at screening support annual MCED screening to intercept late-stage cancers.<br><br>IMPACT: Retrospective analysis of plasma samples from the CPS-3 study supports the potential of GRAIL's MCED test to detect cancers early in the preclinical state.}, }
@article {pmid42066747, year = {2026}, author = {Barrera-Fuentes, GA and Antonioli, C and Pavia-Ruz, N and Che-Mendoza, A and Earnest, JT and Kirstein, OD and Eb-Cordova, AB and Ciau-Carillo, KJ and Jabbarzadeh, S and Granja-Perez, P and Villanueva-Jorge, S and Puerta-Guardo, H and Collins, MH and Ayora-Talavera, G and Halloran, ME and Longini, IM and Dean, N and Waller, LA and Crisp, A and Manrique-Saide, P and Vazquez-Prokopec, GM and Gomez-Dantes, H}, title = {Integrated Surveillance Strategies and Clinical Characteristics of Arboviral Diseases in a Pediatric Cohort in Merida, Mexico, 2021-2023.}, journal = {The American journal of tropical medicine and hygiene}, volume = {}, number = {}, pages = {}, doi = {10.4269/ajtmh.25-0669}, pmid = {42066747}, issn = {1476-1645}, abstract = {Dengue, chikungunya, and Zika are Aedes-borne diseases (ABDs) of global health significance. Epidemiological studies with sensitive case detection are critical for evaluating vector control strategies to prevent ABDs; however, data on which surveillance method is most effective are limited. The performance of five surveillance methods (home visits, phone calls, SMS reminders, toll-free phone line (TF) and the Ministry of Health surveillance platform) was assessed, and the clinical characteristics of ABD cases in the targeted indoor residual spraying trial, which quantified the efficacy of preventive indoor residual insecticide applications against ABDs in Merida, Mexico, were described. A cohort of 4,461 children was monitored over three transmission seasons (July-December 2021-2023), with surveillance methods rotated weekly to detect illnesses. Kaplan-Meier curves and log-rank tests compared the time from symptom onset to laboratory testing across methods. Analysis of variance, t- and χ2 tests assessed differences in utilization of surveillance methods across demographic factors. Of 1,902 illnesses detected, 920 (48.4%) met suspected ABD criteria; 825 provided blood samples (89%), and 422 (51%) were confirmed as ABDs. Dengue represented 70.4% of confirmed cases (n = 297/422). Among confirmed cases, clinical manifestations were diverse, with fever (>94%), myalgia (80-100%), and headache (70-100%) being most frequent. Twenty-seven patients (9%; n = 27/297) had dengue with warning signs. TF detected 55.2% (n = 233/422) of confirmed cases and achieved the fastest time to laboratory testing. These results demonstrate case detection can be optimized. TF proved effective in rapidly identifying symptomatic reports, underscoring the value of integrated, low-barrier reporting systems for early arboviral detection.}, }
@article {pmid42067854, year = {2026}, author = {Schulz, K and Botts, SR and Ellis, K and Scipione, CA and Khyzha, N and Ho, C and Kumaragurubaran, R and Yuki, KE and Wythe, JD and Miller, CL and Wilson, MD and Howe, KL and Fish, JE}, title = {ERG is a regulator of dynamic and reversible endothelial plasticity.}, journal = {Genome medicine}, volume = {18}, number = {1}, pages = {}, pmid = {42067854}, issn = {1756-994X}, support = {R01HL164577/NH/NIH HHS/United States ; PJT-191915/CAPMC/CIHR/Canada ; Medicine by Design//Canada First Research Excellence Fund/ ; }, mesh = {Humans ; *Transcriptional Regulator ERG/genetics/metabolism ; *Endothelial Cells/metabolism/cytology ; Epithelial-Mesenchymal Transition/genetics ; Gene Regulatory Networks ; *Cell Plasticity/genetics ; Atherosclerosis/genetics/metabolism ; Gene Expression Regulation ; }, abstract = {BACKGROUND: Endothelial cells (ECs) orchestrate vascular homeostasis and resilience but can undergo reprogramming into a mesenchymal-like phenotype through an endothelial-to-mesenchymal transition (EndMT). Crucially, EndMT is a linchpin underlying several cardiometabolic diseases, but is almost universally studied as an endpoint. The transcription factor ERG (ETS-related gene) is critical to the maintenance of EC identity and function, yet the dynamic transcriptional and functional consequences of ERG loss on EndMT programs, and whether this can be reversed, has not been explored.<br><br>METHODS: We modeled both acute and chronic ERG loss in human aortic ECs using siRNA knockdown and CRISPR/Cas9-mediated ERG deletion. We profiled temporal changes in chromatin accessibility (ATAC-seq), transcriptomic responses (RNA-seq), and endothelial phenotypes, including migration and barrier integrity. The temporal kinetics of ERG loss and restoration was assessed by comparing stable ERG knockout to transient ERG knockdown and recovery over time. The implications to human disease were deciphered by examining ERG gene regulatory networks in human atherosclerosis and linkage with genetic variation associated with human cardiovascular disease.<br><br>RESULTS: Analysis of gene regulatory networks revealed profound and dynamic rewiring of endothelial and mesenchymal transcriptional programs upon loss of ERG. While endothelial identity was rapidly lost by 24&#xa0;h of ERG knockdown, acquisition of mesenchymal identity, barrier dysfunction, and enhanced cell migration required 72&#xa0;h to manifest. Loss of ERG was accompanied by a rapid reduction in accessibility of ETS motifs and an extensive gain in open chromatin containing AP1 motifs. Disease-relevant endothelial dysfunction programs were associated with dynamically reorganized transcriptional networks. Importantly, restoration of ERG expression reversed EndMT gene regulatory networks and phenotypes.<br><br>CONCLUSIONS: Overall, this study highlights the ETS factor, ERG, as an essential transcriptional safeguard of endothelial identity and function, and demonstrates that ERG loss initiates a progressive, yet reversible, EndMT program with EC identity loss preceding a gain of mesenchymal gene regulatory networks and phenotypes. This study establishes loss of ERG as an early initiating event in EndMT and suggests that ERG-targeted therapies may hold promise for promoting endothelial resilience.}, }
@article {pmid42069409, year = {2026}, author = {Palomba, ML and Patel, MR and Eyre, TA and Jurczak, W and Lewis, D and Gastinne, T and Ma, S and Cohen, JB and Patel, K and Brown, JR and Scarfò, L and Munir, T and Lech-Maranda, E and Hoffmann, MS and Ujjani, CS and Fakhri, B and Wang, ML and Izutsu, K and Nagai, H and Tam, CS and Rhodes, JM and Vose, J and McKinney, M and Gerson, JN and Barve, MA and Kuss, B and Koh, Y and Barrett, A and Treon, SP and Castillo, JJ and Seymour, JF and Ruppert, AS and McNeely, SC and Walgren, RA and Tsai, DE and Bao, K and Nair, B and Woyach, J and Cheah, CY}, title = {Safety and activity of pirtobrutinib in patients with relapsed or refractory Waldenström macroglobulinaemia: 5-year follow-up of the open-label, multicentre, phase 1/2 BRUIN trial.}, journal = {The Lancet. Haematology}, volume = {13}, number = {5}, pages = {e284-e296}, doi = {10.1016/S2352-3026(26)00037-2}, pmid = {42069409}, issn = {2352-3026}, mesh = {Humans ; *Waldenstrom Macroglobulinemia/drug therapy/pathology ; Male ; Female ; Aged ; Middle Aged ; *Pyrimidines/therapeutic use/adverse effects ; Follow-Up Studies ; Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; *Protein Kinase Inhibitors/therapeutic use/adverse effects ; Aged, 80 and over ; Recurrence ; Treatment Outcome ; Pyrazoles ; }, abstract = {BACKGROUND: Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial.<br><br>METHODS: The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenstr&#xf6;m macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenstr&#xf6;m macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenstr&#xf6;m Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed).<br><br>FINDINGS: BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenstr&#xf6;m macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68&#xb7;5 years (IQR 61&#xb7;0-75&#xb7;0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3&#xb7;0 (2&#xb7;0-5&#xb7;0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82&#xb7;5% (95% CI 72&#xb7;4-90&#xb7;1), with one (1&#xb7;3%) patient reaching complete response, eight (10&#xb7;0%) reaching very good partial response, 49 (61&#xb7;3%) reaching partial response, and eight (10&#xb7;0%) reaching minor response. The median study follow-up was 35&#xb7;0 months (17&#xb7;7-47&#xb7;7). The objective response rate was 81&#xb7;0% (69&#xb7;1-89&#xb7;8) for those who received previous covalent BTK inhibitors and 88&#xb7;2% (63&#xb7;6-98&#xb7;5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%).<br><br>INTERPRETATION: Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenstr&#xf6;m macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed.<br><br>FUNDING: Eli Lilly and Company.}, }
@article {pmid42070670, year = {2026}, author = {Hui, D and Mehta, AK and Shalev, D and Rosa, WE and Chwistek, M and Wallace, C and Mehta, A and Case, A and Loggers, E and Casarett, D}, title = {Generative Artificial Intelligence Use in the Peer Review Process.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2026.04.614}, pmid = {42070670}, issn = {1873-6513}, }
@article {pmid42070784, year = {2026}, author = {Rostad, CA and Healy, CM and Nayak, JL and Parameswaran, L and Creech, CB and Martin, JM and Brady, RC and Jones-Beatty, K and Badell, M and Eppes, C and Quinn, M and Mulligan, M and Rolsma, SL and Rick, AM and Forde, B and Avadhanula, V and Piedra, PA and Telu, K and Kunwar, PS and Mu, J and Gao, F and Pasetti, MF and Flach, B and Posavad, CM and Miedema, J and Piper, JM and Kim, S and Beresnev, T and Cardemil, C and Campbell, JD and , }, title = {Maternal RSV Vaccination, Infant Nirsevimab, or Both: Interim Analysis of a Randomized Trial.}, journal = {Pediatrics}, volume = {}, number = {}, pages = {}, doi = {10.1542/peds.2025-075223}, pmid = {42070784}, issn = {1098-4275}, abstract = {BACKGROUND: Although both maternal respiratory syncytial virus (RSV) prefusion F vaccination (RSVpreF) and infant nirsevimab immunization have been approved for the prevention of RSV lower respiratory tract infections, the 2 have not been evaluated in a single study, and their sequential administration has not been studied systematically.<br><br>METHODS: We performed a prospective, randomized, open-label, phase 4 study at 8 US sites of mother-infant pairs randomized 1:1:1:1 during pregnancy: maternal RSVpreF vaccine alone, maternal RSVpreF vaccine/infant nirsevimab at birth, maternal RSVpreF vaccine/infant nirsevimab at 3&#xa0;months, or infant nirsevimab alone at birth. We are following the mother-infant pairs for 12&#xa0;months to ascertain safety, infant tolerability, and the magnitude and durability of RSV-A and -B neutralizing antibodies (nAbs). We report interim data from September 19, 2024, to May 15, 2025, including 4-month infant follow-up.<br><br>RESULTS: In total, 181 mothers were enrolled. Both products alone and in combination were safe. No related serious adverse events were observed in mothers or infants. Nirsevimab was well tolerated, and all local and systemic reactogenicity was mild to moderate in severity. RSVpreF vaccination boosted maternal RSV-A nAb titers 17.35-fold at the time of delivery, and titers were durable through 3&#xa0;months postdelivery. The geometric mean transfer ratio of RSV-A nAbs was higher than 1.3 and similar across groups. RSV nAbs were highly elevated in infants at 6&#xa0;weeks and 3&#xa0;months, irrespective of group, with modest differences in waning.<br><br>CONCLUSIONS: Maternal RSVpreF vaccine and infant nirsevimab administration, either alone or in combination, were safe and provided high RSV nAb titers in infants through interim follow-up.}, }
@article {pmid41072037, year = {2026}, author = {Flerlage, T and Boyd, DF and Clark, B and Marudai, NG and Saini, S and Guy, C and Pobre-Piza, K and Crawford, JC and Poudel, S and High, AA and Zhou, S and Wang, X and Surman, S and Jones, B and Frevert, CW and Thomas, PG}, title = {Integrated longitudinal transcriptomic and proteomic analysis of the murine lung response to influenza a virus.}, journal = {American journal of respiratory cell and molecular biology}, volume = {74}, number = {4}, pages = {480-496}, doi = {10.1165/rcmb.2024-0405OC}, pmid = {41072037}, issn = {1535-4989}, support = {R01 AI136468/AI/NIAID NIH HHS/United States ; 75N93021C00018/CD/ODCDC CDC HHS/United States ; //Center for Influenza Disease and Emergence Research/ ; //University of Georgia/ ; R01HL170121/HB/NHLBI NIH HHS/United States ; }, mesh = {Animals ; *Lung/virology/metabolism/pathology ; *Proteomics/methods ; *Influenza A virus ; *Transcriptome/genetics ; *Orthomyxoviridae Infections/virology/metabolism/genetics/pathology ; Mice ; Fibroblasts/metabolism/virology/pathology ; Mice, Inbred C57BL ; Disease Models, Animal ; Pulmonary Fibrosis/virology/genetics/metabolism/pathology ; Gene Expression Profiling ; }, abstract = {RATIONALE: Lung injury caused by influenza is a leading cause of respiratory infection-related morbidity and mortality worldwide. In its severe form, influenza can cause acute respiratory distress syndrome (ARDS), which manifests as severe hypoxemic respiratory failure. Survivors of the acute stage of ARDS may develop lung fibrosis. The mechanisms underlying fibrotic responses in this context are unknown.<br><br>OBJECTIVES: In this study, we investigate fibroblast responses to influenza challenge.<br><br>METHODS: We used single cell gene expression (scGEX) and two-dimensional liquid chromatography coupled with tandem/mass spectrometry (TMT-LC/LC-MS/MS) on lung tissue collected longitudinally in a murine model of influenza A virus (IAV) infection.<br><br>MEASUREMENTS AND MAIN RESULTS: By TMT-LC/LC-MS/MS, we identified profound changes in the composition of the lung matrisome, which were most evident 10&#x2009;days after infection. In this context, we identified transcriptional heterogeneity amongst proximal/adventitial fibroblasts expressing Pi16 and Col15a1 as well as a myofibroblast activation state characterized by expression of Tnc, Spp1, Grem1, and Cthrc1. This activation state was transcriptionally similar to those previously described in other contexts.<br><br>CONCLUSIONS: Together, these data suggest compartmentalization and conservation of pulmonary fibroblast responses to lung injury of different primary etiologies.}, }
@article {pmid41993295, year = {2026}, author = {Kaiser, AJ and Readshaw, JJ and Doyle, LA and Puiu, M and Kelly, A and McGuire, SF and Peralta Acosta, J and Vu, D and Nelson, A and Smith, DL and Araújo-Bazán, L and Arias-Palomo, E and Luyten, YA and Stoddard, BL and Blower, TR and Kaiser, BK}, title = {Competing forms of protein-protein association and DNA binding exhibited by BrxC from the BREX phage restriction system.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41993295}, issn = {2692-8205}, abstract = {Bacteriophage exclusion (BREX) defense systems restrict phage infection via inhibition of phage DNA replication, while also modifying and protecting the bacterial genome. Type I BREX systems encode six conserved proteins, including a site-specific DNA methyltransferase. Host methylation requires a subset of BREX proteins, whereas phage restriction generally requires them all, suggesting that distinct but overlapping complexes mediate these activities. Full details of the mechanism and regulation of BREX remains to be understood. Here, we characterize the behavior and structures of the conserved BrxC AAA+ ATPase protein. BrxC forms multiple competing assemblages - various self-associating multimers, as well as a complex with BrxB-PglZ - that can be uncoupled via distinct point mutations, leading to differing effects on host methylation versus phage restriction. BrxC's self-association, as well as its ability to bind DNA, is regulated by ATP binding and hydrolysis; BrxA and BrxB appear to also regulate those behaviors. These collective results suggest that BrxC may play a key role in controlling the two activities of BREX, with BrxB, BrxC and PglZ forming a core complex, and the equilibrium among competing assemblies containing those proteins modulating the balance between idling and activated restrictive states.}, }
@article {pmid42062286, year = {2026}, author = {Huang, YJ and Kurniansyah, N and Goodman, MO and Spitzer, BW and Wang, J and Stilp, A and Laurie, C and de Vries, PS and Chen, H and Min, YI and Sims, M and Peloso, GM and Guo, X and Bis, JC and Brody, JA and Raffield, LM and Smith, JA and Zhao, W and Rotter, JI and Rich, SS and Redline, S and Fornage, M and Kaplan, R and Franceschini, N and Levy, D and Morrison, AC and Boerwinkle, E and Smith, NL and Kooperberg, C and Psaty, BM and Zöllner, S and ,  and Sofer, T}, title = {Admixture-informed polygenic risk reporting using the ePRS framework.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-72457-x}, pmid = {42062286}, issn = {2041-1723}, support = {R01AG080598//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; }, abstract = {Polygenic risk score values vary with genetic ancestry due to differences in population-specific allele frequencies and linkage disequilibrium patterns. We present a framework to calibrate polygenic risk scores based on ancestral makeup. We propose the "expected polygenic risk score" or ePRS, defined as the expected value of a polygenic risk score based on one's global or local admixture patterns. We further define the "residual polygenic risk score" or rPRS as measuring the deviation of the polygenic risk score from the ePRS. The ePRS reflects the baseline ancestry-driven component of genetic risk, whereas the rPRS isolates an ancestry-agnostic measure of genetic liability. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the polygenic risk score-outcome association without further adjusting for principal components. Using the TOPMed and the All of Us datasets, effect size estimates for the rPRS (adjusted for ePRS) are similar to those obtained from polygenic risk scores adjusting for genetic principal components. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to interpret genetic risk across diverse populations.}, }
@article {pmid42062589, year = {2026}, author = {Wang, Y and Isasi, CR and Stuebe, AM and Louis-Jacques, AF and Hu, J and Hu, G and Daviglus, ML and Boerwinkle, E and Burk, RD and Kaplan, RC and Qi, Q and Peters, BA}, title = {Gestational diabetes and risk of type 2 diabetes: exploring the role of the gut microbiome in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Diabetologia}, volume = {}, number = {}, pages = {}, pmid = {42062589}, issn = {1432-0428}, support = {11-23-PDF-60//American Diabetes Association/ ; R01DK132011/DK/NIDDK NIH HHS/United States ; K01HL160146; R01HL148094; R01HL140976/HL/NHLBI NIH HHS/United States ; R01MD011389/HL/NHLBI NIH HHS/United States ; U54GM104940/GM/NIGMS NIH HHS/United States ; }, abstract = {AIMS/HYPOTHESIS: Women with a history of gestational diabetes mellitus (GDM) have an elevated risk of type 2 diabetes in their later life, yet the underlying mechanisms of this remain unclear. We aimed to investigate the long-term impact of GDM on gut microbiota and related metabolites and to explore whether such alterations may contribute to type 2 diabetes risk.<br><br>METHODS: Among parous women from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we identified microbial species associated with a history of GDM (visit 2, 2014-2017, n=1525), and serum metabolites associated with both a history of GDM (visit 1, 2008-2011, n=2968) and GDM-related microbiota (visit 2, n=391). We further examined prospective associations of the GDM-related microbiome (visit 2, n=925) with incident type 2 diabetes over 6 years of follow-up, and of microbial-related metabolites (visit 1, n=2341) with incident type 2 diabetes over 12 years.<br><br>RESULTS: Among 1525 US Hispanic/Latino parous women (median age: 58 years), seven species differed between women with and without a history of GDM, including higher abundances of four species (e.g. Parabacteroides merdae CAG:48, a proinflammatory taxon) and lower abundances of three species (e.g. Dialister sp. CAG:588, a short-chain fatty acid producer). Fifteen metabolites were associated with both a history of GDM and the GDM-related microbiome in a consistent direction, nine of which (e.g. saturated sphingomyelins and unsaturated fatty acids) were associated with glycaemic traits and incident type 2 diabetes. Using these microbial-related metabolites as proxy measures, proxy analysis suggested a positive relationship between the GDM-related microbiome and type 2 diabetes (r=0.55, p=0.036). A metabolite score derived from the nine microbial-related metabolites mediated an estimated 20% (95% CI 9%, 42%) of the association between a history of GDM and type 2 diabetes.<br><br>CONCLUSIONS/INTERPRETATION: A history of GDM is associated with an unfavourable gut microbiota and related metabolites in US Hispanic/Latino women, suggesting a potential role of the gut microbiota in GDM-related type 2 diabetes.}, }
@article {pmid42063534, year = {2025}, author = {Kroenke, CH and Aoki, R and Mammini, L and Alexeeff, S and Jones, SMW and Kushi, LH and Mogk, J and Strayhorn-Carter, S and Mosen, D and Cronkite, D and , }, title = {Development and Validation of a Natural Language Processing Algorithm Using Electronic Health Record Data to Identify Breast Cancer Patients With Low Social Support.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {}, pmid = {42063534}, issn = {2994-9750}, abstract = {PURPOSE: Social support is important in the management of breast cancer. We developed a series of structured variables or modules from electronic health record (EHR) data to form the basis for the development of EHRsupport, an EHR-based measure of social support.<br><br>METHODS: We built a natural language processing (NLP) algorithm from clinical notes in 7,989 women diagnosed from January 2006 to September 2021 with invasive breast cancer. Our team reviewed charts, developed a lexicon, manually crafted rules, applied the NLP algorithm to 565,258 EHR notes and 68,760 patient messages -1 to +3 months around diagnosis, combined terms into separate modules, and tuned (N = 40), updated, and tested (N = 100) these versus chart review. We further developed modules from structured data sources.<br><br>RESULTS: We identified and developed 11 modules from unstructured data: spouse/partner status, parenthood status, (clinical) visit support, living situation (alone or with others), friend or other support, positive social support, negative (lack of) social support, deceased person, transportation issues, relationship conflict or stress, and social isolation. Module data availability ranged from 1.4% for social isolation to 92.0% for spouse/partner. Modules were accurate (0.81-0.95). The most highly available groups had moderate to excellent F1 scores (0.75-1.00), precision or positive predictive value (0.61-1.00), and recall or sensitivity (0.75-1.00). Recall and precision were more variable among rarer modules. Five percent of patients lacked an in-state emergency contact and 3% of patients had diagnostic codes for low support at any time point.<br><br>CONCLUSION: The EHRsupport algorithm accurately identified social support data, supporting the development of a clinical tool that can be used to identify patients with low social support.}, }
@article {pmid42063677, year = {2026}, author = {Gill, J and Stiller, C and Lan, J and Jevnikar, A and Halloran, PF and Rush, D and Nickerson, P and Cole, E and Matas, AJ and Formica, R and Sawinski, D and Blosser, CD and Mannon, RB and Keown, PA}, title = {Conference Report-The Past, Current, and Future Challenges in Transplantation: A Festschrift in Honor of Professor Paul Anthony Keown.}, journal = {Canadian journal of kidney health and disease}, volume = {13}, number = {}, pages = {20543581261434082}, pmid = {42063677}, issn = {2054-3581}, abstract = {PURPOSE: Canadian researchers have made significant contributions to the advancement of organ transplantation globally. The COVID-19 pandemic made transparent the importance of reflecting on our accomplishments and the current and future challenges that limit the lives of our patients and to celebrate individual and collective achievement.<br><br>On October 6, 2025, thought leaders in the field of organ transplantation assembled in Vancouver to recognize the contributions of Paul Keown, a clinician scientist and translational researcher, whose work has directly impacted thousands of transplant recipients worldwide.<br><br>KEY FINDINGS: This article summarizes the invited speaker presentations and represents a unique opportunity to celebrate the past and to focus on current challenges and future opportunities to advance the field of organ transplantation.}, }
@article {pmid42065097, year = {2026}, author = {Habel, JR and Nguyen, THO and de Alwis, N and Allen, EK and Li, S and Skinner, MJ and Juno, JA and Kent, SJ and Bond, K and Williamson, DA and Lappas, M and Hannan, NJ and Walker, S and Schroeder, J and Crawford, JC and Thomas, PG and Kedzierska, K and Rowntree, LC}, title = {High-dimensional multiomics reveals perturbations to IL-6/IL-6R axis and RUNX3 in CD4[+] T cells during third-trimester pregnancy.}, journal = {Clinical &amp; translational immunology}, volume = {15}, number = {}, pages = {e70096}, pmid = {42065097}, issn = {2050-0068}, abstract = {OBJECTIVES: CD4[+] T cells play key roles in regulating immune responses during pregnancy; therefore, we aimed to understand the CD4[+] T-cell surface proteome and transcriptome during pregnancy.<br><br>METHODS: CD4[+] T&#xa0;cells were analysed in blood and decidua from term pregnancies (>&#x2009;37&#x2009;weeks) and non-pregnant blood. >&#x2009;350 surface proteins were screened via flow cytometry, and transcriptomes were analysed using single-cell RNA sequencing with >&#x2009;130 CITE-seq barcoded antibodies.<br><br>RESULTS: Surface protein screening identified changes to ILT4/CD85d, CD9, IFN-&#x3b3; receptor &#x3b2;-chain, CX3CR1 and CCR5 in the pregnant blood and decidual CD4[+] T&#xa0;cells. CX3CR1 and CCR5 had the highest expression on the effector-memory T-cell (TEM) subset in the blood, with expression consistent across subsets in decidua. CD126/IL-6R was lower in pregnant blood and decidual CD4[+] T&#xa0;cells, while scRNAseq identified enrichment in the IL-6R signalling pathway in naive CD4[+] T&#xa0;cells in pregnant blood. Both sIL-6R and IL-6 concentrations were increased in plasma during pregnancy, suggesting perturbations to the IL-6/IL-6R signalling axis. Meanwhile, decidual CD4[+] T&#xa0;cells had increased expression of transcription factor RUNX3 in the CD69[+] tissue-resident-like subset.<br><br>CONCLUSIONS: Our findings demonstrate altered molecular expression in CD4[+] T&#xa0;cells during pregnancy. This provides important mechanistic insight of their adaptation and regulation during placental development, which may drive placental dysfunction or pregnancy complications, including preeclampsia, fetal growth restriction and stillbirth. These new data may inform future studies that focus on determining the significance of differentially expressed immune features in pregnancy to identify potential targets for immune modulation to treat pregnancy complications and infections.}, }
@article {pmid42065388, year = {2026}, author = {Khouderchah, C and Henson, L}, title = {Norepinephrine in Major Abdominal Surgery: Comment.}, journal = {Anesthesiology}, volume = {}, number = {}, pages = {}, pmid = {42065388}, issn = {1528-1175}, }
@article {pmid42066237, year = {2026}, author = {Wong, EYT and Damle, SR and Shiu, KK and Cohen, SA and Lieu, CH}, title = {Immunotherapy in Localized Colorectal Cancer: Current Practice and Future Directions.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {46}, number = {3}, pages = {e520600}, doi = {10.1200/EDBK-26-520600}, pmid = {42066237}, issn = {1548-8756}, mesh = {Humans ; *Colorectal Neoplasms/therapy/pathology/immunology ; *Immunotherapy/methods ; Microsatellite Instability ; *Immune Checkpoint Inhibitors/therapeutic use ; }, abstract = {Immune checkpoint inhibitors (ICIs) have fundamentally transformed the treatment landscape for localized colorectal cancer (CRC), particularly for the mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) subgroups. This review evaluates the current clinical evidence and evolving paradigms of immunotherapy in early-stage CRC. In localized MSI-H colon and rectal cancers, neoadjuvant immunotherapy has demonstrated unprecedented efficacy, yielding near-universal major pathologic responses and high rates of pathologic complete responses. For MSI-H rectal cancer, these deep and sustained clinical complete responses have established nonoperative management as a viable, organ-preserving standard of care for highly selected patients undergoing rigorous multidisciplinary surveillance. Despite these rapid advancements, critical questions remain regarding optimal regimen selection, treatment duration, and the integration of circulating tumor DNA (ctDNA) for molecular residual disease monitoring. Although ctDNA is a promising dynamic biomarker, it currently cannot replace definitive pathologic assessment outside of clinical trials. Furthermore, extending the benefits of immunotherapy to the majority of patients with microsatellite-stable (MSS) CRC represents a significant unmet clinical need. Current evidence for ICIs in localized MSS disease remains limited, although investigational combination strategies incorporating radiation, chemotherapy, and novel immune modulators are yielding hypothesis-generating signals. Future progress hinges on precision de-escalation protocols and biomarker-driven, response-adapted trial designs to validate surrogate end points and optimize patient outcomes across all localized CRC subtypes.}, }
@article {pmid42055839, year = {2026}, author = {Kim, D and Ged, Y and Grivas, P and Singh, P and Rahim, B and Zakharia, Y}, title = {Association Between Proto-Oncogene N-RAS Transcript Level and Overall Survival in Node-Negative Muscle-Invasive Bladder Cancer.}, journal = {Clinical genitourinary cancer}, volume = {}, number = {}, pages = {102557}, doi = {10.1016/j.clgc.2026.102557}, pmid = {42055839}, issn = {1938-0682}, abstract = {INTRODUCTION: Despite the unprecedented advancement in the treatment landscape of muscle-invasive bladder cancer (MIBC), prognostic biomarkers remain investigational. In bladder cancer, oncogenic rat sarcoma (RAS) mutations mostly occur in H-RAS or K-RAS, whereas N-RAS mutations are rare. Overexpression of N-RAS has been previously reported, although its clinical implications remain uncertain. This study aimed to investigate the prognostic implications of N-RAS expression in MIBC.<br><br>PATIENTS AND METHODS: Batch-corrected normalized transcript counts of The Cancer Genome Atlas Bladder Cancer project (n = 411) were analyzed, where 218 patients had non-metastatic node-negative MIBC. Tumor N-RAS transcript level of individual patients was classified as "high" or "low" using the cohort median as a reference value, and survival analyses were performed according to this stratification.<br><br>RESULTS: High N-RAS expression was associated with inferior 5-year overall survival in node-negative MIBC (pT2-4a pN0 M0/x) compared to the low N-RAS expression, with a hazard ratio (HR) 1.91 (95% CI, 1.17-3.11, P = .007), although N-RAS expression did not emerge as a significant factor associated with overall survival upon multivariable adjustment for other clinicopathologic variables. Significant overall survival benefit with cisplatin-based chemotherapy was present in the low N-RAS group with HR 0.28 (95% CI, 0.10-0.81, P = .019), but not in the high N-RAS group. The high N-RAS group was associated with higher CD274 (PD-L1) transcript levels compared to the low N-RAS group (median 62.6 vs. 9.2, P < .0001).<br><br>CONCLUSION: This retrospective study demonstrates that N-RAS transcript levels may be prognostic for node-negative MIBC. Low N-RAS transcript levels may also be associated with an overall survival benefit with cisplatin-based chemotherapy.}, }
@article {pmid42056530, year = {2026}, author = {Hodder, A and Mishra, A and Enshaei, A and Baird, S and Bhuller, K and Castleton, A and Clesham, K and Connor, P and Elbeshlawi, I and Gattens, M and George, L and Heaney, N and Ingham, D and Jigoulina, G and Lindsay, K and Madni, M and Malone, A and Mitchell, B and Motwani, J and Nicholson, E and Patrick, K and Ramanathan, S and Taylor, G and Tewari, S and Thakur, I and Samrin, L and McLelland, V and Osborne, C and Hogan, LE and Cooper, S and Ji, L and Bhojwani, D and Brown, PA and Hunger, SP and Loh, ML and Bonney, D and Cummins, M and van Delft, F and Ghorashian, S and Halsey, C and Hough, R and Moorman, A and Moppett, J and Samarasinghe, S and Vora, A and O'Connor, D}, title = {Reduced-intensity reinduction for children and young persons with relapsed acute lymphoblastic leukemia.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {42056530}, issn = {1476-5551}, }
@article {pmid42058096, year = {2026}, author = {Back, AL and McGregor, BA and Thorn, LL and Harvey, K and Blom, D and Callan, G and Guy, J and Kumar, S and Hershberg, R and Layer, M and Levin, J and Myers, S and Perez, J and Salmonson, K and Thompson, P and Whinney, J}, title = {A phase 1 study of a second experience with Group Retreat Psilocybin Therapy for partial responders after a first experience.}, journal = {Frontiers in public health}, volume = {14}, number = {}, pages = {1810904}, pmid = {42058096}, issn = {2296-2565}, mesh = {Humans ; *Psilocybin/therapeutic use/administration &amp; dosage ; Female ; Male ; Middle Aged ; *Hallucinogens/therapeutic use/administration &amp; dosage ; Adult ; *Anxiety/drug therapy ; *Depression/drug therapy ; *Neoplasms/psychology/complications/drug therapy ; Treatment Outcome ; Aged ; }, abstract = {INTRODUCTION: Psilocybin therapy has demonstrated efficacy for cancer-related anxiety and depression, but resource-intensive individual treatment models raise important questions for psychedelic public health about equitable access and scalability. In our prior Phase 1/2 study of group retreat psilocybin therapy for patients with metastatic cancer, we observed partial responders who did not achieve full therapeutic benefit. No published research has examined whether partial responders might benefit from a second psilocybin therapy experience.<br><br>METHODS: We conducted a single-arm Phase 1 study to assess the safety of a second experience of Group Retreat Psilocybin Therapy for partial responders from our prior study. Protocol modifications addressed dose as a potential contributor to partial response: the initial dose was increased to 35 mg, and an optional 10 mg booster could be requested by participants who reported low subjective effect at 60-90 min and passed a safety check. Pre-retreat antidepressant tapering was not required. The intervention was delivered in a group retreat format with four primary facilitators and included three preparation sessions, a single psilocybin dosing day, and four integration sessions.<br><br>RESULTS: Thirteen participants (mean age 56 years, 70% female, 38% on concurrent antidepressants) completed the intervention. No serious adverse events occurred; mild adverse events included transient hypertension (n = 4), nausea (n = 3), and headache (n = 1). Seven participants (54%) received the booster dose. Mean Hospital Anxiety and Depression Scale (HADS) Total scores decreased from 15.08 (SD 4.35) at baseline to 9.00 (SD 4.62) at Day +8, with improvements maintained through 24-week follow-up (mean 10.42, SD 6.93); 69% achieved HADS scores below the clinical threshold. The proportion of participants with a "complete" mystical experience (Mystical Experience Questionnaire &#x2265; 60%) increased from 38% in the first experience to 77% in the second, without an increase in challenging experiences (Challenging Experiences Questionnaire). Social support, social identification, and group cohesion scores showed progressive improvements that persisted at 24 weeks.<br><br>DISCUSSION: A second experience of group retreat psilocybin therapy was safe and feasible for partial responders with metastatic cancer. The protocol modifications-higher dose, optional booster, and no antidepressant tapering requirement-did not introduce new safety concerns and were associated with substantially enhanced mystical experiences and preliminary efficacy signals. These findings support further investigation of retreatment protocols for partial responders and contribute to developing scalable group-based models relevant to psychedelic public health, where the resource intensity of individual treatment remains a fundamental barrier to population-level access.}, }
@article {pmid42058159, year = {2026}, author = {Jurasin, AC and Frank, AR and Biggins, S}, title = {Proteomics reveals extensive phosphoregulation of outer kinetochore protein KNL1.}, journal = {microPublication biology}, volume = {2026}, number = {}, pages = {}, pmid = {42058159}, issn = {2578-9430}, abstract = {Microtubules attach to kinetochores to facilitate chromosome movement to opposite spindle poles. Defective kinetochore-microtubule attachments lead to phosphoryation of the outer kinetochore protein KNL1 at conserved MELT motifs, which triggers spindle assembly checkpoint activation and recruitment of the fibrous corona. To identify additional phosphorylation sites that regulate kinetochores, we treated HEK 293T/17 cells with nocodazole, paclitaxel, or STLC to create defective kinetochore-microtubule attachment states. We then purified KNL1 and performed proteomics and identified 111 phosphorylation sites on KNL1, including several that may be attachment-state specific. These data demonstrate that KNL1 is extensively phosphoregulated in response to treatment with microtubule-disrupting compounds.}, }
@article {pmid42060316, year = {2026}, author = {Boiko, JR and Carpenter, PA}, title = {Boosting "Treg-ulation": a good way to treat chronic GVHD?.}, journal = {Blood advances}, volume = {10}, number = {9}, pages = {3059-3060}, doi = {10.1182/bloodadvances.2026019728}, pmid = {42060316}, issn = {2473-9537}, }
@article {pmid42061715, year = {2026}, author = {Khil, J and Zhao, L and Zhang, X and Chen, Y and Jung, SY and Pichardo, MS and Lopez-Pentecost, M and Rohan, T and Saquib, N and Sun, Y and Tabung, FK and Zheng, T and Wactawski-Wende, J and Manson, JE and Neuhouser, ML and Keum, N and Zhang, X}, title = {Dietary patterns and the risk of liver cancer and chronic liver disease mortality.}, journal = {The Journal of nutrition}, volume = {}, number = {}, pages = {101557}, doi = {10.1016/j.tjnut.2026.101557}, pmid = {42061715}, issn = {1541-6100}, abstract = {BACKGROUND: Accumulating evidence suggests that diet plays an important role in the development of liver disease. Compared with individual nutrients or foods, dietary patterns better represent overall eating behaviors, but their associations with liver cancer and chronic liver disease (CLD) remain poorly understood.<br><br>OBJECTIVE: We evaluated whether greater adherence to healthy dietary patterns was associated with lower liver cancer risk and CLD mortality.<br><br>METHODS: We analyzed data from 78,345 postmenopausal women enrolled in the Women's Health Initiative Observational Study. Four dietary patterns [Alternative Healthy Eating Index-2010 (AHEI-2010), Healthy Eating Index-2020 (HEI-2020), alternate Mediterranean Diet (aMED), Dietary Approach to Stop Hypertension (DASH)] were calculated using dietary data collected via a validated food-frequency questionnaire. Liver cancer incidence and CLD death were ascertained by review of medical records or linkage to the National Death Index. Cox proportional hazards regression was performed to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CIs).<br><br>RESULTS: During a median follow-up of 22.1 years, 176 liver cancer cases and 128 CLD deaths were documented. For liver cancer, significant inverse associations were observed with HEI-2020 (HR Quartile 4 vs. Quartile 1= 0.58, 95% CI=0.37-0.93, Ptrend=0.02) and DASH (HR Q4 vs. Q1=0.58, 95% CI=0.35 -0.98, Ptrend=0.07). For CLD mortality, significant inverse associations were observed with AHEI-2010 (HR Q4 vs. Q1=0.50, 95% CI=0.27-0.92, Ptrend=0.02), HEI-2020 (HR Q4 vs. Q1=0.59, 95% CI=0.33-1.04, Ptrend=0.04), aMED (HR Q4 vs. Q1=0.48, 95% CI=0.25-0.90, Ptrend=0.02), and DASH (HR Q4 vs. Q1=0.49, 95% CI=0.25-0.95, Ptrend=0.02).<br><br>CONCLUSION: Maintaining an overall healthy diet may be associated with lower liver cancer risk and CLD mortality among postmenopausal women.}, }
@article {pmid42061840, year = {2026}, author = {Sala, M and Roos, C and Ascarrunz, D and Stern, CM and Bricker, J and Feldman, JM and Levinson, C and Aslan, M and Hay, JL and Kober, H}, title = {Combining Digital Cognitive Behavioral Therapy With Mindfulness Training for Binge Eating Disorder: Protocol for a Feasibility Trial.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e91761}, doi = {10.2196/91761}, pmid = {42061840}, issn = {1929-0748}, mesh = {Humans ; *Cognitive Behavioral Therapy/methods ; *Mindfulness/methods ; *Binge-Eating Disorder/therapy/psychology ; Feasibility Studies ; Adult ; Female ; Pilot Projects ; Middle Aged ; Male ; Single-Blind Method ; Treatment Outcome ; Adolescent ; Young Adult ; }, abstract = {BACKGROUND: Cognitive behavioral therapy (CBT) is the most effective treatment for binge eating disorder (BED) but is limited by modest efficacy and low reach of in-person delivery. Combining mindfulness training with CBT could enhance efficacy by targeting emotion dysregulation, a key factor in BED that CBT does not adequately target. Digital delivery can enhance the reach of treatment. Accordingly, we developed CBT-based Mindful Courage, a 16-session digital intervention combining CBT and mindfulness training for BED.<br><br>OBJECTIVE: The aim of this study is to conduct a pilot randomized controlled trial to evaluate the feasibility (intervention and assessment completion) and acceptability (usability, overall satisfaction, engagement, visual appeal of content, understandability of program content, desire to continue the program, perceived skill acquisition, perceived confidence in implementing skills, and perceived helpfulness) of CBT-based Mindful Courage. We will also evaluate changes in outcomes (binge eating frequency, eating disorder symptoms, clinical impairment, and depression symptoms) and mechanisms (emotion dysregulation, dietary overrestriction, and trait mindfulness).<br><br>METHODS: This is a parallel-group, single-blinded, randomized controlled trial with a 1:1 allocation ratio. It will be conducted from November 2025 to November 2026, with study assessments at baseline, midtreatment, end-of-treatment, and 2-month follow-up. We will recruit a volunteer sample of adults with BED (N=40) aged 18 to 75 years via online advertisements. Exclusion criteria include a BMI <18.5, current anorexia or bulimia nervosa, and current treatment for BED or weight loss. Participants will be randomly allocated to an active control that includes coached self-monitoring (self-monitoring of food intake in Recovery Record and coaching calls by a research assistant) or to CBT-based Mindful Courage+coached self-monitoring. Both conditions will have a duration of 18 weeks. All study sessions will take place over Zoom.<br><br>RESULTS: The study was funded in April 2023. Data collection began in November 2025, and we anticipate recruitment to be completed by November 2026. Results are expected to be analyzed by May 2027 and published by May 2028.<br><br>CONCLUSIONS: This will be an important first step in creating a scalable and efficacious treatment for BED.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT07212673; https://clinicaltrials.gov/study/NCT07212673.<br><br>DERR1-10.2196/91761.}, }
@article {pmid42049996, year = {2026}, author = {Chen, DD and Zimmer, A and Yang, DD and Francini, E and Patton, R and Crowdis, J and Chandra, P and Bin Riaz, I and Hanratty, B and Rickles-Young, M and Tsuji, J and Cibulskis, C and Fleharty, M and Whelpley, B and Reardon, B and Park, J and Nelson, PS and Huang, FW and Van Allen, EM and Ha, G and Choudhury, AD}, title = {Multi-modal circulating cell-free DNA profiling to predict response to docetaxel in metastatic castration-resistant prostate cancer.}, journal = {NPJ precision oncology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41698-026-01454-6}, pmid = {42049996}, issn = {2397-768X}, support = {K22 CA237746/NH/NIH HHS/United States ; K22 CA237746/NH/NIH HHS/United States ; S10OD028685/RI/ORIP NIH HHS/United States ; }, abstract = {There are currently no clinically validated markers for taxane sensitivity in metastatic castration-resistant prostate cancer (mCRPC), so we aimed to predict docetaxel response from circulating cell-free DNA. We identified 180 patients with pre-treatment plasma specimens collected within 12 months of starting docetaxel for mCRPC at our institution. 138 underwent ultra-low pass whole genome sequencing (ULP-WGS), and tumor fractions (TFx) and copy number alterations (CNAs) were derived using ichorCNA. 79 samples with TFx > 0.04 underwent targeted panel sequencing (TPS). TP53 mutation was significantly associated with docetaxel non-response (p = 0.018); deletions involving bands located in arms 11p, 11q, 10q and 3p were enriched in responders, and amplifications in regions of 1p and 6q were enriched in non-responders. Transcription factor (TF) binding activity was inferred using Griffin, which identified TFs (ZSCAN4, CTCF, PHOX2B) with trends towards increased activity in non-responders (n = 22) and others (including PBX1, MYBL2, OSR2, PDX1 and ZIC2) in responders (n = 24). A combined ensemble binary classifier generated through XGBoost integrating these feature sets to predict docetaxel response outperformed models derived from any single feature set, achieving a training area-under-the-ROC curve of 0.87. Pre-cabazitaxel specimens, representing a docetaxel-resistant population, were used for external validation, with a concordance of 79.6% for predicting non-response.}, }
@article {pmid42051192, year = {2026}, author = {Malhotra, SV and Stefan, K and Lee, JM and Tailor, D and Dheeraj, A and Rolig, AS and Khou, S and Grau, BW and Garcia-Marques, FJ and Bermudez, A and Davis, LE and Pitteri, SJ}, title = {YB-1 inhibition suppresses osteosarcoma growth and reverses tumor immunosuppression.}, journal = {Molecular cancer therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1158/1535-7163.MCT-25-1240}, pmid = {42051192}, issn = {1538-8514}, abstract = {Osteosarcoma (OS), the most common primary bone malignancy in adolescents and young adults, is still marked by poor long-term survival and poor mortality. Although immune checkpoint blockade (ICB) has transformed treatment for several cancers, its benefit in OS has been minimal, largely due to OS's "immune-cold" phenotype characterized by scarce tumor-infiltrating lymphocytes. Novel strategies are urgently needed to overcome this resistance. Y-box binding protein 1 (YB-1), a pro-oncogenic member of the cold-shock protein superfamily, represents a promising target to sensitize OS to ICB. Here, we evaluate SU056, a small-molecule YB-1 inhibitor, which both suppressed intrinsic OS tumor growth and remodeled the tumor microenvironment (TME). SU056 treatment markedly reduced immunosuppressive populations, including regulatory T cells (Tregs) and M2-polarized tumor-associated macrophages (TAMs), while enhancing infiltration of granzyme B-positive cytotoxic CD8[+] T cell and NK cells. Combination therapy with SU056 and anti-PD-1 blockade produced superior tumor growth inhibition and significantly prolonged survival compared with either monotherapy. These findings highlight SU056 as a potent immunomodulatory agent and support its coadministration with ICB as a promising therapeutic approach for OS.}, }
@article {pmid42054051, year = {2026}, author = {Konstantopoulos, A and de Virgilio, C and Childers, CP}, title = {Time Is More Than Money-Reply.}, journal = {JAMA surgery}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamasurg.2026.1147}, pmid = {42054051}, issn = {2168-6262}, }
@article {pmid42054549, year = {2026}, author = {Gill, H and Yacoub, A and Gerds, AT and Shortt, J and Rossetti, JM and Mead, AJ and Göthert, JR and Koschmieder, S and Ewing, J and Halpern, AB and Palandri, F and Passamonti, F and Mesa, RA and Marchetti, M and Harrison, CN and Vannucchi, AM and Watts, JM and Wood, JC and Ross, DM and Peppe, J and Natsoulis, G and Rienhoff, HY}, title = {The lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in myelofibrosis: results from a phase 1/2 study.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018141}, pmid = {42054549}, issn = {2473-9537}, abstract = {Novel therapies for myelofibrosis (MF) are needed, particularly after JAK inhibitor failure. This open-label, phase 1/2 study evaluated bomedemstat, an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), in participants with MF refractory or resistant to, inadequately controlled by, or intolerant of approved therapies. Eighty-nine participants initially received bomedemstat 0.25, 0.5, or 0.6 mg/kg orally once per day titrated to achieve a target platelet count of ≥50 to ≤75 ´ 109/L. Primary end points were safety and change in spleen volume. Hematologic response and change in symptom burden, bone marrow fibrosis score, and variant allele frequency (VAF) were exploratory. Eighty-seven participants (97%) experienced ≥1 any-cause adverse event (AE), most commonly thrombocytopenia (48%) and dysgeusia (36%); 62 participants (69%) experienced ≥1 grade 3-5 AE. Three participants (3%) experienced AEs that led to death; none were related to treatment. Of 35 participants with spleen volume data at week 24, 23 (66%) had a reduction in spleen volume; 9 (26%) had a reduction of ≥20%. Mean platelet and white blood cell counts normalized over 24 weeks; hemoglobin levels remained stable. Participants reported improvement in most symptoms, including fatigue. Of 35 participants with baseline and week 24 data, 8 (23%) had improved bone marrow fibrosis by ≥1 grade per central review, and 21 (60%) were stable. Of 36 participants with CALR, JAK2, or MPL mutations and data at week 24, 56% had a reduction in VAF. Bomedemstat has manageable safety and clinical activity in participants with MF in need of an alternative therapy. This trial was registered at www.cinicaltrials.gov as #NCT03136185.}, }
@article {pmid42045583, year = {2026}, author = {Hazlehurst, MF and Liu, C and Zheng, G and Koch, M and Schreder, E and Salamova, A and Sathyanarayana, S}, title = {Endocrine-disrupting chemicals in breast milk and early life exposure for infants in the United States.}, journal = {Journal of exposure science &amp; environmental epidemiology}, volume = {}, number = {}, pages = {}, pmid = {42045583}, issn = {1559-064X}, abstract = {BACKGROUND: Breastfeeding can be a source of exposure to endocrine-disrupting chemicals (EDCs) for infants, but limited information exists on exposure to commonly used chemicals such as melamine and bisphenols in nursing infants in the US.<br><br>OBJECTIVE: We aimed to measure a suite of EDCs in breast milk and evaluate exposure of nursing infants to these chemicals.<br><br>METHODS: We analyzed EDCs in breast milk samples collected from 50 women in Seattle, Washington during 2019, including melamine, cyanuric acid, ammeline, ammelide, bisphenol A (BPA), 4-hydroxyphenyl sulfone (BPS), 4,4'-methylenediphenol, (4,4'-hexafluoroisopropylidene) diphenol, fluorene-9-bisphenol, and triclosan. We examined associations of infant age at sample collection and maternal characteristics with log10-transformed chemical concentrations using linear regression. Estimated daily intake (EDI) of each chemical through breast milk was calculated for infants 0-12 months old using our sample median chemical concentrations.<br><br>RESULTS: We frequently detected (62-92%) melamine, cyanuric acid, BPA, BPS, and triclosan in breast milk. Median concentrations were 0.48&#x2009;ng/mL melamine, 0.59&#x2009;ng/mL cyanuric acid, 0.311&#x2009;ng/mL BPA, 0.012&#x2009;ng/mL BPS, and 0.072&#x2009;ng/mL triclosan. Older infant age (>6 versus <6 months) was associated with lower melamine concentrations (-0.41, 95% CI: -0.80, -0.01). Maternal obesity was associated with higher BPA (0.68, 95% CI: 0.14, 1.23) and maternal overweight with higher triclosan (0.43, 95% CI: 0.06, 0.80). Other associations with participant characteristics were suggestive but not statistically significant. EDIs for infants in the average exposure scenario ranged by infant age from 40.3 to 72.8&#x2009;ng/kg-bodyweight/day for melamine and 86.5-156&#x2009;ng/kg-bodyweight/day for BPA.<br><br>SIGNIFICANCE: We frequently detected melamine, cyanuric acid, BPA, BPS, and triclosan in breast milk. EDIs through breastfeeding were generally higher than for other exposure pathways (e.g., dermal uptake, dust ingestion or inhalation), and more work is needed to understand potential health effects of chronic infant exposures to even low levels of these ubiquitous chemicals through breast milk.<br><br>IMPACT: This study adds to the limited research to date on endocrine-disrupting chemicals in breast milk, exposure among nursing infants in the US, and differences by infant and maternal characteristics, to further inform cumulative exposure assessment in infants and regulatory thresholds. Melamine, cyanuric acid, BPA, BPS, and triclosan were detected with high frequency in breast milk samples in our study, and our study suggests that breast milk is an important exposure pathway for these chemicals among nursing infants. Given the importance of breastfeeding for infant health, our study highlights the need to investigate potential health effects of these chronic exposures.}, }
@article {pmid42046307, year = {2026}, author = {Kennedy, VE and Peretz, CAC and Koh, A and Tran, E and Dhingra, D and Gulati, S and Sciambi, A and Sala-Torra, O and Beppu, L and Radich, JP and Smith, CC}, title = {Multiomic Single-Cell Sequencing Identifies BCR::ABL1 as an Acquired Resistance Mechanism in FLT3+ AML.}, journal = {European journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ejh.70207}, pmid = {42046307}, issn = {1600-0609}, support = {//Mission Bio/ ; }, abstract = {BCR::ABL1 acquisition is an emerging but poorly characterized resistance mechanism in FLT3-mutated AML. Using multiomic single-cell DNA sequencing, we characterized clonal evolution in a patient with FLT3-ITD AML who acquired BCR::ABL1 with FLT3 inhibitor resistance. Phylogenetic reconstruction confirmed BCR::ABL1 as a branch event co-occurring with FLT3-ITD and restricted to specific blast populations, supporting BCR::ABL1 acquisition as a resistance mechanism.}, }
@article {pmid42047489, year = {2026}, author = {Ralph, DK and Bakis, AG and Galloway, JG and Vora, AA and Araki, T and Victora, GD and Song, YS and DeWitt, WS and Matsen, FA}, title = {Inference of germinal center evolutionary dynamics via simulation-based deep learning.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, doi = {10.7554/eLife.108880}, pmid = {42047489}, issn = {2050-084X}, support = {R01-AI146028//NIH Office of the Director/ ; U01 AI150747/AI/NIAID NIH HHS/United States ; R56-HG013117//NIH Office of the Director/ ; R01-HG013117//NIH Office of the Director/ ; }, mesh = {*Germinal Center/immunology/physiology ; *Deep Learning ; Animals ; Mice ; *B-Lymphocytes/immunology/physiology ; Computer Simulation ; *Biological Evolution ; }, abstract = {B cells and the antibodies they produce are vital to health and survival, motivating research on the details of the mutational and evolutionary processes in the germinal centers (GCs) from which mature B cells arise. It is known that B cells with higher affinity for their cognate antigen (Ag) will, on average, tend to have more offspring. However, the exact form of this relationship between affinity and fecundity, which we call the 'affinity-fitness response function', is not known. Here we use deep learning and simulation-based inference to learn this function from a unique experiment that replays a particular combination of GC conditions many times in mice. All code is freely available at https://github.com/matsengrp/gcdyn, while datasets and inference results can be found at https://doi.org/10.5281/zenodo.15022130.}, }
@article {pmid42047685, year = {2026}, author = {Schaefer-Babajew, D and Binet, L and Silva Santos, GS and Ruprecht, C and Deimel, LP and ElTanbouly, MA and Gharrassi, D and Lima Dos Reis, G and Uhe, C and Yao, KH and Hernandez, B and Agrawal, P and Gazumyan, A and Stamatatos, L and Hartweger, H and Nussenzweig, MC}, title = {Antibody-mediated diversification of primary and secondary humoral immune responses.}, journal = {The Journal of experimental medicine}, volume = {223}, number = {6}, pages = {}, doi = {10.1084/jem.20252590}, pmid = {42047685}, issn = {1540-9538}, support = {XXX//Human Immunome Project/ ; XXX//Michelson Medical Research Foundation/ ; 2P01AI100148-11/NH/NIH HHS/United States ; UM1AI191237/NH/NIH HHS/United States ; 1UM1AI144462-01/NH/NIH HHS/United States ; XXX//Stavros Niarchos Foundation Institute/ ; UL1-TR001866/TR/NCATS NIH HHS/United States ; XXX//Shapiro-Silverberg Fund/ ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Animals ; *Immunity, Humoral/immunology ; Mice ; *Immunoglobulin M/immunology/genetics ; B-Lymphocytes/immunology ; *Antibody Diversity/immunology ; Antibodies, Neutralizing/immunology ; Antibody Affinity/immunology ; Mice, Inbred C57BL ; }, abstract = {Humoral immune responses are characterized by increasing antibody affinity and diversity over time. Increased affinity is mediated by a combination of immunoglobulin gene somatic mutation and iterative cycles of selection in germinal centers. Less is understood about how diversity increases. Here, we examine the role of antibody feedback in diversifying immune responses in mice that produce B cells that are incapable of secreting antibodies. To this end, we produced two strains of mice, one that expresses only membrane and secreted forms of IgM, and a second that produces only the membrane-bound form of IgM. Analysis of primary and secondary immune responses shows that antibody feedback significantly diversifies both primary and secondary immune responses even when antibodies are present at levels that are 10-30-fold lower than physiologic. The data have significant implication for sequential vaccination approaches aimed at shepherding immunity to produce broadly neutralizing antibodies to highly diversified pathogens such as HIV-1 and influenza.}, }
@article {pmid42048449, year = {2026}, author = {Peer, E and Cohen-Lavi, L and Sette, A and Sidney, J and Hertz, T}, title = {Computational design of HLA class I superbinders for broad T cell immunogenicity.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {18}, pages = {e2518820123}, doi = {10.1073/pnas.2518820123}, pmid = {42048449}, issn = {1091-6490}, mesh = {Humans ; *Histocompatibility Antigens Class I/immunology/chemistry/metabolism/genetics ; *T-Lymphocytes/immunology ; *Peptides/immunology/chemistry ; Protein Binding ; *Computational Biology/methods ; Monte Carlo Method ; Markov Chains ; }, abstract = {Human leukocyte antigen (HLA) class I molecules are highly polymorphic, restricting peptide binding to narrow sequence subsets. Designing peptides that bind multiple HLA supertypes-termed superbinders-offers a promising strategy for broad-spectrum T cell vaccines and immunotherapies. Here, we present superHLA, a computational framework that combines Markov Chain Monte Carlo optimization with state-of-the-art major histocompatibility complex binding predictors to design synthetic 9-mer peptides with broad HLA-binding profiles. Using superHLA, we generated over 190,000 candidate superbinders predicted to bind 8 to 12 HLA class I alleles across distinct supertypes. A multitier filtering pipeline-incorporating sequence clustering, synthesis feasibility, cross-predictor validation, and self-peptidome exclusion-yielded a final panel of 100 peptides for experimental testing. Of these, 21 bound 4 to 9 supertypes in vitro. Superbinders displayed distinct anchor residue preferences and showed minimal similarity to human peptides. These results suggest that HLA superbinders are more abundant than previously recognized and can be rationally designed at scale. This approach supports development of pan-HLA immunogens with broad population coverage and may inform applications in vaccine research, neoantigen discovery, and immunotherapy.}, }
@article {pmid42048586, year = {2026}, author = {Ayati, N and Papa, N and Crumbaker, M and Subramaniam, S and Joshua, AM and Alipour, R and Iravani, A and Askari, E and Khan, S and Yadav, S and Eiber, M and Weickhardt, A and Lee, ST and Ng, S and Francis, RJ and Goh, JC and Pattison, DA and Tan, TH and Kirkwood, ID and Nguyen, A and Hofman, MS and Sandhu, S and Hioki, T and van Oorschodt, JCJ and Devitt, K and Willowson, K and Sharma, S and Stancu, A and Chauvie, S and Wilson, P and Martin, AJ and Thomas, H and Stockler, MR and Davis, ID and Emmett, L and , }, title = {[177]Lu-PSMA-617 SPECT/CT for Early Prediction of Overall Survival in Participants with Metastatic Castration-Resistant Prostate Cancer.}, journal = {Radiology}, volume = {319}, number = {1}, pages = {e252672}, doi = {10.1148/radiol.252672}, pmid = {42048586}, issn = {1527-1315}, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/diagnostic imaging/mortality/pathology/drug therapy/radiotherapy ; Aged ; *Lutetium/therapeutic use ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; *Single Photon Emission Computed Tomography Computed Tomography/methods ; *Dipeptides/therapeutic use ; Prospective Studies ; Prostate-Specific Antigen/blood ; *Radioisotopes/therapeutic use ; Nitriles/therapeutic use ; Middle Aged ; Radiopharmaceuticals/therapeutic use ; Phenylthiohydantoin/therapeutic use/analogs &amp; derivatives ; Benzamides/therapeutic use ; }, abstract = {Background Lutetium 177 ([177]Lu) prostate-specific membrane antigen (PSMA)-617 SPECT/CT has demonstrated promise as a response biomarker for [177]Lu-PSMA-617 therapy. Purpose To predict overall survival (OS) after enzalutamide plus [177]Lu-PSMA-617 using quantitative parameters at [177]Lu-PSMA-617 SPECT/CT at 6 weeks, as well as prostate-specific antigen (PSA) response, in participants with metastatic castration-resistant prostate cancer. Materials and Methods This secondary analysis of the multisite prospective ENZA-p trial (August 2020-July 2022) included participants who received enzalutamide plus [177]Lu-PSMA-617 (7.5 GBq). SPECT/CT was performed 24 hours after each treatment, and total tumor volume (TTV) and mean standardized uptake value were compared between the first (baseline) and second (6-week) doses. TTV complete response (CR) at SPECT/CT was defined as TTV less than 1 mL at dose 2, and deep PSA response was defined as 90% or greater PSA reduction at dose 2. Relationships between TTV CR and deep PSA response at dose 2 and OS were examined. Results This analysis included 74 men (median age, 71 years [IQR, 66-78 years]). Median follow-up was 33 months (95% CI: 28, 37). Median OS was 31 months (95% CI: 25, 33), and the 2-year survival rate was 70% (95% CI: 58, 79). Median TTV was 236 mL (IQR, 81-688 mL) at baseline and 65 mL (IQR, 12-215 mL) at 6 weeks. Median change in TTV was -57% (IQR, -89% to -38%); 4.1% (three of 74) of participants had an increase in TTV, and 16% (12 of 74) had TTV CR. Deep PSA response was seen in 63% (45 of 71) of participants. The 2-year survival rate with TTV CR was 83% (95% CI: 48, 96), versus 67% (95% CI: 54, 77) without TTV CR (hazard ratio, 0.26 [95% CI: 0.08, 0.85]; log-rank P = .02). The 2-year survival rate was 76% (95% CI: 58, 87) with deep PSA response without TTV CR (log-rank P = .05 vs TTV CR) and 54% (95% CI: 33, 71) with neither deep PSA response nor TTV CR (log-rank P = .003 vs TTV CR). Conclusion TTV CR at [177]Lu-PSMA-617 SPECT/CT at 6 weeks was associated with improved OS and may be a valuable tool for treatment personalization with [177]Lu-PSMA-617. ClinicalTrials.gov Identifier: NCT04419402 © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Galgano and Turner in this issue.}, }
@article {pmid42048777, year = {2026}, author = {Tosoian, JJ and Meyers, JI and Moore, B and Britton, CJ and Chevli, K and Rayford, W and Gadzinski, AJ and Joseph, JV and Patel, P and Kasraeian, A and Sethi, PS and Robinson, HS and Assani, KD and Rings, V and Pierce, J and Scarpato, KR and Moses, KA and Barocas, DA and Chang, SS and Penson, DF and Sanda, MG and Ross, AE and Cooperberg, MR and Salari, K and Liss, M and Zhang, Y and Siddiqui, J and Singhal, U and Salami, SS and Morgan, TM and Palapattu, GS and Wei, JT and Cao, J and Bala, V and Oh, Y and Heaton, S and Zheng, Y and Chinnaiyan, AM}, title = {Non-Invasive Urine Test Predicts Grade Group Upgrading in Patients on Active Surveillance for Prostate Cancer: Multisite Validation and Comparison with MRI.}, journal = {The Journal of urology}, volume = {}, number = {}, pages = {101097JU0000000000005095}, doi = {10.1097/JU.0000000000005095}, pmid = {42048777}, issn = {1527-3792}, abstract = {PURPOSE: We developed and externally-validated a non-DRE urine test to inform whether biopsy is necessary in patients undergoing active surveillance (AS). Performance and clinical consequences of testing were directly compared to multiparametric magnetic resonance imaging (mpMRI).<br><br>MATERIALS AND METHODS: Biomarker models (MyProstateScore 2.0 - Active Surveillance [MPS2-AS]) were derived to predict upgrading to Grade Group (GG)&#x2265;3 and GG&#x2265;2 and externally validated across 11 practices. Urine was prospectively collected, and patients underwent &#x2265;12-core systematic biopsy (SBx) plus targeted biopsy (TBx) of PI-RADS&#x2265;3 lesions. Diagnostic performance and clinical consequences of urinary testing to determine the need for biopsy were compared to mpMRI.<br><br>RESULTS: The validation cohort included 330 patients with GG1 cancer scheduled for AS biopsy. Overall, 280 (85%) patients had pre-biopsy mpMRI, of which 130 (46%) were PI-RADS 1-2, 42 (15%) were PI-RADS 3, and 108 (39%) were PI-RADS 4-5. On biopsy, 31 (9.4%) patients upgraded to GG&#x2265;3 and 123 (37%) to GG&#x2265;2. MPS2-AS provided higher AUC than mpMRI for upgrading to both GG&#x2265;3 (0.82 vs. 0.73) and GG&#x2265;2 (0.74 vs. 0.64). Clinically, pre-biopsy MPS2-AS would have avoided 64% of unnecessary biopsies while failing to detect only 3.2% of GG&#x2265;3 upgrades. By contrast, use of PI-RADS&#x2265;3 would have failed to detect 18% of GG&#x2265;3 upgrades and avoided fewer unnecessary biopsies (50%). Performance of MPS2-AS was consistent across clinically-pertinent subgroups (confirmatory and surveillance biopsy, Black and non-Black patients).<br><br>CONCLUSIONS: In a multisite AS population, urinary MPS2-AS provided highly accurate and actionable testing for GG&#x2265;3 and GG&#x2265;2 upgrading, meaningfully outperforming mpMRI on direct comparison. These findings suggest that non-invasive monitoring with MPS2-AS could reduce the need for scheduled biopsies and serial mpMRI.}, }
@article {pmid42049931, year = {2026}, author = {Li, C and Ke, F and Zhao, H and Mao, S and Djibo, M and Huang, L and He, M and Wang, M and Wen, H and Liu, Z and Yu, Z and Qi, Z and Xavier, AR and Nenwani, M and Wen, B and Peterson, N and Sahai, V and Nagrath, D and Lucas, CL and Wymann, MP and Gao, W and Fong, L and Sun, D}, title = {Dual targeting of PI3Kγ and STING overcomes regulatory B cell- and myeloid cell-driven immune suppression in pancreatic cancer.}, journal = {Nature cancer}, volume = {}, number = {}, pages = {}, pmid = {42049931}, issn = {2662-1347}, support = {N035800//University of Michigan (U-M)/ ; }, abstract = {Both regulatory B (Breg) and myeloid cells in tumors and lymph nodes drive immune suppression in pancreatic cancer. Current strategies to counter immune suppression emphasize myeloid cells but overlook Breg cells. We discovered that STING agonist expanded Breg cells depended on PI3Kγ but not PI3Kδ in pancreatic cancer, whereas activating myeloid cells were independent of PI3Kγ. Inhibition of PI3Kγ, but not PI3Kδ, decreased STING-induced IRF3 phosphorylation and Breg cell expansion in pancreatic cancer, while sustaining STING-induced IRF3 phosphorylation to activate myeloid cells. We developed a dual targeting compound and its albumin nanoformulation Nano-273, which stimulated STING to activate myeloid cells and inhibited PI3Kγ to decrease STING-induced Breg cell expansion. Nano-273 delivered the drug to tumors and lymph nodes to overcome myeloid cell- and Breg cell-mediated immune suppression in pancreatic cancer. Nano-273, combined with anti-programmed cell death protein 1, achieved durable efficacy in transgenic KPC mice with pancreatic cancer, offering potential for pancreatic cancer treatment.}, }
@article {pmid41929129, year = {2026}, author = {Hedouin, S and Hu, C and Biggins, S}, title = {An interdependent Cbf1-CCAN interaction stabilizes the budding yeast kinetochore.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929129}, issn = {2692-8205}, support = {R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Chromosome segregation requires the proper assembly of kinetochores on centromeric DNA. The kinetochore is a complex multi-protein machine comprising more than 40 distinct proteins, but the functional roles of many components remain unclear. One such protein is the yeast transcription factor Cbf1, which directly binds to budding yeast centromeric DNA. Loss of Cbf1 significantly increases the rate of chromosome missegregation, however its precise molecular mechanism of action is unknown. It was recently found that Cbf1 inhibits transcription through the centromere by preventing the untimely pericentromeric transcriptional readthrough via a roadblock mechanism. Intriguingly, restoring the transcriptional roadblock in the absence of Cbf1 binding only partially rescued chromosome missegregation, indicating that Cbf1 performs additional centromeric activities. Here, we show that Cbf1 promotes inner kinetochore assembly both in vitro and in vivo. This assembly function depends on the direct interaction between Cbf1 and Okp1. Moreover, we found that Cbf1's stable association with the centromere requires its interaction with the inner kinetochore, revealing an interdependent interaction essential for the assembly and stability of the kinetochore. Thus, Cbf1 functions as a centromere-anchored hub that couples transcriptional roadblocking to CCAN assembly and kinetochore stability.}, }
@article {pmid41959409, year = {2026}, author = {Habel, JR and Nguyen, THO and de Alwis, N and Allen, EK and Li, S and Skinner, MJ and Juno, JA and Kent, SJ and Bond, K and Williamson, DA and Lappas, M and Hannan, NJ and Walker, S and Schroeder, J and Crawford, JC and Thomas, PG and Kedzierska, K and Rowntree, LC}, title = {High-dimensional multiomics reveals perturbations to IL-6/IL-6R axis and RUNX3 in CD4[+] T cells during third trimester pregnancy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41959409}, issn = {2692-8205}, abstract = {OBJECTIVES: CD4[+] T cells play key roles in regulating immune responses during pregnancy, therefore we aimed to understand the CD4[+] T cell surface proteome and transcriptome during pregnancy.<br><br>METHODS: CD4[+] T cells were analysed in blood and decidua from term-pregnancies (>37 weeks), and non-pregnant blood. >350 surface proteins were screened via flow cytometry, and transcriptomes were analysed using single-cell RNA sequencing with >130 CITE-seq barcoded antibodies.<br><br>RESULTS: Surface protein screening identified changes to ILT4/CD85d, CD9, IFN-&#x3b3; receptor &#x3b2;-chain, CX3CR1 and CCR5 in the pregnant blood and decidual CD4[+] T cells. CX3CR1 and CCR5 had the highest expression on the effector-memory T cell (TEM) subset in the blood, with expression consistent across subsets in decidua. CD126/IL-6R was lower in pregnant blood and decidual CD4[+] T cells, while scRNAseq identified enrichment in the IL-6R signalling pathway in naive CD4[+] T cells in pregnant blood. Both sIL-6R and IL-6 concentrations were increased in plasma during pregnancy, suggesting perturbations to the IL-6/IL-6R signalling axis. Meanwhile, decidual CD4[+] T cells had increased expression of transcription factor RUNX3 in the CD69[+] tissue-resident-like subset.<br><br>CONCLUSIONS: Our findings demonstrate altered molecular expression in CD4[+] T cells during pregnancy. This provides important mechanistic insight of their adaptation and regulation during placental development, which may drive placental dysfunction or pregnancy complications including preeclampsia, fetal growth restriction and stillbirth. These new data may inform future studies that focus on determining the significance of differentially-expressed immune features in pregnancy to identify potential targets for immune modulation to treat pregnancy complications and infections.}, }
@article {pmid41960310, year = {2026}, author = {Mtisi, TJ and Montano, MA and Chagomerana, MB and Bula, A and Dunda, W and Mugisha, NM and Niyonzima, N and Nassolo, C and Weza, S and Madya, F and Mapanga, W and Joffe, M and Ndlovu, N and Borok, M and Ignacio, RB and Mugo, C}, title = {Application of Process Mapping to catalyze integration of HIV services in cancer care.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41960310}, issn = {2693-5015}, abstract = {INTRODUCTION: The World Health Organization advocates for integrated health services in low- and middle-income countries, with special focus on care for non-communicable diseases within HIV care. HIV diagnosis and management with antiretroviral therapy (ART) are crucial components of whole-person care; in addition to improving overall survival, ART provides basic immunotherapy during cancer treatment. However, most cancer centers in Africa are not currently equipped to provide integrated HIV care. We conducted process mapping at referral cancer centers in Malawi, South Africa, Uganda, and Zimbabwe to identify mechanisms of integrating HIV care interventions within established cancer treatment processes.<br><br>METHODS: Our research consortium identified multidisciplinary clinical and non-clinical staff important to care delivery in four referral cancer hospitals and proximal HIV clinics. Consortium-level researchers met separately in-person or virtually with each site team to conduct training. High-level and detailed levels process maps were developed in process mapping sessions with diverse staff at each site and flow diagrams created to identify sites of opportunity for care integration within cancer centers.<br><br>RESULTS: Forty-five diverse clinical and non-clinical staff participated in the process across the 4 cancer centers. Several points were identified in which care integration was already occurring, including requesting HIV diagnostic and monitoring laboratory tests and clinical consideration of HIV in care plan development. While HIV care was already available in a clinic within the same hospital campus in Soweto and referral and results pathways were more integrated than the other 3 sites, none of the centers provided ART, and all lacked the capacity to provide HIV-specific counseling and management of ART or non-cancer HIV complications.<br><br>DISCUSSION: We identified multiple points at which persons in HIV care were referred for cancer treatment and where people in cancer treatment not previously known to be living with HIV or not currently on ART could be referred for HIV treatment. Some services, while not integrated, had appropriate pathways in place; for others, we identified intervention points to improve care integration of HIV services into the cancer centers. While each cancer center has distinct features, we identified general service points that could be interrogated for HIV care integration opportunities.}, }
@article {pmid42037377, year = {2026}, author = {Sircy, LM and Stevens-Ayers, TL and Krantz, EM and Joncas-Schronce, L and Ozbek, NSO and Blazevic, RL and Mose, L and Kimball, LE and Basom, R and Dasgupta, S and Heit, A and Schmitz, F and Heckerman, D and Bender Ignacio, RA and Hill, JA and Boonyaratanakornkit, J and Boeckh, M and Waghmare, A}, title = {Assessing VirScan serosurvey epitope profiling variability between in-clinic venous blood draw and capillary blood self-sampling device.}, journal = {Microbiology spectrum}, volume = {}, number = {}, pages = {e0245425}, doi = {10.1128/spectrum.02454-25}, pmid = {42037377}, issn = {2165-0497}, abstract = {Timely and ongoing in-clinic sample collections are a common logistical barrier to volunteer participation and retention in longitudinal clinical studies. To remove this barrier, clinical studies have recently begun to implement the use of at-home capillary blood self-sampling devices in place of in-clinic venous blood draws for participant blood sample collection. Thus, we assessed antibody responses to a broad library of over 300 viral, bacterial, and fungal pathogens using VirScan immunoassay testing on adult volunteer capillary (serum) and venous (plasma) blood samples collected by Tasso devices and in-clinic venipunctures on the same day to determine whether self-sampling devices are a more practical and convenient alternative for future clinical studies. Most VirScan measurements of antibodies specific for clinically relevant respiratory viruses and herpesviruses had strong concordance between participant-matched Tasso and venipuncture blood samples. While we did not identify a systematic bias in most pathogen-specific antibody measurements associated with blood collection method, we did observe intrinsic VirScan inter-assay variability across some clinically relevant viruses. Together, our data demonstrate that capillary blood self-sampling devices are a practical alternative to in-clinic venipunctures for VirScan clinical research studies. However, these blood collection methods should not be used interchangeably within longitudinal studies to minimize the introduction of technical variables.IMPORTANCEOur study assessed whether capillary blood self-sampling devices could reliably replace in-clinic venous blood collection methods for the VirScan immunoassay, which can detect antibodies specific to hundreds of pathogens. Longitudinal studies requiring multiple in-clinic visits for sample collection often experience low volunteer retention because of the inconvenience of traveling to research sites. Allowing volunteers to use at-home self-sampling devices reduces the burden of travel for participants and increases access to outreach for volunteers who would otherwise not participate in research. Importantly, VirScan only requires a small sample volume, so blood self-sampling devices would be appropriate to use despite their volume collection limitations. Overall, capillary blood self-sampling devices can be a reliable and efficient method for research studies to investigate antibody responses longitudinally using VirScan. However, to limit the introduction of technical variables, collection methods should not be used interchangeably within a longitudinal study.}, }
@article {pmid42038100, year = {2025}, author = {Wang, R and Dai, R and Huang, Y and Neuhouser, ML and Lampe, JW and Raftery, D and Tabung, FK and Zheng, C}, title = {Variable Selection with FDR Control for Noisy Data - An Application to Screening Metabolites that Are Associated with Breast Cancer and Colorectal Cancer.}, journal = {Journal of data science : JDS}, volume = {23}, number = {3}, pages = {499-520}, pmid = {42038100}, issn = {1680-743X}, abstract = {The rapidly expanding field of metabolomics presents an invaluable resource for understanding the associations between metabolites and various diseases. However, the high dimensionality, presence of missing values, and measurement errors associated with metabolomics data can present challenges in developing reliable and reproducible approaches for disease association studies. Therefore, there is a compelling need for robust statistical analyses that can navigate these complexities to achieve reliable and reproducible disease association studies. In this paper, we construct algorithms to perform variable selection for noisy data and control the False Discovery Rate when selecting mutual metabolomic predictors for multiple disease outcomes. We illustrate the versatility and performance of this procedure in a variety of scenarios, dealing with missing data and measurement errors. As a specific application of this novel methodology, we target two of the most prevalent cancers among US women: breast cancer and colorectal cancer. By applying our method to the Women's Health Initiative data, we successfully identify metabolites that are associated with either or both of these cancers, demonstrating the practical utility and potential of our method in identifying consistent risk factors and understanding shared mechanisms between diseases.}, }
@article {pmid42038745, year = {2026}, author = {Bock, AM and Hao, P and Xu, Y and Luttwak, E and Thiruvengadam, SK and Sekaran, K and Sano, D and Vaughn, J and Sharp, J and Major, A and Patel, V and Smilnak, G and Araujo, N and Mynam, R and Reef, D and Palmeri, M and Gerber, D and Abhyankar, A and Baek, G and Falade, A and Iqbal, M and Hu, B and Geethakumari, PR and Durani, U and Di, M and Niu, A and Cherng, HJ and Rhodes, JM and Grover, N and Pophali, P and Feldman, T and Shanmugasundaram, K and Svoboda, J and Voorhees, T and Diefenbach, C and Karimi, Y and Karmali, R and Herrera, AF and Torka, P and Epperla, N}, title = {Nivolumab in combination with AVD as frontline treatment for patients with classic Hodgkin lymphoma: A real-world analysis from 20 US centers.}, journal = {HemaSphere}, volume = {10}, number = {4}, pages = {e70346}, pmid = {42038745}, issn = {2572-9241}, }
@article {pmid42039685, year = {2026}, author = {Cho, BC and Nishio, M and Ahn, MJ and García-Campelo, R and Ponce, S and Baik, C and Salgia, R and Kim, SW and Lee, JS and Yoshida, T and Yu, HA and Goldberg, SB and Johannes de Langen, A and Le, X and Piotrowska, Z and Riess, JW and Tanaka, K and Ambrose, H and Cosaert, J and Fraenkel, PG and Tang, KH and Lehman, JM and Smith, P and Goldman, JW}, title = {Durvalumab Plus Chemotherapy in Patients With EGFR-Mutated Advanced NSCLC Whose Disease Progressed on First-Line Osimertinib: ORCHARD.}, journal = {JTO clinical and research reports}, volume = {7}, number = {4}, pages = {100937}, pmid = {42039685}, issn = {2666-3643}, abstract = {INTRODUCTION: ORCHARD (NCT03944772) was a phase II, biomarker-directed platform study designed to characterize resistance mechanisms and evaluate novel therapy combinations after progressive disease (PD) on first-line osimertinib. We report results of the module assessing durvalumab plus chemotherapy.<br><br>METHODS: Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with PD on first-line osimertinib whose tumors did not harbor a prespecified alteration by next-generation sequencing of a post-osimertinib biopsy, or for whom a biomarker-matched treatment was not available, were eligible. Patients received 4 to 6 cycles of durvalumab 1500 mg plus carboplatin target area under the curve 5 and pemetrexed 500 mg/m[2]. After platinum-based chemotherapy, patients without PD could continue to receive durvalumab plus pemetrexed maintenance. Primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator assessment.<br><br>RESULTS: Overall, 25 patients received more than or equal to 1 dose of durvalumab plus chemotherapy; all had discontinued treatment at the primary analysis data cutoff. Confirmed ORR was 16% (80% confidence interval [CI]: 7-30); response was maintained for more than 6 months in the four patients with confirmed response. Furthermore, 22 patients (88%) had PD and median progression-free survival was 4.8 months (95% CI: 2.6-7.6). Ten patients (40%) had died, and median overall survival was 23.4 months (95% CI: 8.8-not calculable). Nine patients (36%) had grade 3 or higher adverse events, most often neutrophil count decreased (20%).<br><br>CONCLUSIONS: Durvalumab plus chemotherapy demonstrated limited clinical benefit for EGFR-mutated NSCLC after PD on first-line osimertinib. Although the combination was well tolerated, the overall risk-benefit profile did not warrant further evaluation.}, }
@article {pmid42043297, year = {2026}, author = {Rosero, M and Bai, J}, title = {AFD thermosensory neurons mediate tactile-dependent locomotion modulation in C. elegans.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, doi = {10.7554/eLife.106496}, pmid = {42043297}, issn = {2050-084X}, support = {R01NS109476/NS/NINDS NIH HHS/United States ; R01NS115974/NS/NINDS NIH HHS/United States ; T32GM136534/GM/NIGMS NIH HHS/United States ; F31NS129545/NS/NINDS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/physiology ; *Sensory Receptor Cells/physiology ; *Locomotion ; Cyclic GMP/metabolism ; *Touch ; Caenorhabditis elegans Proteins/metabolism/genetics ; Signal Transduction ; Taxis Response ; *Thermosensing ; }, abstract = {Sensory neurons drive animal behaviors by detecting environmental stimuli and relaying information to downstream circuits. Beyond their primary roles in sensing, these neurons often form additional synaptic connections outside their main sensory modality, suggesting broader contributions to behavior modulation. Here, we uncover an unexpected role for the thermosensory neuron AFD in coupling tactile experience to locomotion modulation in Caenorhabditis elegans. We show that while AFD employs cyclic guanosine monophosphate (cGMP) signaling for both thermotaxis and tactile-dependent modulation, the specific molecular components of the cGMP pathway differ between these two processes. Interestingly, disrupting the dendritic sensory apparatus of AFD, which is essential for thermotaxis, does not impair tactile-based locomotion modulation, indicating that AFD can mediate tactile-dependent behavior independently of its thermosensory apparatus. In contrast, ablating the AFD neuron eliminates tactile-dependent modulation, pointing to an essential role for AFD itself, rather than its sensory dendritic endings. Further, we find tactile-dependent modulation requires the AIB interneuron, which connects AFD to touch circuits via electrical synapses. Removing innexins expressed in AFD and AIB abolishes this modulation, while re-establishing AFD-AIB connections with engineered electrical synapses restores it. Collectively, these findings uncover a previously unrecognized function of AFD beyond thermosensation, highlighting its influence on context-dependent neuroplasticity and behavioral modulation through broader circuit connectivity.}, }
@article {pmid42044061, year = {2026}, author = {Landovitz, RJ and Fogel, JM and Gao, F and Hanscom, B and Piwowar-Manning, E and Moser, A and Marzinke, MA and Cyktor, J and Seisa, M and Halvas, EK and Kofron, R and Jennings, A and Clement, M and Viet Tran, H and Gaur, A and Fichtenbaum, CJ and Asmelash, A and Soto-Torres, L and Rooney, JF and Rinehart, AR and Cohen, MS and Grinsztejn, B and Eshleman, SH}, title = {Prospective HIV RNA screening with long-acting cabotegravir pre-exposure prophylaxis in HPTN 083.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciag285}, pmid = {42044061}, issn = {1537-6591}, abstract = {BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention. However, breakthrough infections can occur, even with optimal adherence. We evaluated the performance of prospective HIV RNA screening in cisgender men and transgender women who have sex with men using long-acting injectable cabotegravir (CAB-LA) pre-exposure prophylaxis (PrEP) in HPTN 083.<br><br>METHODS: In the Open Label Extension of HPTN 083, sites performed HIV rapid, antigen/antibody (Ag/Ab) and RNA testing at each visit. Results from site testing and retrospective HIV testing were used to determine final HIV status and identify the first HIV positive visit.<br><br>RESULTS: HIV RNA screening was associated with fewer diagnostic delays (7% vs. 47% of cases, p=0.02) and earlier treatment initiation (median 15 vs. 62 days, p=0.02). Drug resistance was less frequent with RNA screening (15% vs. 31% of cases, p=0.22). Five cases were first detected with RNA testing only. Sensitivity and specificity of RNA testing were 93% (95% CI: 76, 99) and 99.92% (95% CI: 99.88, 99.95), respectively. However, positive predictive value (PPV) was low overall (55%; 95% CI: 40, 69) and was lower if CAB-LA was administered <6 months earlier (29%; 95% CI: 13, 49). Some false positive RNA test results led to delay or discontinuation of CAB-LA injections.<br><br>CONCLUSIONS: HIV RNA screening improved clinical outcomes in the setting of CAB-LA PrEP, but the PPV for RNA screening was low which could compromise patient care.}, }
@article {pmid42044462, year = {2026}, author = {Milano, F and Dahlberg, A and Pedersen, J and Roberts, L and Azure, A and Martin, L and Mazziotta, F and Hadland, B and Chapuis, AG and Delaney, C}, title = {Safety and Clinical Outcomes of Pooled Donor, Nonengrafting Expanded Progenitor Cells in Single-Unit Cord Blood Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2502510}, doi = {10.1200/JCO-25-02510}, pmid = {42044462}, issn = {1527-7755}, abstract = {PURPOSE: Cord blood transplantation (CBT) is limited by delayed hematopoietic recovery leading to frequent use of double-unit grafts. This phase II study evaluated the safety of adding dilanubicel, a cryopreserved, cord blood (CB)-derived, non-human leukocyte antigen-matched expanded progenitor cell product generated from pooled donors to single-unit CBT.<br><br>MATERIALS AND METHODS: Between March 2022 and July 2025, we enrolled 28 patients with hematologic malignancies in this single-center phase II trial. The infusion of a matched single CB unit was followed by a target dose of 800 &#xd7; 10[6] CD34[+] cells of dilanubicel. All patients received a myeloablative conditioning regimen and graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine and mycophenolate mofetil.<br><br>RESULTS: The median age was 36 years (range, 10-63). Underlying diagnoses included acute leukemias (n = 25) and other hematologic malignancies (n = 3). All patients engrafted neutrophils (median, 18 days; range, 14-30) and platelets (median, 31 days; range, 26-43). Dilanubicel induced transient myelomonocytic recovery, peaking on day 7 and absent by day 14. An early lymphocyte expansion, derived exclusively from the CB graft, occurred by day 9 and peaked by day 11. No grade 3 to 4 acute or chronic GVHD was observed. At a median follow-up of 1.4 years, 27 patients remain alive and disease-free. When evaluated alongside a contemporaneous institutional cohort receiving standard single- or double-unit CBT, patients treated with dilanubicel demonstrated faster hematopoietic recovery and a markedly lower incidence of severe acute GVHD.<br><br>CONCLUSION: The addition of dilanubicel to single-unit CBT demonstrated a favorable safety profile, with no severe acute or chronic GVHD, and was associated with excellent clinical outcomes. These findings support further investigation of this strategy.}, }
@article {pmid42044466, year = {2026}, author = {Stepan, L and Ansari, S and Abramson, JS and Okal, A and Dell'Aringa, J and Thompson, EG and Crotta, A and Chow, VA and Kamdar, M and Solomon, SR and Johnston, PB and Glass, B and Mutsaers, P and Arnason, J and Mielke, S and Shadman, M and Hernandez-Ilizaliturri, F and Izutsu, K and Bachanova, V and Ibrahimi, S and Chabon, JJ and Kurtz, DM and Alizadeh, AA and Peiser, L}, title = {Circulating Tumor DNA Assessment of Disease Response in Large B-Cell Lymphoma: Lisocabtagene Maraleucel Versus Autologous Stem Cell Transplantation Standard Therapy.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2503051}, doi = {10.1200/JCO-25-03051}, pmid = {42044466}, issn = {1527-7755}, abstract = {We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD][neg]) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel-treated patients achieving MRD[neg]. Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRD[neg]. ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRD[neg] remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.}, }
@article {pmid42044624, year = {2026}, author = {Wendel, SO and Brooke, GM and Hu, C and Sandoval, AR and Haratipour, P and Gu, L and Young, M and Zangi, M and Rasche, BL and Banerjee, NS and Jossart, J and Garvin, K and Geisbrecht, BV and Cianciolo, R and Cawley, J and Perry, JJP and Hickey, RJ and Malkas, LH and Wallace, NA}, title = {Targeting Cancer-Associated PCNA with AOH1996 Induces Mitotic Catastrophe and Enhances Cisplatin Therapy in Cervical Cancer.}, journal = {Cancer research communications}, volume = {}, number = {}, pages = {}, doi = {10.1158/2767-9764.CRC-25-0648}, pmid = {42044624}, issn = {2767-9764}, abstract = {Cervical cancers (CaCx) remain a significant health burden. Limitations on CaCx chemotherapeutic intervention caused by toxic side effects are a persistent barrier to care. Here, we show that the human papillomavirus oncogenes that cause most CaCx also increase the levels of a cancer-associated isoform of PCNA known as caPCNA. The abundance of caPCNA is specifically elevated in CaCx. Similar to observations in other cancers, we found that a small molecule inhibitor of caPCNA (AOH1996) selectively killed cell line, organoid, and xenograft models of CaCx. Our subsequent molecular analysis identified a novel ability of AOH1996 to induce cell death by disrupting the interaction between PCNA and gamma tubulin, resulting in mitotic arrest. We show AOH1996 selectively induces mitotic death in transformed cells, because these cells attempt to progress through mitosis, rather than decondensing their chromosomes and reforming their nuclear membranes like untransformed control cells. Further, we show that these differences allow AOH1996 to specifically sensitize CaCx cells to cisplatin, a frontline chemotherapeutic used to treat CaCx. We found that subtherapeutic doses of AOH1996 and cisplatin could reduce CaCx xenograft growth and improve survival, similarly to a therapeutic dose of cisplatin without the cisplatin-induced toxicity that restricts care. To our knowledge, this study provides the first evidence that AOH1996 can function as a cisplatin-sensitizing agent in cervical cancer models.}, }
@article {pmid42045564, year = {2026}, author = {Prentice, RL and Aragaki, AK}, title = {The semi-competing risk problem revisited.}, journal = {Lifetime data analysis}, volume = {32}, number = {2}, pages = {}, pmid = {42045564}, issn = {1572-9249}, mesh = {Humans ; Proportional Hazards Models ; Female ; Disease-Free Survival ; Incidence ; Cohort Studies ; Hormone Replacement Therapy ; Risk Assessment/methods ; }, abstract = {Clinical trials and cohort studies often aim to assess treatment effects or exposure associations in relation to the risk of one or more diseases, with death of the study participant as a competing risk. If the diseases under study are major health concerns, it may not be appropriate to assume that death acts as an independent source of right-censoring. When this occurs, a summary of treatment or exposure influences should consider disease incidence and death jointly. Here we consider some modeling approaches to doing so, starting with type-specific (cause-specific) hazard functions. We also model marginal hazard rates for disease-free survival and death, along with their dual outcome hazard functions, with emphasis on Cox models for each hazard function. Furthermore, a simple hazard ratio summary statistic is proposed for covariate effects on disease incidence and death jointly. Analyses of data from the Women's Health Initiative hormone therapy trials provide illustration.}, }
@article {pmid41929033, year = {2026}, author = {Andrews, KR and Chang, J and Roemer, C and Hadfield, J and Lin, V and Brito, AF and Daodu, RO and Joia, IA and Kistler, K and Li, A and Moncla, LH and Paredes, MI and Kühnert, D and Torres, LM and Voitl, L and Aksamentov, I and Hodcroft, EB and Huddleston, J and McCrone, JT and Anderson, JSJ and Sibley, TR and Lee, J and Neher, RA and Bedford, T}, title = {Nextstrain automates real-time phylodynamic analysis of open data for endemic and emerging pathogens.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929033}, issn = {2692-8205}, abstract = {MOTIVATION: Genome sequencing provides an exceptional window into the evolutionary and epidemiological dynamics of endemic and emerging pathogens, and thus allows for better, more targeted, public health interventions. Online genomic surveillance platforms can provide near real-time insight into these dynamics.<br><br>RESULTS: Nextstrain provides continually updated real-time genomic surveillance for 21 viruses and the bacterial pathogen Mycobacterium tuberculosis, with most analyses relying solely on open sequence data. Each pathogen includes steps to fetch and curate open data, classify sequences using established nomenclature systems, perform phylodynamic analyses, and share the results publicly. These analyses are automated, with most running daily to provide continually updated snapshots of pathogen evolution.<br><br>All source code is available at https://github.com/nextstrain. Phylodynamic results can be visualized and downloaded at https://nextstrain.org/pathogens, and open sequence data and curated metadata are available at https://nextstrain.org/pathogens/files.}, }
@article {pmid41929074, year = {2026}, author = {Yang, Q and Padilla-Galvez, M and Uhl, S and Eggenberger, J and Kogut, S and Becker, S and Chen, S and Rosenberg, BR and Blanco-Melo, D}, title = {Pluripotency Factors Modulate Interferon Signaling in Embryonic Stem Cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929074}, issn = {2692-8205}, abstract = {Despite lacking a robust interferon response, pluripotent stem cells remain highly resistant to viral infection, in part through the constitutive expression of immune genes traditionally classified as interferon-stimulated genes. While interferon signaling has been shown to be incompatible with the maintenance of pluripotency, the molecular mechanisms underlying this relationship remain poorly understood. Here, we investigate the transcriptional response of human embryonic stem cells (hESCs) to infection with a potent activator of the interferon response, an influenza A virus mutant lacking the viral NS1 protein. Single-cell RNA sequencing revealed that while most hESCs remain unresponsive to infection, a distinct subpopulation expresses type I and III interferons. Notably, only interferon-expressing cells mounted a robust antiviral response, characterized by strong induction of interferon-stimulated genes. In contrast to the bulk hESC population, interferon responding cells exhibited reduced expression of core pluripotency factors as well as negative regulators of interferon signaling, such as SOCS1 and SPRY4. Depletion of SOCS1 enabled hESCs to respond robustly to interferon stimulation, showing that this negative regulator is a key suppressor of interferon signaling in pluripotent stem cells. We further show that SOCS1 and additional negative regulators of IFN signaling are intrinsically expressed in hESCs and are transcriptionally controlled by pluripotency factors, such as NANOG, SOX2 and OCT4. Together, our findings support a model in which pluripotency factors regulate intrinsic immune gene expression, including negative regulators of interferon signaling, thereby suppressing canonical interferon signaling to preserve pluripotency while maintaining antiviral resistance.}, }
@article {pmid42028578, year = {2026}, author = {Eaton, EJ and Wick, BJ and Chacón, JS and Wang, AJ and Kluesner, M and Barnes, JT and Kar, B and Wang, M and Johnson, MJ and Skeate, JG and Webber, BR and Moriarity, BS}, title = {Adenine base editor for knockout of proteins: A practical guide from design to analysis with updated MultiEditRbatch.}, journal = {Molecular therapy. Nucleic acids}, volume = {37}, number = {2}, pages = {102908}, pmid = {42028578}, issn = {2162-2531}, abstract = {Adenine base editors (ABEs) are a promising yet underutilized tool for inducing protein knockout compared to Cas9 nuclease, owing in part to a lack of user-friendly platforms for reagent design and implementation. Here, we present a comprehensive workflow to achieve high-efficiency gene knockouts with ABE as an alternative to Cas9 nuclease-based approaches. This includes optimized guide RNA (gRNA) design using SpliceR, a web-based application, followed by genomic and functional validation of ABE-mediated knockouts for several target genes. We validated gRNAs for 14 immunologically relevant targets, using both NGG and NG PAM compatible ABE8e-variants in primary immune cells. To facilitate data analysis, we developed MultiEditRbatch, an updated version of MultiEditR as a user-friendly analysis tool with addition of batch mode for high-throughput analysis of Sanger sequencing data. MultiEditRbatch is available as a web-based application and an R package, enabling robust assessment of base editing outcomes.}, }
@article {pmid42030147, year = {2026}, author = {Ukogu, OA and Montague, Z and Altan-Bonnet, G and Nourmohammad, A}, title = {Design principles of the cytotoxic CD8[+] T cell response.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {17}, pages = {e2528202123}, doi = {10.1073/pnas.2528202123}, pmid = {42030147}, issn = {1091-6490}, support = {2045054//National Science Foundation (NSF)/ ; R35 GM142795/GM/NIGMS NIH HHS/United States ; ZIA BC 012007//HHS | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Animals ; Mice ; *T-Lymphocytes, Cytotoxic/immunology ; *CD8-Positive T-Lymphocytes/immunology ; Lymphocyte Activation/immunology ; *Models, Immunological ; Humans ; }, abstract = {Cytotoxic T lymphocytes eliminate infected or malignant cells, safeguarding surrounding tissues. Although experimental and systems-immunology studies have cataloged many molecular and cellular actors involved in an immune response, the design principles governing how the speed and magnitude of T cell responses emerge from cellular decision-making remain elusive. Here, we recast the T cell response as a feedback-controlled program, wherein the rates of activation, proliferation, differentiation, and death are regulated through antigenic, pro- and anti-inflammatory cues. By exploring a broad class of feedback-controller designs as potential immune programs, we demonstrate how the speed and magnitude of T cell responses emerge from optimizing signal-feedback to protect against diverse infection settings. We recover an inherent trade-off: infection clearance at the cost of immunopathology. We show how this trade-off is encoded into the logic of T cell responses by hierarchical sensitivity to different immune signals. Notably, we find the designs that balance harm from acute infections and autoimmunity produce immune responses consistent with the experimentally observed patterns of T cell effector expansion in mice. Extending our model to immune-based T cell therapies for cancer tumors, we quantify the trade-off between the affinity for tumor antigens ("quality") and the abundance ("quantity") of infused T cells necessary for effective treatment. Finally, we show how therapeutic efficacy can be improved by targeted genetic perturbations to T cells. Our findings offer a unified control-logic for cytotoxic T cell responses and point to specific regulatory programs that can be engineered for more robust T cell therapies.}, }
@article {pmid42030410, year = {2026}, author = {Omole, TE and Nguyen, HM and Marcinow, A and Jahan, N and Severini, G and Naicker, N and Thomas, K and Celum, C and Mugo, N and Mujugira, A and Kublin, J and Corey, L and Sivro, A and Lingappa, J and Gray, G and McKinnon, LR}, title = {Pre-Human Immunodeficiency Virus (HIV) infection Th17 CD4+ T cells as predictors of early HIV disease progression.}, journal = {PLoS pathogens}, volume = {22}, number = {4}, pages = {e1013852}, doi = {10.1371/journal.ppat.1013852}, pmid = {42030410}, issn = {1553-7374}, abstract = {Interleukin-17-producing T helper (Th17) CD4+ T cells are highly susceptible to HIV infection and are depleted early in people living with HIV. Here, we investigated whether systemic Th17 cell levels prior to HIV infection are associated with subsequent HIV disease progression. We analyzed archived cryopreserved peripheral blood mononuclear cells (PBMCs) collected within one year prior to HIV acquisition from participants enrolled in a South African cohort (HIV Vaccine Trials Network [HVTN] 503; n = 35) and an East African cohort (Partners Pre-exposure Prophylaxis/Couples' Observational Study [PP/COS]; n = 32). Th17 cell frequencies were quantified by flow cytometry. In HVTN 503, higher pre-HIV IL-17+ CD4+ T cell frequencies were inversely correlated with CD4/CD8 ratio measured both within 180 days (Spearman rank rs = -0.42, p = 0.012) and ≥180 days (rs = -0.55, p = 0.001) after HIV infection, and were associated with faster CD4+ T cells decline (adjusted hazard ratio [aHR] = 3.5, 95% CI: 1.2 - 9.9, p = 0.020). In contrast, no significant association with CD4 decline was observed in the PP/COS cohort (HR = 1.2, 95% CI: 0.4 - 3.4, p = 0.795). Sex-stratified analyses in HVTN 503 indicated a more pronounced association between pre-HIV IL-17+ CD4+ T cells and faster CD4 decline in males than females. In analyses combining all cohorts, higher pre-HIV IL-17+ CD4+ T cell frequencies remained associated with faster CD4 decline, particularly among younger participants (HR = 3.5; 95% CI: 1.35 - 9.22, p = 0.010). Pre-HIV IL-17+ CD4+ T cell frequencies were not associated with peak or set-point viral load in either cohort. Together, these findings suggest that pre-HIV Th17 cells abundance may influence subsequent HIV disease progression independently of early viral replication.}, }
@article {pmid42031341, year = {2026}, author = {Chalitsios, CV and Chan, WC and Markozannes, G and Aglago, EK and Berndt, SI and Buchanan, DD and Campbell, PT and Cao, Y and Dimou, N and Drew, DA and French, AJ and Gallinger, S and Georgeson, P and Giannakis, M and Gruber, SB and Gunter, MJ and Harrison, TA and Brenner, H and Hoffmeister, M and Urruchúa-Rodríguez, MJ and Hsu, L and Huang, WY and Hullar, MAJ and Huyghe, JR and Jenkins, MA and Jayasekara, H and Moreno, V and Newton, CC and Nowak, JA and Obón-Santacana, M and Ogino, S and Pellatt, AJ and Peoples, A and Qu, C and Schmit, SL and Steinfelder, RS and Sun, W and Thomas, CE and Toland, AE and Trinh, QM and Ugai, T and Um, CY and Van Guelpen, B and Zaidi, SH and Peters, U and Phipps, AI and Tsilidis, KK}, title = {Alcohol consumption and molecular subtypes of colorectal cancer: Pooled observational and Mendelian randomisation analyses.}, journal = {The American journal of clinical nutrition}, volume = {}, number = {}, pages = {101308}, doi = {10.1016/j.ajcnut.2026.101308}, pmid = {42031341}, issn = {1938-3207}, abstract = {BACKGROUND: Alcohol consumption is associated with colorectal cancer (CRC) risk, yet its association with distinct molecular subtypes remains unclear. Clarifying this could reveal insights into alcohol's carcinogenic mechanisms.<br><br>OBJECTIVE: We examined the association between alcohol consumption and the risk of CRC subtypes defined by individual tumour markers (and marker combinations), namely microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutations.<br><br>METHODS: Pooled observational (ncases=11,826, ncontrols=10,888; nstudies=10) and genome-wide association data (ncases=8,178, ncontrols=10,472; nstudies=10) were utilised. Multivariable logistic regression models and Mendelian randomisation (MR) analyses were conducted to assess the association between alcohol consumption, modelled in MR as genetically predicted average drinks per week per one standard deviation increase (&#x2248;2.9 drinks/week), and risk of CRC subtypes defined by individual tumour markers (and marker combinations). Case-only analyses tested for differences between molecular subtypes. Bonferroni correction was applied for multiple tests.<br><br>RESULTS: Among drinkers, each additional 14 g/day of alcohol was associated with a 10% higher CRC risk (OR=1.10; 95%CI: 1.07, 1.13), but this association was primarily driven by heavy alcohol consumption (>28g/d). Including non-drinkers revealed a J-shaped association (Pnon-linearity=0.002). The associations with higher alcohol consumption were stronger in males compared to females. No significant heterogeneity was observed across MSI, CIMP, BRAF, or KRAS-defined subtypes. All associations were similar across smoking status, folate intake, tumour anatomical site, study design, early/late onset CRC, and across individual studies (Pheterogeneity>0.05). MR analyses supported that higher genetically predicted alcohol consumption was associated with CRC risk (ORIVW-per 1SD=1.25; 95%CI: 1.01, 1.57), but similarly to the observational analysis, without evidence of heterogeneity across molecular subtypes.<br><br>CONCLUSIONS: Heavy alcohol consumption may initiate colorectal carcinogenesis through mechanisms that operate across all examined molecular pathways for CRC. Although the largest available data were used, power is lower for subtype heterogeneity analyses, and modest interaction effects cannot be excluded.}, }
@article {pmid42031598, year = {2026}, author = {Pluguez-Turull, CW and Koshy, J and McBee, MP and Oluyemi, E and Lam, DL and Desoky, SM and Desouches, SL and Siddiqui, S and Lodhi, T and Capiro, N and Agarwal, V and Kongara, T and Lampen-Sachar, K and Hui, LT and Choe, AI}, title = {Optimizing Timeliness of Healthcare Delivery in Diagnostic Radiology at U.S. Academic Centers.}, journal = {Academic radiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.acra.2026.03.057}, pmid = {42031598}, issn = {1878-4046}, abstract = {RATIONALE AND OBJECTIVES: Timely radiology access is essential for accurate diagnosis, treatment planning, and efficient care delivery. U.S. academic health centers face distinctive pressures, including workforce shortages, complex workflows, health inequities, and the need to balance trainee education with increasing clinical demand.<br><br>MATERIALS AND METHODS: This article summarizes consensus conclusions and literature review findings from the Radiology Research Alliance task force on optimizing healthcare delivery in U.S. academic centers. Task force members reviewed operational and systemic contributors to delayed imaging access and radiology report turnaround time (RTAT), with attention to disparities, workflow design, trainee involvement, and emerging artificial intelligence (AI) applications.<br><br>RESULTS: Delays in radiology care arise from social and insurance-related barriers, staffing shortages, workflow inefficiencies, and reporting delays. Underserved populations experience reduced access to preventive imaging, which may be improved through culturally tailored outreach, frontline staff engagement, and patient navigation. In academic settings, RTAT is influenced by image transmission, case complexity, reporting practices, and trainee participation. Evidence suggests that structured reporting, subspecialty or optimized workflow organization, critical results notification, and dual-reader trainee-attending models can improve efficiency while maintaining educational value. AI and machine learning (ML) show promise for clinical decision support&#xa0;(CDS), scheduling, no-show reduction, risk prediction, workflow optimization, and demand forecasting.<br><br>CONCLUSION: Improving radiology delivery in academic centers requires coordinated system-level strategies that address equity, staffing, workflow, and reporting efficiency. Thoughtful integration of AI, alongside operational redesign that preserves trainee development, can help academic radiology advance timely, high-quality, and equitable care.}, }
@article {pmid42031709, year = {2026}, author = {Brcic, A and Lalic, H and Smoljo, T and Bardač, K and Dembitz, V and Penker, R and Rodriguez Blanco, G and Bedalov, A and Visnjic, D}, title = {Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.}, journal = {Cell death discovery}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41420-026-03105-y}, pmid = {42031709}, issn = {2058-7716}, support = {IP-2022-10-9146//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; DOK-2020-01-2873//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; DOK-NPOO-2023-10-9321//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; DOK-2025-02-6776//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; DOK-NPOO-2023-10-9321//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; HRZZ IP-2022-10-9146//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; HRZZ IP-2022-10-9146//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; DOK-2025-02-6776//Hrvatska Zaklada za Znanost (Croatian Science Foundation)/ ; EHA Innovation Award//European Hematology Association (EHA)/ ; RO1 GM117446//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, abstract = {Differentiation therapy offers a promising approach in acute myeloid leukemia (AML) by overcoming the developmental block that maintains leukemic blasts. Increasing evidence indicates that DNA replication stress can promote differentiation rather than cytotoxicity; however, the metabolic mechanisms linking replication stress to differentiation remain poorly defined. Here, we investigated how perturbations in nucleotide metabolism regulate replication stress-driven differentiation. Using metabolomic and functional analyses in AML cell lines, we show that agents inducing differentiation through replication stress, including 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), dihydroorotate dehydrogenase (DHODH) inhibition, and low-dose cytarabine, converge on disruption of nucleotide pool balance. Low-dose AICAr induced a pyrimidine-purine imbalance, S phase arrest, and enhanced differentiation, whereas high-dose reduced these effects. Although brequinar and cytarabine altered nucleotide metabolism through distinct mechanisms, differentiation induced by all agents was abolished by supplementation with high levels of ribo- and deoxyribonucleosides, confirming that nucleotide imbalance is a central driver. We further identify ribonucleotide reductase (RNR) as a critical modulator of this process. Replication stress induced context-dependent regulation of RNR subunits, with RRM2 upregulated in p53-mutant U937 cells and the p53-responsive RRM2B isoform predominating in p53-wild-type MOLM-13 cells. Consistent with these differences, RRM2 depletion enhanced differentiation in U937 cells without affecting viability but impaired differentiation and survival in MOLM-13 cells. These findings position nucleotide metabolism as a key regulator of AML differentiation and suggest that combining RNR-targeted and checkpoint-modulating strategies could optimize therapeutic responses.}, }
@article {pmid41959482, year = {2026}, author = {Jurasin, AC and Frank, AR and Biggins, S}, title = {Proteomics reveals extensive phosphoregulation of outer kinetochore protein KNL1.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41959482}, issn = {2692-8205}, abstract = {Microtubules attach to kinetochores to facilitate chromosome movement to opposite spindle poles. Defective kinetochore-microtubule attachments lead to phosphorylation of the outer kinetochore protein KNL1 at conserved MELT motifs, which triggers spindle assembly checkpoint activation and recruitment of the fibrous corona. To identify additional phosphorylation sites that regulate kinetochores, we treated HEK 293T/17 cells with nocodazole, paclitaxel, or STLC to create defective kinetochore-microtubule attachment states. We then purified KNL1 and performed proteomics and identified 111 phosphorylation sites on KNL1, including several that may be attachment-state specific. These data demonstrate that KNL1 is extensively phosphoregulated in response to treatment with microtubule-disrupting compounds.}, }
@article {pmid42021259, year = {2026}, author = {Yu, EY and Wesselius, A and Mehrkanoon, S and Goosens, M and Brinkman, M and van den Brandt, P and Grant, EJ and White, E and Weiderpass, E and Le Calvez-Kelm, F and Gunter, MJ and Huybrechts, I and Riboli, E and Tjonneland, A and Masala, G and Giles, GG and Milne, RL and Zeegers, MP}, title = {Correction: Vegetable intake and the risk of bladder cancer in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {42021259}, issn = {1741-7015}, }
@article {pmid42021581, year = {2026}, author = {Banerjee, R and Mohan, M and Shah, B and Prince, P and Gautam, N and Beebe, E and Pajerowski, W and Cantu, C and Meiseles, H and Hughes, D and Nador, G and Sandin, R and Hlavacek, P and Li, B and Meche, A and Hyun Kim, C and Perez Cruz, I and Sumaya, M and DiBonaventura, M}, title = {Real-world treatment patterns and outcomes of patients with multiple myeloma initiating elranatamab: results from the ALTITUDE-1 and ALTITUDE-2 retrospective cohort studies.}, journal = {Future oncology (London, England)}, volume = {}, number = {}, pages = {1-10}, doi = {10.1080/14796694.2026.2662504}, pmid = {42021581}, issn = {1744-8301}, abstract = {BACKGROUND AND AIM: Elranatamab is a bispecific antibody currently approved in the United States (US) for the treatment of relapsed/refractory multiple myeloma (MM). Given its recent approval, real-world data are limited.<br><br>METHODS: Results from two real-world (RW) studies using administrative claims (ALTITUDE-1) and fee-for-service data (ALTITUDE-2) are collectively reported here. US patients with MM who initiated elranatamab after August 2023 were included and followed through September/October 2025. Patient characteristics, clinical history, treatment patterns, and effectiveness outcomes were reported.<br><br>RESULTS: One hundred and eighty-three and 391 patients were included from ALTITUDE-1 and -2, respectively. Median ages were 73 and 75, 43.2% and 33.0% were penta-drug exposed, and 17.5% and 21.0% were previously BCMA-exposed, respectively. RW treatment patterns showed less frequent dosing (27.9 and 27.1 elranatamab vials used per year) compared with expected on-label dosing (39 vials per year). Neither median time-to-next-treatment or death or median overall survival were reached; landmark analyses for each study estimated 70.0% (ALTITUDE-1) and 60.7% (ALTITUDE-2) of patients alive at 18&#x2009;months.<br><br>CONCLUSION: US patients treated with elranatamab in the RW setting were heavily pre-treated. RW treatment patterns suggest less frequent administration of elranatamab compared with the label and effectiveness consistent with clinical trial results (MagnetisMM-3 trial [NCT04649359]).}, }
@article {pmid42023116, year = {2026}, author = {Bender Ignacio, R and Rowan, K and Cook, D}, title = {Correction: How would Marie Kondo design a protocol? In favor of subtractive change in clinical trials.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1838161}, doi = {10.3389/fmed.2026.1838161}, pmid = {42023116}, issn = {2296-858X}, abstract = {[This corrects the article DOI: 10.3389/fmed.2026.1776929.].}, }
@article {pmid42023513, year = {2026}, author = {Goel, U and Dragomirescu, C and Zanwar, S and Cassano, RC and Cicero, KI and Cowan, AJ and Banerjee, R and Anwer, F and Khouri, J and Dima, D}, title = {Functional high-risk phenotype predicts poor survival in multiple myeloma independent of front-line treatment: A secondary analysis of CIBMTR data.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.70490}, pmid = {42023513}, issn = {1365-2141}, support = {//American Society of Hematology/ ; }, abstract = {Functional high-risk (FHR) multiple myeloma (FHRMM) is often defined as progression within 12-24 months of front-line autologous hematopoietic stem cell transplantation (AHSCT). For patients with early progression after suboptimal front-line therapies, it is challenging to assign the disease progression to a true FHR phenotype versus less effective front-line therapy. In this study, we combined data from three Center for International Blood and Marrow Transplant Research studies (MM18-02, MM19-01 and MM20-03). We included patients who received front-line AHSCT between 2008 and 2018 and had progression <12 (FHR12, n = 465), <18 (FHR18, n = 672) or <24 months (FHR24, n = 853) after AHSCT. We classified induction therapy as standard lenalidomide-containing triplets (bortezomib, lenalidomide, dexamethasone [VRD]/carfilzomib, lenalidomide, dexamethasone [KRD]) versus other (bortezomib, thalidomide, dexamethasone [VTD]/bortezomib, cyclophosphamide, dexamethasone [VCD]/bortezomib, dexamethasone [VD]/lenalidomide, dexamethasone [RD]) and studied the impact of front-line therapy on post-FHR overall survival (OS). In the FHR12 cohort (follow-up 48 months), the OS after VRD/KRD (n = 238) was 21 versus 17 months with other regimens (n = 227, hazard ratio [HR] = 1.2, 95% confidence interval [CI]: 0.6-1.06). In a multivariable model, the HR for OS was 0.94 (95% CI: 0.7-1.3, p = 0.69) for VRD/KRD versus other regimens. There was no significant interaction between type of first-line (1L) therapy and time from 1L AHSCT to first relapse in predicting OS. Similar results were seen for FHR18 and FHR24. FHRMM remains a negative prognostic factor irrespective of front-line therapy and warrants consideration of T-cell engagers' second-line therapy.}, }
@article {pmid42024416, year = {2026}, author = {Unger, JM and Hershman, DL}, title = {Reassessing Treatment Outcomes Following Immune-Related Adverse Events-Reply.}, journal = {JAMA oncology}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamaoncol.2026.0785}, pmid = {42024416}, issn = {2374-2445}, }
@article {pmid42024654, year = {2026}, author = {Korber, B and Seaman, MS and Mkhize, NN and Greene, K and Gao, H and Shen, X and Domin, E and Tang, H and Theiler, J and Wagh, K and Moore, PL and Williamson, C and Mullins, JI and Doria-Rose, NA and Montefiori, D and Giorgi, EE}, title = {Contemporary HIV-1 envelope pseudovirus panels for detecting and assessing B cell lineages with broadly neutralizing antibody potential.}, journal = {PLoS pathogens}, volume = {22}, number = {4}, pages = {e1013739}, doi = {10.1371/journal.ppat.1013739}, pmid = {42024654}, issn = {1553-7374}, mesh = {Humans ; *HIV-1/immunology ; *HIV Antibodies/immunology ; *HIV Infections/immunology/virology/prevention &amp; control ; *env Gene Products, Human Immunodeficiency Virus/immunology ; *AIDS Vaccines/immunology ; *B-Lymphocytes/immunology ; *Antibodies, Neutralizing/immunology ; *Broadly Neutralizing Antibodies/immunology ; Cell Lineage/immunology ; }, abstract = {Although a protective HIV-1 vaccine has not yet been realized, significant progress has been made in vaccine designs that trigger B cell lineages with potential to produce broadly neutralizing antibodies (bnAbs). Advancing these strategies by optimizing vaccine boosting regimens requires early detection of maturing antibodies with neutralizing activity against native envelope glycoprotein (Env) trimers and streamlined strategies to identify antibodies as they begin to manifest desired levels of breadth and potency. Thus, we designed three types of pseudovirus screening panels based on Envs of contemporary HIV-1 isolates to facilitate detection of bnAb lineages that are on favorable trajectories during a vaccination course. The panels were selected from Tier 2 Transmitted Founder Lineage (TFL) HIV-1 Envs from placebo participants in the Antibody Mediated Prevention (AMP) efficacy trials. Using 15 bnAbs to evaluate the neutralization sensitivity of the viruses, we selected 8-member bnAb class-specific panels most sensitive to bnAbs representing their class: V2-apex, V3-glycan, CD4-receptor binding site (CD4bs), Membrane-Proximal External Region (MPER), or fusion peptide (FP). Next, we combined the most sensitive viruses among the class-specific panels to create a 12-virus panel to enable optimal detection of low-titer bnAb activity across epitope specificities. Finally, as HIV-1 continues to evolve greater levels of antigenic diversity and as current global pseudoviruses bnAb panels rely on viruses collected more than twenty years ago, we showed the importance of using contemporary viral panels to assess bnAb breadth and potency and designed a 12-virus panel representative of the spectrum neutralization profiles among AMP placebo viruses. We characterized pseudoviruses bearing each selected Env using standardized human sera to confirm their Tier 2 status and biological relevance. These updated panels enable sensitive screening of neutralization activity in vaccine studies and can also provide a realistic assessment of the expected breadth and potency of maturing responses against contemporary HIV-1 Envs.}, }
@article {pmid42025961, year = {2026}, author = {Hajibandeh, S and Tao, YA and Hsieh, MH and Liu, HG and Cheng, YF and Lee, KH and Hsieh, SY and Lu, CH}, title = {Semaglutide for obesity management: A narrative review of efficacy, safety, and future directions.}, journal = {Journal of the American Pharmacists Association : JAPhA}, volume = {}, number = {}, pages = {103117}, doi = {10.1016/j.japh.2026.103117}, pmid = {42025961}, issn = {1544-3450}, abstract = {BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have demonstrated substantial efficacy for glycemic control and weight management and are increasingly prescribed across diverse populations. Rapid expansion of indications, formulations, and real-world use has outpaced comprehensive evaluation of long-term safety, tolerability, and adherence, raising important concerns for clinical practice.<br><br>OBJECTIVES: This narrative review aims to synthesize current evidence on the efficacy and safety profile of semaglutide, with a focus on adverse events, treatment persistence, perioperative considerations, and use in special populations, to support clinical decision-making and pharmacist-led patient care.<br><br>METHODS: A review of clinical trials, observational studies, pharmacovigilance reports, regulatory communications, and professional guidelines was conducted. Evidence was drawn from randomized controlled trials, post-marketing safety reports, systematic reviews, and relevant clinical and regulatory documents.<br><br>RESULTS: From 1525 records, 34 studies and reports were included. Clinical trials consistently demonstrated meaningful weight reduction with semaglutide. Evidence regarding acute pancreatitis remains limited, although cases have been reported in clinical trials and postmarketing safety analyses. Evidence regarding suicidal ideation associated with semaglutide is mixed, with some analyses suggesting potential safety signals while others report no increased risk. Recent multi society clinical guidelines have addressed perioperative management of GLP-1 RAs, generally supporting individualized perioperative assessment. Emerging literature also examines semaglutide use in special populations, including patients with Alzheimer disease and individuals following bariatric surgery, although long-term neurologic and post-bariatric safety outcomes remain incompletely characterized.<br><br>CONCLUSIONS: Semaglutide represents an important therapeutic option for chronic weight management. As clinical use expands, continued evaluation of long-term safety, tolerability, and treatment persistence will be important. Pharmacists play a key role in counseling patients, monitoring adverse effects, supporting adherence, and contributing to multidisciplinary obesity care.}, }
@article {pmid42016169, year = {2026}, author = {Schuster, DJ and Li, SS and Mielke, D and Seaton, KE and Brackett, C and Li, K and Shen, X and Wesley, MS and Eisel, N and Yates, NL and Zhang, L and Sawant, S and De Rosa, SC and Cohen, KW and Stanfield-Oakley, S and Sholukh, AM and Germain, RS and Li, X and Hu, J and Premkumar, L and Gallardo-Cartagena, JA and Randhawa, AK and Dennison, SM and Hural, JA and Corey, L and Karuna, S and McElrath, MJ and Ferrari, G and Hyrien, O and Tomaras, GD}, title = {Coordinated immune response distinguishes duration of SARS-CoV-2 viral particle shedding in humans.}, journal = {iScience}, volume = {29}, number = {4}, pages = {115277}, pmid = {42016169}, issn = {2589-0042}, abstract = {SARS-CoV-2 acquisition induces a spectrum of COVID-19 disease severity and duration among people. Prolonged viral antigen shedding (PVS) is defined as when a person tests positive by direct antigen tests performed a minimum of 21 days apart. It is unclear why some people exhibit delayed SARS-CoV-2 viral antigen clearance. In this cross-sectional observational study enrolling vaccine naive adults from the USA and Peru following recovery from SARS-CoV-2 acquisition, we examined a suite of blood-derived immune measures to understand differences between participants with PVS (n = 36) and without PVS (non-PVS, n = 223). While PVS participants demonstrated lower overall SARS-CoV-2-specific antibody magnitudes, over-representation analysis revealed that immune feature magnitude alone could not fully explain cohort differences. Hierarchical clustering and network analyses identified more highly coordinated antibody responses, T cell activation, and Fc-mediated function among non-PVS compared to PVS participants. These findings link control of viral antigen shedding to a coordinated immune response.}, }
@article {pmid42016725, year = {2026}, author = {Gold, RS and Henrikson, NB and Issaka, RB and Gillespie, EF and Schuttner, L and Weiner, BJ and Marcotte, LM}, title = {How and Under What Conditions Do Patient Portals Improve Cancer Screening Completion: A Scoping Review.}, journal = {AJPM focus}, volume = {5}, number = {3}, pages = {100481}, pmid = {42016725}, issn = {2773-0654}, abstract = {INTRODUCTION: Studies have shown that patient portals facilitate cancer screening, but less is known about how. Causal pathway diagrams, which include influencing factors such as mechanisms and moderators, can be used to understand how portals improve screening. The authors conducted a scoping review of influencing factors to inform early causal pathway diagrams of the portal as a strategy to increase cancer screening.<br><br>METHODS: The authors searched PubMed for U.S. studies published from 2014 to 2024, including average-risk patients; portal interventions/evaluations; and primary outcomes of breast, cervical, colorectal, or lung cancer screening. Two authors completed manuscript screening and data extraction and synthesized findings to create causal pathway diagrams.<br><br>RESULTS: Thirty-two studies met inclusion criteria. Studies were often set in large academic health systems (n=13) or utilized survey data from nationally representative cohorts (n=11); 6 were RCTs. Most studies focused on breast (n=10) or colorectal (n=9) cancer screening. Of 21 studies comparing portal use with no use, 18 found that portals were associated with increased screening. Most proposed influencing factors were hypothetical, citing findings from prior literature rather than observed directly. Of the 10 studies that performed statistical analysis, significant moderators included provider recommendation for self-scheduling; significant mechanisms included cancer worry and patient activation for general portal use, cancer fatalism and patient activation for secure messaging with providers, and choice architecture for interventions delivered through secure messaging.<br><br>DISCUSSION: Few studies directly tested influencing factors, suggesting a significant research gap. More research is needed to further evaluate proposed mechanisms to understand how portals facilitate cancer screening and optimize implementation.<br><br>REGISTRATION: The protocol for this scoping review was registered through Open Science Framework.}, }
@article {pmid42017274, year = {2026}, author = {Whalen, AM and Ma, W and Filigrana, P and Perreira, KM and Cai, J and Cordero, C and Daviglus, M and Kaplan, R and Lee, DJ and Llabre, MM and Penedo, FJ and Pichardo, MS and Pirzada, A and Suglia, SF and Gallo, LC and Isasi, CR}, title = {Intergenerational Socioeconomic Mobility and Adulthood All-Cause Mortality in the Hispanic Community Health Study/Study of Latinos.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwag086}, pmid = {42017274}, issn = {1476-6256}, abstract = {Socioeconomic mobility, the transition of an individual across different levels of socioeconomic position (SEP), may aid in understanding overall mortality trends in Hispanic/Latino adults by identifying subgroups with varying mortality experiences. We investigated whether intergenerational socioeconomic mobility was associated with all-cause mortality among US Hispanic/Latino adults aged 25-74 in the Hispanic Community Health Study/Study of Latinos (n = 12 095). Childhood SEP was measured as parental education, and adulthood SEP was measured using a 5-indicator index (income, homeownership, employment, occupation, education); both indicators were combined into a 4-group socioeconomic mobility measure: enduring adversity, downward mobility, upward mobility, and enduring advantage. Cox proportional hazards models were adjusted for potential confounders. Downward mobility (HR = 1.74; 95% CI: 1.19-2.55) and enduring adversity (HR = 1.44, 95% CI: 1.06-1.96) were significantly associated with an increased hazard of mortality compared to enduring advantage; the association was stronger among those born in the US. Adjustment for adulthood SEP confounders attenuated the association to non-significance. Socioeconomic mobility, particularly downward mobility, was associated with all-cause mortality in US Hispanic/Latino adults and may be partially explained by adulthood clinical and behavioral factors. Interventions should target structural barriers to socioeconomic advancement for Hispanic/Latino adults to improve health.}, }
@article {pmid42018610, year = {2026}, author = {Petersdorf, EW and McKallor, C and Malkki, M and He, M and Spellman, SR and Gooley, TA and Stevenson, PA}, title = {Extended HLA Haplotypes and Transplant Survival.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025033031}, pmid = {42018610}, issn = {1528-0020}, abstract = {The benefit of extended HLA class I~class III~class II haplotypes in the reduction of mortality after hematopoietic-cell transplantation is unknown and requires information on functional class III variation. We identified a robust class III single-nucleotide-polymorphism (SNP), rs915654, informative for mortality and relapse in 1,436 patients and their haploidentical related donors through multivariable regression analysis of 26 candidate class III SNPs. Three-marker haplotypes as defined by one class I locus, one class II locus and rs915654 were determined in patients separately from donors. Inclusion of rs915654 into relapse and mortality models already containing patient HLA-E~DRB1 and donor HLA-B~DRB1 improved each model (likelihood ratio test P=0.06 and 0.004 respectively for relapse; P=0.10 and 0.01 respectively for mortality). The risks of mortality and relapse increased with decreasing numbers of favorable patient and donor markers. Re-testing in an independent cohort of 1,141 haploidentical transplants yielded similar results. The number of unfavorable markers additionally increased non-relapse mortality. HLA-A~C~B~DRB1~DQB1 haplotypes were defined according to their expected numbers of favorable markers, and the theoretical utility for selecting donors was explored. In summary, extended HLA class I~class III~class II haplotypes influence the success of transplantation and inform the biology of the MHC in health and disease. The selection of haploidentical donors for future patients may be optimized with knowledge of donor HLA haplotypes.}, }
@article {pmid41929148, year = {2026}, author = {Keiser, DJ and Buddy, MS and Mojarad-Jabali, S and Li, Q and Kohler-Skinner, M and Parrish, AG and Gillespie, D and Nix, D and Holmen, S and Colman, H and Couldwell, W and Jensen, R and Szulzewsky, F}, title = {Comprehensive analysis of TEAD inhibition in meningioma identifies MEK and mTOR inhibition as effective combination therapies against resistant lines.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929148}, issn = {2692-8205}, abstract = {Meningiomas are the most common primary central nervous system tumors in adults, posing a significant burden to society. Although a large percentage of lower-grade meningiomas are curable by surgery or radiation alone, high-grade and a subset of low-grade meningiomas demonstrate recurrences and complications from treatment. Systemic therapies for meningioma remain ineffective, and no targeted treatments are approved. Despite the central role of YAP1/TAZ-TEAD signaling in NF2-deficient/mutant tumors, no studies have systematically examined TEAD inhibition across molecularly defined meningioma subtypes or investigated mechanisms of resistance in this disease. We have recently shown that YAP1/TAZ signaling is an oncogenic driver of meningioma. Here, using established and patient-derived meningioma cell lines, we demonstrate that genetic ablation of YAP1/TAZ suppresses growth in both NF2 mutant and NF2 wild type cell lines, establishing YAP1/TAZ-TEAD signaling as a shared oncogenic dependency. Pharmacologic TEAD inhibition suppressed growth of benign NF2 mutant and a subset of higher-grade NF2 mutant meningiomas, whereas NF2 wild type meningiomas were generally more resistant. RNA-Seq and Western Blot analysis identified compensatory activation of MEK-ERK, mTOR-S6, and FAK signaling in resistant lines exhibit. Importantly, co-targeting these pathways was able to overcome resistance to TEADi and was superior to MEK/mTOR/FAK inhibition alone. These studies provide a compelling proof-of-concept that TEADi represents a novel therapeutic vulnerability in meningioma and reveal adaptive signaling responses that can be therapeutically exploited.}, }
@article {pmid41959788, year = {2026}, author = {Walsh, SR and Hahn, WO and Williams, WB and Hyrien, O and Yu, PC and Parks, KR and Edwards, RJ and Parks, R and Barr, M and Polakowski, LL and Tindale, I and Jones, M and Yurdadon, C and Burnham, R and Yeh, CH and Heptinstall, J and Seaton, KE and Andriesen, JG and Sagawa, Z and Miner, MD and De Rosa, S and McElrath, MJ and Corey, L and Tomaras, GD and Montefiori, DC and Haynes, BF and Mayer, KH and Baden, LR and , }, title = {Safety and immunogenicity of an HIV envelope trimer immunogen that elicits CD4 binding site neutralizing antibody precursors (HVTN 300).}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41959788}, abstract = {BACKGROUND: Induction of HIV envelope (Env)-specific broadly neutralizing antibodies (bnAbs) is considered a key objective for HIV-1 vaccine development. One approach is to vaccinate with HIV Env immunogens that initially target the naïve B cell receptors of a bnAb type and boost with a series of HIV Env variants. We chose a priming immunogen, the CH505 transmitted/founder Env with high affinity for the naïve B cell receptor of the prototype CD4 binding site (bs) bnAb lineage, CH103, as a candidate priming immunogen to induce the initial critical step in CD4bs bnAb development.<br><br>METHODS: HVTN 300 is a first-in-human, open-label Phase 1 study evaluating the safety and immunogenicity of a CH505 TF chimeric (ch) Trimer adjuvanted with 3M-052-AF (a TLR7/8 agonist) + Alum. The immunogen is a recombinant, stabilized chimeric Env trimer protein with the N-terminal sequence of CH505 TF gp120 Env transplanted into the BG505 SOSIP sequence. Participants received the adjuvanted protein administered in both deltoid muscles at months 0, 2, 4, 8, and 12.<br><br>RESULTS: Adults (n=18) aged 18 to 55 were screened at a single site in Boston, USA, and 13 were enrolled. Local and systemic reactogenicity was typically mild to moderate. One participant had severe pain/tenderness, and five participants reported transient severe systemic symptoms at least once. Five participants chose to stop further vaccination due to reactogenicity. No vaccine-related SAEs occurred. Vaccine-specific B-cell response rates reached 100% two weeks post third and fifth vaccinations. Antibody blocking experiments with monoclonal antibodies demonstrated that most participants had antibodies directed to the CD4bs. Four out of 11 participants had serum neutralization signatures for CD4bs bnAb precursors.<br><br>CONCLUSIONS: No safety concerns were identified. The adjuvanted CH505 TF chTrimer elicited serum antibodies capable of CD4bs-mediated neutralization against strains designed to detect early precursors of the CD4bs B-cell lineages.<br><br>TRIAL REGISTRATION: NCT04915768.}, }
@article {pmid42008267, year = {2026}, author = {Shankaran, V and Li, L and Khor, S and Yu, K and Kwendakwema, CN and Fedorenko, C and Kreizenbeck, K and Khan, HM and Kestner, S and Wright, W and Ramsey, S}, title = {Financial Hardship, End-of-Life Health Care Use, and Costs in Patients With Cancer.}, journal = {JAMA network open}, volume = {9}, number = {4}, pages = {e267923}, doi = {10.1001/jamanetworkopen.2026.7923}, pmid = {42008267}, issn = {2574-3805}, mesh = {Humans ; *Neoplasms/economics/therapy ; Male ; Female ; *Terminal Care/economics/statistics &amp; numerical data ; Aged ; United States ; *Health Care Costs/statistics &amp; numerical data ; *Financial Stress/economics/epidemiology ; Middle Aged ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; Emergency Service, Hospital/statistics &amp; numerical data/economics ; Aged, 80 and over ; *Health Expenditures/statistics &amp; numerical data ; Cohort Studies ; SEER Program ; Washington ; Hospitalization/economics/statistics &amp; numerical data ; }, abstract = {IMPORTANCE: Patients with cancer are at higher risk of adverse financial events (AFEs) compared with individuals without cancer. However, little is known about how personal finances affect cancer care, particularly at the end of life (EOL).<br><br>OBJECTIVE: To investigate the association between AFEs and health care use and costs at EOL among patients with cancer.<br><br>In this cohort study, Western Washington Surveillance, Epidemiology, and End Results cancer registry cases were linked to claims from commercial payers and Medicare and to credit records from TransUnion. Patients with American Joint Committee on Cancer stage I to IV solid tumors who died between January 1, 2013, and December 31, 2019, were identified. Data analysis was performed from January 2023 and June 2025.<br><br>MAIN OUTCOMES AND MEASURES: Emergency department (ED) and inpatient visits in the last 3 months of life, place of death, and mean adjusted health care costs per patient were compared between patients with vs without new AFEs in the 2 years preceding EOL (charge-offs, third-party collections, tax liens, delinquent mortgage payments, foreclosures, or repossessions). A multivariate logistic regression analysis evaluated the association between AFEs and the outcomes of ED or inpatient visits and inpatient death. Health care costs in the last 3 and 6 months of life were analyzed using 2-part models to account for zero costs and right-skewed positive expenditures; adjusted average treatment effects were estimated.<br><br>RESULTS: A total of 10&#x202f;826 patients (median [IQR] age, 75 [69-83] years; 5877 [54%] male; 932 [8.6%] with AFEs) were included. Patients with AFEs were more likely to have multiple ED or inpatient visits (odds ratio [OR], 1.41; 95% CI, 1.22-1.62; P&#x2009;<&#x2009;.001) and die in a hospital (OR, 1.50; 95% CI, 1.30-1.75; P&#x2009;<&#x2009;.001). Mean (SD) adjusted total health care costs were higher in patients with AFEs than those without in the last 3 months ($35&#x202f;115 [$1415] vs $31&#x202f;031 [$389]) and 6 months ($57&#x202f;401 [$2181] vs $51&#x202f;602 [$581]) of life, yielding a mean adjusted incremental costs in the AFE group of $4084 (95% CI, $1287-$7087; P&#x2009;=&#x2009;.006) and $5799 (95% CI, $1235-$9996; P&#x2009;=&#x2009;.01), respectively.<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study, AFEs were associated with greater ED and inpatient use, higher risk of inpatient death, and higher care costs at EOL. These findings point to the need for future studies investigating whether interventions that mitigate financial hardship could improve the EOL experience and decrease health care costs for patients with cancer.}, }
@article {pmid42008824, year = {2026}, author = {Kanwal, F and Feng, Z and Hoshida, Y and Chhatwal, J and Wong, VW and Ioannou, GN and Nahon, P and Lotter, W and Ning, J and Taouli, B and Marquez, G and Fu, SW and Singal, AG}, title = {Development and validation of risk stratification models for hepatocellular cancer: A framework from the translational liver cancer consortium.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, pmid = {42008824}, issn = {1527-3350}, abstract = {Clinical practice guidelines recommend hepatocellular cancer (HCC) surveillance in patients with cirrhosis from any etiology and those with chronic hepatitis B virus (HBV) infection and additional risk factors. However, HCC incidence varies across groups. Several risk stratification models using clinical factors and/or biomarkers have been derived to facilitate tailored HCC surveillance. Although risk stratification models are used for patients with hepatitis B, few have been sufficiently validated in patients with cirrhosis. Indeed, many unanswered questions related to the development, validation, and impact evaluation of risk stratification models must be addressed before widespread implementation can be recommended. The National Cancer Institute's Translational Liver Cancer (TLC) Consortium was established to advance research focused on risk stratification and early detection of liver cancer. The TLC convened a multidisciplinary group, including clinicians, scientists, biostatisticians, and technology experts from the United States, Asia, and Europe, to provide a framework for the development, validation, and implementation of risk stratification models. The framework defines 4 phases of risk stratification model development and validation: phase 1-development and internal validation, phase 2-decision rule development, phase 3-external validation, and phase 4-impact evaluation. The group also defined a set of recommendations to improve the rigor of development and validation of HCC risk stratification strategies. This framework can inform best practices and highlight necessary steps for endorsement by practice guidelines and regulatory agencies, highlighting a path toward implementation in clinical practice.}, }
@article {pmid42009282, year = {2026}, author = {Liu, Y and Goldrich, N and Redmond, KJ and Gabriel, J and Zhou, N and Swensen, S and Skalina, KA and Fekrmandi, F and Vellayappan, B and Guckenberger, M and Foote, M and Connell, PP and Hsu, CC and Vuong, W and Gillespie, EF and Tykodi, SS and Nguyen, TK and Mayerson, JL and Nguyen, QN and de Moraes, FY and Siva, S and Palmer, JD and Kim, M and Yang, JT and Sahgal, A and Lo, SS}, title = {Stereotactic Body Radiation Therapy for Non-Spine Bone Metastases: A Case-Based Radiosurgery Society Review.}, journal = {Practical radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.prro.2026.04.004}, pmid = {42009282}, issn = {1879-8519}, abstract = {PURPOSE: Growing evidence supports stereotactic body radiation therapy (SBRT) over conventional radiation therapy for spine bone metastases, with an expanding role in non-spine bone metastases (NSBM). Our case-based review aims to inform radiation oncologists in the appropriate utilization of SBRT for representative cases of NSBM.<br><br>METHODS AND MATERIALS: Three cases were selected for discussion: (1) rib, (2) skull base, and (3) femur. Relevant literature was reviewed, and areas for future investigation were discussed.<br><br>RESULTS: SBRT can be effectively delivered in NSBM with appropriate patient selection, target volume delineation, prescription dose, organs at risk dose constraints, and treatment planning.<br><br>CONCLUSIONS: The Radiosurgery Society's case-based review offers guidance on the appropriate use of SBRT in NSBM with discussions and consensus recommendations from experts. SBRT can be considered for an oligometastatic patient with favorable prognosis in whom the goal is durable local control and/or symptom relief. It can be considered for radioresistant histologies and improved OAR sparing. Available MRI or PET/CT should be fused to improve target volume delineation. A CTV margin, generally of 5 mm, should be considered to cover microscopic disease. As bones are easily visualized on daily images acquired for accurate and precise set-up of patients, a PTV margin should be kept less than or equal to 3 mm. While SBRT can be delivered in 1 fraction, fractionated SBRT may be preferred to meet dose constraints when the CTV is adjacent to the OARs. NSBM of long bones that are weight bearing, lytic, or have a high MIRELS score should be evaluated by an orthopedic surgeon.}, }
@article {pmid42010121, year = {2026}, author = {Saifudeen, M and Zhu, S and Liang, S and Eason, M and Goupil, A and Mische, DF and Loch, CM and Ma, H and Chan, M and Gujral, TS}, title = {Comprehensive profiling of clinically approved kinase inhibitors reveals mutation-specific inhibitors and opportunities for drug repurposing.}, journal = {Nature biotechnology}, volume = {}, number = {}, pages = {}, pmid = {42010121}, issn = {1546-1696}, abstract = {Protein kinases are central to cell signaling and key drug targets in cancer. To inform potential repurposing of kinase inhibitors, we profiled 86 of the ~100 approved kinase inhibitors against 758 kinases, including 409 wild-type and 349 oncogenic variants using a biochemical kinase assay. Our results increase the number of druggable kinases from 89 to 235, revealing that 94% of mutations and 97% of fusions represented in our samples are inhibited by at least one existing drug. The dataset revealed mutation-specific selectivity, especially in tyrosine kinases FGFR and MET, highlighting gaps and repurposing opportunities. We experimentally validated several actionable findings, including tepotinib to target the IRAK1/4-cholesterol pathway in glioblastoma, brigatinib to target the MARK2/3-Hippo pathway in pancreatic cancer and gilteritinib to overcome MET mutation-driven drug resistance and metastasis. To facilitate exploration of our data, we provide KIRHub, a web-based tool that allows identification of existing inhibitors of wild-type and mutated kinases to guide precision oncology.}, }
@article {pmid42011792, year = {2026}, author = {de Abreu, M and Kowalski, LP and López, RM and Barul, C and Radoi, L and Bidoli, E and Polesel, J and Wunsch-Filho, V and Olshan, AF and Zevallos, J and Negri, E and Edefonti, V and Świątkowska, B and Mates, D and Fabianova, E and Lissowska, J and Shangina, O and Brennan, P and Pandics, T and Maso, LD and Morgenstern, H and Zhang, ZF and Kelsey, K and McClean, M and La Vecchia, C and Garavello, W and Chen, C and Schwartz, SM and Ramroth, H and Winkler, V and Cadoni, G and Boccia, S and Brenner, H and D'Souza, G and Gross, N and Muscat, J and Abedini, M and Sassano, M and Boffetta, P and Hashibe, M and Lee, YA and Curado, MP}, title = {Risk of Head and Neck Cancer in Former Smokers by Subsite: A Multicenter Analysis From the INHANCE Consortium.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.70497}, pmid = {42011792}, issn = {1097-0215}, support = {R03CA11315//National Cancer Institute grant/ ; //French National Research Agency (ANR)/ ; //French National Cancer Institute (INCA)/ ; //French Agency for Food, Environmental and Occupational Health and Safety (ANSES)/ ; //French Institute for Public Health Surveillance (InVS)/ ; //Fondation pour la Recherche Medicale (FRM)/ ; //Fondation de France/ ; //Fondation ARC pour la Recherche sur le Cancer/ ; //French Ministry of Labour (Direction Generale du Travail)/ ; //French Ministry of Health (Direction Generale de la Sante)/ ; GENCAPO 04/12054-9//Sao Paulo Research Foundation (FAPESP)/ ; 10/51168-0//Sao Paulo Research Foundation (FAPESP)/ ; NCI R01CA90731-01//North Carolina (2002-2006) study/ ; NIEHS P30ES010126//North Carolina (2002-2006) study/ ; //Italian Association for Research on Cancer (AIRC)/ ; //Italian League Against Cancer/ ; //World Cancer Research Fund/ ; IC15-CT98-0332//European Commission INCO-COPERNICUS Program/ ; P50CA090388/GF/NIH HHS/United States ; R01DA011386/GF/NIH HHS/United States ; R03CA077954/GF/NIH HHS/United States ; T32CA009142/GF/NIH HHS/United States ; U01CA096134/GF/NIH HHS/United States ; R21ES011667/GF/NIH HHS/United States ; R01CA078609/GF/NIH HHS/United States ; R01CA100679/GF/NIH HHS/United States ; R01CA048996/GF/NIH HHS/United States ; R01DE012609/GF/NIH HHS/United States ; R01CA051845/GF/NIH HHS/United States ; P01CA068384/GF/NIH HHS/United States ; K07CA104231/GF/NIH HHS/United States ; //Alper Research Program for Environmental Genomics of the UCLA Jonsson Comprehensive Cancer Center/ ; PRIN 2009 X8YCBN//Italian Ministry of Education/ ; 01GB9702/3//German Ministry of Education and Research/ ; //Ministry of Science/ ; //Research and Arts Baden-Wurttemberg/ ; //Johns Hopkins Richard Gelb Cancer Prevention Award/ ; 88887.929140/2023-00//Coordena&#xe7;&#xe3;o de Aperfei&#xe7;oamento de Pessoal de N&#xed;vel Superior-Brasil (CAPES)/ ; }, abstract = {This study investigated risk factors associated with HNC by subsite including oral cavity cancer (OCC), oropharyngeal cancer (OPC), and laryngeal cancer (LC) among former smokers in the International Head and Neck Cancer Epidemiology Consortium (INHANCE). Case-control study including former smokers from the pooled INHANCE data, with information on sociodemographic, smoking, and alcohol history. Associations were assessed using logistic regression with 95% confidence intervals (CI). The study included 2143 cases with HNC and 5799 controls. Cancer cases were categorized by their respective subsites: 954 LC (44.5%), 685 OPC (32.0%), 504 OCC (23.5%). The risk of developing OCC was 2.8-fold higher [CI: 1.9-4.1], LC 2.6-fold higher [CI: 1.9-3.5], and OPC 2.1-fold higher [CI: 1.5-2.8] in individuals who smoked > 50 pack-years, compared to < 10 pack-years. The risk of OCC/OPC/LC increased with tobacco consumption in North-America, whereas in Western/Southern-Europe and South-America the association plateaued beyond 31-50 pack-years. Cessation after age 55 increased the risk of LC by 3.0-fold [CI: 2.2-4.2], and OCC by 2.2-fold [CI: 1.4-3.3] versus cessation age ≤ 45 years. Consuming ≥ 5 drinks/day was associated with 5-fold higher risk of OPC [CI: 3.7-6.6], 4.4-fold higher risk of OCC [CI: 3.2-6.1] and 3.1-fold higher risk of LC [CI: 2.4-3.9] compared to 0-0.9 drinks/day. The risk of HNC among former smokers is not homogeneous across regions and that there were distinct patterns for OCC, OPC, and LC. The amount of tobacco and alcohol consumption are key risk factors, with alcohol being more important for OCC/OPC, and tobacco being more strongly associated with LC risk.}, }
@article {pmid42013417, year = {2026}, author = {Campbell, KM and Chen, DG and Bustami, ZE and Naser Al Deen, N and Medina, E and Gonzalez, CR and Maxey, J and Thompson, MA and Samorodnitsky, S and Kuklinski, LF and Perez Garcilazo, I and Baselga-Carretero, I and Vega-Crespo, A and Chen, JM and Elumalai, R and Visitacion, M and Schiemann, R and Padron, L and Chang, C and Zelin, AE and Chelluri, SS and Boffo, S and Kendra, KL and Chmielowski, B and Truong, TG and Khushalani, NI and Collichio, F and Ikeguchi, AP and Victor, AI and Margolin, KA and Johnson, DB and Chen, Y and Sosman, JA and Patel, SP and Hu-Lieskovan, S and Moon, J and Wells, DK and Spencer, CN and Bellasea, S and Vanderwalde, AM and Wu, MC and Scumpia, PO and Ribas, A}, title = {Cellular neighborhoods govern antitumor T-cell infiltration following anti-CTLA-4 in melanoma with primary resistance to anti-PD-1.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-25-1745}, pmid = {42013417}, issn = {2159-8290}, abstract = {In the phase 2 trial SWOG S1616 (NCT03033576), patients with advanced melanoma with primary resistance to anti-PD-1/L1 therapies had improved outcomes on the combination of the anti-CTLA-4 antibody ipilimumab with continued anti-PD-1 with nivolumab, over ipilimumab alone. Baseline biopsies from patients responsive to combination therapy had increased transcriptomic expression of complement by myeloid cells, interferon pathways by endothelial cells, and oxidative phosphorylation and lipid metabolism by melanoma cells. Using spatial proteomics, some on-therapy biopsies from patients responding to combination therapy had networks of activated CD8 T cells nearby melanoma cells, while others had T cells and myeloid cells, reflective of different timepoints in a dynamic antitumor response. Conversely, biopsies from patients progressing on combination immunotherapy displayed impaired T-cell infiltration adjacent to plasma cells. Our results define cellular neighborhoods and transcriptomes in melanoma biopsies when reversing resistance to anti-PD-1 with the addition of anti-CTLA4, and plasma cell sheets in non-responding biopsies.}, }
@article {pmid42013838, year = {2026}, author = {Rathore, U and Dugan, E and Thornton, H and Kumar, VE and Dajani, R and Burdick, RC and Young, JM and Steinhart, Z and Lao, R and Delviks-Frankenberry, KA and Choi, W and Henriques, WS and Echeverria, I and Dann, E and Dureja, I and Pathak, N and Arce, MM and McKetney, J and Umhoefer, JM and Parulekar, S and Schmidt, R and Polacco, BJ and Neidleman, J and Montano, M and Nguyen, VQ and Sali, A and Levy, JA and Tenthorey, JL and Cheng, Y and Roan, NR and Swaney, DL and Kaake, RM and Dodgson, SE and Hiatt, J and Pathak, VK and Malik, HS and Krogan, NJ and Marson, A}, title = {Systematic discovery of pro- and anti-HIV host factors in primary human CD4+ T cells.}, journal = {Cell}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cell.2026.03.046}, pmid = {42013838}, issn = {1097-4172}, abstract = {Host factors that promote or restrict human immunodeficiency virus (HIV) infection in human CD4+ T cells have not been comprehensively identified. We employed orthogonal genome-wide CRISPR activation (CRISPRa) and CRISPR knockout screens in primary CD4+ T cells to discover pro- and anti-HIV host factors systematically. Secondary pooled screens and individual perturbations validated high-confidence hits and revealed diverse mechanisms of action. CRISPRa uncovered multiple potent antiviral factors, including PI16, PPID, SHISA3, and ITM2A. PI16 interacts with host factors involved in HIV fusion and inhibits viral entry, whereas PPID (Cyp40), a paralog of the proviral cyclophilin CypA, binds capsid and reduces nuclear import of the HIV core. Structural modeling, evolutionary analyses, and targeted mutagenesis revealed domains and residues required for PPID-mediated HIV restriction, including non-human primate ortholog substitutions that enhance antiviral activity. Together, these data define the functional HIV-host interaction landscape in primary human T cells and uncover new mechanisms modulating infection.}, }
@article {pmid42014940, year = {2026}, author = {Chari, A and Costello, C and Krishnan, A and Patel, K and Banerjee, R and Berdeja, JG and Biran, N and Callander, N and Costa, LJ and Dhakal, B and Gasparetto, C and Hansen, DK and Kumar, A and Nooka, AK and Pan, D and Richard, S}, title = {Integrating Recent Evidence and Expert Perspectives Into the Management of Multiple Myeloma: Consensus Recommendations From the 2025 Bridging the Gaps Conference.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70339}, pmid = {42014940}, issn = {1096-8652}, abstract = {The rapid expansion of therapeutic options for multiple myeloma (MM) has created uncertainty regarding optimal sequencing and clinical application. To address gaps in evidence, the 2025 Bridging the Gaps Consensus Conference convened 16 US MM experts who reviewed data, debated controversies, and voted on 51 questions that were developed using a modified Delphi approach. Eleven consensus recommendations were developed spanning smoldering MM, frontline therapy, transplant, maintenance, and relapsed/refractory disease. Key themes included integration of quadruplet induction, individualized maintenance, and early referral for CAR-T therapy. These expert-derived recommendations provide practical guidance while highlighting areas requiring further investigation.}, }
@article {pmid42001456, year = {2026}, author = {McCulloch, DJ and Khawaja, F and Tverdek, FP and Ford, ES and Vora, SB and Waghmare, A and Vuong, N and Chemaly, RF and Hill, JA}, title = {First report on remdesivir use for the treatment of respiratory syncytial virus in five allogeneic hematopoietic cell transplant recipients.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiag213}, pmid = {42001456}, issn = {1537-6613}, abstract = {Respiratory syncytial virus (RSV) infection causes substantial morbidity among hematopoietic cell transplant (HCT) patients and lacks approved therapies. Remdesivir demonstrates antiviral activity in vitro, but data in humans are lacking. We describe 5 HCT recipients with RSV lower respiratory tract infection who were treated with remdesivir with clinical improvement.}, }
@article {pmid42001506, year = {2026}, author = {Brady, SW and Arnold, MA and Wang, M and Alsallaq, R and Dong, L and Khan, MA and Yang, W and Stratton, KL and Liu, W and Chen, Y and Plyler, E and Steele, JA and Powers, BB and Rosenfeld, D and Edmonson, MN and Feng, Y and Terekhanova, NV and Hagiwara, K and Arunachalam, S and Mulder, HL and Srivastava, DK and Rusch, M and Nolan, VG and McDonald, A and Sapkota, Y and Gramatges, MM and Turcotte, LM and Im, C and Howell, RM and Easton, J and Ma, X and Wang, Z and Leisenring, WM and Conces, M and Neglia, JP and Yasui, Y and Bhatia, S and Ellison, DW and Zhang, J and Armstrong, GT}, title = {Therapy-related mutational signatures in subsequent neoplasms among survivors of childhood cancer.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-25-0231}, pmid = {42001506}, issn = {2159-8290}, abstract = {Childhood cancer survivors have heightened risk of developing subsequent neoplasms (SNs) related to therapy. We analyzed whole-genome, exome and RNA sequencing of 200 breast, meningioma, and thyroid SNs, which developed a median of 26.4 years after childhood cancer, among 160 survivors. Meningioma and thyroid SNs were enriched for driver gene rearrangements compared to de novo tumors, including NF2-disrupting alterations and kinase fusions potentially induced by radiation. Radiation correlated with increased insertion-deletion signature ID5. Nitrogen mustard treatment correlated with elevated "flat" signature SBS5 in breast and meningioma SNs; in vitro, these agents caused an unresolved flat signature associated with multiple flat COSMIC signatures. In meningioma, platinum therapy correlated with NF2 splice-site variants. Analysis of 19 multi-sample survivors revealed intrapatient heterogeneity in meningioma, including clonally independent tumors. These results demonstrate the long-term impact of childhood cancer treatment on the genomes of SNs developing in adulthood, which may guide SN treatment and prevention.}, }
@article {pmid42001993, year = {2026}, author = {Zhou, D and Nouet, J and Mesa, E and Yegneshwaran, V and Geukgeuzian, G and Adibemma, ID and Ramirez, E and Ali, NK and Hilfiker, S and Li, H and Liu, T and Yehia, G and Romanienko, PJ and Rodney, GG and Wehrens, XHT and Lampe, PD and Gourdie, RG and Xie, LH and Fraidenraich, D}, title = {Phospho-mimic βIII-tubulin rescues microtubule and cardiac defects in Duchenne muscular dystrophy mice.}, journal = {Journal of molecular and cellular cardiology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.yjmcc.2026.04.004}, pmid = {42001993}, issn = {1095-8584}, abstract = {Duchenne muscular dystrophy (DMD) cardiomyopathy is caused by mutations in the dystrophin gene and characterized by profound cytoskeletal disorganization, particularly pathological remodeling of the cardiomyocyte microtubule network. While the role of dystrophin in maintaining sarcolemmal integrity is well-established, its specific association with microtubule dynamics through post-translational modifications (PTMs) remains underinvestigated. Here, we identified βIII-tubulin Ser172 phosphorylation as a specific regulatory residue in cardiac DMD microtubule pathology. Using CRISPR-generated mdx mice carrying a phospho-mimic S172E mutation in βIII-tubulin, we demonstrate rescue of microtubule organization defects, including normalization of orthogonal microtubule misalignment, and restoration of physiological density and polymerization kinetics. Microtubule stabilization further improved secondary phenotypes, including connexin-43 (Cx43) phosphorylation and retention to intercalated discs, critical for electrical coupling and signal transduction. Furthermore, S172E expression protected against isoproterenol-induced arrhythmias and cardiac fibrosis in the mdx mouse model. Lentiviral expression of S172E-mutant βIVb-tubulin confirmed conservation of these effects across cardiac β-tubulin isoforms. Our findings reveal a regulatory link between microtubule dynamics and Cx43, establish β-tubulin Ser172 phosphorylation as a key regulator of microtubule dynamics in dystrophic hearts, and will help develop novel therapeutic strategies targeting microtubule stabilization in DMD cardiomyopathy.}, }
@article {pmid42007251, year = {2026}, author = {Davis, JA and McElwee, J and Gonzalez, R and Julian, K and Nachar, VR and Snyder, J and Mahmoudjafari, Z and Granger, K and Warrick, M and Smith, D and Baek, G and Huang, I and Portuguese, A and Dima, D and Banerjee, R and Atrash, S and Sborov, DW and Grajales-Cruz, A and Puglianini, OC and Dominick, A and Hansen, DK and Elsey, G and Moore, DC}, title = {Safety of MMR vaccination for patients with myeloma receiving daratumumab after autologous stem cell transplantation.}, journal = {Blood neoplasia}, volume = {3}, number = {2}, pages = {100220}, pmid = {42007251}, issn = {2950-3280}, }
@article {pmid41129124, year = {2025}, author = {Su, CT and Ramsey, SD and Shankaran, V}, title = {Can We Use Credit Data to Assess Cancer Financial Hardship?.}, journal = {JAMA oncology}, volume = {11}, number = {12}, pages = {1420-1422}, doi = {10.1001/jamaoncol.2025.4371}, pmid = {41129124}, issn = {2374-2445}, }
@article {pmid41129142, year = {2026}, author = {Jani, S and Bencomo, T and Shasha, C and Pulliam, T and Jojic, A and Church, CD and Gooley, TA and Koelle, DM and Newell, EW and Nghiem, P}, title = {Circulating Neoantigen- and Viral Oncoprotein-Specific CD8+ T Cells Share a Transcriptional Signature.}, journal = {Cancer immunology research}, volume = {14}, number = {1}, pages = {22-31}, pmid = {41129142}, issn = {2326-6074}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; F30 CA254168/CA/NCI NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; CA225517//National Cancer Institute (NCI)/ ; CA254168//National Cancer Institute (NCI)/ ; CA080416//National Cancer Institute (NCI)/ ; CA264646//National Cancer Institute (NCI)/ ; CA015704//National Cancer Institute (NCI)/ ; A187769//Odyssey Group Foundation/ ; //National Foundation for Cancer Research (NFCR)/ ; }, mesh = {Humans ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; *Carcinoma, Merkel Cell/immunology/genetics/virology/blood ; *Antigens, Viral, Tumor/immunology ; *Antigens, Neoplasm/immunology ; Female ; Male ; *Transcriptome ; Aged ; *Skin Neoplasms/immunology/genetics ; Gene Expression Profiling ; Middle Aged ; }, abstract = {Tumor-specific CD8+ T cells in blood seem to be important for and predictive of response to anti-PD-1 therapies. However, as most tumor antigens are unique to a given patient, the identification of tumor-specific CD8+ T cells is not routinely feasible. In this study, we characterized polyomavirus-specific CD8+ T cells from the blood of 17 patients with virus-driven Merkel cell carcinoma. We identified a 98-gene signature [Signature of Peripheral Tumor-specific CD8+ T cells (SPoTT)] that discriminated circulating tumor-specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus those from tumor. In validation cohorts of Merkel cell carcinoma, as well as neoantigen-driven cancers, the signature of peripheral tumor-specific CD8+ T cells was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCRPBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize Merkel cell polyomavirus-specific T cells with a sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor-specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally driven cancers.}, }
@article {pmid41129365, year = {2026}, author = {Watling, CZ and Campbell, PT and Graubard, BI and Wang, Y and Gewirtz, AT and Zhang, X and Barnett, MJ and Buring, JE and Chen, Y and Eliassen, AH and Gaziano, JM and Hofmann, JN and Huang, WY and Kang, JH and Koshiol, J and Loftfield, E and Lee, IM and Moore, SC and Mucci, LA and Neuhouser, ML and Newton, CC and Purdue, MP and Sesso, HD and Shrubsole, M and Sinha, R and Tinker, L and Triplette, M and Um, CY and Visvanathan, K and Watts, EL and Wactawski-Wende, J and Willett, W and Wu, F and Zheng, W and Barupal, D and Petrick, JL and McGlynn, KA}, title = {Pre-diagnostic immunological markers of bacterial translocation and liver cancer risk: A nested case-control analysis of 12 prospective cohorts.}, journal = {International journal of cancer}, volume = {158}, number = {7}, pages = {1801-1812}, pmid = {41129365}, issn = {1097-0215}, support = {187861/CAPMC/CIHR/Canada ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HL26490/NH/NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; 75N92021D00005/NH/NIH HHS/United States ; U01CA202979/NH/NIH HHS/United States ; 75N92021D00004/NH/NIH HHS/United States ; 75N92021D00001/NH/NIH HHS/United States ; NCI U01 167552/NH/NIH HHS/United States ; U24 ES035386/ES/NIEHS NIH HHS/United States ; UM1 CA182913/CA/NCI NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; U01CA164974/NH/NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 CA063673/CA/NCI NIH HHS/United States ; CA097193/NH/NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; HL080467/NH/NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; U01CA63673/NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; HL043851/NH/NIH HHS/United States ; HL09935/NH/NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; HL34595/NH/NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; UM1CA186107/NH/NIH HHS/United States ; CA40360/NH/NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; 75N92021D00003/NH/NIH HHS/United States ; U24ES035386/NH/NIH HHS/United States ; //National Institutes of Health Intramural/ ; 75N92021D00002/NH/NIH HHS/United States ; CA047988/NH/NIH HHS/United States ; R01 CA040360/CA/NCI NIH HHS/United States ; U01CA167462/NH/NIH HHS/United States ; U01 CA182913/CA/NCI NIH HHS/United States ; U01 CA202979/CA/NCI NIH HHS/United States ; UM1CA167462/NH/NIH HHS/United States ; CA182913/NH/NIH HHS/United States ; RC1 HL099355/HL/NHLBI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; //American Cancer Society/ ; CA34944/NH/NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Male ; Case-Control Studies ; *Liver Neoplasms/immunology/microbiology/blood/epidemiology ; Female ; Middle Aged ; *Bacterial Translocation/immunology ; Prospective Studies ; Lipopolysaccharide Receptors/blood/immunology ; Aged ; Carrier Proteins/blood/immunology ; Membrane Glycoproteins/blood ; Risk Factors ; Flagellin/immunology ; Immunoglobulin G/blood ; Acute-Phase Proteins ; Lipopolysaccharides/immunology ; Adult ; Immunoglobulin A/blood ; Biomarkers, Tumor ; }, abstract = {The gut-liver axis may play an important role in hepatocarcinogenesis. However, limited prospective research has explored associations with liver cancer risk. We conducted a nested case-control study based in 12 prospective cohort studies from across the United States, which included 867 cases of liver cancer and 867 matched controls. We measured bacterial translocation markers, specifically immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide and flagellin; soluble CD14 (a co-receptor for lipopolysaccharide); and lipopolysaccharide-binding protein. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) between bacterial translocation marker concentrations per doubling in concentrations and liver cancer risk. Lipopolysaccharide-binding protein concentrations were most strongly associated with higher liver cancer risk (OR per doubling in concentrations: 1.48, 95% CI: 1.23-1.79). Concentrations of anti-flagellin IgA (1.13, 1.01-1.28) and IgG (1.13, 1.01-1.28), anti-lipopolysaccharide IgG (1.20, 1.01-1.42), and soluble CD14 (1.12, 1.01-1.24) were also associated with liver cancer risk. When analyses were separated into hepatocellular carcinoma (HCC, N = 436 cases) and intrahepatic cholangiocarcinoma (ICC, N = 110 cases), no evidence of heterogeneity was observed except for lipopolysaccharide-binding protein concentrations, which were positively associated with HCC (1.77, 1.34-2.33) but not ICC (0.67, 0.37-1.22; p-heterogeneity = .003). Associations did not differ by time to liver cancer diagnosis or other subgroups. These findings support the role of gut barrier dysfunction in hepatocarcinogenesis, necessitating further research to understand the complex interplay among the mechanisms and risk factors disrupting the gut barrier, microbiota, and liver cancer.}, }
@article {pmid41129758, year = {2025}, author = {Bagshaw, P and Potter, JD and Griffiths, N and Hornblow, A and Cox, B and Gower, K}, title = {Nurse endoscopists: a rational response to rising rates of young-onset colorectal cancer in Aotearoa New Zealand.}, journal = {The New Zealand medical journal}, volume = {138}, number = {1624}, pages = {76-86}, doi = {10.26635/6965.7100}, pmid = {41129758}, issn = {1175-8716}, mesh = {Humans ; New Zealand/epidemiology ; *Colorectal Neoplasms/epidemiology/diagnosis/nursing ; Middle Aged ; *Colonoscopy/nursing ; *Early Detection of Cancer ; Sigmoidoscopy/nursing ; Age of Onset ; Incidence ; *Mass Screening ; Aged ; Adult ; Female ; Male ; }, abstract = {Young-onset (<50 years) colorectal cancer (YOCRC) has been increasing in Aotearoa New Zealand since the birth cohort born around the mid-1950s. Possible responses include education and public health measures, none of which are likely to make a major impact in the foreseeable future. Many YOCRCs are presenting at late stages with predominantly distal cancers. Our current National Bowel Screening Programme (NBSP), screening people 60-75 years, was introduced with inadequate resources; as a result, some colonoscopy services have been moved from symptomatic cases to screening, resulting in diagnostic delays and poorer outcomes. Extending screening to 40 or 45 years will markedly increase the need for follow-up colonoscopies and stretch services beyond breaking point. Sigmoidoscopy is associated with a substantial and sustained reduction in risk of distal colorectal cancer incidence and mortality. As there are too few endoscopists for the existing workload, increasing the nurse endoscopist workforce is a rational step. Initial training would focus on flexible sigmoidoscopy (FS) and concentrate on symptomatic patients <50 years. Steadily increasing nurse endoscopist numbers will contribute to management of the rising incidence of YOCRC. Without disrupting the NBSP or putting much extra strain on need for follow-up colonoscopies, nurse-led FS clinical services can expand to anyone with relevant symptoms and, as a longer-term goal, eventually become part of an expanded screening programme that could include one-off FS at age 50. If we are agreed that this is essential, training and service must be adequately funded and accompanied by a public advocacy campaign to ensure sufficient resources.}, }
@article {pmid41129763, year = {2025}, author = {Einstein, DJ and Abel, ML and Aragon-Ching, JB and Arlen, PM and Autio, KA and Bilusic, M and Carducci, MA and Choyke, PL and Citrin, DE and Figg, WD and Graff, JN and Gulley, JL and Halabi, S and Karzai, F and Lindenberg, L and Markowski, MC and Marshall, CH and McNeel, DG and Mena, E and Moon, H and Pachynski, RK and Paller, CJ and Patel, KR and Posadas, EM and Pienta, KJ and Regan, MM and Sena, LA and Walmsley, CS and Wei, XX and Yu, EY and Tran, PT and Madan, RA}, title = {National Cancer Institute's Working Group on Biochemically Recurrent Prostate Cancer: Clinical Trial Design Considerations.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {34}, pages = {3672-3683}, doi = {10.1200/JCO-25-01693}, pmid = {41129763}, issn = {1527-7755}, support = {U54 CA273956/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/therapy/pathology/diagnostic imaging/blood ; *Neoplasm Recurrence, Local/therapy/diagnostic imaging/blood ; United States ; National Cancer Institute (U.S.) ; *Research Design ; *Clinical Trials as Topic/methods ; Quality of Life ; Prostate-Specific Antigen/blood ; }, abstract = {PURPOSE: Biochemical recurrence (BCR) of prostate cancer (PCa) after definitive surgery and/or radiation (including salvage strategies) is a burgeoning area of clinical research inspired by ultrasensitive next-generation imaging. Most phase III trials in PCa have focused on metastatic disease, defined by conventional imaging. Despite the emergence of new imaging, clinical trial principles from metastatic studies will not optimize future BCR trials.<br><br>METHODS: A Working Group convened at the National Cancer Institute on November 13, 2024 (NCI BCR WG). Key areas of discussion included nomenclature, baseline criteria for data capture, imaging considerations, delineation of high-risk populations to be targeted for trial development, requirements of metastasis-directed therapy (MDT) or hormonal therapy, quality-of-life considerations, and potential study end points.<br><br>RESULTS: The NCI BCR WG defined the novel term "prostate-specific membrane antigen (PSMA)+BCR" to identify the emerging concept of recurrent PCa identifiable only on PSMA positron emission tomography (PET), overlapping with BCR and distinct from metastatic hormone-sensitive PCa as traditionally defined by conventional imaging. The WG suggested defining high-risk BCR with a prostate-specific antigen doubling time of &#x2264;6 months, regardless of PET findings. The WG provided recommendations for baseline data capture and imaging requirements. Neither systemic therapy nor MDT were considered mandatory for control arms. The WG also discussed novel end points and quality-of-life metrics in this disease space.<br><br>CONCLUSION: These discussions should inform future clinical BCR trials in this distinct disease space relative to metastatic disease defined by conventional imaging. The NCI BCR WG strongly advocates that future trials explore deintensification of treatment to minimize toxicity in this relatively indolent disease state.}, }
@article {pmid41130408, year = {2026}, author = {Le, X and Baik, C and Cho, BC and Riess, JW and Piotrowska, Z and Johannes de Langen, A and Goldberg, SB and Goldman, JW and Reguart, N and Shiraishi, Y and Ambrose, H and Fraenkel, PG and Ruiz, BM and Smith, PE and Tang, KH and Yu, HA}, title = {Osimertinib Plus Savolitinib in Patients With EGFR-Mutated Advanced NSCLC With MET Alterations After First-Line Osimertinib: Clinical Outcomes, Safety, and Biomarker Analysis: A Brief Report.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {21}, number = {2}, pages = {318-327}, doi = {10.1016/j.jtho.2025.10.009}, pmid = {41130408}, issn = {1556-1380}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology ; *Lung Neoplasms/drug therapy/pathology/genetics ; Female ; Male ; *Acrylamides/therapeutic use/pharmacology/administration &amp; dosage ; *Aniline Compounds/therapeutic use/pharmacology ; Middle Aged ; Aged ; ErbB Receptors/genetics ; Mutation ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology ; *Proto-Oncogene Proteins c-met/genetics ; Biomarkers, Tumor/genetics ; Survival Rate ; Adult ; Prognosis ; Aged, 80 and over ; Indoles ; Pyrazines ; Pyrimidines ; Triazines ; }, abstract = {INTRODUCTION: The ORCHARD (NCT03944772) study was conducted to characterize resistance mechanisms and identify optimal treatments after progressive disease (PD) on first-line osimertinib. We report results from the osimertinib plus savolitinib module.<br><br>METHODS: Patients with EGFR-mutated NSCLC with PD on first-line osimertinib with MET gene amplification (&#x2265;4 copies of MET over tumor ploidy) per next-generation sequencing of a post-progression biopsy received osimertinib plus savolitinib. Primary end point was investigator-assessed objective response rate (ORR). Secondary end points included progression-free survival, duration of response, overall survival, and safety. Correlation of ORR with baseline molecular alterations was an exploratory analysis.<br><br>RESULTS: A total of 32 patients were enrolled; all had tumors with MET amplification. At primary analysis cutoff (January 2023), confirmed ORR was 47% (80% confidence interval [CI]: 34-60). Median duration of response was 14.5 months (95% CI: 5.6-18.7). Median progression-free survival was 7.6 months (95% CI: 3.2-15.9). There was a trend toward increased ORR in patients with high MET gene copy number (&#x2265;10 versus <10). Furthermore, 14 patients (44%) had grade 3 or higher treatment-emergent adverse events; most often pneumonia (n = 3; 9%). At final database lock (May 2024), 20 patients (63%) had died; median overall survival was 20.7 months (95% CI: 9.9-34.8).<br><br>CONCLUSIONS: Osimertinib plus savolitinib demonstrated encouraging clinical benefit in patients with EGFR-mutated advanced NSCLC and MET amplification after PD on first-line osimertinib. Safety was consistent with profiles of the individual drugs.}, }
@article {pmid41134118, year = {2025}, author = {Chua, KJ and Quilang, RC and Sallinger, K and Aktipis, CA and Arck, P and Bianchi, DW and Chang, HD and Cleaves, HJ and Eikmans, M and Fjeldstad, HES and Haig, D and Harrington, WE and Horsnell, W and Jacobsen, DP and Kamper-Jørgensen, M and Kanaan, SB and Khosrotehrani, K and Lambert, NC and Nelson, JL and Olsen, MB and Pan, TD and Prins, JR and Schildberg, FA and Staff, AC and Ståhlberg, A and Stelzer, IA and Urbschat, C and Way, SS and Wilson, MA and Ye, J and Kroneis, T and Boddy, AM}, title = {Identifying Key Questions and Challenges in Microchimerism Biology.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {48}, pages = {e14969}, pmid = {41134118}, issn = {2198-3844}, support = {62214//John Templeton Foundation/ ; //Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health/ ; }, mesh = {Animals ; Female ; Humans ; *Chimerism ; Male ; }, abstract = {Microchimerism research has recently gained renewed attention despite known existence of these rare cells for decades. Fetal and maternal microchimeric-derived cells may have functional capabilities, and are increasingly associated with both beneficial and adverse health outcomes. Yet, establishing the role of microchimerism in health has been largely constrained methodologically and theoretically. The Microchimerism, Human Health, and Evolution Project address these challenges by calling on 29 leading microchimerism experts to put forth key research questions that can substantially advance the field. Seven major categories are identified: function and mechanism; microchimerism in interventions, treatment, and transplant; mapping "generational microchimerism"; evolution; microchimerism detection; appropriate experimental model systems; and definition of microchimerism. Identifying these questions - and continuing to find answers - will be crucial for advancing the knowledge of microchimerism in health and disease.}, }
@article {pmid41135058, year = {2026}, author = {Adesina, OO and Voutsinas, J and Wu, QV and Teos, LY and Rokni, M and Nalbant, H and Nardo, L and Wun, T and Zemel, B}, title = {Low bone mineral density and pain impact in adults with sickle cell disease.}, journal = {Blood advances}, volume = {10}, number = {3}, pages = {748-758}, pmid = {41135058}, issn = {2473-9537}, support = {K23 HL148310/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Anemia, Sickle Cell/complications ; Female ; Male ; Adult ; *Bone Density ; *Pain/etiology ; Middle Aged ; Absorptiometry, Photon ; Quality of Life ; }, abstract = {Low bone mineral density (BMD) is a prevalent skeletal finding in sickle cell disease (SCD), but its clinical consequences are poorly understood. We hypothesized that low BMD, independent of osteonecrosis (ON), would associate with pain in adults with SCD. In the SCD Bone Pain study, 53 ambulatory adults (64% females; mean age, 38 ± 11 years; 66% hemoglobin [Hb] SS/Sβ0 thalassemia) underwent dual-energy X-ray absorptiometry scans of their lumbar spine, hip, forearm, and whole body. They also completed the Adult Sickle Cell Quality of Life Measurement Information System pain impact questionnaire. Twenty-three participants (43%) had low BMD, defined as lumbar spine, total hip, or femoral neck BMD z scores of -2 or less. In multivariate linear regression, lumbar spine BMD z scores significantly changed by +0.31, -0.29, -0.14, and -1.3 for every unit increase in Hb, indirect bilirubin, and white blood cell count, and with crizanlizumab use, respectively. Pain impact T-scores significantly decreased (worsened) by 6.0 and 6.5 with reduced estimated glomerular filtration rate and chronic opioid therapy but increased (improved) by 3.8 for every unit increase in serum phosphate. The median [interquartile range] pain impact T-scores were significantly lower in participants with low BMD and ON (38.3 [37.4, 40.1]) than those with either low BMD (49.5 [43.6, 54.4]; P = 3 × 10-5) or ON (52.7 [45.3, 57]; P = 2 × 10-4) alone. Whether sickle cell-related low BMD results from impaired bone formation and/or accelerated bone loss remains unclear. Understanding how low bone density, with or without ON, mediates SCD pain warrants further investigation. This trial was registered at www.clinicaltrials.gov as #NCT05283148.}, }
@article {pmid41135920, year = {2026}, author = {Medlin, AR and Abrams, HR and Kent, EE and Ogunjesa, BA and Park, S and Tan, KR}, title = {Variations in Mental Distress Among Caregivers of Individuals With Chronic Illnesses and Comorbid Cognitive Impairment.}, journal = {American journal of preventive medicine}, volume = {70}, number = {4}, pages = {108165}, doi = {10.1016/j.amepre.2025.108165}, pmid = {41135920}, issn = {1873-2607}, mesh = {Humans ; *Caregivers/psychology/statistics &amp; numerical data ; Male ; Female ; *Cognitive Dysfunction/epidemiology/psychology ; Middle Aged ; Chronic Disease/psychology ; Aged ; Adult ; Behavioral Risk Factor Surveillance System ; *Mental Disorders/epidemiology ; Comorbidity ; Alzheimer Disease ; *Stress, Psychological/epidemiology ; *Psychological Distress ; }, abstract = {INTRODUCTION: This study was aimed to examine the rates of mentally unhealthy days and frequent mentally unhealthy days among caregivers of patients with cancer, heart disease, mental illness, and Alzheimer's disease and related dementias on the basis of caregiving intensity and how cognitive impairment in non-Alzheimer's disease and related dementias caregiving moderates these relationships.<br><br>METHODS: Data from 22,550 caregivers in the 2019-2023 Behavioral Risk Factor Surveillance System were used to explore the relationship between caregiving intensity, mentally unhealthy days, and the presence of cognitive impairment. Zero-inflated negative binomial regressions assessed the associations of caregiving intensity on mentally unhealthy days, and logistic regressions examined the patterns in frequent mentally unhealthy days, controlling for demographics and survey weighting.<br><br>RESULTS: Caregivers of individuals with mental illness reported the highest frequent mentally unhealthy days (27.53%), followed by caregivers of those with cancer (20.3%), heart disease (18.57%), and Alzheimer's disease and related dementias (17.82%). Increased caregiving intensity correlated with higher mentally unhealthy day rates, particularly among caregivers of patients with cancer, heart disease, and Alzheimer's disease and related dementias. Caregivers of those with cancer showed increased mentally unhealthy days when moderating for cognitive impairment. Higher caregiving intensity was linked to increased frequent mentally unhealthy days in the caregivers of patients with cancer and Alzheimer's disease and related dementias, with cancer caregivers showing more frequent mentally unhealthy days when moderating for cognitive impairment.<br><br>CONCLUSIONS: Caregiving intensity affects mental health outcomes differently across illnesses. Tailored support is needed for caregivers, especially those providing care for individuals with comorbid cognitive impairment.}, }
@article {pmid41136348, year = {2025}, author = {Duran, MC and Shah, PD and Bell-Brown, AM and Rojina, J and Glascock, M and Ramirez, M and Ibarra, G and Garza, L and Linde, S and Bishop, S and Garrison, MM and Pascoe, KM and Drain, PK and Zhou, C and Ko, LK}, title = {Back to school: a qualitative study evaluating a community-informed COVID-19 risk communication intervention for rural elementary school children and their families.}, journal = {Translational behavioral medicine}, volume = {15}, number = {1}, pages = {}, pmid = {41136348}, issn = {1613-9860}, support = {UL1 TR002319/TR/NCATS NIH HHS/United States ; OT2 HD107544/GF/NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/prevention &amp; control ; Child ; Qualitative Research ; Female ; Male ; Rural Population ; Focus Groups ; Schools ; Parents/psychology ; SARS-CoV-2 ; *Students/psychology ; *Return to School ; Communication ; School Health Services ; Health Knowledge, Attitudes, Practice ; Adult ; }, abstract = {BACKGROUND: ReOpening Schools Safely and Educating Youth (ROSSEY) was a cluster randomized controlled trial of a risk communication intervention for COVID-19 prevention to promote safe return to school among students in a rural, agricultural community.<br><br>PURPOSE: This qualitative study evaluated the implementation of a risk communication intervention and a school district's COVID-19 testing program through parent focus groups and interviews with school staff and students.<br><br>METHODS: Parents (n&#x2009;=&#x2009;37), students (n&#x2009;=&#x2009;19), and school staff (n&#x2009;=&#x2009;14) from seven schools that received the intervention shared their experience via focus groups and interviews informed by the RE-AIM framework. Deductive and inductive coding was conducted by four data analysts. Themes were validated with community members.<br><br>RESULTS: Parent focus groups, student and staff interviews provided insight into the ROSSEY study implementation. We identified five main themes: (i) social and financial drivers of participation; (ii) personal beliefs and unique challenges to research participation; (iii) intervention reinforced knowledge and shifted behavior; (iv) the appeal of comic books and videos supported adoption; and (v) multimodal communication and partnerships enhanced implementation.<br><br>CONCLUSIONS: The risk communication intervention was deemed culturally appropriate, reinforced previous knowledge, and encouraged adoption of preventive behaviors. The partnership with the school district and collaboration with the district's COVID-19 testing program ensured success of recruitment, study implementation, and adoption of preventive behaviors.}, }
@article {pmid41136629, year = {2025}, author = {Corey, L and Ratevosian, J and Beyrer, C and Currier, J and Eron, J and Cohen, MS and Deeks, SG}, title = {How HIV research drives health innovation in multiple diseases.}, journal = {Nature medicine}, volume = {31}, number = {12}, pages = {3965-3967}, pmid = {41136629}, issn = {1546-170X}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1AI068636//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1AI068619//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068614/AI/NIAID NIH HHS/United States ; }, }
@article {pmid41137757, year = {2025}, author = {Fong, Y and Huang, Y and Huang, Y and Woo, W and McGarry, A and Áñez, G and Dunkle, LM and Cho, I and Houchens, CR and Martins, K and Jayashankar, L and Castellino, F and Petropoulos, CJ and Leith, A and Haugaard, D and Webb, W and Lu, Y and Yu, C and Carpp, LN and Randhawa, AK and Andrasik, MP and Kublin, JG and Hutter, J and Keshtkar-Jahromi, M and Beresnev, TH and Rodriguez, CA and Tapia, M and Turley, CB and Zorrilla, CD and Cohen, SH and Kline, SE and Barranco, E and Corey, L and Neuzil, KM and Follmann, D and Ake, JA and Gay, CL and Kotloff, KL and Jones, T and Koup, RA and Donis, RO and Gilbert, PB}, title = {Analysis of antibody markers as immune correlates of risk of severe COVID-19 in the PREVENT-19 efficacy trial of the NVX-CoV2373 recombinant protein vaccine.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, pmid = {41137757}, issn = {1537-6591}, support = {S10 OD028685/OD/NIH HHS/United States ; C0000008/CL/CLC NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: We previously showed that ancestral-specific anti-Spike binding IgG concentration and 50% inhibitory dilution neutralizing antibody titer (nAb-ID50) measured at 2 weeks post-dose 2 (∼peak) were inverse correlates of risk (CoRs) of COVID-19 over 2 months post ∼peak in the PREVENT-19 trial of the NVX-CoV2373 vaccine; there were not sufficient data to assess CoRs of severe COVID-19.<br><br>METHODS: Here we assessed, in the same vaccinated cohort, Delta- and ancestral-specific Spike IgG and nAb-ID50 at &#x223c;peak and over time as CoRs of severe COVID-19 and of Delta COVID-19 over 3.5-10 months post &#x223c;peak (287 breakthrough Delta cases, including 8 severe; 446 non-cases).<br><br>RESULTS: &#x223c;Peak antibody levels were much higher for non-cases vs. severe cases (all inferred Delta), with nAb-ID50 Delta geometric mean 209.5 arbitrary units (AU)/mL (95% CI: 176.1, 249.1) vs. 9.6 AU/mL (95% CI: 2.4, 38.6), respectively. Frequency of detectable nAb-ID50 titer was 98.3% (97.2, 99.0) for non-cases vs. 62.5% (22.3, 93.9) for severe cases. All markers were inverse CoRs of severe COVID-19, with a &#x223c;peak hazard ratio (HR) of 0.13 (95% CI: 0.03, 0.57) per 10-fold nAb-ID50 Delta increase. Severe COVID-19 risk through 305 days post-Day 35 was 0.0338 (0.0043, 0.206) at the nAb-ID50 Delta 2.5th percentile (8.4 AU/ml), and 0.002 (0.0000, 0.0108) and 0.0002 (0.0000, 0.0035) at the 50th and 95th percentiles (210, 2522 AU/ml).<br><br>CONCLUSIONS: Post-vaccination NVX-CoV2373 antibody levels are stronger predictors of severe COVID-19 than any-severity Delta COVID-19. Low antibody responses indicate vulnerability to severe COVID-19.}, }
@article {pmid41138741, year = {2025}, author = {Anderson, BO and Duggan, C}, title = {Lessons from CONCORD and VENUSCANCER: closing global gaps in cancer care for women.}, journal = {Lancet (London, England)}, volume = {406}, number = {10517}, pages = {2298-2300}, doi = {10.1016/S0140-6736(25)01580-6}, pmid = {41138741}, issn = {1474-547X}, }
@article {pmid41138816, year = {2026}, author = {Shadman, M and Ahmed, S and Byrne, MT and Chavez, JC and Kamdar, M and Sorror, ML and Perales, MA and Hill, JA and Moslehi, J and Miklos, DB}, title = {Who Is Eligible for Chimeric Antigen Receptor T Cell Therapy? Expert Perspectives on Overcoming Referral Barriers.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {3}, pages = {277-287}, doi = {10.1016/j.jtct.2025.10.025}, pmid = {41138816}, issn = {2666-6367}, mesh = {Humans ; *Immunotherapy, Adoptive/methods ; *Referral and Consultation ; *Receptors, Chimeric Antigen/immunology ; *Hematologic Neoplasms/therapy/immunology ; }, abstract = {CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies, including lisocabtagene maraleucel, axicabtagene ciloleucel, and tisagenlecleucel, have revolutionized the treatment landscape for patients with hematologic malignancies. However, identification and referral of patients who could benefit from treatment remains a significant challenge, Here, we report expert recommendations for CAR-T therapy referral gathered from 10 experts in oncology, hematology, cardiology, and infectious diseases from a roundtable meeting and/or subsequent reviews between November 13, 2024, and June 9, 2025. We considered the following potential factors: age, performance status, disease status, cardiovascular function, pulmonary function, renal function, hepatic function, infections, and psychological health. Based on existing evidence, we agreed that none of the factors discussed should preclude patients from receiving referrals/further evaluation for CAR-T therapy, particularly with current advances in supportive care and integration of services from other specialties. Timely referral should be made by the patient's primary oncologist to specialists as early as the disease is deemed relapsed or refractory, preferably before the starting the subsequent line of therapy to allow better access to care and improve treatment outcomes. Before CAR-T therapy, holding therapy (before leukapheresis) and/or bridging therapy (after leukapheresis) may be given to patients with high-volume disease, in consultation with CAR-T therapy specialists. Based on the safety profile of CAR-T therapies, experts recommended flexible monitoring and transfer of care back to primary/community oncology physicians, starting from 2 weeks after infusion to improve access to this potentially curative therapy. Adaptations to clinical practice based on the most recent regulations, policy requirements, and institutional guidelines should be made as needed. In summary, a panel of 10 experts provided recommendations for timely patient referral for CAR-T therapy on the occurrence of relapsed or refractory disease and before the initiation of subsequent lines of therapy to improve care access and treatment outcomes. Experts noted that with close collaboration between CAR-T therapy specialists and other medical disciplines, CAR-T therapy remains a feasible option for most patients despite their comorbidities. © 2025 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.}, }
@article {pmid41138914, year = {2026}, author = {Zhang, Y and Alver, S and Shan, Z and Mossavar-Rahmani, Y and Hu, J and Zhang, J and St-Onge, MP and Kaplan, R and Xue, X and Qi, Q}, title = {The timing of macronutrient and major food group intake and associations with mortality among United States adults, 1999‒March 2020: a serial cross-sectional study.}, journal = {The American journal of clinical nutrition}, volume = {123}, number = {1}, pages = {101097}, pmid = {41138914}, issn = {1938-3207}, support = {R35 HL155670/HL/NHLBI NIH HHS/United States ; R01 DK128154/DK/NIDDK NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; R01 HL170904/HL/NHLBI NIH HHS/United States ; R01 HL142648/HL/NHLBI NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Cross-Sectional Studies ; Male ; Female ; United States/epidemiology ; Adult ; Middle Aged ; Nutrition Surveys ; *Nutrients/administration &amp; dosage ; *Diet ; Energy Intake ; Aged ; Time Factors ; *Feeding Behavior ; *Mortality ; Young Adult ; *Eating ; }, abstract = {BACKGROUND: Eating timing has been increasingly linked to health, yet national trends in macronutrient/food group timing and their health implications remain unclear.<br><br>OBJECTIVES: To characterize trends in the timing of energy, macronutrient, and food group intake among United States adults and examine their associations with mortality.<br><br>METHODS: In this serial cross-sectional study of adults aged &#x2265;20 y with &#x2265;1 valid 24-h dietary recall (National Health and Nutrition Examination Survey, 1999&#x2012;March 2020), we examined secular trends in timing of energy, macronutrients, and major food group intake. Associations with mortality (through December 2019) were examined using Cox models.<br><br>RESULTS: Among 50,264 adults, evening (18:00-22:00) accounted for the highest daily energy intake (weighted mean proportions across years, 31.9%&#x2012;33.3%), followed by noon (10:00-14:00, 24.7%&#x2012;26.8%), afternoon (14:00-18:00, 19.9%&#x2012;21.8%), morning (06:00-10:00, 13.5%&#x2012;14.9%), and overnight (22:00-06:00, 5.6%&#x2012;6.5%); midnight (22:00-02:00) eating occurred in 23.4%&#x2012;28.0% of the population. Macronutrient and food groups followed similar patterns, except whole grain (peaked in the morning) and fruit, egg, and dairy intake (more evenly distributed). Over the years, noon and midnight energy intake proportions declined, whereas the afternoon proportion increased; secular trends varied by macronutrients/food groups. Fasting started at 20:34-20:51 and ended at 08:41-08:51; intake midpoint was 14:37-14:48; intake duration was 11.9&#x2012;12.2 h. Male, non-Hispanic Black, and socioeconomically disadvantaged groups had greater midnight intake proportions and later intake midpoints. Reallocating 5% of daily energy to midnight was associated with higher cardiovascular mortality (hazard ratio: 1.09; 95% confidence interval: 1.02,1.17), driven by carbohydrates; reallocating 5% to predawn (02:00-06:00) was associated with higher cancer mortality (hazard ratio: 1.22; 95% confidence interval: 1.05, 1.41), driven by proteins. Each 1-h delay in fasting and intake midpoint was associated with an 8%&#x2012;9% higher cardiovascular mortality.<br><br>CONCLUSIONS: Overnight intake and delayed eating timing are prevalent among United States adults, especially between socioeconomically disadvantaged groups, and were associated with higher mortality, particularly for specific macronutrients/foods, supporting eating timing recommendations integrating food composition.}, }
@article {pmid41141367, year = {2025}, author = {Wick, BJ and Kluesner, MG and Slipek, NJ and Skeate, JG and Niemeyer, EM and Webber, BR and Moriarity, BS}, title = {Installation of dominant-negative mutations in FAS and TGFβR2 via base editing in primary T cells.}, journal = {Molecular therapy. Oncology}, volume = {33}, number = {4}, pages = {201063}, pmid = {41141367}, issn = {2950-3299}, support = {R01 AI161017/AI/NIAID NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; F30 CA305905/CA/NCI NIH HHS/United States ; R61 AG090358/AG/NIA NIH HHS/United States ; U54 CA232561/CA/NCI NIH HHS/United States ; R21 AI163731/AI/NIAID NIH HHS/United States ; T32 HL007062/HL/NHLBI NIH HHS/United States ; U24 OD026641/OD/NIH HHS/United States ; R21 CA237789/CA/NCI NIH HHS/United States ; R37 CA276345/CA/NCI NIH HHS/United States ; P01 CA254849/CA/NCI NIH HHS/United States ; R01 AI146009/AI/NIAID NIH HHS/United States ; U54 CA268069/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {Adoptive cell transfer (ACT) of engineered T cells is effective against B cell malignancies but has faltered against solid tumors due to the immunosuppressive tumor microenvironment (TME). FAS ligand (FASL) and transforming growth factor β (TGF-β) are key mediators of T cell dysfunction in the TME and overexpressing dominant negative (dn) forms of their receptors in T cells increases anti-tumor efficacy in solid tumor models. However, an approach that directly targets the endogenous genes would be more amenable to multiplex editing and reduce competition with WT alleles. Here, we employ base editing (BE) in primary human T cells to install naturally occurring dominant negative FAS and TGFβR2 mutations. In vitro survival and proliferation assays demonstrate that BE T cells are resistant to pro-apoptotic and anti-proliferative effects of FAS and TGF-β signaling. Chimeric antigen receptor (CAR)-T cells with BE-installed dn TGFβR2 or dn FAS exhibit improvements in cytotoxicity, while dn TGFβR2 CAR T demonstrate increased persistence and reduced expression of phenotypic markers of exhaustion compared to controls. Moreover, BE-engineered dn CAR T outperform lentiviral-engineered cDNA over expression counterparts in several functional assays. Considering the efficiency of BE and its amenability for multiplex editing, our approach lends itself to engineering strategies necessary to overcome T cell dysfunction in solid tumors.}, }
@article {pmid41141393, year = {2026}, author = {Choudhury, SR and Kaushal, A and Biswas, P and Padilla, C and Sarthy, JF and Chavan, A and Gonzalez, GA and Meshinchi, S and Farrar, JE}, title = {Transcriptional rewiring by enhancer methylation in CBFA2T3-GLIS2-driven pediatric acute megakaryoblastic leukemia.}, journal = {Genes &amp; diseases}, volume = {13}, number = {1}, pages = {101843}, pmid = {41141393}, issn = {2352-3042}, abstract = {Resistance to chemotherapy and subsequent relapse remain the primary challenge in pediatric acute myeloid leukemia (pAML), particularly in CBFA2T3-GLIS2 (C/G) fusion-positive acute megakaryoblastic leukemia. Here we demonstrate that the C/G fusion drives extensive DNA methylation changes and oncogenic enhancer activation at cis-regulatory elements (CREs), reshaping gene expression. This multi-omics analysis reveals a distinct hypermethylation pattern at promoters of up-regulated genes in C/G[+] pAML across patient samples (n = 24) and representative cell lines, notably enriched in adhesion-related, TGFβ, or Wnt signaling pathways. Hypermethylated regions adjacent to transcription start sites (TSS) maintain open chromatin with H3K27ac enrichment, supporting a mechanism of de novo chromatin looping and active transcription in a non-canonical manner. Additionally, C/G fusion binding near the DNA methyltransferase 3B (DNMT3B) promoter correlates with elevated DNMT3B expression, implicating its role in aberrant DNA methylation changes at CREs. This study elucidates the epigenetic mechanisms driving C/G[+] pAML, showing how the fusion reshapes chromatin and DNA methylation landscapes by impacting the expression (and likely activity) of epigenetic modifiers like DNMT3B. Functionally, DNMT3B inhibition enhances apoptotic sensitivity to BCL2 blockade, indicating that targeting DNMT3B may overcome apoptotic resistance in C/G[+] leukemic cells and offer a therapeutic strategy for this high-risk subtype.}, }
@article {pmid41141451, year = {2025}, author = {Reed, JC and Hall, L and McKhann, A and Kwak, G and Goecker, EA and Coombs, RW and Chen, H and Roa, J and Vecchio, A and Daar, ES and Hunt, PW and Marra, CM and Campbell, TB and Ma, Q and Swaminathan, S and Macatangay, BJC and Morse, GD and Miller, T and Rusin, D and Ha, B and Alston-Smith, B and Paul, R and Letendre, SL and Spudich, SS and Greninger, AL}, title = {Antiretroviral Therapy Intensification With Dolutegravir and/or Maraviroc Did Not Affect HIV-1 Cell-Associated DNA, RNA, and 2--LTR Circles Over 12 Weeks.}, journal = {Open forum infectious diseases}, volume = {12}, number = {10}, pages = {ofaf594}, pmid = {41141451}, issn = {2328-8957}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; U01 AI068634/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Neurocognitive impairment (NCI) among people living with human immunodeficiency virus (HIV; PWH) on antiretroviral therapy (ART) may result from residual viral replication. The A5324 trial found that ART intensification with dolutegravir (DTG) with or without maraviroc (MVC) did not affect NCI in PWH. We evaluated the impact of ART intensification on peripheral virological measures during the first 12 weeks of intensification.<br><br>METHODS: The A5324 study was a randomized, double-blind, placebo (PBO)-controlled, 96-week trial of ART intensification with either dual PBO, DTG + PBO, or DTG + MVC in PWH with NCI on ART who were naive to integrase strand transfer inhibitors and MVC. At baseline and weeks 2, 4, and 12, HIV-1 RNA was measured in plasma with a low-copy assay, while HIV-1 cell-associated DNA (caDNA), cell-associated unspliced RNA (caRNA), and cell-associated 2-long terminal repeat circles (ca2LTR) were quantified from peripheral blood mononuclear cells using droplet digital polymerase chain reaction.<br><br>RESULTS: Of the 171 participants, 59 were randomized to dual PBO, 57 to DTG + PBO, and 55 to DTG + MVC. Changes in caDNA and caRNA and detection of plasma RNA did not differ between treatment arms over 12&#x2005;weeks (P > 0.05). Detection of ca2LTR was less frequent at weeks 2-4 in the DTG + MVC arm (40.4%) than in the dual-PBO (70.7%; P =0 .02) and DTG + PBO (68.4%; P = 0.03) arms. However, this difference diminished by week 12, and baseline ca2LTR detection in the DTG + MVC arm was lower than in the other groups.<br><br>CONCLUSIONS: DTG intensification had no effect on peripheral markers of HIV-1 persistence. DTG + MVC intensification reduced ca2LTR detection at weeks 2-4, though this effect did not persist through week 12. These findings indicate the minimal impact of intensification on the HIV-1 peripheral reservoir, consistent with prior studies.}, }
@article {pmid41143136, year = {2025}, author = {Tanaka, K and Chikowore, TJB and Deeks, SG and Estes, JD and Ho, YC and Jiang, S and Lee, MJ and Li, C and Machinda, A and Martins, M and Mdletshe, P and Ndhlovu, ZM and Neogi, U and Ott, MM and Rasmussen, TA and Reddy, K and Rutishauser, RL and Farrell-Sherman, A and Tiemessen, CT and Voss, JE and Kityo, C and Lewin, SR and Ndung'u, T and McCune, JM}, title = {Meeting Summary for Keystone Symposia on HIV Cure: Antiretroviral Therapy (ART)-Free Control of HIV Infection in Durban, South Africa, 2025.}, journal = {Pathogens &amp; immunity}, volume = {10}, number = {2}, pages = {196-229}, pmid = {41143136}, issn = {2469-2964}, abstract = {Antiretroviral therapy (ART) can effectively control human immunodeficiency virus (HIV) replication; however, lifelong treatment is required due to viral reservoirs, which fuel viral rebound. This necessitates curative interventions that can achieve either eradication of the reservoir or durable remission off ART. Advances in technology have fostered development of multi-omic techniques encompassing molecular tools, proteomic analyses, imaging, and artificial intelligence (AI)-driven data analysis to understand HIV reservoir biology and persistence. These have informed the investigation of therapeutic interventions such as broadly neutralizing antibodies, latency reversal, immune cell augmentation, antivirals, and gene therapy. From April 7-10, 2025, experts in the field convened at the Keystone Symposia conference, HIV Cure: Antiretroviral Therapy (ART)-Free Control of HIV Infection in Durban, South Africa, to discuss novel strategies for eradication and/or durable ART-free control of HIV.}, }
@article {pmid41143601, year = {2026}, author = {Cliff, ERS and Pelaez, GD and Wan, F and Iyengar, V and Zhou, J and Chung, K and Abdel-Razeq, N and Allen, J and Major, A and Sharp, J and Epperla, N and Gould, P and Cherng, HJ and Houshyar, S and Wallace, DS and Lynch, RC and Kallam, A and Mei, MG and Merryman, RW and Fleyshman, M and Rhodes, JM and Kidwell, A and Fenske, TS and Malakhov, N and Mulvey, E and Watkins, MP and Alhaj Moustafa, M and Hilal, T and Nowakowski, GS and Wang, Y and Torka, P and Russler-Germain, DA}, title = {Cell-of-Origin Subtype Predicts Response to Polatuzumab Vedotin in Large B-cell Lymphoma.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {32}, number = {1}, pages = {159-168}, pmid = {41143601}, issn = {1557-3265}, support = {T32CA247815//National Cancer Institute (NCI)/ ; K12 CA167540/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; K12CA167540//National Cancer Institute (NCI)/ ; //Lymphoma Research Foundation (LRF)/ ; T32 CA247815/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/pathology/mortality ; Male ; Female ; Middle Aged ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Adult ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration &amp; dosage ; *Immunoconjugates/administration &amp; dosage/therapeutic use ; Aged, 80 and over ; Prognosis ; Treatment Outcome ; Antibodies, Monoclonal ; }, abstract = {PURPOSE: Polatuzumab vedotin (polatuzumab) was approved for up-front treatment of diffuse large B-cell lymphoma in combination with chemoimmunotherapy (Pola-R-CHP) based on the POLARIX trial. However, when stratified by cell of origin (COO), polatuzumab seems to have greater efficacy in activated B-cell than germinal center B-cell (GCB) subtype disease. Most studies of polatuzumab used RNA expression to assess COO, whereas in routine clinical practice, the immunohistochemistry-based Hans algorithm is used.<br><br>EXPERIMENTAL DESIGN: To assess the impact of COO by immunohistochemistry on polatuzumab efficacy, we conducted a multicenter real-world study of adults with large B-cell lymphoma (LBCL) receiving polatuzumab from 2015 to 2024, split by receipt of polatuzumab in first-line versus relapsed/refractory settings. The primary endpoint was overall response rate (ORR) to polatuzumab-based treatment in GCB versus non-GCB relapsed/refractory LBCL.<br><br>RESULTS: Of 740 patients, 305 received polatuzumab in the first-line setting and 435 in the relapsed/refractory setting. In the relapsed/refractory cohort, the ORR in non-GCB versus GCB LBCL was 59.7% versus 36.3% [OR, 2.6; 95% confidence interval (CI), 1.77-3.84; P < 0.0001], with a complete response rate of 35.7% versus 17.7% (OR, 2.6; 95% CI, 1.66-4.02; P < 0.0001). Progression-free survival was longer for patients with non-GCB versus GCB COO (HR, 0.64; 95% CI, 0.5-0.83; P = 0.0006). In the first-line cohort, ORR, complete response rate, and progression-free survival were similar in non-GCB versus GCB LBCL, as hypothesized based on outcomes in the Pola-R-CHP arm of POLARIX, suggesting that the addition of polatuzumab overcomes the adverse risk of non-GCB COO in patients receiving R-CHOP.<br><br>CONCLUSIONS: Based on these data, COO classification by the Hans algorithm is a strong predictor of polatuzumab efficacy in LBCL, informing real-world treatment decisions.}, }
@article {pmid41145253, year = {2025}, author = {Kataria, I and Selmouni, F and Duggan, C and Sullivan, R and Purushotham, A and Sankaranarayanan, R and Taghavi, K and Basu, P}, title = {Application of implementation science methods and theories for cancer control planning in low-income and middle-income countries: a scoping review.}, journal = {BMJ open}, volume = {15}, number = {10}, pages = {e108755}, pmid = {41145253}, issn = {2044-6055}, support = {001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Neoplasms/prevention &amp; control/therapy ; *Developing Countries ; *Implementation Science ; Health Policy ; Delivery of Health Care/organization &amp; administration ; *Health Planning ; }, abstract = {INTRODUCTION: Implementation science (IS) is increasingly recognised as vital in cancer control planning and integrating evidence-based interventions across the cancer care continuum. Contextual differences often cause variability in delivering optimised healthcare, which IS approaches could mitigate. While IS improves planning effectiveness, many programme and policy planners remain unaware of its benefits. To address this, we examined IS theories applied to national cancer control plans (NCCPs)/strategies across five domains: stakeholder engagement, situational analysis, capacity assessment, economic evaluation and impact assessment.<br><br>METHODS: We conducted a scoping review using the Arksey and O'Malley framework to analyse NCCPs and strategies from 16 and 17 countries belonging to low and medium categories of Human Development Index (HDI), focusing on resource-constrained settings. We identified plans through the International Cancer Control Partnership portal, categorised them by WHO region and included only those available in English or French. We extracted data into a Microsoft Excel database and performed thematic analysis across five IS domains. Multiple IS experts, selected purposively based on their familiarity with resource-constrained settings, validated the findings, assessed policy relevance and helped develop a pathway for integrating IS into national cancer control planning. They reviewed structured questions in advance and provided feedback on analyses, practical utility, dissemination and simplifying IS application, which was used to refine the pathway and reach consensus.<br><br>RESULTS: While many NCCPs incorporated key IS elements such as stakeholder engagement, situational analysis and impact measurement, these often needed to be more explicit and consistently applied. None of the plans assessed health system capacity to determine readiness for implementing new interventions. Although most plans described stakeholder engagement, it was typically unstructured and incomplete. Four low HDI and nine medium HDI countries included costed plans, generally using an activity-based approach. All plans included impact measures (eg, key performance indicators), but five lacked mechanisms for engaging stakeholders or responsible entities to achieve the targets. These findings informed a proposed pathway to integrate IS principles into cancer control planning.<br><br>CONCLUSION: Integrating IS into national cancer control planning offers a structured framework for achieving equitable and feasible cancer control policies, particularly in resource-constrained settings, by enabling realistic goal setting and benchmarking against regional and global standards.}, }
@article {pmid41146877, year = {2025}, author = {Kuhlmann, AS and Madkhali, N and Moskovitz, E and Parrott, JE and Raman, SS and Riker, AO and Martinez-Reyes, J and Gupta, M and Jang, RA and Nelson, V and Gray, MD and Taylor, JJ and Peterson, CW and Kiem, HP}, title = {Heavy-chain immunoglobulin locus editing in rhesus macaque B cells to confer antibody production.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {33}, number = {4}, pages = {101598}, pmid = {41146877}, issn = {2329-0501}, support = {P51 OD011092/OD/NIH HHS/United States ; R01 AI167004/AI/NIAID NIH HHS/United States ; }, abstract = {Antibody-based immunotherapies are promising; however, their application remains limited to acute diseases due to rapid clearance of antibodies in vivo. Some chronic conditions could benefit from sustained therapeutic antibody expression. One such instance is human immunodeficiency virus type 1 (HIV-1), where the efficiency of broadly neutralizing antibodies by passive immunization has been limited in clinical trials. B cell editing to enable sustained production of an antibody of interest in vivo could address this issue. However, the long-term potential of this approach and feasibility to perform editing in B cells from people living with HIV remain to be determined. We investigated editing of rhesus macaque B cells from healthy or simian/human immunodeficiency virus (SHIV)-infected animals to model this approach. An antibody-encoding cassette was inserted in the immunoglobulin locus by CRIPSR-Cas9-mediated ex vivo B cell editing. Similar indel efficiencies were achieved in B cells from both uninfected and infected animals, and expression of the antibody of interest was detected in up to 10% of uninfected B cells. This study paves the way for future in vivo work to assess the long-term potential of this approach and its impact on B cell development and function in an immunocompetent in vivo nonhuman primate model of HIV persistence and cure.}, }
@article {pmid41147516, year = {2025}, author = {Thomas, AB and Matthews, AL and Brooks, O and Winquist, A and Nelson, LA and Arias-Fontenot, R and Buchwald, D and Casaletto, KB and Weintraub, S and Heaton, RK and French, BF and Suchy-Dicey, A and Barbosa-Leiker, C}, title = {Psychometric properties of the NIH Toolbox Cognition Battery composites in older adults at risk for Alzheimer's disease and related dementias: A systematic review.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {21}, number = {10}, pages = {e70673}, pmid = {41147516}, issn = {1552-5279}, support = {P30 AG066509/AG/NIA NIH HHS/United States ; R01 AG071677/AG/NIA NIH HHS/United States ; 1RF1AG071677-01//National Institute of Health/National Institute on Aging/ ; }, mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; *Psychometrics ; United States ; National Institutes of Health (U.S.) ; *Neuropsychological Tests ; *Dementia/diagnosis/psychology ; Aged ; *Cognition ; }, abstract = {This systematic review evaluated the psychometric performance of the National Institutes of Health's Toolbox Cognition Battery (NIHTB-CB) composite scores in older adults with and without Alzheimer's disease and related dementias (ADRD). A systematic literature search was conducted using MEDLINE, Embase, PsycINFO, and CINHAL databases. The evidence quality of NIHTB-CB measurement properties was assessed using integrated Consensus-based Standards for the Selection of Health Measurement Instrument (COSMIN) methodology and the Interpretation/Use Argument framework. Fourteen studies met inclusion criteria for this review of the NIHTB-CB. Evidence supporting the scoring, generalization, and extrapolation inferences of the Total, Crystallized, and Fluid composite scores in older adults ranged from developing through exemplary ratings. Findings indicate additional research is warranted on the NIHTB-CB in older adult and ADRD populations. The present study highlights the importance of continued use and research of the NIHTB-CB in diverse, older populations who are at risk for ADRD. HIGHLIGHTS: Limited research focuses on the National Institutes of Health's Toolbox Cognition Battery (NIHTB-CB) composites in older adults. The general psychometric robustness of the NIHTB-CB has been es. The Crystallized composite shows proficient psychometric evidence. The psychometric evidence of Fluid composite is developing due to limited data.}, }
@article {pmid41149505, year = {2025}, author = {Rios-Doria, E and Reichel, JB and Radke, MR and Manhardt, E and Rubin-Saika, M and Lockwood, C and Swisher, EM and Banda, K}, title = {Dynamic Monitoring of Recurrent Ovarian Cancer Using Serial ctDNA: A Real-World Case Series.}, journal = {Current oncology (Toronto, Ont.)}, volume = {32}, number = {10}, pages = {}, pmid = {41149505}, issn = {1718-7729}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; 0000//Brotman Baty Institute/ ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/genetics/blood/pathology ; *Circulating Tumor DNA/blood/genetics ; *Neoplasm Recurrence, Local/blood/genetics ; Middle Aged ; Aged ; *Biomarkers, Tumor/blood/genetics ; Adult ; CA-125 Antigen/blood ; }, abstract = {Recurrent ovarian cancer (OC) is challenging to detect early using current methods like CA-125 and imaging. Circulating tumor DNA (ctDNA) may improve disease monitoring. Here, we assess the real-world clinical utility of serial ctDNA analyses in patients with recurrent OC. We analyzed serial plasma samples (N = 23) from six patients with recurrent OC using a tumor-informed next-generation sequencing assay targeting 68 cancer-related genes developed at the University of Washington. ctDNA variant allele frequencies (VAFs) were correlated with CA-125 levels, radiographic findings, and clinical outcomes. ctDNA levels generally reflected clinical status, accurately mirroring disease progression and therapeutic response. In one patient, rising ctDNA preceded clinical recurrence by four months, despite normal CA-125 and imaging, highlighting its potential advantage. Conversely, some patients exhibited clinical progression with undetectable ctDNA, indicating limitations in assay sensitivity, biological factors, or metastatic sites (e.g., brain metastases). ctDNA and CA-125 showed complementary value in most cases, suggesting potential combined use in clinical monitoring. Our findings demonstrate that ctDNA is a promising biomarker to complement existing monitoring approaches for recurrent OC. In some cases, capable of predicting relapse and treatment response ahead of current clinical indicators. However, identified discordances underscore technical and biological challenges that warrant further investigation. Larger prospective studies are necessary to refine ctDNA's clinical utility and integration into personalized OC care.}, }
@article {pmid41152111, year = {2026}, author = {Jindal, T and Jiang, CY and Alhalabi, O and Davidsohn, M and Freeman, D and Epstein, IY and Bakaloudi, DR and Talukder, R and Nizam, A and Nguyen, CB and Oh, E and Tsung, I and Glover, MJ and Khaki, AR and Taylor, AK and Jaime-Casas, S and Jang, A and Lemke, E and Pywell, C and Evans, ST and Shin, D and Bilen, MA and Basu, A and Kilari, D and Tripathi, A and Brown, J and Emamekhoo, H and Davis, NB and Shah, S and Gupta, S and Grivas, P and Bellmunt, J and Alva, A and Campbell, MT and Koshkin, VS}, title = {Efficacy of sacituzumab govitecan after enfortumab vedotin in advanced urothelial carcinoma: Analysis of the UNITE study.}, journal = {Urologic oncology}, volume = {44}, number = {1}, pages = {65.e1-65.e11}, doi = {10.1016/j.urolonc.2025.09.025}, pmid = {41152111}, issn = {1873-2496}, mesh = {Humans ; Male ; Female ; Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Retrospective Studies ; Middle Aged ; *Immunoconjugates/therapeutic use ; *Carcinoma, Transitional Cell/drug therapy/pathology/mortality ; *Camptothecin/analogs &amp; derivatives/therapeutic use ; Treatment Outcome ; *Urologic Neoplasms/drug therapy/pathology ; *Urinary Bladder Neoplasms/drug therapy/pathology/mortality ; Aged, 80 and over ; Antibodies, Monoclonal/therapeutic use ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {BACKGROUND: Sacituzumab govitecan (SG) is an antibody-drug conjugate used for advanced urothelial carcinoma (aUC) refractory to platinum-based chemotherapy and immune checkpoint inhibitors (ICI). Real-world data are needed to better define SG outcomes, particularly following treatment with enfortumab vedotin (EV). In this analysis, we aim to evaluate efficacy of SG after EV and assess putative biomarkers associated with outcomes.<br><br>METHODS: In the UNITE retrospective study, we identified patients who received &#x2265;1 SG cycle after therapy with EV. Observed response rate (ORR) was assessed in evaluable patients and correlated with baseline clinical characteristics and biomarkers. ORRs were compared using logistic regression, while progression free survival (PFS) and overall survival (OS) from SG start were estimated via Kaplan-Meier and Cox proportional hazard (PH) model. Biomarkers of response were evaluated in multivariate Cox PH models after accounting for relevant clinical variables.<br><br>RESULTS: Among 107 patients treated with SG after EV, 97 (91%) had NGS data. Median age was 69 years, 73% were male, 33% had &#x2265;4 prior lines of therapy, and 42% received G-CSF. ORR was 18% (95% CI: 10%-26%), median PFS 3.2 months, and median OS 6.0 months. In patients with disease control on EV, ORR was 22% compared to 8% in primary progressors on EV. No significant associations were found between molecular biomarkers and SG outcomes in the multivariate analysis.<br><br>CONCLUSION: SG showed modest activity after EV in heavily pretreated patients with aUC. ORR with SG after EV was lower than reported in phase 2 and phase 3 clinical trials for SG in the postplatinum/ICI setting.}, }
@article {pmid41152450, year = {2025}, author = {Ding, F and Liu, S and Sun, W}, title = {Exploration of the roles of HLAs when predicting infection status by T cell receptors.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {37638}, pmid = {41152450}, issn = {2045-2322}, support = {R01 GM105785/GM/NIGMS NIH HHS/United States ; R56 AI169192/AI/NIAID NIH HHS/United States ; GM105785/GM/NIGMS NIH HHS/United States ; R56AI169192//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Receptors, Antigen, T-Cell/genetics/immunology ; *HLA Antigens/genetics/immunology ; Alleles ; T-Lymphocytes/immunology ; *Virus Diseases/immunology/genetics ; }, abstract = {T cells are critical components of the human immune system. When a cell is infected by a virus, it presents viral peptides on its surface using human leukocyte antigen (HLA) proteins. These peptide-HLA complexes are recognized by T cells through interactions with T cell receptors (TCRs). A human blood sample can contain millions of unique TCRs, which is a sample from the individual's TCR repertoire. TCR repertoire-wide association studies (TReWAS) aim to evaluate the associations between individual TCRs and disease or exposure status. Previous studies have shown that TCRs associated with viral infections can be identified using TReWAS, and these TCRs can be used to predict current or past infection with high accuracy. Many TCRs are strongly associated with specific HLA alleles, suggesting that the incorporation of HLA information could improve the precision of TReWAS analyses and predictions based on TCRs. In this study, we evaluated TCR-based predictions while conditioning on individual HLA alleles or their k-nearest neighbors. We observed improved prediction accuracy for some HLA alleles. Furthermore, these HLA-specific predictions provide insight into the role of specific HLAs in coordinating immune response to immunogenic antigens, demonstrating the benefit of HLA-aware analysis of TCR data.}, }
@article {pmid41155216, year = {2025}, author = {Qin, R and Hua, M and Wang, Y and Zhang, Q and Cao, Y and Dai, Y and Ma, C and Zheng, X and Ge, K and Zhang, H and Li, S and Liu, Y and Cao, L and Wang, L}, title = {Multiomics Investigation of Exhausted T Cells in Glioblastoma Tumor Microenvironment: CCL5 as a Prognostic and Therapeutic Target.}, journal = {International journal of molecular sciences}, volume = {26}, number = {20}, pages = {}, pmid = {41155216}, issn = {1422-0067}, support = {82304250//National Natural Science Foundation of China/ ; 82273734//National Natural Science Foundation of China/ ; 82173629//National Natural Science Foundation of China/ ; }, mesh = {*Glioblastoma/immunology/genetics/drug therapy/pathology/metabolism ; Humans ; *Tumor Microenvironment/immunology/genetics ; *Chemokine CCL5/genetics/metabolism ; Prognosis ; *T-Lymphocytes/immunology/metabolism ; Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic ; *Brain Neoplasms/immunology/genetics/drug therapy/pathology ; Multiomics ; }, abstract = {Glioblastoma multiforme (GBM) is a common malignancy with poor prognosis, and exhausted T (TEX) cells, a subset of T cells characterized by progressive loss of effector functions, play a critical role in its progression. This study aimed to investigate the impact of TEX-related genes on immune function, prognosis, and drug sensitivity in GBM through multiomics analysis. Initially, we identified a novel set of TEX-related genes specific to GBM and screened hub genes (CCL5, IL18, CXCR6, FCER1G, TNFSF13B) using conventional statistical methods combined with machine learning. A prognostic risk model was subsequently constructed based on TCGA data and validated in the CGGA cohort. Single-cell and pharmacogenomic analyses revealed significant differences in tumor microenvironment composition and drug sensitivity between risk groups. Notably, Palbociclib emerged as a potential therapeutic agent targeting the novel discovered biomarker CCL5. RT-qPCR results showed that T cells with low CCL5 expression exhibited reduced expression of immune checkpoint-related genes (PD1, TIM3, LAG3) and increased expression of CD28, suggesting enhanced immune function. In conclusion, our findings highlight five hub genes as prognostic markers that could stratify GBM patients with different immune landscapes and levels of drug sensitivity. Furthermore, experimental results suggest that low CCL5 expression could alleviate T cell exhaustion and represent a promising therapeutic target, offering new strategies for improving GBM prognosis.}, }
@article {pmid41158962, year = {2025}, author = {Cummings, CL and Stephan, SB and Fitzgerald, K and Stephan, MT}, title = {Bedside manufacturing of engineered stem cells using gene therapy foam.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {33}, number = {4}, pages = {101612}, pmid = {41158962}, issn = {2329-0501}, abstract = {Hematopoietic stem cell (HSC) gene therapies hold immense potential for treating a growing list of genetic disorders, but the field has reached an inflection point where novel technologies are needed to overcome significant challenges, including high costs, unequal access, and prolonged disruption of daily life. Here, we describe a bedside cell manufacturing strategy in which HSCs are genetically targeted within gene therapy foam that is mixed with freshly isolated bone marrow aspirate concentrate and then directly injected back into the marrow. We demonstrate that highly efficient genetic reprogramming of CD34+ HSCs can be accomplished within methylcellulose-based foam, using low vector doses that are inefficient with conventional liquid-based approaches. In an ex vivo model of perfused bone marrow, we show that foam retains vector at the injection site and locally boosts gene transfer into embedded CD34+ progenitor cells while minimizing off-target events. We also establish that this foam technology is compatible with freshly harvested human bone marrow aspirate. Once implemented in the clinic, this new method, which can be performed in an outpatient setting of any regional hospital, could improve the effectiveness of stem cell-based gene therapies, while concomitantly lowering costs to make these treatments accessible to all who need them.}, }
@article {pmid41159270, year = {2025}, author = {Farooq, MS and Amini, N and Sun, V and Deutsch, GB and Deneve, JL and Grant, M and Arnold, KB and Secord, AA and Anderson, G and Krouse, RS}, title = {Optimizing Palliative Cancer Surgery Trial Completion: Lessons Learned From Qualitative Content Analysis of S1316 - Comparative Effectiveness Trial for Malignant Bowel Obstruction.}, journal = {The American journal of hospice &amp; palliative care}, volume = {}, number = {}, pages = {10499091251391420}, doi = {10.1177/10499091251391420}, pmid = {41159270}, issn = {1938-2715}, abstract = {BackgroundMalignant bowel obstruction (MBO) is a complex clinical entity and there remains a relative lack of high-quality comparative trials on surgical management, in part due to a heterogeneous patient population and different treatment modalities which contribute to challenges in trial design and completion. SWOG S1316 is the only prospective randomized trial evaluating surgical vs non-surgical management of MBO and involved a trial framework in which patients were recruited for a randomization pathway as well as a patient choice pathway. Importantly, successful completion of S1316 required numerous amendment modifications to the trial during its course. We aimed to highlight aspects of S1316 trial design, execution, and modification that potentially contributed to trial completion.MethodsIterative qualitative content analysis of trial modification amendments through the course of the trial from 2015 to 2020.Results133 unique amendments were made to S1316 from 2015 to 2020. We found four dominant domains for the amendments: Accrual Barriers, Study Design Changes, Data Collection Issues, and Clarifications. Accrual amendments were essential to completing the trial and included increasing participating sites from six to 30 (including international sites) and the inclusion of Spanish-speaking participants (11% of final study population).ConclusionsContent analysis of S1316 trial amendments highlighted that Accrual amendments were important in trial completion. Future investigators may benefit from better anticipating trial modifications as they design their studies. It is likely that rapid initiation of trial amendments can lead to improved accrual and study completion.}, }
@article {pmid41159377, year = {2026}, author = {Smith, KS and Dhanda, SK and Billups, CA and Sioson, E and Lu, C and Peraza, AZ and Gangwani, K and Li, Y and Li, Q and Lin, T and Michalski, JM and Packer, RJ and Olson, JM and Leary, SES and Fouladi, M and Gajjar, A and Zhou, X and Onar-Thomas, A and Northcott, PA and Robinson, GW}, title = {An integrated analysis of three medulloblastoma clinical trials refines risk-stratification approaches for reducing toxicity and improving survival.}, journal = {Neuro-oncology}, volume = {28}, number = {1}, pages = {268-281}, pmid = {41159377}, issn = {1523-5866}, support = {//St. Baldrick's Foundation/ ; P01CA096832//CCSG 5P30CA021765-43 Developmental Funds/ ; //American Lebanese Syrian Associated Charities/ ; R50 CA275857/CA/NCI NIH HHS/United States ; P30CA021765//the National Cancer Institute/ ; 1R01CA270785-01A1//CCSG 5P30CA021765-43 Developmental Funds/ ; }, mesh = {Humans ; *Medulloblastoma/therapy/mortality/genetics/pathology ; *Cerebellar Neoplasms/mortality/therapy/genetics/pathology ; Female ; Male ; Child ; Child, Preschool ; Adolescent ; Survival Rate ; Prognosis ; Craniospinal Irradiation/mortality ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Risk Assessment ; Follow-Up Studies ; Young Adult ; DNA Methylation ; *Chemoradiotherapy/mortality ; Clinical Trials as Topic ; Adult ; Mutation ; }, abstract = {BACKGROUND: The identification of clinical and molecular heterogeneity in medulloblastoma has produced risk-stratified therapy, but establishing the most effective yet least toxic regimens has remained elusive owing to numerous treatment options. To improve risk-stratification, we performed an integrated analysis from three clinical trials.<br><br>METHODS: Medulloblastoma patients from ACNS0331/NCT00085735, ACNS0332/NCT00392327, and SJMB03/NCT00085202 were included if they had methylation profiling. Molecular groups [WNT, SHH, Group 3 (G3), and Group 4 (G4)], subgroups, and copy number variations were procured from methylation profiles and mutations from next-generation sequencing. Data was assembled into an interactive portal to capture patient characteristics. Cross-trial comparisons, univariable, and multivariable analyses were conducted and used to derive a risk-stratification schema.<br><br>RESULTS: Eight hundred ninety-eight patients (WNT&#x2009;=&#x2009;131, SHH&#x2009;=&#x2009;151, G3&#x2009;=&#x2009;220, G4&#x2009;=&#x2009;396) were included. Progression-free-survival (PFS) distributions among analogous cross-trial cohorts were not different, demonstrating no survival advantage of any one therapy over another. The addition of carboplatin to high-dose craniospinal irradiation (HDCSI) containing regimen was selectively superior in PFS in G3/G4 subgroup 3 (P&#x2009;=&#x2009;0.048) and G3/G4 subgroup 2 (P&#x2009;=&#x2009;0.035) to HDCSI regimens without carboplatin. Nine actionable risk-stratified groups were identified consisting of 2 WNT groups (low, high-risk), 3 SHH groups (low-, average-, very-high-risk), and 4 G3/G4 groups (low-, average-, high-, and very-high-risk).<br><br>CONCLUSIONS: Our integrated cross-trial analysis suggests toxicity can be reduced by eliminating disproportionate differences in therapy in favor of a more uniform treatment backbone. Moreover, we propose and model a risk-classification system that identifies the most appropriate cohorts on which to trial significant dose reductions in craniospinal irradiation or select treatment intensifications.}, }
@article {pmid41159380, year = {2026}, author = {Arora, S and Nuechterlein, N and Jensen, M and Glatzer, G and Sievers, P and Varadharajan, S and Korshunov, A and Sahm, F and Mack, SC and Taylor, MD and Gujral, TS and Holland, EC}, title = {Integrated transcriptomic landscape of medulloblastoma and ependymoma reveals novel tumor subtype-specific biology.}, journal = {Neuro-oncology}, volume = {28}, number = {2}, pages = {505-519}, pmid = {41159380}, issn = {1523-5866}, support = {1R35 CA253119-01A1/NH/NIH HHS/United States ; U54 CA243125/NH/NIH HHS/United States ; C11orf95/NH/NIH HHS/United States ; //RELA fusion-driven ependymoma/ ; 1R35 CA253119-01A1//Fred Hutch Cancer Center/ ; }, mesh = {Humans ; *Medulloblastoma/genetics/classification/pathology ; *Ependymoma/genetics/classification/pathology ; *Transcriptome ; *Cerebellar Neoplasms/genetics/classification/pathology ; *Biomarkers, Tumor/genetics ; Child ; Gene Expression Profiling ; DNA Copy Number Variations ; Female ; Male ; Child, Preschool ; Prognosis ; Gene Expression Regulation, Neoplastic ; Adolescent ; }, abstract = {BACKGROUND: Medulloblastoma and ependymoma are common pediatric central nervous system tumors with significant molecular and clinical heterogeneity. While molecular subgrouping has enabled classification into molecular subtypes, the extent of heterogeneity within these subgroups remains poorly defined.<br><br>METHODS: We collected bulk RNA sequencing data from 888 medulloblastoma and 370 ependymoma tumors to establish a comprehensive reference landscape. After rigorous batch effect correction, normalization, and dimensionality reduction, we generated a unified landscape to explore gene expression, signaling pathways, RNA fusions, and copy number variations.<br><br>RESULTS: Our transcriptional analysis revealed distinct clustering patterns, including two primary ependymoma compartments, EPN-E1 and EPN-E2, each with specific RNA fusions and molecular signatures. In medulloblastoma, we observed precise stratification of Group 3/4 tumors by subtype and in Sonic Hedgehog (SHH) tumors by patient age. We also identified subtype-specific pathways and gene fusions, enriched in each group.<br><br>CONCLUSIONS: This transcriptomic landscape serves as a resource for biomarker discovery, diagnostic refinement, and prediction of tumor biology and outcome. By enabling projection of new patients' bulk RNA-seq data onto the reference map using nearest neighbor analysis, the framework supports accurate subtype classification. The landscape is publicly available via Oncoscape, an interactive platform for global exploration and application.}, }
@article {pmid41160408, year = {2026}, author = {Nyquist, MD and Nelson, PS}, title = {Targeting the Androgen Receptor Pathway in Prostate Cancer: A PROTrACted Struggle.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {32}, number = {1}, pages = {13-15}, pmid = {41160408}, issn = {1557-3265}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; P50CA097186//National Cancer Institute (NCI)/ ; R01CA266452//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Male ; *Receptors, Androgen/metabolism/genetics ; *Signal Transduction/drug effects ; *Prostatic Neoplasms/drug therapy/metabolism/pathology ; *Androgen Receptor Antagonists/therapeutic use/pharmacology ; Molecular Targeted Therapy ; Drug Resistance, Neoplasm/drug effects ; Animals ; }, abstract = {The androgen receptor (AR) is the most important therapeutic target for metastatic prostate cancer. Though clinical responses to AR inhibition are nearly universal, so is progression, usually accompanied by reactivation of AR signaling. A new small-molecule dual AR degrader/inhibitor shows promise in overcoming resistance and improving clinical outcomes. See related article by Nayak et al., p. 224.}, }
@article {pmid41160804, year = {2026}, author = {Rashidi, A and Gao, F}, title = {Antibiotic risk score for acute graft-versus-host disease.}, journal = {Blood advances}, volume = {10}, number = {3}, pages = {555-561}, pmid = {41160804}, issn = {2473-9537}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology/diagnosis/epidemiology ; Middle Aged ; Male ; Female ; Adult ; *Anti-Bacterial Agents/adverse effects/therapeutic use ; Aged ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Risk Factors ; Young Adult ; Acute Disease ; Risk Assessment ; Transplantation, Homologous/adverse effects ; }, abstract = {Certain antibiotic exposures have been associated with increased rates of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplant (alloHCT). Using data from 2023 alloHCTs performed at our center (2010-2021), we recently developed an antibiotic risk score based on antibacterial antibiotic exposure between days -7 and +30 of alloHCT. The objective was to estimate the added risk for aGVHD due to exposures to antibiotics in the early peritransplant period. Here, we validated the score in an independent, more recent cohort. Data from 297 recipients of alloHCT (2022-2023) including 8382 antibiotic use records (9 antibiotic classes) were analyzed. Median (range) age was 61 (19-78) years, and 175 (59%) patients were male. Higher scores predicted a greater added antibiotic-related risk for grade 3 to 4 (severe) aGVHD, with the upper 25% score quantile identifying a distinctly high-risk subset of patients (hazard ratio for the upper 25% risk quantile was 2.37 compared with the lower 75%; 95% confidence interval, 1.21-4.63; P = .01). A similar, though less strong, pattern was observed for grade 2 to 4 aGVHD. A free online antibiotic risk calculator was developed, identifying antibiotic exposures associated with higher added risk for severe aGVHD. In addition to its potential future use to identify patients who were at higher risk for aGVHD due to antibiotic exposures, the antibiotic-based risk score provided here can be included as a single continuous covariate in multivariable analysis of future GVHD prophylaxis trials.}, }
@article {pmid41161981, year = {2025}, author = {Vishnu, P and Aboulafia, DM}, title = {Hemostatic Disorders Following Severe Acute Respiratory Syndrome Coronavirus 2 Infection, COVID-19 Vaccination, and Long-COVID Syndrome: Current Evidence and Controversies in Clinical Practice.}, journal = {Clinics in laboratory medicine}, volume = {45}, number = {4}, pages = {643-655}, doi = {10.1016/j.cll.2025.07.008}, pmid = {41161981}, issn = {1557-9832}, mesh = {Humans ; *COVID-19/complications/prevention &amp; control ; *COVID-19 Vaccines/adverse effects ; *Hemostatic Disorders/etiology ; SARS-CoV-2 ; *Vaccination/adverse effects ; }, abstract = {The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented profound global health challenges. Beyond acute illness, a substantial proportion of individuals experience persistent symptoms including fatigue, brain fog, and post-exertional malaise, collectively known as Long-COVID. Among the complications associated with SARS-CoV-2 infection and vaccination, hemostatic disorders ranging from mild platelet dysfunction to severe thromboembolic events, and rare but serious coagulation-related adverse effects, such as vaccine-induced immune thrombotic thrombocytopenia, have emerged as a significant concern. Herein we provide an overview of current information and controversies surrounding hemostatic complications in SARS-CoV-2 infection and COVID-19 vaccination.}, }
@article {pmid41161982, year = {2025}, author = {Vishnu, P and Aboulafia, DM}, title = {Recent Advances in Extended Half-Life Products, Nonfactor Replacement Therapies, and Gene Therpy for the Treatment of Hemophilia.}, journal = {Clinics in laboratory medicine}, volume = {45}, number = {4}, pages = {657-673}, doi = {10.1016/j.cll.2025.07.010}, pmid = {41161982}, issn = {1557-9832}, mesh = {*Hemophilia A/therapy/genetics ; Humans ; *Genetic Therapy/methods ; Half-Life ; *Blood Coagulation Factors/therapeutic use/pharmacokinetics ; Factor VIII/therapeutic use/pharmacokinetics ; }, abstract = {Hemophilia, a rare X-linked hereditary bleeding disorder, is characterized by deficiency of coagulation factors. Symptoms range from spontaneous joint and muscle bleeds to life-threatening hemorrhage, for which patients require frequent infusion of coagulation factors, profoundly impacting their quality of life. Novel therapeutics and advances in gene therapy now offer patients long-term disease control and improved quality of life. Here, we focus on important developments in the use of extended half-life factor products, non-factor replacement therapies, and gene therapy. We also highlight the mechanism of action, clinical efficacy, and safety of these newer approaches.}, }
@article {pmid41161984, year = {2025}, author = {Zhang, C and Lam, BD and Lucas, F and Foy, BH}, title = {Machine Learning and Artificial Intelligence-Based Clinical Decision Support for Modern Hematology.}, journal = {Clinics in laboratory medicine}, volume = {45}, number = {4}, pages = {691-705}, doi = {10.1016/j.cll.2025.07.011}, pmid = {41161984}, issn = {1557-9832}, mesh = {*Machine Learning ; Humans ; *Hematology/methods ; *Decision Support Systems, Clinical ; *Artificial Intelligence ; *Hematologic Diseases/diagnosis ; }, abstract = {Hematology is one of the most data-rich areas of medicine and has consistently been at the forefront of technological innovation. With the increasing integration of machine learning (ML) into the diagnostic process, it is vital that both patient-facing and laboratory-facing members of the care team understand how these tools may interact with existing workflows and affect their work. We review the current landscape of ML research and clinical applications. We cover a wide variety of subdomains (eg, hematopathology, hemoglobinopathies, and coagulopathy) and explore both the success and limitations of corresponding research and deployments.}, }
@article {pmid41162424, year = {2025}, author = {Fergus, KB and Newberg, J and Greenstein, R and Fejerman, L and Carvajal-Carmona, L and Collisson, E and Dixit, N and Frampton, G and Huang, FW and Neuhausen, SL and Ziv, E}, title = {Association between ancestry and tumor somatic mutations in a large national cohort of women with breast cancer.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {117}, pmid = {41162424}, issn = {2374-4677}, support = {2023YIA-9977333099//American Society of Clinical Oncology/ ; R01CA223978, U54CA283766 and U54CA280811/CA/NCI NIH HHS/United States ; OPR18111//California Initiative to Advance Precision Medicine/ ; OPR18111//California Initiative to Advance Precision Medicine/ ; }, abstract = {Somatic mutations and copy number alterations in breast tumors are important to determine prognosis, predict treatment response, and identify targets for therapy. We utilized somatic sequencing data of breast tumors from Foundation Medicine Inc. to evaluate the association between genetic ancestry and somatic mutations. We used germline variants to infer genetic ancestry with both principal components analysis and ADMIXTURE. Overall, we identified 91 ancestry-specific somatic differences across 58 unique genes, which included potentially targetable genes such as PIK3CA found in higher frequency in European ancestry, and EGFR found in higher frequency in East Asian ancestry. Pan-cancer analysis of East Asian ancestry and EGFR also found higher frequency in prostate, thyroid, and kidney cancers. African ancestry was associated with increased frequency of copy number alterations overall and decreased frequency of multiple genes on the PI3K-AKT pathway. Future research is warranted to elicit the genetic and environmental conditions that underly these findings.}, }
@article {pmid41162557, year = {2025}, author = {Damera, S and Lee, JR and Hong, YR and Nyame, YA and Hammarlund, N}, title = {Negative perceptions of the health system and racial inequities in PSA screening.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {41162557}, issn = {1476-5608}, abstract = {BACKGROUND: Black individuals in the U.S. experience significantly higher prostate cancer mortality and are more likely to be diagnosed at younger ages with aggressive disease. This disparity may be influenced by negative healthcare perceptions and racial discordance between patients and providers, impacting lower rates of prostate-specific antigen (PSA) screening. We hypothesized that these factors would be associated with reduced PSA screening uptake, particularly among Black men.<br><br>OBJECTIVES: This study aimed to examine the association between negative healthcare perceptions and PSA screening, assess whether this relationship differs by race, and evaluate the role of racial discordance in influencing screening behavior.<br><br>METHODS: We analyzed data from the 2018-2022 Medical Expenditure Panel Survey. The sample included 2373 men aged 45-70 who self-identified as non-Hispanic White or Black and had complete data on PSA screening, healthcare perceptions, and demographics. Negative healthcare perceptions were measured using a Health Perceptions Index (HePI), constructed from MEPS items (higher scores reflect more negative perceptions).<br><br>RESULTS: Higher HePI scores were significantly associated with lower PSA screening rates (p&#x2009;<&#x2009;0.01). Interaction models indicated that Black men with higher HePI scores were disproportionately less likely to undergo screening. Racial discordance with providers was independently associated with reduced screening likelihood (~10.2 percentage points; p&#x2009;<&#x2009;0.01). Models including interaction terms (age, race, and discordance) showed that older Black men with high HePI scores and discordant providers were least likely to be screened.<br><br>CONCLUSIONS: PSA screening disparities are shaped by negative healthcare perceptions and racial discordance, particularly among older Black men. Addressing these barriers through culturally tailored education, improved workforce diversity, and strengthened provider-patient relationships may help close screening gaps. These findings highlight the relevance of healthcare system perceptions in understanding screening disparities and may inform future strategies to identify at-risk individuals.}, }
@article {pmid41165693, year = {2025}, author = {Shadman, M and Gopal, AK}, title = {Bispecific antibodies in action: the reality of engagement.}, journal = {Blood}, volume = {146}, number = {18}, pages = {2148-2150}, doi = {10.1182/blood.2025030376}, pmid = {41165693}, issn = {1528-0020}, }
@article {pmid41165705, year = {2025}, author = {MacKay, EJ and Talham, CJ and Szeto, WY and Brown, CR and Augoustides, JG and Desai, ND and Groeneveld, PW and Zhang, B}, title = {Surgical Volume and Outcomes of Intraoperative Transesophageal Echocardiography in Coronary Artery Bypass Graft.}, journal = {JAMA network open}, volume = {8}, number = {10}, pages = {e2540559}, pmid = {41165705}, issn = {2574-3805}, mesh = {Humans ; *Coronary Artery Bypass/mortality/statistics &amp; numerical data/methods ; Male ; Female ; *Echocardiography, Transesophageal/statistics &amp; numerical data/methods ; Retrospective Studies ; Aged ; Middle Aged ; Treatment Outcome ; *Intraoperative Care/methods ; }, abstract = {IMPORTANCE: The routine use of intraoperative transesophageal echocardiography (TEE) during coronary artery bypass graft (CABG) surgery remains controversial. Its benefit across different patient populations is unclear.<br><br>OBJECTIVES: To identify patient subgroups with the greatest or least likelihood to benefit from intraoperative TEE during CABG, stratified by hospital surgical volume.<br><br>This 2-stage, matched retrospective cohort study applied target trial emulation methodologies to the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) to quantify the conditional treatment effect of intraoperative TEE among subpopulations undergoing isolated CABG at low, medium, and high surgical volume hospitals. The study cohort consisted of patients aged 18 years or older who underwent isolated CABG surgery between July 1, 2014, and June 30, 2022. Data analysis was conducted from August 8, 2023, to December 15, 2024.<br><br>EXPOSURE: Receipt of an intraoperative TEE during CABG surgery.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was mortality within 30 days of surgery. Statistical analyses included multivariable logistic regression and multiple TEE vs without TEE matched comparisons stratified by surgical volume and patient subpopulations.<br><br>RESULTS: Of 1&#x202f;266&#x202f;055 patients who underwent isolated CABG, 963&#x202f;976 (76.1%) were male, and the mean (SD) age was 65.7 (10.0) years. Among these patients, 61.8% received TEE and 39.0% did not receive TEE. Intraoperative TEE use (vs without TEE) was associated with a significant survival benefit among patients treated at hospitals with low surgical volume (2.47% vs 2.94%; odds ratio [OR], 0.83 [95% CI, 0.78-0.89], P&#x2009;<&#x2009;.001) and medium surgical volume (2.09% vs 2.34%; OR, 0.89 [95% CI, 0.85-0.93], P&#x2009;<&#x2009;.001) but not high surgical volume (1.72% vs 1.77%; OR, 0.97 [95% CI, 0.91-1.03], P&#x2009;=&#x2009;.48). Among patients who underwent isolated CABG at low and medium surgical volume hospitals, TEE provided the greatest survival benefit to subpopulations with greater than 50% (vs &#x2264;50%) left-main coronary stenosis, 3 or more (vs <3) diseased coronaries, and (3) a preoperative inotropic requirement.<br><br>CONCLUSIONS AND RELEVANCE: In isolated CABG, intraoperative TEE was associated with survival benefit at low- and medium-volume hospitals, particularly in patients with complex coronary disease or hemodynamic instability, but not at high-volume hospitals. These results highlight persistent equipoise and the need for randomized evaluation.}, }
@article {pmid41168411, year = {2025}, author = {Jiang, SJ and Thomas, M and Rosenthal, EA and Phipps, AI and Sakoda, LC and van Duijnhoven, FJB and Pellatt, AJ and Avery, CL and Berndt, SI and Bishop, DT and Castellví-Bel, S and Chan, AT and Grant, RC and Gignoux, C and Gsur, A and Gunter, MJ and Haiman, CA and Hoffmeister, M and Jarvik, GP and Jenkins, MA and Keku, TO and Küry, S and Lee, JK and Marchand, LL and Moreno, V and Newcomb, PA and Newton, CC and Ogino, S and Palmer, JR and Pearlman, R and Qu, C and Schoen, RE and Um, CY and Van Guelpen, B and Visvanathan, K and Vymetalkova, V and White, E and Woods, MO and Platz, EA and Brenner, H and Corley, DA and Vogelaar, IL and Hsu, L and Peters, U}, title = {Multiple polygenic score approach in colorectal cancer risk prediction.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {38006}, pmid = {41168411}, issn = {2045-2322}, support = {001/WHO_/World Health Organization/International ; U01 CA164973, R01 CA126895, R01 CA060987, R01 CA072520, U24 CA074806/CA/NCI NIH HHS/United States ; U01HG008657/HG/NHGRI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; *Multifactorial Inheritance/genetics ; *Genetic Predisposition to Disease ; Female ; Male ; Machine Learning ; Aged ; Middle Aged ; Risk Factors ; Risk Assessment ; Genome-Wide Association Study ; ROC Curve ; Polymorphism, Single Nucleotide ; Case-Control Studies ; }, abstract = {Recent studies have demonstrated that for various diseases, incorporating polygenic risk scores (PRSs) for other traits and diseases into the PRS-based risk prediction model may improve predictive performance - known as Multiple Polygenic Score (MPS) approach. We aimed to examine whether the MPS approach improves colorectal cancer (CRC) risk prediction. We included 2,187 non-CRC PRSs from the polygenic Score (PGS) Catalog and used machine learning (ML) models to select the most predictive non-CRC PRSs, utilizing individual-level data from 31,257 CRC cases and 33,408 controls. An independent dataset from the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (4,852 cases and 67,939 controls) was randomly split into subsets for model estimation and validation. The model combined MPS with two existing CRC-PRSs based on known loci and genome-wide genotyping. We then assessed model performance by calculating the area under the receiver operating curve (AUC) in the validation set and performed 1,000 bootstrapped iterations to evaluate AUC improvements. The ML model selected 337 non-CRC PRSs predictive of CRC risk. Adding MPS to the CRC-PRSs significantly improved AUC by 0.017 (95% CI: 0.011-0.022, p < 0.0001) when combined with known-loci CRC-PRS, 0.005 (95% CI: 0.002-0.007, p = 0.0005) with genome-wide CRC-PRS, and 0.004 (95% CI: 0.002-0.006, p = 0.0005) with both the known loci and genome-wide CRC-PRSs. These findings demonstrate MPS's potential to refine CRC risk prediction models and highlight opportunities for further advancements in risk prediction.}, }
@article {pmid41168431, year = {2025}, author = {Jabbar, KS and Priya, S and Xu, J and Das Adhikari, U and Pishchany, G and Mohamed, ATM and Johansen, J and Thurimella, K and McCabe, C and Vlamakis, H and Okello, S and Delorey, TM and Lankowski, A and Mosepele, M and Siedner, MJ and Plichta, DR and Kwon, DS and Xavier, RJ}, title = {Human immunodeficiency virus and antiretroviral therapies exert distinct influences across diverse gut microbiomes.}, journal = {Nature microbiology}, volume = {10}, number = {11}, pages = {2720-2735}, pmid = {41168431}, issn = {2058-5276}, support = {R01 DK101354/DK/NIDDK NIH HHS/United States ; DK120485//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 HL141053/HL/NHLBI NIH HHS/United States ; R01 HL138646/HL/NHLBI NIH HHS/United States ; R01 DK120485/DK/NIDDK NIH HHS/United States ; K24 HL166024/HL/NHLBI NIH HHS/United States ; R21 HL124712/HL/NHLBI NIH HHS/United States ; P30 DK043351/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome/drug effects ; *HIV Infections/drug therapy/microbiology ; Uganda ; Alkynes ; Metagenomics ; Benzoxazines/therapeutic use/adverse effects ; Male ; Female ; Feces/microbiology ; Cyclopropanes ; Adult ; Botswana ; *Anti-Retroviral Agents/therapeutic use ; Middle Aged ; United States ; Reverse Transcriptase Inhibitors/therapeutic use ; *Anti-HIV Agents/therapeutic use ; Bacteria/classification/genetics/drug effects/isolation &amp; purification ; }, abstract = {Human immunodeficiency virus (HIV) infection alters gut microbiota composition and function, but the impact of geography and antiretroviral therapy remains unclear. Here we determined gut microbiome alterations linked to HIV infection and antiretroviral treatment in 327 individuals with HIV and 260 control participants in cohorts from Uganda, Botswana and the USA via faecal metagenomics. We found that while HIV-associated taxonomic differences were mostly site specific, changes in microbial functional pathways were broadly consistent across the cohorts and exacerbated in individuals with acquired immunodeficiency syndrome. Microbiome perturbations associated with antiretroviral medications were also geography dependent. In Botswana and Uganda, use of the non-nucleoside reverse transcriptase inhibitor efavirenz was linked to depletion of Prevotella, disruption of interspecies metabolic networks, exacerbation of systemic inflammation and atherosclerosis. Efavirenz-associated Prevotella depletion may occur through cross-inhibition of prokaryotic reverse transcriptases involved in antiphage defences, as shown by computational and in vitro experiments. These observations could inform future geography-specific and microbiome-guided therapy.}, }
@article {pmid41169120, year = {2025}, author = {Marzinke, MA and Hanscom, B and Haines, D and Scarsi, KK and Agyei, Y and Piwowar-Manning, E and Hendrix, CW and Gollings, R and Rose, S and Mathew, C and Panchia, R and Spooner, E and Singh, N and Bock, P and Rinehart, AR and Ford, SL and Rooney, JF and Soto-Torres, L and Cohen, MS and Hosseinipour, MC and Delany-Moretlwe, S and , }, title = {Evaluation of pharmacokinetic interactions between long-acting cabotegravir or emtricitabine/tenofovir disoproxil fumarate and hormonal contraceptive agents: a tertiary analysis of South African participants in HPTN 084.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {11}, pages = {e70056}, pmid = {41169120}, issn = {1758-2652}, support = {P30 AI094189/AI/NIAID NIH HHS/United States ; UM1AI068617/NH/NIH HHS/United States ; OPP1154174//Bill and Melinda Gates Foundation/ ; UM1AI068619/NH/NIH HHS/United States ; UM1AI068613/NH/NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Young Adult ; *Anti-HIV Agents/pharmacokinetics ; *Contraceptive Agents, Hormonal/pharmacokinetics/administration &amp; dosage ; Desogestrel/pharmacokinetics/blood ; Drug Interactions ; *Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/pharmacokinetics/administration &amp; dosage ; *HIV Infections/prevention &amp; control ; Medroxyprogesterone Acetate/pharmacokinetics/blood ; Norethindrone/analogs &amp; derivatives/pharmacokinetics/blood ; Pre-Exposure Prophylaxis ; *Pyridones/pharmacokinetics/administration &amp; dosage ; South Africa ; Diketopiperazines ; }, abstract = {INTRODUCTION: HPTN 084 found that long-acting cabotegravir (CAB-LA) was well-tolerated and significantly reduced the risk of HIV acquisition in women compared to tenofovir disoproxil fumarate/emtricitabine (F/TDF). During the blinded phase of the trial, participants were required to use an effective method of contraception, including an injectable or implantable hormonal contraceptive (HC) agent. A contraceptive sub-study assessed the pharmacokinetic interactions between pre-exposure prophylaxis agents (CAB-LA or F/TDF) and etonogestrel (ENG), medroxyprogesterone acetate (MPA) or norethindrone enanthate (NET-EN).<br><br>METHODS: Participants were enrolled in a nested sub-study between 24 February 2020 and 26 October 2020. Via a convenience sampling strategy, plasma concentrations of ENG, MPA and NET-EN were evaluated at enrolment and weeks 25, 49 and 73; plasma tenofovir (TFV) and CAB concentrations were determined at contemporaneous visits. Participants were allowed to switch contraceptives, and HC assessments were adjusted accordingly. Geometric mean concentrations were calculated and compared using t-tests or Fisher's exact tests.<br><br>RESULTS: One hundred and seventy participants were included in this analysis. Hormone concentrations at all study visits were comparable between the CAB-LA and F/TDF study arms. Among participants randomized to the CAB-LA arm, geometric mean concentrations declined from enrolment to the follow-up period for ENG (335 to 202 pg/ml), MPA (1520 to 1138 pg/ml) and NET-EN (3715 to 1888 pg/ml); similar findings were observed among participants randomized to the F/TDF arm. Observed HC declines are likely attributed to the timing of contraceptive administration relative to sampling; the percentage of participants with hormone concentrations above thresholds associated with ovulation suppression was high (73-100%) and did not differ between arms. CAB concentrations were comparable across contraceptive types, with 97.8-98.1% of participants yielding trough CAB concentrations above the protocol-specified target threshold. TFV concentrations were unquantifiable for most participants, irrespective of contraceptive agent, rendering comparisons largely uninformative.<br><br>CONCLUSIONS: Given the comparable hormone concentrations between arms and the likely influence of the timing of sample collection on observed measurements, clinically significant interactions between CAB-LA and HC are not expected. Associations between F/TDF and hormone concentrations could not be effectively evaluated due to low adherence to F/TDF.<br><br>CLINICAL TRIAL REGISTRATION: NCT0316456.}, }
@article {pmid41171480, year = {2025}, author = {Mahdi, J and Gust, JA and Vitanza, NA and Scott, B and Monje, M and Ronsley, R}, title = {Neurotoxicity in central nervous system tumors treated with CAR T cell therapy: a review.}, journal = {Journal of neuro-oncology}, volume = {176}, number = {1}, pages = {60}, pmid = {41171480}, issn = {1573-7373}, }
@article {pmid41172559, year = {2025}, author = {Ebadi, M and Fan, X and Schoch, G and Gooley, T and Rashidi, A and Smith, SD and Shadman, M and Holmberg, L and Ujjani, C and Poh, C and Raghunathan, V and Ali, N and Vo, PT and Manjappa, S and Menon, M and Di, M and Lynch, R and Ho, C and Till, BG and Ermoian, R and Gopal, AK and Tseng, YD}, title = {Total Body Irradiation Versus Chemotherapy-Only Conditioning in Autologous Haematopoietic Stem Cell Transplantation for Relapsed/Refractory Large B-cell Lymphoma.}, journal = {Clinical oncology (Royal College of Radiologists (Great Britain))}, volume = {48}, number = {}, pages = {103959}, doi = {10.1016/j.clon.2025.103959}, pmid = {41172559}, issn = {1433-2981}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Transplantation Conditioning/methods ; *Lymphoma, Large B-Cell, Diffuse/therapy/pathology/mortality ; *Hematopoietic Stem Cell Transplantation/methods ; Retrospective Studies ; *Whole-Body Irradiation/methods ; Transplantation, Autologous ; Aged ; Adult ; *Neoplasm Recurrence, Local/therapy ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {AIMS: In the era of chimeric antigen receptor T-cell (CAR-T) therapy, there remains a role for autologous stem cell transplant (ASCT) for patients with large B-cell lymphoma (LBCL) without access to CAR T-cell therapy or who have late, chemosensitive relapse (>12 months). Typically, the ASCT conditioning regimen is chemotherapy only. Given the radioresponsiveness of LBCL, we retrospectively evaluated whether ASCT outcomes are improved with total body irradiation (TBI)-based conditioning compared to chemo-only conditioning.<br><br>MATERIALS AND METHODS: We included patients with relapsed/refractory (r/r) LBCL who underwent ASCT at our centre (2012-2021). As TBI is generally offered only to younger patients, we excluded patients in the chemo-only group who were older than the oldest patient in the TBI group, leaving 56 patients in the final dataset (TBI: 19; chemo: 37).<br><br>RESULTS: The TBI cohort had more adverse features including male sex (89.5% vs 62.2%), relapse &#x2264;12 months (52.6% vs 32.4%), and shorter time between diagnosis and ASCT (median: 11.7 vs 21.8 months). Two-year progression-free survival (PFS) was 58% (95% confidence interval [CI]: 39%-85%) and 67% (53%-84%) in TBI and chemotherapy cohorts, respectively. Two-year overall survival (OS) was 79% (63%-100%) and 80% (68%-95%) in TBI and chemotherapy cohorts, respectively. Multivariable hazard ratio (HR) of PFS failure (TBI vs chemo) was 1.35 (95% CI: 0.59-3.12). The HR of death was 1.33 (95% CI: 0.49-3.58). While conditioning regimen was not associated with PFS, positron emission tomography (PET) positivity at time of ASCT (HR: 6.97, 95% CI: 2.98-16.27, P < 0.001) was associated with PFS failure.<br><br>CONCLUSION: Despite the presence of more adverse features among patients treated with TBI, there was no difference in PFS or OS among patients that underwent chemo-only vs TBI-based conditioning. Though hypothesis generating, this suggests that TBI may be able to partially compensate for adverse fatures.}, }
@article {pmid41173578, year = {2025}, author = {Fairlie, L and Szydlo, DW and Mayo, A and Bunge, K and Mhlanga, F and Piper, J and Dadabhai, S and Gatsi, VM and Horne, E and Ssemambo, PK and Mandiwa, V and Mgodi, NM and Owor, M and Anderson, PL and Marzinke, MA and Nakabiito, C and Scheckter, R and Chappell, C and Hillier, SL and , }, title = {Safety outcomes among infants whose mothers used the dapivirine vaginal ring or oral PrEP during pregnancy (MTN-042/DELIVER): a randomised phase 3b study.}, journal = {The lancet. HIV}, volume = {12}, number = {11}, pages = {e763-e773}, doi = {10.1016/S2352-3018(25)00261-9}, pmid = {41173578}, issn = {2352-3018}, support = {UM1 AI069518/AI/NIAID NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Infant ; Infant, Newborn ; Male ; Pregnancy ; Young Adult ; Administration, Oral ; *Anti-HIV Agents/administration &amp; dosage/adverse effects ; *Contraceptive Devices, Female ; Emtricitabine/administration &amp; dosage ; *HIV Infections/prevention &amp; control ; *Infectious Disease Transmission, Vertical/prevention &amp; control ; *Pre-Exposure Prophylaxis/methods ; *Pregnancy Complications, Infectious/prevention &amp; control/drug therapy ; *Pyrimidines/administration &amp; dosage/adverse effects ; South Africa ; Tenofovir/administration &amp; dosage ; Uganda ; }, abstract = {BACKGROUND: HIV acquisition risk during pregnancy remains high and additional data supporting pre-exposure prophylaxis (PrEP) in pregnancy are needed. The aim of the MTN-042/DELIVER study was to evaluate the dapivirine vaginal ring (DVR) and daily oral tenofovir disoproxil fumarate plus emtricitabine use as PrEP during pregnancy. We report infant outcomes following confirmed in-utero exposure.<br><br>METHODS: This randomised, controlled, open-label, phase 3b study was conducted in four clinical research sites in Malawi, South Africa, Uganda, and Zimbabwe. Pregnant, HIV-negative, healthy women aged 18-40 years were enrolled at 36-37 weeks' (cohort 1), 30-35 weeks' (cohort 2), and 12-29 weeks' (cohort 3) gestation and randomly assigned 2:1 (cohorts 1 and 2) and 4:1 (cohort 3) to receive the DVR (dapivirine 25 mg) or oral PrEP (tenofovir disoproxil fumarate 300 mg plus emtricitabine 200 mg). All infants born to maternal participants were enrolled and included in the primary infant analysis to evaluate infant safety with in-utero exposure to study product. Infant visits were conducted at less than 2 weeks, 6 weeks, 6 months, and 12 months of age. The primary infant composite safety outcome included serious adverse events and grade 3 or higher adverse events. Birth outcomes (livebirth or stillbirth, prematurity), adverse events (including frequency between each study visit), and growth up to 12 months were evaluated and collected. This study is registered with ClinicalTrials.gov (NCT03965923). The trial is completed and the database closed.<br><br>FINDINGS: The study was conducted between Feb 7, 2020, and May 13, 2024. In total, 545 infants were included: 147 in cohort 1, 154 in cohort 2, and 244 in cohort 3. Mean intrauterine exposure was 23&#xb7;3, 59&#xb7;7, and 113&#xb7;8 days, respectively. Overall, 545 (99%) of 550 pregnancy outcomes were livebirths. Serious adverse events occurred in 66 (17%) of 398 infants in the DVR group and 15 (10%) of 147 in the oral PrEP group. Grade 3 or higher adverse events occurred in 95 (24%) of 398 and 29 (20%) of 147 infants, respectively, none related to product exposure. 41 (51%) of 81 new-onset serious adverse events occurred by age 6 weeks, and ten (91%) of 11 congenital anomalies were diagnosed by age 6 months. There were no maternal or infant HIV acquisitions.<br><br>INTERPRETATION: Over 12 months of follow-up of infants, the DVR and oral PrEP were generally safe, with no composite adverse events related to study product. Together with available maternal safety data, this supports use of the DVR and oral PrEP by pregnant women to prevent HIV.<br><br>FUNDING: US National Institutes of Health.}, }
@article {pmid41175446, year = {2025}, author = {Levine, KM and Uy, NF and Gooley, TA and Voutsinas, J and Tratt, M and Eaton, KD and Santana-Davila, R and Berger, AH and Baik, CS}, title = {Osimertinib retreatment for patients with advanced EGFR-mutated non-small cell lung cancer.}, journal = {Cancer treatment and research communications}, volume = {45}, number = {}, pages = {101026}, pmid = {41175446}, issn = {2468-2942}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Aniline Compounds/therapeutic use/pharmacology ; *Acrylamides/therapeutic use/pharmacology ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology/mortality ; Male ; *Lung Neoplasms/drug therapy/genetics/pathology/mortality ; Female ; Middle Aged ; Aged ; ErbB Receptors/genetics ; Retrospective Studies ; Mutation ; Retreatment ; *Protein Kinase Inhibitors/therapeutic use ; Adult ; Aged, 80 and over ; Indoles ; Pyrimidines ; }, abstract = {Resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a key challenge in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). Although retreatment with earlier-generation EGFR tyrosine kinase inhibitors has been studied, data on osimertinib rechallenge are limited. We conducted a single institution retrospective analysis of patients with EGFR-mutated NSCLC who were rechallenged with osimertinib following progression on prior osimertinib and interim systemic therapy, including chemotherapy. Seventeen patients met inclusion criteria, all with adenocarcinoma histology and either EGFR exon 19 deletions or L858R mutations. Median interval between osimertinib treatments was 10.5 months. Osimertinib retreatment resulted in a partial response in 18 % (3/17) and stable disease in 35 % of patients (6/17), for a disease control rate of 53 % (9/17). Median retreatment duration was 4.3 months, and median overall survival following retreatment initiation was 8.9 months. Among patients with central nervous system involvement, several experienced intracranial stability without additional radiation. Duration of initial osimertinib therapy did not strongly predict retreatment benefit. These findings suggest that osimertinib rechallenge may provide clinically meaningful disease control in a subset of patients, especially given its tolerability and oral formulation. Further research is needed to identify biomarkers of sensitivity and to optimize patient selection for osimertinib retreatment following interval chemotherapy.}, }
@article {pmid41176371, year = {2025}, author = {Carpenter, PA and Warkentin, PI}, title = {Improving Outcomes in Hematopoietic Cell Transplantation and Cellular Therapy: Evolution of ASTCT Practice Guidelines and FACT Inspections.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {11}, pages = {843-848}, doi = {10.1016/j.jtct.2025.10.008}, pmid = {41176371}, issn = {2666-6367}, }
@article {pmid41176373, year = {2025}, author = {Biernacki, MA}, title = {Capturing the Big Picture of HY Antigens and Transplantation Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {11}, pages = {851-853}, doi = {10.1016/j.jtct.2025.10.009}, pmid = {41176373}, issn = {2666-6367}, }
@article {pmid41176520, year = {2025}, author = {Yu, EY and Suzuki, H and Pieczonka, CM and Gotto, G and Briganti, A and Luz, M and Murphy, D and Malone, R and Hamilton, J and Chan, JE and Sieber, P and Given, RW and Hellmis, E and Kretz, T and Spiegelhalder, P and Gómez-Caamaño, A and Amela, YM and Artignan, X and Uemura, H and Fujita, N and Adorjan, P and Ghadessi, M and Verholen, F and Armstrong, AJ}, title = {DARolutamide ObservationaL (DAROL) study in patients with nonmetastatic castration-resistant prostate cancer: prespecified third interim analysis.}, journal = {Prostate cancer and prostatic diseases}, volume = {}, number = {}, pages = {}, pmid = {41176520}, issn = {1476-5608}, abstract = {BACKGROUND: DAROL is an ongoing study of real-world safety and effectiveness of darolutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).<br><br>SUBJECTS/METHODS: This prespecified interim analysis included 550 patients with nmCRPC who completed &#x2265;6 months of treatment with darolutamide 600&#x2009;mg twice daily.<br><br>RESULTS: Darolutamide showed consistent safety and effectiveness in DAROL vs ARAMIS. Most treatment-emergent adverse events were grade 1/2. Two-year overall survival and metastasis-free survival rates and prostate-specific antigen responses were similar to ARAMIS.<br><br>CONCLUSIONS: These findings indicate that darolutamide offers effectiveness and a favorable safety profile in the broad range of patients seen in clinical practice.}, }
@article {pmid41177463, year = {2025}, author = {Jons, CK and Kasse, CM and Mayer, BT and Hyrien, O and Sen, S and Meany, EL and d'Aquino, AI and Ganesh, P and Eckman, N and Dong, C and Yan, J and Nguyen, LT and Doulames, VM and Song, YE and Saouaf, OM and Williams, CM and Williams, SC and Paredes, J and Raghavan, R and Palomares, M and Alpert, M and Yates, NL and Tomaras, GD and Seaman, MS and Farzan, M and Appel, EA}, title = {Hydrogel formulations for sustained-release of broadly neutralizing antibodies.}, journal = {Journal of controlled release : official journal of the Controlled Release Society}, volume = {388}, number = {Pt 2}, pages = {114349}, pmid = {41177463}, issn = {1873-4995}, support = {INV-036842/GATES/Gates Foundation/United States ; R01 AI154989/AI/NIAID NIH HHS/United States ; INV-010680/GATES/Gates Foundation/United States ; INV-032929/GATES/Gates Foundation/United States ; T32 GM008412/GM/NIGMS NIH HHS/United States ; K01 EB033870/EB/NIBIB NIH HHS/United States ; INV-027411/GATES/Gates Foundation/United States ; S10 OD026831/OD/NIH HHS/United States ; }, mesh = {Animals ; Delayed-Action Preparations/pharmacokinetics/administration &amp; dosage/chemistry ; *Hydrogels/chemistry/administration &amp; dosage ; *Antibodies, Neutralizing/administration &amp; dosage ; Mice ; Humans ; *Broadly Neutralizing Antibodies/administration &amp; dosage ; Female ; Rats ; Nanoparticles/chemistry/administration &amp; dosage ; Male ; Drug Liberation ; Rats, Sprague-Dawley ; }, abstract = {Sustained serum levels of broadly neutralizing antibodies (bnAbs) are crucial for effective passive immunization against infectious diseases as protection persists only while these bnAbs remain at adequate concentrations within the body. Current obstacles, such as poor pharmacokinetics (PK) and burdensome administration, must be overcome to make bnAbs a viable option for pre- and post-exposure prophylaxis. In this work, we explore how a polymer-nanoparticle (PNP) hydrogel depot technology can be engineered to prolong protein delivery and enable drug exposure on the order of weeks to months. In-vivo studies in mice and rats demonstrate extended protein release compared to bolus administration, and modeling efforts predict the impact of both the elimination half-life of the active pharmaceutical ingredient and hydrogel depot volume on overall pharmacokinetics. Moreover, flow cytometry characterization reveals that immune cell infiltration into the hydrogel depot can result in faster-than-expected release of antibody cargo on account of active transport via cellular uptake. We then demonstrate that co-formulation of antibodies with an anti-inflammatory agent reduces cellular infiltration and resulting active transport, further extending delivery and pharmacokinetics. Finally, multicompartmental modeling predicts the human PK profiles of clinically relevant HIV bnAbs delivered via subcutaneous hydrogel injection. These findings aid in the development of next generation hydrogel materials that stabilize and slowly release bnAbs for long-term pre-exposure immunoprophylaxis.}, }
@article {pmid41178332, year = {2025}, author = {Newell, EW}, title = {Seeing First: Introducing the Resource Report at Cancer Immunology Research.}, journal = {Cancer immunology research}, volume = {13}, number = {11}, pages = {1696-1697}, doi = {10.1158/2326-6066.CIR-25-1175}, pmid = {41178332}, issn = {2326-6074}, support = {R01 CA264646/CA/NCI NIH HHS/United States ; }, }
@article {pmid41178673, year = {2026}, author = {Gong, IY and Rafinejad-Farahani, B and Majeed, H and Soto, MJ and Oza, A and Ehrlich, T and Fernandez Lynch, H and Guerra, CE and Lofters, A and Unger, JM and Conti, RM and Rosenthal, M and Rodin, D}, title = {Reporting and enrollment disparities in hematologic malignancy trials between 2000-2023.}, journal = {Leukemia &amp; lymphoma}, volume = {67}, number = {1}, pages = {176-189}, doi = {10.1080/10428194.2025.2579735}, pmid = {41178673}, issn = {1029-2403}, mesh = {Humans ; *Hematologic Neoplasms/therapy/epidemiology ; *Healthcare Disparities/statistics &amp; numerical data ; *Patient Selection ; *Clinical Trials as Topic/statistics &amp; numerical data ; United States/epidemiology ; SEER Program ; Ethnicity/statistics &amp; numerical data ; Male ; Female ; }, abstract = {Despite initiatives to enhance diversity in clinical trials (CTs), disparities persist in hematologic malignancy (HM) studies. We reviewed 1,230 US-based phase II-III HM CTs (2000-2023) including 149,434 participants and compared enrollment to SEER benchmarks. Race was reported in 59% of trials and ethnicity in 40%, with significant improvement over time. Trials initiated in 2016 or later were more likely to report race (OR 36.3) and ethnicity (OR 8.0) than those before 2008. Compared with NIH-sponsored studies, institutional (OR 0.34) and industry trials (OR 0.52) had lower odds of reporting demographics. Black and Hispanic individuals were consistently underrepresented, most notably in multiple myeloma (7.0% vs. 20.0% expected) and acute lymphoblastic leukemia (21.5% vs. 36.9% expected). NIH-funded trials enrolled more Black participants than other sponsor types. These findings emphasize the need for enforceable mandates on race and ethnicity reporting, as well as representation targets, to ensure equitable access and generalizability.}, }
@article {pmid41180004, year = {2025}, author = {Sadowska-Klasa, A and Xie, H and Zamora, D and Waghmare, A and Hill, JA and Duke, ER and Green, ML and Oshima, MU and Sandmaier, BM and Jerome, KR and Leisenring, WM and Boeckh, M}, title = {Cytomegalovirus Viral Load Continues to Predict Poor Outcomes in Adults and Children Despite Improved Hematopoietic Cell Transplantation Success.}, journal = {Open forum infectious diseases}, volume = {12}, number = {11}, pages = {ofaf612}, pmid = {41180004}, issn = {2328-8957}, support = {K23 AI163343/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Recent advances of graft-versus-host disease prevention strategies have led to improved overall survival after hematopoietic cell transplantation (HCT). Whether cytomegalovirus (CMV) viral load continues to predict CMV disease, overall mortality, and nonrelapse mortality is poorly defined.<br><br>METHODS: CMV-seropositive patients undergoing allogeneic HCT between 2007 and 2017 with weekly CMV DNA polymerase chain reaction surveillance and preemptive therapy were analyzed. Multivariate Cox proportional hazards models were used to estimate the association between CMV viral load by day 100 at different thresholds with CMV disease and overall and nonrelapse mortality up to 1 year post-HCT.<br><br>RESULTS: Of 1539 patients who received a transplant in the study period, 1349 survived >100 days after HCT and were included in the analyses. By day 100 post-HCT, CMV reactivation at any level was observed in 76%, with the lowest incidence at all levels in young children. Pediatric patients had significantly less CMV disease compared to the adult population. CMV reactivation was associated with a higher risk of CMV disease (adjusted hazard ratio, 6.8 [95% confidence interval, 3.54-13]); it was also associated with overall and nonrelapse mortality among day 100 survivors, although the association was diminished recently. The strongest correlation was still apparent between viral load and mortality in patients with a viral load >3 log10 and lymphocyte count <300 cells/&#x3bc;L.<br><br>CONCLUSIONS: CMV viral load continued to be a strong predictor for CMV disease. With improved transplantation techniques, the association of viral load with overall and nonrelapse mortality is diminished, but the effect was still present in patients with severe immunosuppression.}, }
@article {pmid41180007, year = {2025}, author = {Moore, HP and Fogel, JM and Marzinke, MA and Halvas, EK and Parikh, UM and Mellors, JW and Penrose, KJ and Seisa, M and Petropoulos, C and Price, AL and Moser, A and Wang, Z and McCauley, M and Valencia-Huamaní, J and Rinehart, AR and Rooney, JF and Soto-Torres, L and Grinsztejn, B and Landovitz, RJ and Eshleman, SH}, title = {Sustained HIV Suppression With Co-formulated Tenofovir Disoproxil Fumarate/Lamivudine/Dolutegravir in a Person With Transmitted Dolutegravir Resistance and Pretreatment Resistance to Lamivudine: a Case Report From HPTN 083.}, journal = {Open forum infectious diseases}, volume = {12}, number = {11}, pages = {ofaf645}, pmid = {41180007}, issn = {2328-8957}, support = {P30 AI094189/AI/NIAID NIH HHS/United States ; }, abstract = {Integrase strand transfer inhibitors (INSTIs) are recommended in most first-line HIV treatment regimens. We describe a participant in a clinical trial with transmitted INSTI resistance. The participant had no history of INSTI use and had no evidence of INSTI exposure prior to HIV acquisition. Treatment with tenofovir disoproxil fumarate, lamivudine (3TC), and dolutegravir (DTG) was started 3 weeks after HIV diagnosis. Viral suppression was achieved within a year and was sustained for >3 years on treatment. Retrospective HIV genotyping of a pretreatment sample detected major resistance mutations in 3 drug classes, with predicted high-level resistance to DTG and 3TC. HIV phenotyping confirmed that the transmitted virus had DTG and 3TC resistance but retained susceptibility to DTG at higher drug concentrations. Pharmacologic testing indicated that the DTG concentrations observed in this case were sufficient to overcome the effects of 2 major baseline INSTI resistance mutations (G140S and Q148H).}, }
@article {pmid41180139, year = {2025}, author = {Terry, KL and Shafrir, A and Laliberte, A and Vitonis, AF and Garbutt, K and DePari, M and Becker, C and Sasamoto, N and Zondervan, KT and Missmer, SA}, title = {Circulating inflammatory biomarkers and endometriosis lesion characteristics in the WisE consortium.}, journal = {npj women's health}, volume = {3}, number = {1}, pages = {62}, pmid = {41180139}, issn = {2948-1716}, support = {R01 HD111242/HD/NICHD NIH HHS/United States ; }, abstract = {Endometriosis is a chronic inflammatory condition requiring surgical or imaging visualization for definitive diagnosis. How endometriotic lesion characteristics relate to circulating inflammatory markers remains unclear. We evaluated 11 inflammatory biomarkers, including interleukin (IL)-1β, -6, -8, -10, -16, tumor necrosis factor (TNF)-α, thymus and activation regulated chemokine (TARC), monocyte chemotactic protein (MCP)-1, -4, and Interferon gamma-induced protein (IP)-10, in 566 participants with endometriosis from the Women's Health Study: From Adolescence to Adulthood (A2A), Endometriosis Oxford Care &amp; Research (CaRe) study (ENDOX) and Endometriosis: Natural History, Diagnosis, and Outcome (ENDO) study to evaluate associations with endometriosis characteristics, including macrophenotype (superficial lesions only, versus endometrioma and/or deep lesions), lesion appearance (color, vascularity), and anatomic location. We observed nominally statistically significant variation in circulating inflammatory markers by lesion color, vascularity, and location but no significant associations between circulating inflammatory markers and rASRM stage or macrophenotype, which could be due to a small number of participants with non-superficial lesions.}, }
@article {pmid41183215, year = {2025}, author = {Teets, E and Singhvi, A}, title = {Changing minds epigenetically: Germline genes in neurons disrupt animal behavior.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {45}, pages = {e2525456122}, pmid = {41183215}, issn = {1091-6490}, support = {50005899//Washington Research Foundation (WRF)/ ; T32AG066574//HHS | NIH | National Institute on Aging (NIA)/ ; 227823//Esther A. and Joseph Klingenstein Fund (EAJK Fund)/ ; R01 NS114222/NS/NINDS NIH HHS/United States ; BRFSG-2023-10//Brain Research Foundation (BRF)/ ; T32 AG066574/AG/NIA NIH HHS/United States ; NS114222//HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; }, }
@article {pmid41187024, year = {2026}, author = {Pareek, A and Nguyen, E and Rashidi, A}, title = {Successful Treatment of Steroid-refractory Acute Graft-versus-host Disease With Ruxolitinib in a Liver Transplant Recipient.}, journal = {Transplantation}, volume = {110}, number = {1}, pages = {e277-e278}, doi = {10.1097/TP.0000000000005563}, pmid = {41187024}, issn = {1534-6080}, }
@article {pmid41187375, year = {2025}, author = {Bashi, A and Chen, L and Rouse, K and Elkin, EB and Ferris, JS and Xu, X and Bickell, NA and Blank, S and Rossi, EC and Hazelton, WD and Wright, JD and Havrilesky, LJ and Myers, ER}, title = {Cost-effectiveness of biomarker-based and universal strategies for the treatment of advanced-stage endometrial cancer.}, journal = {Gynecologic oncology}, volume = {203}, number = {}, pages = {130-138}, doi = {10.1016/j.ygyno.2025.09.019}, pmid = {41187375}, issn = {1095-6859}, support = {U01 CA265739/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Cost-Benefit Analysis ; *Endometrial Neoplasms/drug therapy/economics/pathology ; Trastuzumab/economics/administration &amp; dosage ; Neoplasm Staging ; *Antineoplastic Combined Chemotherapy Protocols/economics/therapeutic use ; Quality-Adjusted Life Years ; Biomarkers, Tumor/analysis ; Markov Chains ; Immunotherapy/economics/methods ; Antibodies, Monoclonal, Humanized/economics/administration &amp; dosage ; Erb-b2 Receptor Tyrosine Kinases ; Black or African American ; White ; }, abstract = {OBJECTIVE: To compare cost-effectiveness of targeted therapeutic strategies for non-Hispanic Black (NHB) and non-Hispanic White (NHB) patients with newly diagnosed, advanced-stage endometrial cancer.<br><br>METHODS: A Markov-based cost-utility model using a third-party payer perspective compared concurrent and maintenance treatment strategies incorporating dostarlimab and trastuzumab for newly diagnosed stage III-IV endometrial cancer: chemotherapy alone; 3 universal immunotherapy strategies (universal concurrent and maintenance dostarlimab +/- trastuzumab for HER2/neu-positive serous and/or carcinosarcomas); and 3 targeted immunotherapy strategies (dostarlimab for mismatch repair deficient (dMMR) tumors +/- trastuzumab for HER2/neu positive serous and/or carcinosarcomas). Costs (2024 USD), utilities, and clinical estimates were derived from published literature and the National Cancer Database. The base case analysis was a microsimulation with 10,000 runs, accompanied by a Monte Carlo probabilistic sensitivity analysis with 20,000 trials. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $150,000/quality-adjusted life year (QALY). We performed one-way and two-way sensitivity analyses on key parameters and analyses stratified by race/ethnicity.<br><br>RESULTS: All targeted immunotherapy strategies were cost-effective compared to chemotherapy alone in both NHB and NHW, while universal immunotherapy was never cost-effective. Targeted strategies were more cost-effective in NHB than NHW. Targeted dostarlimab for dMMR plus trastuzumab for HER2 serous and carcinosarcomas was the most cost-effective strategy compared to chemotherapy, with an ICER of $119,945/QALY. In sensitivity analysis, assuming longer durations of treatment benefit resulted in lower ICERs.<br><br>CONCLUSIONS: Personalized treatment strategies incorporating HER2 and MMR testing should be considered to optimize both cost-effectiveness and equity in care.}, }
@article {pmid41187759, year = {2026}, author = {Qi, G and Lila, E and Ji, Z and Shojaie, A and Battle, A and Sun, W}, title = {Transcriptome-wide association studies at cell-state level using single-cell eQTL data.}, journal = {Cell genomics}, volume = {6}, number = {1}, pages = {101060}, pmid = {41187759}, issn = {2666-979X}, mesh = {*Quantitative Trait Loci/genetics ; Humans ; *Single-Cell Analysis/methods ; *Transcriptome/genetics ; *Genome-Wide Association Study/methods ; Autoimmune Diseases/genetics ; Gene Expression Profiling/methods ; }, abstract = {Transcriptome-wide association studies (TWASs) are widely used to prioritize genes for diseases. Current methods test gene-disease associations at the bulk tissue or cell-type-specific pseudobulk level, which do not account for the heterogeneity within cell types. We present TWiST, a statistical method for TWAS at cell-state resolution using single-cell expression quantitative trait locus (eQTL) data. Our method uses pseudotime to represent cell states and models the effect of gene expression on the trait as a continuous pseudotemporal curve. Therefore, it allows flexible hypothesis testing of global, dynamic, and nonlinear associations. Through simulation studies and real data analysis, we demonstrated that TWiST leads to significantly improved power compared to pseudobulk methods. Application to the OneK1K study identified hundreds of genes with dynamic effects on autoimmune diseases along the trajectory of immune cell differentiation. TWiST presents great promise to understand disease genetics using single-cell studies.}, }
@article {pmid41190251, year = {2025}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Bricker, JB}, title = {Does living near a tobacco retailer impact the efficacy of smoking cessation treatments?: Analysis from a randomized trial.}, journal = {Addictive behaviors reports}, volume = {22}, number = {}, pages = {100635}, pmid = {41190251}, issn = {2352-8532}, abstract = {INTRODUCTION: Whether living near a tobacco retailer impacts the efficacy of smoking cessation treatments remains largely unknown. We used data from a randomized trial comparing two smoking cessation apps among 2415 adults: iCanQuit, based on Acceptance and Commitment Therapy, and QuitGuide, based on standard U.S. Clinical Practice Guidelines. We examined whether tobacco retailer density impacted the efficacy of the treatments on 12-month cessation outcomes.<br><br>METHODS: Data on tobacco retailer density per 1,000 people (i.e., "one unit") was linked to each participant's residential ZIP Code. Cessation outcomes included 30-day point prevalence abstinence (PPA) from cigarette smoking, prolonged abstinence, 30-day PPA from nicotine/tobacco products, and relapse. We examined the interaction between density and treatment arm on 12-month 30-day PPA and compared cessation outcomes separately by arm.<br><br>RESULTS: The interaction between density and treatment arm on cessation did not reach statistical significance (P&#xa0;=&#xa0;0.09). For each one-unit increase in density, there was no change in quit rates in the iCanQuit arm (P&#xa0;=&#xa0;0.62). In the QuitGuide arm, higher density was associated with lower quit rates (OR&#xa0;=&#xa0;0.54; 95&#xa0;% CI, 0.27-1.06; P&#xa0;=&#xa0;0.07), although not-statistically significant. There was a significant interaction between density and treatment arm on prolonged cigarette abstinence (P&#xa0;=&#xa0;0.03). We found no change in prolonged abstinence in the iCanQuit arm (P&#xa0;=&#xa0;0.44). In the QuitGuide arm, higher density was associated with lower prolonged abstinence (OR&#xa0;=&#xa0;0.27; 95&#xa0;% CI, 0.07-1.02; P&#xa0;=&#xa0;0.054), although not-statistically significant. Conclusions: Living near tobacco retailers may undermine the effectiveness of standard behavioral treatment but appears to have no impact on the effectiveness of acceptance-based smoking cessation treatments.}, }
@article {pmid41191519, year = {2026}, author = {Farhadfar, N and El Jurdi, N and Baker, KK and Ghosh, S and Bat-Erdene, M and Chen, H and Sahu, R and Weiss, R and Mi, J and Desatnik, G and Williams, LR and Tkaczyk, ER and Lee, SJ}, title = {Reproducibility and repeatability of the Myoton to quantify sclerotic chronic graft-versus-host disease.}, journal = {Blood advances}, volume = {10}, number = {4}, pages = {1145-1152}, pmid = {41191519}, issn = {2473-9537}, support = {I01 CX002721/CX/CSRD VA/United States ; IK2 CX001785/CX/CSRD VA/United States ; R01 HL169944/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/diagnosis/etiology/pathology ; Adult ; Male ; Female ; Reproducibility of Results ; Middle Aged ; Chronic Disease ; Sclerosis ; Observer Variation ; Aged ; Skin/pathology ; Hematopoietic Stem Cell Transplantation/adverse effects ; }, abstract = {There is an urgent need for validated tools to measure sclerotic cutaneous chronic graft-versus-host disease (scGVHD). We examined the interobserver reproducibility within a session and intraobserver repeatability between sessions of the Myoton device for quantifying skin sclerosis in 36 adults with scGVHD. The Myoton was used to measure oscillation frequency and relaxation time of soft tissues at 7 bilateral sites (14 anatomic sites) by 2 study personnel at 2 study sessions. Agreement was measured using mean pairwise absolute difference (MPD), and reliability was measured using intraclass correlation coefficient (ICC). For each of the 2 Myoton parameters, the overall interobserver MPD was <5% of the average overall values and the interobserver ICC was >0.90 between the 2 observers, indicating excellent agreement and reliability within a measurement session. The median time between sessions 1 and 2 was 47.5 days. The overall normalized intraobserver MPD was <7% of the average overall values for each of the 2 Myoton parameters, reflecting good agreement between sessions. The intraobserver ICC for frequency and relaxation time parameters were 0.85 and 0.84, respectively, indicating good reliability between sessions. The reproducibility and repeatability of a bonus site selected at each study visit were similar to the standard 14 anatomic sites. However, no individual site was nearly as reproducible or repeatable as the overall Myoton measurements averaged across the patient. Our findings emphasize the utility of the Myoton for assessing skin properties in scGVHD with patient-level measurements.}, }
@article {pmid41192776, year = {2026}, author = {Abrams, HR and Starks, H and Bandini, L and Harrington, T and Percival, MM and Walter, RB and Russell, K and Mawad, R and Appelbaum, J and Sorror, ML and Halpern, AB}, title = {National Landscape of Logistical and Nonmedical Requirements for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {2}, pages = {209.e1-209.e13}, doi = {10.1016/j.jtct.2025.10.031}, pmid = {41192776}, issn = {2666-6367}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Surveys and Questionnaires ; *Cell- and Tissue-Based Therapy/methods ; United States ; Caregivers ; }, abstract = {BACKGROUND: New disease indications and supportive care advances have expanded the populations who may benefit from cellular therapies, including autologous or allogeneic hematopoietic cell transplant (HCT) and/or chimeric antigen receptor T-cell therapy (CAR T). However, nonmedical requirements for these therapies, such as caregiver and housing availability, may limit access. We sought a detailed national assessment of nonmedical requirements for HCT and CAR T-cell therapy to describe and quantify barriers.<br><br>OBJECTIVE: Describe the national landscape and implementation of logistical and nonmedical requirements for HCT and CAR T-cell therapy.<br><br>STUDY DESIGN: We developed a web-based survey of HCT/CAR T-cell therapy requirements and obtained pilot feedback from 3 centers that regularly perform HCT/CAR T-cell therapy. We distributed the survey via the NCCN Best Practices Committee, which is composed of physician, nursing, and administrative leaders from 34 member institutions. We requested survey completion by an institutional content area expert.<br><br>RESULTS: The response rate was 91% (31/34). >80% of centers required a caregiver, local housing, and local transportation, but the number of days required, institutional supports, and acceptable distances varied widely. A subset of centers offered "all-outpatient" procedures and required more stringent logistical criteria, including autologous HCT by 13/19 centers (68%), allogeneic HCT by 4/8 centers (50%), and CAR T-cell therapy by 10/16 centers (63%). Many centers excluded patients with a history of medication nonadherence, substance use, or psychiatric comorbidity, but most did not employ formal adjudication or definition of patient eligibility. Institutions noted "soft" contraindications or case-by-case review for these patients and those experiencing homelessness, lack of insurance, or without citizenship. Overall, caregiving, housing, cost, and insurance coverage emerged as the top nonmedical barriers to HCT and CAR T-cell therapy.<br><br>CONCLUSIONS: Significant variability exists in nonmedical requirements for HCT and CAR T-cell therapy, with a lack of standard policies across institutions. We recommend that centers formally track reasons for noneligibility to identify nonmedical barriers to HCT and CAR T-cell therapy and develop targeted interventions to reduce the number of patients who are excluded for nonmedical reasons.}, }
@article {pmid41193051, year = {2025}, author = {,  and Morgan, RL and Bathala, TK and Arora, SS and Chandhok, N and Corey, AS and Dandapani, SV and Kim, L and Law, L and Mansoori, B and Morin, CE and Trout, AT and Wolfman, DJ and Wong, TZ}, title = {ACR Appropriateness Criteria® Staging and Follow-Up of Leukemia.}, journal = {Journal of the American College of Radiology : JACR}, volume = {22}, number = {11S}, pages = {S658-S688}, doi = {10.1016/j.jacr.2025.08.034}, pmid = {41193051}, issn = {1558-349X}, mesh = {Humans ; Neoplasm Staging ; United States ; *Leukemia/diagnostic imaging/pathology ; Societies, Medical ; Evidence-Based Medicine ; Follow-Up Studies ; }, abstract = {Imaging associated with staging and follow-up of leukemia can play an important role in accurately assessing disease; however, the type of imaging and usefulness varies significantly by the subtype of leukemia. This document reviews the current literature regarding the impact of imaging for both staging and surveillance of several of the most common leukemic variants. These include acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, Richter transformation, and chronic myeloid leukemia. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.}, }
@article {pmid41193657, year = {2025}, author = {Li, H and Melnyk, JE and Fu, BXH and Shrestha, R and Zhang, M and Sjöström, M and Feng, S and Anderson, JA and Han, W and Chesner, LN and Shin, HJ and Farsh, T and Suarez, HJ and Nath, S and Chou, J and Das, R and Egusa, EA and Calvert, M and Kishishita, A and Barpanda, A and Zhu, J and Maheshwari, A and Chen, WS and Alshalalfa, M and Winters, A and Hua, JT and Liu, T and Davicioni, E and Wiita, AP and Stohr, BA and Siddiqui, J and Huang, B and Small, EJ and Shokat, KM and Nelson, PS and Quigley, DA and Wasmuth, EV and Gilbert, LA and Feng, FY}, title = {Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer.}, journal = {Nature genetics}, volume = {57}, number = {12}, pages = {3027-3038}, pmid = {41193657}, issn = {1546-1718}, support = {YI//Prostate Cancer Foundation (PCF)/ ; P50 CA097186/CA/NCI NIH HHS/United States ; R01GM131641//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 2018-00382//Vetenskapsr&#xe5;det (Swedish Research Council)/ ; R01 CA221969/CA/NCI NIH HHS/United States ; 1R01CA244550//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; PC230420//Prostate Cancer Foundation (PCF)/ ; young investigator//Prostate Cancer Foundation (PCF)/ ; R01 GM131641/GM/NIGMS NIH HHS/United States ; 1R01CA227025//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; DP2 CA239597/CA/NCI NIH HHS/United States ; P50 CA186786/CA/NCI NIH HHS/United States ; 1F32CA236347-01//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 GM124334/GM/NIGMS NIH HHS/United States ; 1R01CA230516-01//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01GM124334//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; W81XWH-20-1-0136//U.S. Department of Defense (United States Department of Defense)/ ; P50CA097186 PNW Prostate Cancer SPORE Career Enhancement Program//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P41 GM103481/GM/NIGMS NIH HHS/United States ; P50 CA275741/CA/NCI NIH HHS/United States ; R01 CA227025/CA/NCI NIH HHS/United States ; CA230516-02S1//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R00 CA204602/CA/NCI NIH HHS/United States ; CA204602//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; V2024-016//V Foundation for Cancer Research (V Foundation)/ ; K99 CA204602/CA/NCI NIH HHS/United States ; HT9425-23-1-0462//U.S. Department of Defense (United States Department of Defense)/ ; R01 CA290875/CA/NCI NIH HHS/United States ; 1R01CA221969-01//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA234715/CA/NCI NIH HHS/United States ; S10 OD016229/OD/NIH HHS/United States ; 17CHAL06//Prostate Cancer Foundation (PCF)/ ; R01 CA230516/CA/NCI NIH HHS/United States ; Young Investigator Award//Prostate Cancer Foundation (PCF)/ ; R01 CA244550/CA/NCI NIH HHS/United States ; R00 GM140264/GM/NIGMS NIH HHS/United States ; 21YOUN12//Prostate Cancer Foundation (PCF)/ ; F32 CA236347/CA/NCI NIH HHS/United States ; Prostate Cancer Program 2021 Pilot Research Awards//UC | UC San Francisco | Department of Medicine, University of California, San Francisco (UCSF Department of Medicine)/ ; P50CA186786//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA266452/CA/NCI NIH HHS/United States ; }, mesh = {Male ; *Receptors, Androgen/genetics/metabolism ; Humans ; *Prostatic Neoplasms/genetics/pathology/metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; CRISPR-Cas Systems/genetics ; Homeodomain Proteins/genetics/metabolism ; GATA2 Transcription Factor/genetics/metabolism ; Drug Resistance, Neoplasm/genetics ; }, abstract = {The androgen receptor (AR) is a critical driver of prostate cancer (PCa). Here, to study regulators of AR protein levels and oncogenic activity, we developed a live-cell quantitative endogenous AR fluorescent reporter. Leveraging this AR reporter, we performed genome-scale CRISPRi flow cytometry sorting screens to systematically identify genes that modulate AR protein levels. We identified and validated known AR protein regulators, including HOXB13 and GATA2, and also unexpected top hits including PTGES3-a poorly characterized gene in PCa. PTGES3 repression resulted in loss of AR protein, cell-cycle arrest and cell death in AR-driven PCa models. Clinically, analysis of PCa data demonstrates that PTGES3 expression is associated with AR-directed therapy resistance. Mechanistically, we show PTGES3 binds directly to AR, regulates AR protein stability and is necessary for AR function in the nucleus at AR target genes. PTGES3 represents a potential therapeutic target for overcoming known mechanisms of resistance to existing AR-directed therapies in PCa.}, }
@article {pmid41195517, year = {2025}, author = {Patel, J and Gopal, A and Cherniawsky, H and Ram, R and Kamble, R and Hamadani, M}, title = {CD19 directed CAR T therapy for intravascular large B-cell lymphoma.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.288838}, pmid = {41195517}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid41196629, year = {2025}, author = {Mehta, RS and Sparapani, RA and Kanakry, CG and McCurdy, SR and Saultz, J and Lazaryan, A and Milano, F and Lee, SJ}, title = {Unrelated Donor Age and Recipient Outcomes After Posttransplant Cyclophosphamide vs Conventional Prophylaxis.}, journal = {JAMA oncology}, volume = {12}, number = {1}, pages = {28-37}, pmid = {41196629}, issn = {2374-2445}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {IMPORTANCE: Advanced age in unrelated donors (URDs) is a well-established risk factor in allogeneic hematopoietic cell transplant (HCT), leading registries to prioritize younger donors. However, this paradigm relevance is uncertain in the era of posttransplant cyclophosphamide (PTCy) for graft-vs-host disease (GVHD) prophylaxis, a strategy increasingly adopted for its effectiveness. Clarifying this association is crucial for optimizing donor selection and potentially expanding the donor pool.<br><br>OBJECTIVE: To determine whether the association of older URD age with overall survival differs between patients receiving PTCy-based vs conventional calcineurin inhibitor (CNI)-based GVHD prophylaxis.<br><br>This was a multicenter cohort study using registry data from the Center for International Blood and Marrow Transplant Research for January 2017 through June 2021. Eligible participants were adult patients with acute leukemia or myelodysplastic syndrome who underwent an allogeneic HCT from a URD who was fully matched for 8 of 8 human leukocyte antigen loci (MUD) or mismatched for 7 of 8 human leukocyte antigen loci (MMUD). Data were analyzed from January to June 2025.<br><br>EXPOSURES: GVHD prophylaxis regimen (PTCy-based vs CNI-based) and donor age (analyzed continuously and categorically).<br><br>MAIN OUTCOMES AND MEASURES: Overall survival was the primary outcome, with associations assessed using a multipronged approach including least absolute shrinkage and selection operator (LASSO)-penalized Cox proportional hazards models, inverse probability of treatment weighting (IPTW), and XGBoost machine learning.<br><br>RESULTS: The study analysis included 10&#x202f;025 patients (mean [SD] age, 56.5 [14.4] years; 4379 female [43.7%] and 5646 male [56.3%] individuals) among whom 7272 (72.5%) had received MUD-CNI; 1681 (16.8%%) MUD-PTCy; 613 (6.1%) MMUD-PTCy; and 459 (4.6%) MMUD-CNI. Increasing donor age was associated with worse OS in CNI-based MUD (hazard ratio [HR], 1.004-1.009 per year increase) and MMUD (HR, 1.022-1.034) cohorts. Conversely, this association was not observed in the combined PTCy cohort (HR, 1.001-1.007). These findings were robust across standard and overlap weighted IPTW, LASSO-penalized models, and XGBoost analyses. The attenuated association in the PTCy cohort was primarily driven by a lack of association between donor age and nonrelapse mortality.<br><br>CONCLUSIONS AND RELEVANCE: The findings of this cohort study indicate that the association of donor age with URD HCT outcomes appears to be mitigated in the PTCy setting, suggesting that PTCy may counteract some of the adverse effects associated with increased unrelated donor age. This observation challenges existing paradigms and warrants validation in independent cohorts, and if validated, could substantially expand the donor pool.}, }
@article {pmid41198236, year = {2026}, author = {Mirshahvalad, SA and Iravani, A and Fendler, WP and Maurer, T and Eiber, M and Sharifian, F and Manoochehry, S and Rendl, G and Schweighofer-Zwink, G and Pirich, C and Sathekge, M and Beheshti, M}, title = {Rechallenge and Extended [[177]Lu]Lu-PSMA Therapy in Metastatic Prostate Cancer.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {67}, number = {1}, pages = {4-11}, doi = {10.2967/jnumed.125.270889}, pmid = {41198236}, issn = {1535-5667}, mesh = {Humans ; Male ; *Lutetium/therapeutic use ; Neoplasm Metastasis ; Radioisotopes/therapeutic use ; *Prostatic Neoplasms/pathology/radiotherapy ; Radiopharmaceuticals/therapeutic use ; Prostatic Neoplasms, Castration-Resistant/radiotherapy/pathology ; Prostate-Specific Antigen ; }, abstract = {Continuation of effective and well-tolerated systemic treatment is often performed in care for metastatic castration-resistant prostate cancer. Likewise, continued administration of [[177]Lu]Lu-PSMA radiopharmaceutical therapy beyond the approved number of cycles holds promising potential to enhance therapeutic efficacy. Rechallenge therapy involves readministration of [[177]Lu]Lu-PSMA cycles after a break, whereas extended therapy continues treatment beyond the standard 6 cycles without interruption. Both approaches aim to improve disease control and prolong survival in patients with metastatic castration-resistant prostate cancer. However, practices vary: some clinicians continue treatment in patients with early favorable responses, whereas others recommend pausing therapy after significant prostate-specific antigen declines, even after a few cycles. In this narrative review, we show that safety profiles for continued [[177]Lu]Lu-PSMA radiopharmaceutical therapy are generally favorable, and most adverse events are mild to moderate in severity. Hematotoxicity, particularly anemia and thrombocytopenia, is the most significant concern, with few patients experiencing high-grade adverse events. In addition, cumulative irradiation, particularly during extended therapy, necessitates careful monitoring of hematologic and renal function. Biochemical responses to rechallenge and extended [[177]Lu]Lu-PSMA therapy are promising, with at least 50% reductions in prostate-specific antigen levels observed in a significant proportion of highly selected patients. Moreover, survival outcomes are encouraging, showing the extension of overall and progression-free survival beyond the known data for standard therapy. Despite these advances, challenges remain in optimizing patient selection, managing cumulative toxicities, and harmonizing treatment protocols. In addition, variability in trial designs, influenced by international regulatory differences, limits the current evidence and necessitates consideration of each treatment approach within its regulatory context. Prospective studies are needed to refine therapeutic strategies, implement consistent clinical and imaging response criteria, and identify predictive biomarkers to improve both efficacy and safety.}, }
@article {pmid41201189, year = {2025}, author = {Meyer, J and Tran, A and Ma, TM and Chiang, BH and Egan, T and Chen, JJ and Tao, Y and Cao, N and Kim, KH and Liao, JJ and Koufigar, S and Vuong, W and Weg, ES}, title = {A hybrid IGRT workflow using SGRT and CBCT for prostate SBRT: Feasibility, efficiency, and safety.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {11}, pages = {e70339}, pmid = {41201189}, issn = {1526-9914}, mesh = {Humans ; Male ; *Prostatic Neoplasms/surgery/diagnostic imaging/radiotherapy ; *Cone-Beam Computed Tomography/methods ; *Radiosurgery/methods ; *Radiotherapy Planning, Computer-Assisted/methods ; *Workflow ; Radiotherapy Dosage ; *Radiotherapy, Intensity-Modulated/methods ; Feasibility Studies ; Prospective Studies ; *Radiotherapy, Image-Guided/methods ; Organs at Risk/radiation effects ; Aged ; Image Processing, Computer-Assisted/methods ; }, abstract = {BACKGROUND AND PURPOSE: Safe delivery of prostate stereotactic body radiotherapy (SBRT) relies on precise target localization. Without access to real-time intrafraction motion management, careful optimization of IGRT protocols is necessary to safeguard treatment accuracy and patient outcomes.<br><br>METHODS: An IGRT workflow is proposed that incorporates surface-monitoring (SGRT) to complement cone-beam CT (CBCT) imaging. The study evaluates 23 consecutive SBRT prostate patients who were treated on a prospective registry study. Each patient received pre- and mid-treatment and a subset received post-treatment CBCTs. The frequency and magnitude of SGRT triggered beam interruptions as well as treatment times were recorded.<br><br>RESULTS: The median number of CBCTs acquired per fraction was four and the median treatment time was 23 min (IQR 19-27). SGRT detected intra-fraction surface-based motion beyond a combined 4&#xa0;mm vector isocenter tolerance in 62% of all fractions treated, with a maximum motion of 15&#xa0;mm. On average&#xa0;<&#xa0;2 beam interruptions were triggered by SGRT per treatment fraction. There was no statistically significant correlation between overall treatment time and SGRT-triggered beam interruptions (r&#xa0;=&#xa0;0.048, p&#xa0;=&#xa0;0.645). There was a weak but statistically relevant correlation of overall treatment time with the maximum detected motion (r&#xa0;=&#xa0;0.23, p&#xa0;=&#xa0;0.026). SGRT detected five fractions where the patients had persistently moved outside the SGRT tolerance, and for three of these (60%), a CBCT verified that the target was out of tolerance.<br><br>CONCLUSION: SGRT is a valuable tool that complements CBCT-based IGRT. An SGRT motion vector tolerance of 4&#xa0;mm provides a pragmatic compromise between detecting patient motion and treatment efficiency. Overall, persistent patient motion during treatment was infrequent in this cohort, however, SGRT was able to detect several cases where the internal target was outside of the tolerance highlighting that patient monitoring with SGRT can contribute to improved quality and safety for prostate SBRT.}, }
@article {pmid41201469, year = {2026}, author = {Damle, SR and Carter, JA and Goodsell, KE and Pineda, JMB and Dickerson, LK and Jiang, X and Mudd, JL and Walsh, T and Kenerson, HL and Cernak, J and Chauhan, SSB and Beirne, E and Jana, S and Koehne, AL and Vij, KR and Ruzinova, MB and Yeung, R and Akilesh, S and Collisson, EA and Fields, RC and Crispe, IN and Pillarisetty, VG}, title = {Intratumoral Three-Cell-Type Clusters Are a Conserved Feature of Endogenous Antitumor Immunity.}, journal = {Cancer immunology research}, volume = {14}, number = {2}, pages = {205-218}, pmid = {41201469}, issn = {2326-6074}, support = {U24 CA258407/CA/NCI NIH HHS/United States ; //Fibrolamellar Cancer Foundation (FCF)/ ; U24CA258407//National Cancer Institute (NCI)/ ; CA230890//U.S. Army Medical Research Acquisition Activity (USAMRAA)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; CA180067//U.S. Army Medical Research Acquisition Activity (USAMRAA)/ ; R38 AI181011/AI/NIAID NIH HHS/United States ; R01 CA181445/CA/NCI NIH HHS/United States ; //Swim Across America (SAA)/ ; CRI Award 4093//Cancer Research Institute (CRI)/ ; R33 CA263703/CA/NCI NIH HHS/United States ; R33CA263703//National Cancer Institute (NCI)/ ; R01CA256969//National Cancer Institute (NCI)/ ; R01 CA256969/CA/NCI NIH HHS/United States ; R01CA181445//National Cancer Institute (NCI)/ ; SR-202221337//M.J. Murdock Charitable Trust (MJMCT)/ ; }, mesh = {Humans ; *Dendritic Cells/immunology ; Tumor Microenvironment/immunology ; *Pancreatic Neoplasms/immunology/pathology ; *T-Lymphocytes, Cytotoxic/immunology ; *Carcinoma, Pancreatic Ductal/immunology/pathology ; *Lymphocytes, Tumor-Infiltrating/immunology ; *T-Lymphocytes, Helper-Inducer/immunology ; }, abstract = {Effective antitumor immunity ultimately depends on the priming and activation of tumor-specific cytotoxic CD8+ T cells; however, the role of intratumoral cell-cell immune interactions remains incompletely understood. Recent work has revealed that the temporospatial co-localization of dendritic cells (DC), T helper (Th) cells, and cytotoxic T lymphocytes (CTL) within the tumor immune microenvironment following immune checkpoint blockade correlates with clinical response. In this study, we report the integration of more than 1 million spatially resolved single-cell profiles across six spatial proteomic and transcriptomic assays, which demonstrated that DC:Th:CTL three-cell-type clusters were common even in immunotherapy-naïve and highly desmoplastic tumors, such as fibrolamellar carcinoma and pancreatic ductal adenocarcinoma. We found that these immune triads were enriched for functionally important type 1 conventional DC, mature DCs enriched in immunoregulatory molecules, CXCL13+ Th, and GZMK+ effector CTL phenotypes. Subsequent multiplex immunofluorescence imaging of more than 450 primary pancreatic ductal adenocarcinoma tumors showed that the density of antigen-presenting cell:Th:CTL three-cell-type clusters was correlated with intratumoral T-cell clonal expansion and improved overall survival. These findings suggest that DC:Th:CTL triads are conserved across solid tumors and highlight the importance of intratumoral spatial niches in mediating endogenous antitumor immunity.}, }
@article {pmid41202812, year = {2026}, author = {Hoi, XP and Stangis, MM and Glass, SE and Kim, JH and Kang, SW and Brennen, WN and Li, Z and Grady, WM and Yegnasubramanian, S and Kuhn, P and Lyssiotis, CA and Sagara, A and Shrubsole, MJ and Kadara, H and Yuan, Y and Coffey, RJ and Lau, KS and De Marzo, AM and Maitra, A and Min, J and Yu, M and Chan, KS and , }, title = {Cellular senescence in precancer lesions and early-stage cancers.}, journal = {Cancer cell}, volume = {44}, number = {1}, pages = {6-11}, doi = {10.1016/j.ccell.2025.10.006}, pmid = {41202812}, issn = {1878-3686}, support = {R50 CA233042/CA/NCI NIH HHS/United States ; U54 CA274374/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Precancerous Conditions/pathology/metabolism ; *Cellular Senescence/physiology ; Tumor Microenvironment ; *Neoplasms/pathology/metabolism ; Senescence-Associated Secretory Phenotype ; Animals ; }, abstract = {Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.}, }
@article {pmid41202991, year = {2026}, author = {Gillespie, EF and Silverwood, S and Lapen, K and Verdini, NP and Bryl, K and Baser, RE and Khan, AJ and Mao, JJ}, title = {A Virtual Mind-Body Exercise Program During Breast Radiation: Results From a Randomized Controlled Basket Trial.}, journal = {International journal of radiation oncology, biology, physics}, volume = {124}, number = {4}, pages = {961-970}, pmid = {41202991}, issn = {1879-355X}, support = {K08 CA252640/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: National guidelines recommend fitness and mind-body exercise to reduce cancer-related fatigue, but substantial barriers to implementation exist. Virtual programs offer a scalable approach to address this gap. This study aims to evaluate the efficacy of a virtual fitness and mind-body exercise program (Integrative Medicine at Home [IM@Home]) in reducing fatigue in patients undergoing radiation therapy (RT) for breast cancer.<br><br>METHODS AND MATERIALS: A prospective randomized controlled patient-reported outcome basket clinical trial was conducted. Patients undergoing breast RT who reported moderate or greater fatigue were randomly assigned 1:1 ratio to either IM@Home, which provided live virtual fitness and mind-body exercise classes, or enhanced usual care (EUC). The primary outcome, fatigue, was measured using the total Brief Fatigue Inventory, a composite score including severity and impact on daily functioning, weekly over 12 weeks. Secondary outcomes included the Insomnia Severity Index, Edmonton Symptom Assessment Scale, and Hospital Anxiety and Depression Scale collected every 4 weeks. Statistical analysis included linear mixed models to compare group differences over time using a statistical significance threshold of P < .05.<br><br>RESULTS: Among 73 enrolled patients, 35 were randomly assigned to IM@Home and 38 to EUC. At week 12, patients in the IM@Home group had significantly less fatigue compared to those in the EUC group (2.06 vs 2.79, P = .009). Compared to EUC, patients in the IM@Home group showed greater reductions in insomnia (P = .005), symptom distress (P = .013), and depression (P = .04), but not anxiety (P = .14).<br><br>CONCLUSIONS: The IM@Home program significantly reduced fatigue and comorbid symptoms among women with breast cancer undergoing RT. Future research is needed to confirm these findings, explore mechanisms of the observed benefit, and evaluate scalability as well as barriers and facilitators to implementation.}, }
@article {pmid41203676, year = {2025}, author = {Duggan, C and de Dieu Tapsoba, J and Warner, J and Dash, A and Wang, CY and McTiernan, A}, title = {Effects of acute exercise on inflammatory and metabolic biomarkers in women: a randomized controlled trial.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {122}, pmid = {41203676}, issn = {2374-4677}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; BRCF-18-107; BCRF-19-107; BCRF-20-107; BRCF-21-107; BRCF-22;107//Breast Cancer Research Foundation,United States/ ; }, abstract = {Mechanisms linking exercise to reduced breast cancer risk are poorly understood. 103 healthy women, 18-75, were randomized to 45-minutes of acute exercise at 60% VO2max (N = 54, intervention), or 45-minutes of rest (N = 49, control). Blood samples were collected at baseline, 45- and 105-minutes, analytes measured by immunoassay, and mean changes from baseline to 45- and 105-minutes modelled using generalized estimating equations, adjusted for confounders. Mean percent changes levels (Δ%) increased in exercisers vs. controls for monocyte chemoattractant protein (MCP)-1 Δ[45 min] + 17.1% (P < 0.0001), Δ[105 min] + 12.0% (P = 0.005); interleukin(IL)-6, Δ[45 min] + 103.5%, Δ[105 min] + 92.3%; and at 45-minutes for glucose Δ[45 min] + 8.8%; insulin Δ[45 min] + 82.4% (all P < 0.0001). Differences between arms for vascular endothelial growth factor (VEGF) Δ[45 min] + 9.8%; c-reactive protein Δ[45 min]-6.6%; irisin Δ[45 min]-5.1%; or plasminogen activator inhibitor (PAI)-1, Δ[45 min]-3.6% were non-statistically significant, with similar results at 105-minutes. Results suggest that acute exercise has specific effects on circulating metabolic and inflammatory biomarkers, implicated in breast cancer etiology, which differ from weight-loss-induced changes. Trial registration: Clincialtrials.gov identifier NCT03779867.}, }
@article {pmid41205698, year = {2025}, author = {Dunk, MM and Delac, L and Rapp, SR and Driscoll, I and Latorre-Leal, M and Farland, LV and Haring, B and Harris, HR and Jung, SY and Manson, JE and Ochs-Balcom, HM and Shadyab, AH and Weitlauf, JC and Xu, H and Westman, E and Maioli, S}, title = {Exploring biomarkers of neurodegenerative risk: associations of oxysterols, sex hormones, and reproductive characteristics in older women.}, journal = {Journal of lipid research}, volume = {66}, number = {12}, pages = {100938}, pmid = {41205698}, issn = {1539-7262}, mesh = {Humans ; Female ; Biomarkers/blood ; Aged ; *Oxysterols/blood ; *Gonadal Steroid Hormones/blood ; Middle Aged ; Hydroxycholesterols/blood ; *Neurodegenerative Diseases/blood ; Risk Factors ; *Reproduction ; Apolipoprotein E4/genetics ; Alzheimer Disease/blood ; }, abstract = {Women face a higher lifetime risk of developing neurodegenerative diseases such as Alzheimer's disease and related dementias. The menopausal transition, characterized by a decline in estrogen levels, may affect cholesterol metabolism and neurodegenerative processes. Oxysterols, oxidized cholesterol derivatives, play a role in these pathways, with 24(S)-hydroxycholesterol (24HC) reflecting brain cholesterol turnover and 27-hydroxycholesterol (27HC) linked to systemic cholesterol metabolism. We investigated associations of plasma oxysterols with circulating sex hormones and characteristics of reproductive history in 1,974 postmenopausal women with no history of dementia from the Women's Health Initiative, taking into account APOE4 status and cholesterol-lowering medication. We found that higher levels of bioavailable estradiol were associated with higher 24HC and 27HC levels, and higher estrone was associated with higher 24HC (all P values <0.05). Associations of estradiol with 24HC and 27HC were stronger among APOE4 carriers and those not using cholesterol-lowering medication, with a significant interaction between bioavailable estradiol and APOE4 in relation to 27HC (p for interaction = 0.04). Having an older age at menopause was associated with lower 24HC among those taking cholesterol medication (p for interaction = 0.03). Our findings suggest that 24HC and 27HC may be proxy biomarkers of neuronal health and estrogen status in postmenopausal women. The stronger associations between estradiol and oxysterols among APOE4 carriers and those not using cholesterol medication suggest the need to account for hormonal, genetic, and pharmacological factors when evaluating neurodegenerative risk. Longitudinal studies are warranted to further investigate oxysterols as potential early biomarkers of risk for Alzheimer's disease and related dementias.}, }
@article {pmid41205872, year = {2026}, author = {Vaquera-Alfaro, HA and Jeon, Y and Wu, QV and Liang, EC and Portuguese, A and Gómez-De León, A and Valdespino-Valdes, J and Gauthier, J}, title = {A Practical Guide to Competing Risk Analysis for Transplant and Cell Therapy Research.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {4}, pages = {489-500}, pmid = {41205872}, issn = {2666-6367}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; *Cell- and Tissue-Based Therapy/methods ; Risk Assessment/methods ; }, abstract = {Competing risks are common in hematopoietic cell transplantation (HCT) and immune effector cell (IEC) therapy research. Competing risks refer to events that cannot co-occur and complicate time-to-event analyses. The typical example of competing risk in the context of HCT and IEC research is treatment-related mortality, which competes with disease relapse. In this primer, we first aim to introduce - in a clinician-friendly fashion - the core concepts underlying the statistical modelling of competing risks. Next, we propose a practical, step-by-step guide to analyze time-to-event outcomes in the context of competing risks using the open access R environment. Relevant R packages are introduced, enabling the generation of publication-ready tables and figures. We hope our manuscript will encourage more robust analyses in the fields of HCT and IEC therapy when competing risks are at play.}, }
@article {pmid41206027, year = {2026}, author = {Hanscom, B and Marzinke, MA and Li, X and Donnell, D and Bies, R and Hendrix, CW and Wang, Z and Acuipil, C and Rinehart, A and Collins, JW and Rooney, JF and Soto Torres, L and Richardson, P and Chariyalerstsak, S and Valdez Ramalho Madruga, J and Hurt, CB and Magnus, M and Frank, I and McCauley, M and Grinsztejn, B and Landovitz, RJ}, title = {Estimation of Prevention-Effective CAB-LA Concentrations Among Men Who Have Sex With Men (MSM) and Transgender Women (TGW) in HPTN 083.}, journal = {The Journal of infectious diseases}, volume = {233}, number = {2}, pages = {e454-e461}, pmid = {41206027}, issn = {1537-6613}, support = {//National Institute of Allergy and Infectious Diseases/ ; /CD/ODCDC CDC HHS/United States ; /NH/NIH HHS/United States ; /MH/NIMH NIH HHS/United States ; UM1AI068619/DA/NIDA NIH HHS/United States ; UM1AI068617//HIV Prevention Trials Network [HPTN] Leadership and Operations Center/ ; UM1AI068613//HPTN Statistical and Data Management Center/ ; //HPTN Laboratory Center/ ; //ViiV Healthcare/ ; //Gilead Sciences/ ; }, mesh = {Humans ; Male ; *HIV Infections/prevention &amp; control ; *Transgender Persons ; Adult ; *Pre-Exposure Prophylaxis/methods ; Case-Control Studies ; Female ; *Homosexuality, Male ; *Anti-HIV Agents/blood/administration &amp; dosage/therapeutic use ; *Pyridones/blood/administration &amp; dosage/therapeutic use/pharmacokinetics ; Young Adult ; Middle Aged ; Tenofovir/therapeutic use ; Diketopiperazines ; }, abstract = {BACKGROUND: The HIV Prevention Trials Network (HPTN) 083 Trial demonstrated the superiority of long-acting, injectable cabotegravir (CAB) over daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis among cisgender men (MSM) and transgender women (TGW) who have sex with men. Plasma CAB concentrations associated with HIV protection in humans are unknown.<br><br>METHODS: We conducted a nested case-control study to investigate the association between plasma CAB concentrations and HIV risk. Plasma CAB concentrations were estimated for participants with confirmed HIV and for HIV-negative controls, who were matched on region, gender, and race. The window of HIV acquisition for cases was defined as the time between the last HIV-negative visit and the first HIV-positive visit; this window was used to evaluate CAB exposure for cases and their matched controls. Participants were categorized by the minimum estimated CAB concentration (CABmin) during this window relative to the protein-adjusted 90% CAB inhibitory concentration (1&#xd7; PA-IC90) and 4&#xd7; PA-IC90. HIV risk was modeled using conditional logistic regression.<br><br>RESULTS: Plasma CABmin was &#x2265;4&#xd7; PA-IC90 in 26% of HIV-positive cases, compared with 76% of matched controls. Plasma CABmin &#x2265;4&#xd7; PA-IC90 was associated with a 93% reduction in risk of HIV acquisition compared with CABmin <1&#xd7; PA-IC90 (95% CI: 76%, 98%, P < .001). CABmin between 1&#xd7; and 4&#xd7; PA-IC90 had an estimated risk reduction of 79% compared with CABmin <1&#xd7; PA-IC90 (95% CI: -19%, 96%, P = .07).<br><br>CONCLUSIONS: Consistent plasma CAB concentrations &#x2265;4&#xd7; PA-IC90 were estimated to provide 93% protection against HIV in MSM and TGW.}, }
@article {pmid41206886, year = {2025}, author = {Seth, L and Bhave, A and Kollapaneni, S and Shah, V and Nahle, T and Blaes, A and Dent, S and Hurvitz, SA and Guha, A}, title = {Cardiotoxic Effects of Antibody Drug Conjugates vs Standard Chemotherapy in ERBB2-Positive Advanced Breast Cancer: A Systematic Review and Meta-Analysis.}, journal = {JAMA network open}, volume = {8}, number = {11}, pages = {e2540336}, pmid = {41206886}, issn = {2574-3805}, mesh = {Humans ; *Breast Neoplasms/drug therapy ; Female ; Erb-b2 Receptor Tyrosine Kinases ; *Cardiotoxicity/etiology ; Trastuzumab/adverse effects/therapeutic use ; Ado-Trastuzumab Emtansine/adverse effects/therapeutic use ; *Immunoconjugates/adverse effects/therapeutic use ; *Antineoplastic Agents, Immunological/adverse effects ; Camptothecin/analogs &amp; derivatives ; }, abstract = {IMPORTANCE: Antibody-drug conjugates (ADCs), such as trastuzumab emtansine and trastuzumab deruxtecan, are effective in treating erb-b2 receptor tyrosine kinase 2 (ERBB2)-positive breast cancer (BC) that has progressed on prior ERBB2-targeted therapy, warranting evaluation of their cardiotoxic profiles.<br><br>OBJECTIVE: To compare the incidence of cardiotoxic effects of ADCs vs standard-of-care chemotherapy regimens for ERBB2-positive locally advanced or metastatic BC.<br><br>DATA SOURCES: PubMed, ScienceDirect, Cochrane Library, and ClinicalTrials.gov databases were searched in December 2024 for studies published between 2000 and 2024.<br><br>STUDY SELECTION: The included studies were (1) phase 3 clinical trials that investigated locally advanced or metastatic ERBB2-positive BC; (2) clearly defined left ventricular ejection fraction (LVEF) decrease or heart failure definitions; (3) clearly defined LVEF monitoring frequency by echocardiography or multigated acquisition scan; (4) included studies consisted solely of either trastuzumab emtansine, trastuzumab deruxtecan, or one of the first-line to fourth-line chemotherapy regimens for unresectable stage IV ERBB2-positive breast cancer per the 2025 National Comprehensive Cancer Network guidelines; and (5) clearly defined cardiovascular eligibility criteria.<br><br>DATA EXTRACTION AND SYNTHESIS: Data from eligible studies were extracted by 3 reviewers. A random-effects model was used for the pooled analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was cardiotoxic effects, which were defined as the incidence of LVEF decrease. The pooled analysis was performed using logit-transformed proportions with the inverse variance method and a DerSimonian-Laird random-effects model for between-study variance, with Wilson score 95% CIs.<br><br>RESULTS: In this meta-analysis of 9538 patients, a pooled analysis demonstrated a 0.94% (95% CI, 0.56%-1.57%) incidence of LVEF decrease with trastuzumab emtansine, a 4.20% (95% CI, 2.91%-6.01%) incidence with trastuzumab deruxtecan, a 4.85% (95% CI, 3.73%-6.28%) incidence with trastuzumab plus chemotherapy, and a 5.52% (95% CI, 3.41%-8.83%) incidence with trastuzumab plus pertuzumab plus chemotherapy. A trim-and-fill analysis was used if evidence of publication bias was found.<br><br>CONCLUSIONS AND RELEVANCE: This meta-analysis found that trastuzumab emtansine was associated with the lowest incidence of LVEF decrease, and trastuzumab deruxtecan, trastuzumab plus chemotherapy, and trastuzumab plus pertuzumab plus chemotherapy had similar incidences. More research is needed into the cardiotoxic effects of these therapies.}, }
@article {pmid41206919, year = {2026}, author = {El Kassar, N and DeZern, AE and Abkowitz, J and Artz, A and Beerman, I and Bolton, K and Brooks, MM and Borate, U and Ershler, WB and Ganz, T and Kalfa, TA and Kuaban, A and Leng, S and Nakada, D and Nazha, A and Grossmann, C and Pfeilstöcker, M and Qiu, C and Sauver, JS and Sekeres, MA and Simonsick, EM and White, KE and Zhang, D and Ferrucci, L and Kuchel, GA}, title = {A proposed path to explaining the unexplained anemia of aging.}, journal = {The journals of gerontology. Series A, Biological sciences and medical sciences}, volume = {81}, number = {1}, pages = {}, pmid = {41206919}, issn = {1758-535X}, support = {R33 AG058738/AG/NIA NIH HHS/United States ; /NH/NIH HHS/United States ; //US Department of Health and Human Services/ ; }, mesh = {Aged ; Humans ; *Aging/physiology ; *Anemia/epidemiology/etiology/diagnosis ; Erythropoiesis ; United States/epidemiology ; }, abstract = {Approximately 17% of people aged 65 years and older are anemic, and 10% of death certificates report anemia as a secondary cause of death in the United States. Nonetheless, anemia remains unexplained in 30%-50% of older adults. This unexplained anemia of aging (UAA) is a diagnosis of exclusion. The mechanism, impact, and progression of UAA remain unknown. At older ages, anemia adds to pre-existing co-morbidities with significant adverse health consequences, representing a compelling unmet clinical concern. The National Institute on Aging held a workshop in 2024 to discuss current knowledge and research opportunities. Topics included the epidemiology of anemia at older age and its clinical implications; probable mechanism(s) underlying UAA, that is, low-grade inflammation's effects on erythropoiesis; the role of microbiota in iron regulation in bone marrow; the importance of ruling out a diagnosis of leukemic clonal hematopoiesis (CH), which is more prevalent in older age; the role of senescence and aging governing hematopoiesis; and the effects of sex hormones on hematopoietic stem cell aging. Understanding the roles of these factors could reduce the proportion of the older anemic population whose anemia remains unexplained and offer insights into new potential diagnostic and intervention strategies. Speakers reviewed previous clinical trials in patients with UAA and CH. They discussed lessons learned and future research priorities, including efforts to develop new diagnostic algorithms and potential uses of machine learning.}, }
@article {pmid41206949, year = {2026}, author = {Zhang, T and Hua, X and Mohindroo, C and Wang, X and Dutta, D and Liu, J and Katta, S and Li, SA and Wang, J and Antwi, SO and Arslan, AA and Beane Freeman, LE and Bracci, PM and Canzian, F and Du, M and Gallinger, S and Goodman, PJ and Katzke, V and Kooperberg, C and Le Marchand, L and Neale, RE and Patel, AV and Perdomo, S and Shu, XO and Visvanathan, K and Van Den Eeden, SK and White, E and Zheng, W and Albanes, D and Andreotti, G and Bamlet, WR and Brennan, P and Buring, JE and Chanock, SJ and Chen, Y and Darst, B and Ferrari, P and Giovannucci, EL and Goggins, M and Haiman, C and Hassan, M and Holly, EA and Hung, RJ and Jones, MR and Kraft, P and Kurtz, RC and Malats, N and Moore, SC and Ng, K and Oberg, AL and Orlow, I and Peters, U and Porta, M and Rabe, KG and Rothman, N and Sánchez, MJ and Sesso, HD and Silverman, DT and Southey, MC and Um, CY and Yarmolinsky, J and Yu, H and Yuan, C and Zhong, J and Wolpin, BM and Risch, HA and Amundadottir, LT and Klein, AP and Yu, K and Zhang, H and Stolzenberg-Solomon, RZ}, title = {Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis.}, journal = {Journal of the National Cancer Institute}, volume = {118}, number = {3}, pages = {437-447}, pmid = {41206949}, issn = {1460-2105}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; Z01 CP010193/ImNIH/Intramural NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; 001/WHO_/World Health Organization/International ; 75N910D00024/NH/NIH HHS/United States ; P50 CA257911/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; /HH/HHS/United States ; ZIA CP010193/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Mendelian Randomization Analysis ; *Carcinoma, Pancreatic Ductal/genetics/epidemiology/etiology ; *Pancreatic Neoplasms/genetics/epidemiology/etiology ; Genome-Wide Association Study ; *Diabetes Mellitus, Type 2/genetics/complications ; Genetic Predisposition to Disease ; *Diabetes Mellitus, Type 1/genetics ; Polymorphism, Single Nucleotide ; Risk Factors ; Case-Control Studies ; }, abstract = {BACKGROUND: The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood.<br><br>METHODS: We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242&#xa0;283 cases, 1&#xa0;569&#xa0;734 controls), T1D (18&#xa0;942 cases, 501&#xa0;638 controls), and PDAC (10&#xa0;244 cases and 360&#xa0;535 controls) in individuals of European ancestry.<br><br>RESULTS: Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR&#x2009;=&#x2009;1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR&#x2009;=&#x2009;1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR&#x2009;=&#x2009;1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR&#x2009;=&#x2009;1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P&#x2009;=&#x2009;1.5&#x2009;&#xd7;&#x2009;10-8), which remained after excluding 20 known PDAC GWAS loci (P&#x2009;=&#x2009;7.6&#x2009;&#xd7;&#x2009;10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions.<br><br>CONCLUSIONS: Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.}, }
@article {pmid41207381, year = {2026}, author = {Wolff, D and Cutler, C and Mercep, I and Jaki, T and Robertson, DS and Schultz, KR and Lee, SJ and Martin, PJ and Pavletic, SZ}, title = {Toward Better and More Effective Clinical Trials for Chronic Graft-Versus-Host Disease.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {4}, pages = {388-397}, doi = {10.1016/j.jtct.2025.11.008}, pmid = {41207381}, issn = {2666-6367}, mesh = {*Graft vs Host Disease/therapy/drug therapy ; Humans ; Chronic Disease ; *Clinical Trials as Topic ; }, abstract = {While the incidence of chronic Graft-versus-Host Disease (chronic GVHD) is declining due to advances in prophylaxis and survival is improving due to better supportive care, first-line treatment of chronic GVHD continues to be based on corticosteroids. Numerous attempts to establish more effective or less toxic treatment alternatives have largely failed, likely due to the biological heterogeneity of chronic GVHD and uncontrolled use of systemic corticosteroids, indicating the need for new approaches. The 2020 NIH consensus conference proposed the systematic evaluation of steroid-free initial treatment combining clinical and biological assessment to establish personalized approaches. While the first generation of trials evaluating steroid-free single agent first-line therapy approaches are recruiting, they are still not able to consider the biological heterogeneity of chronic GVHD in deciding therapeutic approaches. To advance the field, we propose a two-stage adaptive trial design starting with an intervention under consideration followed by a replication phase after the first phase has identified candidate clinical features and or biomarker predicting success. For second and subsequent lines of treatment, current treatment decisions regarding the use of the four FDA approved agents are based on the product label or a trial-and-error approach, sometimes in combination regimens despite the lack of prospective data. Future trials and prospective observational studies should focus on the development of predictive markers to provide a biological rationale for sequencing treatment options and to identify synergistic combination treatments. The recently released FDA draft guidance document for developing drugs and treatments in GVHD serves as the starting point for clinical trials planning that should yield results during the next several years.}, }
@article {pmid41207382, year = {2025}, author = {Locke, FL and Nikiforow, S and Frigault, MJ and Maloney, DG and Davila, M and Miklos, DB and Lin, Y and Vong, J and Shah, NN and Neelapu, SS and Welch, J and Ng, E and Jacobson, C and Maus, MV}, title = {Recommendations for Defining Chimeric Antigen Receptor T-Cell (CAR T) Dose-Limiting Toxicities (DLTs) for Future Early-Phase CAR T Therapy Studies.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.11.004}, pmid = {41207382}, issn = {2666-6367}, abstract = {Chimeric antigen receptor T-cell (CAR T) therapies have demonstrated potential to provide long-term remission in incurable hematologic malignancies, and novel approaches for CAR T therapy continue to be developed for treating cancer and other indications. Acute class-effect toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, remain significant concerns despite their potential reversibility. Given the complexities of balancing safety and efficacy of CAR T therapies, the US Food and Drug Administration (FDA) recently published Guidance for Industry, which included suggested definitions for dose-limiting toxicities (DLTs) for clinical trials of emerging CAR T therapies. However, the DLT definitions in the guidance do not reflect what was used in the phase 1 and/or registrational studies for the approved CAR Ts; for example, these studies defined DLTs as treatment-related, included exceptions, and/or allowed for time to resolve the adverse event. Using DLT definitions from the guidance could have prematurely stopped the early-phase studies of the now approved CAR Ts. In 2023, while designing a first-in-human, phase 1 study of a logic-gated cell therapy, an expert panel of academic cell therapists collaborated with industry partners at A2 Biotherapeutics to assess the practical implications of the FDA guidance. This led the panel to draft the revised recommendations contained herein, which integrate the permissibility of reversible events during dose-escalation for trial sponsors, investigators, health authorities, and other parties who may be involved in future CAR T therapy trials. These expert recommendations balance the safety of patients in early-phase trials with the potential long-term therapeutic opportunities for patients with terminal malignancies.}, }
@article {pmid41207385, year = {2026}, author = {Richardson, AB and Ng, K and Gooley, TA and Cheng, GS and Salit, RB}, title = {Pulmonary Complications Following Hematopoietic Cell Transplantation in Patients with Myelofibrosis: A Single-Center Retrospective Cohort Analysis.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {3}, pages = {300.e1-300.e11}, doi = {10.1016/j.jtct.2025.10.027}, pmid = {41207385}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Retrospective Studies ; Male ; Female ; *Primary Myelofibrosis/therapy/complications ; Middle Aged ; Adult ; Aged ; Respiratory Function Tests ; *Lung Diseases/etiology ; Graft vs Host Disease/etiology ; }, abstract = {Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder that frequently results in extramedullary hematopoiesis. Hematopoietic cell transplantation (HCT) is the only cure. While a 2-fold increase in pneumonia and respiratory-related mortality was recently reported in MF patients compared to the general population, the incidence and etiology of HCT-related pulmonary complications have not been well studied. We performed a retrospective chart review of consecutive MF patients who underwent HCT between 2002 and 2022. Patients with evidence of pulmonary impairment on pulmonary function tests, defined as a ≥10-point decline in forced expiratory volume in 1 second (FEV1) compared to pre-HCT and/or a decline in the FEV1/forced vital capacity (FVC) ratio to <0.7, received further chart review to determine the etiology of this decline. Of 228 patients evaluated, 126 (55%) met either the FEV1 or FEV1/FVC criteria for pulmonary impairment. After further chart review, 35 patients (15.4%) were diagnosed with broncholitis obliterans (BOS) by a pulmonologist or graft-versus-host disease specialist. Other common causes of impairment included respiratory infections (n =10), cryptogenic organizing pneumonia (n = 8), and deconditioning (n = 8). MF patients have a >50% likelihood of developing pulmonary impairment following HCT and a higher-than-expected incidence of BOS. This study supports increased pulmonary monitoring post-HCT in patients with MF.}, }
@article {pmid41210691, year = {2025}, author = {Meng, L and Psutka, SP and Gheeya, J and Li, M and Noonavath, M and Orcutt, D and Gross, E and Collier, KA and Mortazavi, A and Folefac, E and Monk, P and Yang, Y}, title = {Tyrosine Kinase Inhibitors Outperform Immune Checkpoint Inhibitors in Bone-Predominant Metastatic Renal Cell Carcinoma: A Multicenter Real-World Analysis.}, journal = {Journal of Cancer}, volume = {16}, number = {14}, pages = {4047-4054}, pmid = {41210691}, issn = {1837-9664}, abstract = {Background: Bone-predominant metastatic renal cell carcinoma (mRCC) presents significant clinical challenges due to its associated morbidities and poor prognosis. Optimal first-line treatment remains unclear, largely because these patients are often excluded from clinical trials due to difficulties in measuring bone lesions. Emerging evidence suggests that bone metastases exhibit high angiogenesis gene signatures, potentially predicting favorable responses to tyrosine kinase inhibitors (TKIs). Methods: We conducted a multicenter retrospective analysis of patients with bone-predominant mRCC treated at The Ohio State University Comprehensive Cancer Center and Fred Hutchinson Cancer Center from January 2008 to June 2021. Bone predominance was defined as having a greater number of osseous metastases compared to extra-osseous sites using computed tomography or bone scans. Patients receiving first-line TKIs or immune checkpoint inhibitors (ICIs) were included; those treated with combination TKI-ICI therapies were excluded due to limited numbers. Demographic, clinical, and treatment data were collected. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and compared using the log-rank test. Univariate Cox regression analysis was conducted to identify factors associated with OS. Results: A total of 69 patients with bone-predominant mRCC were identified, with 40 receiving TKIs and 29 receiving ICIs as first-line therapy. Baseline characteristics were comparable between groups. The median OS was significantly longer for patients treated with TKIs compared to those receiving ICIs (41.3 months vs. 19.3 months; log-rank P = 0.036). A trend toward improved median PFS was observed in the TKI group (7.9 months vs. 4.9 months; P = 0.075). Univariate analysis showed that treatment with ICIs was associated with an increased risk of death compared to TKIs (hazard ratio = 1.96; P = 0.040). Objective response rates were higher in the TKI group (22.9% vs. 12.0%), although this difference was not statistically significant (P = 0.332). Conclusions: In this multicenter real-world analysis, first-line treatment with TKIs was associated with significantly improved OS compared to ICIs in patients with bone-predominant mRCC. These findings suggest that TKI-containing regimens may be the preferred front-line therapy for this patient subgroup. Prospective studies are warranted to validate these results and to optimize treatment strategies for bone-predominant mRCC.}, }
@article {pmid41210956, year = {2025}, author = {Luedtke, A and Fong, Y and van der Laan, L and Heng, F and Huang, Y and Lu, Y and Yu, C and Carpp, LN and Roels, S and Le Gars, M and Van Roey, GA and Stieh, DJ and Van Dromme, I and Kenny, A and Carone, M and Hyrien, O and Ayala, V and Jayashankar, L and Castellino, F and Amoa-Awua, O and Basappa, M and Flach, B and Lin, BC and Moore, C and Naisan, M and Naqvi, M and Narpala, S and O'Connell, S and Mueller, A and Serebryannyy, L and Castro, M and Wang, J and Dziubla, G and Randhawa, AK and Andrasik, MP and Hendriks, J and Truyers, C and Struyf, F and Schuitemaker, H and Douoguih, M and Kublin, JG and Corey, L and Neuzil, KM and Bekker, LG and Garrett, N and Cardoso, SW and DelaFontaine, P and Magaret, CA and Vingerhoets, J and Casapia, M and Losso, MH and Little, SJ and Gaur, A and Swann, E and Petropoulos, CJ and McDermott, AB and Sadoff, J and Gray, GE and Grinsztejn, B and Goepfert, PA and Follmann, D and Roychoudhury, P and Greninger, AL and Koup, RA and Donis, RO and Gilbert, PB and ,  and ,  and , }, title = {Immune correlates analysis of antibody responses against SARS-CoV-2 variants in the ENSEMBLE vaccine efficacy trial.}, journal = {iScience}, volume = {28}, number = {11}, pages = {113660}, pmid = {41210956}, issn = {2589-0042}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; }, abstract = {In Latin American sites of the ENSEMBLE trial of the Ad26.COV2.S vaccine vs. placebo, binding antibodies and neutralizing antibodies measured 4 weeks post-vaccination (∼peak) against circulating lineages (Ancestral, Gamma, Lambda, Mu, Zeta) were assessed as a correlate of risk of, and correlate of protection against, lineage-specific COVID-19. Comparison of lineage-matched controlled vaccine efficacy (VE) curves showed similar relationships across lineages of lineage-specific antibody with VE against lineage-matched COVID-19, supporting a "variant-invariant correlate of protection model" that undergirds immunobridging inferences of efficacy against new variants based on variant-matched neutralizing antibody titers. Lambda departed from this model at undetectable/just-detectable titers: at ∼ peak Reference-specific titers of 2.7 arbitrary units (AU)/mL (just-detectable) and 30 AU/ml, VE against Ancestral COVID-19 was 53.0% (95% CI: 30.7%, 67.9%) and 84.5% (73.6%, 93.0%), respectively; at the same Lambda-specific titers, VE against Lambda COVID-19 was 12.3% (-54.1%, 50.3%) and 91.1% (68.9%, 98.0%). Additional research is needed for Omicron variants.}, }
@article {pmid41213032, year = {2025}, author = {El-Khoueiry, AB and Kim, RD and Harris, WP and Sung, MW and Waldschmidt, D and Cabrera, R and Garosi, VL and Ploeger, BA and Zebger-Gong, H and Brennan, BJ and Wang, YA and Mueller, U and Weispfenning, A and Seidel, H and Coppieters, S and Ishida, TC and Galle, PR}, title = {A multicenter dose-defining/expansion phase 1b study of first-line regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1097/HEP.0000000000001585}, pmid = {41213032}, issn = {1527-3350}, abstract = {BACKGROUND AND AIMS: Combinations including an immune checkpoint inhibitor are preferred first-line treatments for advanced HCC. We investigated the safety of regorafenib plus pembrolizumab as first-line systemic therapy for advanced HCC.<br><br>APPROACH AND RESULTS: This was a dose-defining/expansion phase 1b study in adults with advanced HCC without prior systemic treatment. Patients received regorafenib 80 or 120&#xa0;mg/day for 3 weeks plus pembrolizumab 200&#xa0;mg every 3 weeks in 4-week cycles (rego-80/pembro or rego-120/pembro): rego-80/pembro in the dose-defining phase; rego-80/pembro or rego-120/pembro in 2 dose-expansion cohorts. The primary objective was to assess safety; antitumor activity was a secondary objective. The MTD of regorafenib was 120&#xa0;mg/day plus pembrolizumab; 4/19 patients receiving rego-120/pembro experienced dose-limiting toxicities [grade 3 increased AST with grade 1/2 increased bilirubin (n=2), and grade 3 rash (n=2)]. The most common treatment-emergent adverse events (TEAEs) in the overall safety cohort (n=57) were diarrhea (53%) and fatigue (51%). The most common grade &#x2265;3 TEAEs were increased AST (18%) and hypertension (16%). Dose modifications due to study drug-related adverse events were less frequent with rego-80/pembro than with rego-120/pembro. The objective response rate (ORR) in 54 response-evaluable patients was 31% and the disease control rate (DCR) was 89%. Exploratory analyses suggested an association between lower angiogenesis and transforming growth factor-&#x3b2; signaling before treatment and response.<br><br>CONCLUSIONS: Treatment with rego/pembro is feasible in patients with advanced HCC with a manageable safety profile. ORR and DCR are promising and consistent with other immunotherapy combinations in this setting.}, }
@article {pmid41213454, year = {2025}, author = {Rioseco, A and Puschel, K and Soto, G and Vescovi, Z and Fuentes, I and Dibiase, F and Ulloa, G and Goic, C and Emery, J and Thompson, B and Martinez-Gutierrez, J}, title = {National cancer plans and primary care a systematic analysis comparing Latin American and non-Latin American countries.}, journal = {Journal of cancer policy}, volume = {46}, number = {}, pages = {100659}, doi = {10.1016/j.jcpo.2025.100659}, pmid = {41213454}, issn = {2213-5383}, mesh = {*Primary Health Care/organization &amp; administration ; Humans ; Latin America/epidemiology ; *Neoplasms/therapy/prevention &amp; control/epidemiology ; United States ; Canada ; *Health Policy ; *National Health Programs ; }, abstract = {BACKGROUND: Cancer is a growing global health issue, particularly in middle- and high-income countries. National Cancer Control Plans (NCCPs) have emerged as a strategic response to reduce this burden. Primary care plays a crucial role across the cancer care continuum, yet its systematic inclusion in NCCPs remains unclear-especially in countries facing significant epidemiological challenges.<br><br>METHODS: This study employed a systematic qualitative design based on document analysis. Using the READ (Ready material, Extract data, Analyze, Distil) model, we examined the integration of primary care policies and practices in eight NCCPs: four from non-Latin American high-income countries (NLAHIc-Australia, Canada, the United States, and the United Kingdom) and four from Latin American middle-income countries (LATAMc-Argentina, Colombia, Chile, and Mexico). Covidence software facilitated the systematic text review, and a set of evidence-based key performance indicators (KPIs) was developed to guide the analysis.<br><br>RESULTS: Primary care integration varied across countries. LATAMc NCCPs showed greater inclusion of primary care than NLAHIc. Health promotion strategies were more consistently present in NLAHIc, while LATAMc better integrated primary prevention into primary care. However, only 50&#x202f;% of KPIs for secondary prevention and 15&#x202f;% for survivorship care were included in LATAMc. Palliative care was more consistently integrated in LATAMc (75&#x202f;%) than in NLAHIc (33&#x202f;%). Policy Summary This is the first study to benchmark NCCPs from Latin American and high-income countries using evidence-based KPIs to assess primary care involvement in cancer control. Findings highlight an urgent need to strengthen primary care integration. LATAMc should improve secondary prevention and survivorship care, while NLAHIc need to better incorporate primary prevention and palliative care into their NCCPs.}, }
@article {pmid41213499, year = {2026}, author = {Dehn, JG and Logan, B and Lee, SJ and Shaw, BE and Devine, S and Ciurea, SO and Horowitz, M and He, N and Pusic, I and Srour, SA and Arai, S and Juckett, M and Uberti, J and Hill, L and Vasu, S and Hogan, WJ and Hayes-Lattin, B and Westervelt, P and Bashey, A and Farhadfar, N and Grunwald, MR and Leifer, E and Symons, H and Saad, A and Vogel, J and Erickson, C and Buck, K and Pidala, J}, title = {Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: BMT CTN 1702 Trial.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {3}, pages = {346-357}, pmid = {41213499}, issn = {2666-6367}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; UG1 HL138645/HL/NHLBI NIH HHS/United States ; UG1 HL108945/HL/NHLBI NIH HHS/United States ; UG1 HL108987/HL/NHLBI NIH HHS/United States ; UG1 HL069246/HL/NHLBI NIH HHS/United States ; UG1 HL109137/HL/NHLBI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Female ; Male ; Transplantation, Homologous ; Middle Aged ; Prognosis ; Adult ; *Unrelated Donors ; Adolescent ; *Tissue Donors ; *Donor Selection ; Young Adult ; Aged ; }, abstract = {Patients requiring allogeneic hematopoietic cell transplantation (HCT) have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor (MUD). A Search Prognosis calculator can estimate the likelihood. This study (NCT#03904134; https://clinicaltrials.gov/study) evaluates if using a Search Prognosis algorithm results in similar incidence of transplant between patients Very Likely (>90%) versus Very Unlikely (<10%) to have a MUD. An additional objective included understanding barriers resulting in a delay or cancellation of a patient transplant. The national multicenter Blood and Marrow Transplant Clinical Trial Network (BMT CTN) 1702 interventional trial utilized Search Prognosis-based biologic assignment to guide donor selection. HCT eligible patients at participating transplant centers were invited to enroll. Patients assigned to the Very Likely arm were to proceed with MUD, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (∼25%), were observed under standard center practices, but were not part of the primary objective. We report here the cumulative incidence of HCT by Search Prognosis group and barriers to HCT. Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Seach Prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely, and 276 (16%) Very Unlikely. About 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1234 patients (Very Likely versus Very Unlikely), the adjusted cumulative incidence (95% CI) of HCT at 6 months was 59.8% (56.7 to 62.8) in Very Likely versus 52.3% (46.1 to 58.5) in Very Unlikely (P = .113). Median time to HCT were similar in all Seach Prognosis groups. The predominant barriers resulting in a delay or cancellation of transplant were due to poor patient health (59%). Around 9% of delays and cancellations were attributed to excellent patient disease response, with only 14% of delays and 2% of cancellations due to donor reasons. A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial, with donor related barriers to transplant representing a small proportion of cases. This approach resulted in rapid alternative donor identification and no statistical difference in rates of HCT in patients Very Likely and Very Unlikely to find a MUD.}, }
@article {pmid41216598, year = {2025}, author = {Wang, R and Stempel, JM and Shallis, RM and Huntington, SF and Zeidan, AM and Neparidze, N and Di, M and Bewersdorf, JP and Mendez, L and Ma, X and Podoltsev, NA}, title = {Second malignancies among older patients with classical myeloproliferative neoplasms treated with ruxolitinib.}, journal = {Blood neoplasia}, volume = {2}, number = {4}, pages = {100159}, pmid = {41216598}, issn = {2950-3280}, support = {N01 PC035136/CA/NCI NIH HHS/United States ; N01 PC035139/CA/NCI NIH HHS/United States ; N02 PC015105/PC/NCI NIH HHS/United States ; T32 CA233414/CA/NCI NIH HHS/United States ; }, abstract = {Polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) associated with an increased risk of development of second primary malignancies (SMs). The reasons for solid and lymphoid SMs are unclear, but a therapy-related effect has been invoked. Although an increased risk of nonmelanoma skin cancers is associated with the use of ruxolitinib (RUX), its influence on the development of other forms of SMs remains controversial. We conducted a retrospective cohort analysis to assess associations between RUX and SMs among older patients diagnosed with MPN from 2012 to 2019 in the Surveillance, Epidemiology, and End Results-Medicare-linked database. We identified 6043 patients (2396 with PV, 2944 with ET, 703 with MF) with a median age of 76 years (interquartile range [IQR], 71-82). After a median follow-up of 3.66 (IQR, 2.25-5.17) and 3.02 years (IQR, 1.84-4.75) for 513 RUX users and 5530 nonusers, respectively, 469 patients developed an SM: 383 solid and 86 lymphoid. In the multivariable proportional subdistribution hazard regression model with death as a competing risk, the risk of developing any SM did not differ by RUX use status (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.65-1.42; P = .84) or by proportion of days covered by RUX (every 10% increase; HR, 1.00; 95% CI, 0.96-1.05; P = .95). RUX exposure did not affect the risk of solid SM (HR, 0.77; 95% CI, 0.48-1.23; P = .27) or lymphoid SM (HR, 1.73; 95% CI, 0.79-3.80; P = .17). Our results suggest that RUX use does not increase the risk of SM in older patients with MPN.}, }
@article {pmid41217670, year = {2025}, author = {Liu, ZY and Chen, GC and LaMonte, MJ and Kamensky, V and Evenson, KR and Shadyab, AH and Luo, J and Allison, M and Wild, RA and Going, SB and Eaton, CB and Stone, KL and Bea, JW and Seguin-Fowler, RA and Johnson, KC and Kaplan, RC and Rohan, TE and Wassertheil-Smoller, S and Qi, Q}, title = {Longitudinal transitions in sedentary behavior and physical activity in relation to all-cause and cause-specific mortality among postmenopausal women.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {41217670}, issn = {2509-2723}, support = {K01HL129892/HL/NHLBI NIH HHS/United States ; R01HL060712/HL/NHLBI NIH HHS/United States ; R01HL140976/HL/NHLBI NIH HHS/United States ; R01-HL146132-01/HL/NHLBI NIH HHS/United States ; R01DK119268/DK/NIDDK NIH HHS/United States ; R01DK120870/DK/NIDDK NIH HHS/United States ; 5R01CA227122//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; }, abstract = {To evaluate longitudinal transitions in sedentary behavior and physical activity for the associations with all-cause and cause-specific mortality (i.e., cardiovascular disease [CVD], cancer, respiratory, and Alzheimer's disease/dementia mortality) among postmenopausal women. This prospective cohort study included 58,168 multiethnic US postmenopausal women from the Women's Health Initiative Observational Study, who had self-reported data on various sedentary behaviors and recreational physical activity at baseline (Y0: 1993-1998; age range: 50-79 years) and after 6 years (Y6). According to sedentary time (≥ 8 h/day or not) or physical activity (≥ 8.5 MET-h/week or not) at Y0 and Y6 assessments, participants were grouped by transition in sedentary behavior (consistently non-sedentary, sedentary to non-sedentary, non-sedentary to sedentary, and consistently sedentary) or physical activity levels (consistently low, high to low, low to high, and consistently high). Over a median follow-up of 15.0 years (from Y6 to March 2019), 17,354 all-cause deaths occurred, ranging from 1336 respiratory to 5111 CVD deaths. Compared to the consistently non-sedentary group, the two groups with unfavorable transitions in sedentary behavior (i.e., from non-sedentary to sedentary or being consistently sedentary) both had a higher risk of all-cause mortality and mortality from CVD, cancer, and respiratory disease. Conversely, the two groups with favorable transitions in physical activity (i.e., transitioning to or maintaining high activity), as compared with the consistently-low activity group, both had a lower risk mortality from all causes and several specific causes. Significant interactions were observed between transitions in sedentary behavior and physical activity on the risk of all-cause and CVD mortality (P-interaction < 0.01). Specifically, unfavorable sedentary transitions were associated with an elevated risk only among women with unfavorable transitions in physical activity. Among US postmenopausal women, maintaining or transiting to a sedentary lifestyle over 6 years was associated with a higher risk of mortality, predominantly among those not achieving regular physical activity over the years.}, }
@article {pmid41218661, year = {2026}, author = {Ford, EC and Evans, S and Salter, B and Bazan, JG and Weintraub, SM and Moran, JM and Olsen, JR and Dalton, AP and Kujundzic, K and Wilson, E and Marks, LB}, title = {Operations and Impact of a Specialty-Specific National Incident Learning System: Ten Years of Radiation Oncology Incident Learning System (RO-ILS).}, journal = {International journal of radiation oncology, biology, physics}, volume = {124}, number = {2}, pages = {265-277}, doi = {10.1016/j.ijrobp.2025.10.027}, pmid = {41218661}, issn = {1879-355X}, mesh = {*Radiation Oncology/education/organization &amp; administration/standards ; Humans ; United States ; *Patient Safety ; *Risk Management/organization &amp; administration ; *Medical Errors/prevention &amp; control/statistics &amp; numerical data ; }, abstract = {Incident learning is recognized by national and international organizations as a key component of maintaining safety and quality in health care. In 2014, RO-ILS: Radiation Oncology Incident Learning System was launched by the American Society for Radiation Oncology and the American Association of Physicists in Medicine with the goal of facilitating safer and higher-quality care in radiation oncology. This review discusses the structure of the RO-ILS program, its foundations and operations, as well as outcomes in terms of engagement and learning opportunities. RO-ILS operates under the auspices and protection of patient safety organization in the United States. As of the end of 2024, 781 facilities have enrolled in the program, representing a mixture of United States practice settings (private practice, community/academic, free-standing/hospital-based, and small/large). A cumulative 41,516 events have been reported to the patient safety organization, the largest volume of events compared to other national and international aggregated incident learning systems in radiation oncology. A minority of events (24%) are incidents, that is, events that actually reached a patient regardless of harm. Approximately 10% of events were rated as potentially severe or critical. A key feature of the RO-ILS program is reports and other releases aimed at education and quality improvement. Over 100 releases have been issued, including case studies, great catches, safety notices, and themed reports, as well as industry webinars and user meetings. While there is evidence of success and engagement in the RO-ILS program, current and future challenges include the quantity and quality of reported data, the ability to effectively extract information, further engagement of key stakeholders, and program sustainability. These must be addressed for RO-ILS to continue to fulfill the mission of supporting safer and higher-quality care in radiation oncology.}, }
@article {pmid41219045, year = {2025}, author = {Chen, F and Sheng, X and Wang, A and Xu, Y and Hughley, R and Xiong, W and Pooler, L and Wan, P and Gundell, SM and Kigozi, G and Nakigozi, G and Nalugoda, F and Kagaayi, J and Kigozi, GN and Mugamba, S and Kyasanku, E and Nkale, J and Olwa, VO and Lubwama, A and Daama, A and Nakajugo, R and Adusei, B and Jalloh, M and Gueye, SM and Adjei, AA and Mensah, J and Fernandez, PW and Adebiyi, AO and Olufemi Ogunbiyi, J and Aisuodionoe-Shadrach, OI and Petersen, L and Chen, WC and McBride, J and Bensen, JT and Mohler, JL and Taylor, JA and Andrews, C and Kigongo, M and Colline, A and Kiddu, V and Namugambe, J and Owamaani, S and Job, K and Masaba, BJ and Asiimwe, F and Muwanga, P and Namulondo, J and Nagawa, F and Kayiraba, C and Ogwang, M and Okidi, R and Oweka, D and Kitara, E and Obonyo, J and Lajul, D and Matovu, P and Muheki, PA and Natumanya, J and Agaba, E and Aculokin, E and Twongyeirwe, A and Mutema, G and Bitamazire, D and Butler, EN and Ingles, SA and Rybicki, BA and Stanford, JL and Zheng, W and Berndt, SI and Chanock, SJ and Huff, CD and Lachance, J and Multigner, L and Darst, BF and Rebbeck, TR and Brureau, L and Watya, S and Conti, DV and Haiman, CA}, title = {Integrating Pathogenic Variants, Polygenic Risk Score, and Family History for Prostate Cancer Risk Estimation in Men of African Ancestry.}, journal = {European urology}, volume = {}, number = {}, pages = {}, pmid = {41219045}, issn = {1873-7560}, support = {U01 CA164973/CA/NCI NIH HHS/United States ; U19 CA214253/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) remains understudied in large populations of African ancestry. This study aims to characterize the range of genetic risk of PCa and aggressive disease phenotypes in men of African ancestry.<br><br>METHODS: We analyzed 7176 PCa cases and 4873 controls from seven countries across North America and Africa to assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were used to estimate lifetime absolute risk based on family history, polygenic risk score (PRS), and PV carrier status.<br><br>KEY FINDINGS AND LIMITATIONS: PVs in ATM, BRCA2, CHEK2, HOXB13, and PALB2 were presented in 4% of aggressive/metastatic PCa cases and were significantly associated with an increased risk of aggressive PCa (odds ratio 2.18-5.96, p&#xa0;<&#xa0;0.05). Lifetime absolute risk varied widely depending on PV carrier status, PRS, and family history, ranging from 3.0% to 74% for overall PCa, 0.6% to 41% for aggressive PCa, and 0.2% to 37% for metastatic PCa. PV carriers with a positive family history and a PRS in the 90th percentile had seven, 18, and 34 times the risks of overall, aggressive, and metastatic PCa, respectively, compared with average-risk individuals. Oversampling of aggressive cases may limit the generalizability of these findings to screening populations.<br><br>Integration of PV status, PRS, and family history enables more refined PCa risk estimates. The wide range of PCa risk observed among men of African ancestry in our study supports future prospective studies in the development of risk-stratified cancer screening programs to identify high-risk individuals who may benefit from screening at an earlier age.}, }
@article {pmid41221958, year = {2026}, author = {Rees, MJ and Khouri, J and Grajales-Cruz, AF and Zanwar, SS and Goel, U and Midha, S and Kelley, J and Puglianini, OC and Corraes, AMS and Raza, S and Davis, JA and Green, K and Hansen, DK and Banerjee, R and Sidana, S and Patel, KK and Bianchi, G and Sborov, DW and Lee, S and Kumar, SK and Baz, R and Anwer, F and Mikkilineni, L and Nadeem, O and Lin, Y and Anderson, LD}, title = {The Real-World Safety and Efficacy of Bispecific T-Cell Engager Therapy in Systemic AL Amyloidosis.}, journal = {American journal of hematology}, volume = {101}, number = {1}, pages = {187-192}, doi = {10.1002/ajh.70140}, pmid = {41221958}, issn = {1096-8652}, }
@article {pmid41222477, year = {2026}, author = {Takashima, Y and Dias Costa, A and Akimoto, N and Ugai, T and Bell, P and Väyrynen, JP and Hornick, JL and Mino-Kenudson, M and Zhong, Y and Ugai, S and Haruki, K and Yao, Q and Matsuda, K and Higashioka, M and Buchanan, DD and Phipps, AI and Peters, U and Giannakis, M and Song, M and Chan, AT and Fuchs, CS and Nowak, JA and Ogino, S}, title = {T-cell Subset Features and Distributions Evolve across the Colorectal Precancer-Cancer Spectrum.}, journal = {Cancer immunology research}, volume = {14}, number = {1}, pages = {46-59}, pmid = {41222477}, issn = {2326-6074}, support = {R01 CA248857/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; C10674/A27140//Cancer Research UK Grand Challenge Award/ ; //American Institute for Cancer Research (AICR)/ ; P01 CA87969//National Institutes of Health (NIH)/ ; R35 CA197735/CA/NCI NIH HHS/United States ; R21 CA230873/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P01 CA55075//National Institutes of Health (NIH)/ ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; R50 CA274122/CA/NCI NIH HHS/United States ; //Prevent Cancer Foundation (PCF)/ ; U01 CA261961/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/immunology/pathology ; Female ; Male ; *T-Lymphocyte Subsets/immunology/metabolism ; Tumor Microenvironment/immunology ; Aged ; *Precancerous Conditions/immunology/pathology ; Middle Aged ; *Lymphocytes, Tumor-Infiltrating/immunology ; Prospective Studies ; }, abstract = {The immune microenvironment is a crucial component of colorectal carcinoma that has been well characterized, but much less is known about the immune microenvironment of colorectal carcinoma precursors. We hypothesized that T-cell infiltrates might differ across the colorectal neoplastic spectrum. We leveraged the prospective cohort incident-tumor biobank method, which provided formalin-fixed, paraffin-embedded tumor tissue specimens (N = 1,825) from 790 colorectal carcinoma precursors (including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, tubular adenomas, tubulovillous adenomas, and villous adenomas) and 1,035 colorectal carcinomas. We performed an in situ multispectral immunofluorescence assay for CD3, CD4, CD8, FOXP3 (negative, low, or high expression), PTPRC (CD45RO and CD45RA), MKI67 (Ki-67), and KRT (keratin) combined with supervised machine learning. CD3+CD4+ cells were more abundant than CD3+CD8+ cells in most precursors. In conventional adenomas, greater villous component correlated with fewer intraepithelial CD3+CD8+ cells. Serrated lesions, including hyperplastic polyps and sessile serrated lesions, exhibited higher densities of intraepithelial CD3+CD8+ cells compared with other precursors and carcinomas. Age strata of patients with precursors (including early-onset precursors) were not associated with differential T-cell infiltration patterns. Compared with invasive colorectal carcinoma, precursors generally showed higher densities of CD3+CD4+ cells and CD3+CD8+ cells with phenotypes of naive (CD45RA+CD45RO-), memory (CD45RA-CD45RO+), and regulatory (FOXP3+Low and FOXP3+High) in intraepithelial and lamina propria/stromal regions. In conclusion, T-cell infiltration patterns vary across different histopathologic types of the colorectal neoplastic spectrum from precursors to invasive carcinomas. Our findings shed light on how the tumor-immune microenvironment evolves during precursor development and progression to colorectal carcinoma.}, }
@article {pmid41224138, year = {2026}, author = {Minus, E and Coley, RY and Shortreed, SM and Williamson, BD}, title = {Behavior of prediction performance metrics with rare events.}, journal = {Journal of clinical epidemiology}, volume = {189}, number = {}, pages = {112046}, pmid = {41224138}, issn = {1878-5921}, support = {R01 MH125821/MH/NIMH NIH HHS/United States ; U19 MH092201/MH/NIMH NIH HHS/United States ; U19 MH121738/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; *Area Under Curve ; ROC Curve ; Computer Simulation ; *Suicide, Attempted/statistics &amp; numerical data ; Predictive Value of Tests ; Models, Statistical ; }, abstract = {OBJECTIVE: Area under the receiver operating characteristic curve (AUC) is commonly reported alongside prediction models for binary outcomes. Recent articles have raised concerns that AUC might be a misleading measure of prediction performance in the rare event setting. This setting is common since many events of clinical importance are rare. We aimed to determine whether the bias and variance of AUC are driven by the number of events or the event rate. We also investigated the behavior of other commonly used measures of prediction performance, including positive predictive value, accuracy, sensitivity, and specificity.<br><br>STUDY DESIGN AND SETTING: We conducted a simulation study to determine when or whether AUC is unstable in the rare event setting by varying the size of datasets used to train and evaluate prediction models. This plasmode simulation study was based on data from the Mental Health Research Network; the data contained 149 predictors and the outcome of interest, suicide attempt, which had event rate 0.92% in the original dataset.<br><br>RESULTS: Our results indicate that poor AUC behavior-as measured by empirical bias, variability of cross-validated AUC estimates, and empirical coverage of confidence intervals-is driven by the number of events in a rare-event setting, not event rate. Performance of sensitivity is driven by the number of events, while that of specificity is driven by the number of nonevents. Other measures, including positive predictive value and accuracy, depend on the event rate even in large samples.<br><br>CONCLUSION: AUC is reliable in the rare event setting provided that the total number of events is moderately large; in our simulations, we observed near zero bias with 1000 events.<br><br>PLAIN LANGUAGE SUMMARY: Predicting self-harm or suicidal behavior is medically important for guiding clinicians in providing care to patients. Several research teams have developed and evaluated suicide risk prediction models based on health records data. Part of evaluating these models is calculating area under the receiver operating characteristic curve (AUC) and other prediction performance metrics. Self-harm and suicide are rare events. Recent research has raised concerns with using AUC in rare-event settings. We aimed to determine whether having a sufficiently large dataset could remove these concerns. In our experiments, we found that AUC can be used without concern in settings with 1000 events or more. Thus, AUC is a valid measure of suicide risk prediction model performance in many large healthcare databases.}, }
@article {pmid41228468, year = {2025}, author = {Teruel Camargo, J and Recinos, G and Hinerman, AS and Duong, C and Rodriquez, EJ and Juarez, JJ and McClain, AC and Alver, SK and Daviglus, ML and Van Horn, L and Pérez-Stable, EJ}, title = {Pulse Consumption and Metabolic Syndrome: Findings from the Hispanic Community Health Study/Study of Latinos.}, journal = {Nutrients}, volume = {17}, number = {21}, pages = {}, pmid = {41228468}, issn = {2072-6643}, support = {N01HC65233, N01HC65234, N01HC65235, N01HC65236, N01HC65237/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Diet ; *Hispanic or Latino/statistics &amp; numerical data ; *Metabolic Syndrome/epidemiology/ethnology/physiopathology/prevention &amp; control ; Risk Factors ; }, abstract = {Background/Objectives: Metabolic syndrome affects half of middle-aged (ages 45-64) Hispanic or Latino (Latino) adults. Pulses, fiber-rich plant proteins common in Latino diets (e.g., dry beans and lentils), may mitigate metabolic syndrome. We evaluated the association between pulse intake and metabolic syndrome. Methods: We analyzed data from 6,958 adults aged ≥ 50 in the Hispanic Community Health Study/Study of Latinos (2008-2011) Visit 1. Pulse intake was assessed using two 24 h dietary recalls and categorized into no, low (<1/2 cup), moderate (≥1/2 to 3/4 cup), and high pulse (>3/4 cup) daily intake groups. Metabolic syndrome was defined by criteria including blood pressure ≥130/85 mmHg or medication use, triglycerides ≥150 mg/dL or medication use, high-density lipoprotein cholesterol (men <40 mg/dL and women <50 mg/dL), and waist circumference (men ≥102 cm and women ≥88 cm). We used multivariate logistic regression models with predicted probability proportions to assess the association adjusted for sociodemographic factors, acculturation, diet quality, energy intake, and physical activity. Results: Of the 6,958 participants, 53.1% had metabolic syndrome and 53.4% had a moderate or high pulse intake. Pulse intake varied, where 19.4% had a high intake, 33.9% had a moderate intake, 12.5% had a low intake, and 34.2% had no intake. Moderate (predicted marginal = 0.52, 95% confidence interval [CI] = 0.49, 0.55) and high (predicted marginal = 0.49, 95%CI = 0.45, 0.53) intakes were associated with a lower prevalence of metabolic syndrome. Conclusions: Among Latino adults ≥50 years old, a moderate or high pulse intake was associated with a lower prevalence of metabolic syndrome. Increasing the pulse intake in the population may be linked to reduced metabolic syndrome.}, }
@article {pmid41233693, year = {2025}, author = {Dussault, N and Henderson, K and Daniel, K and Mitchell, NM and Nickolopoulos, E and Hemming, P and Casarett, D and Cho, A and Ma, JE}, title = {Reply to the Letter to the Editor re: Evaluating a Clinical Chaplain Pilot Intervention to Facilitate Advance Care Planning in a Primary Care Clinic.}, journal = {Journal of general internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1007/s11606-025-10044-4}, pmid = {41233693}, issn = {1525-1497}, }
@article {pmid41235976, year = {2026}, author = {Hunter, BD and Lunning, M and Shadman, M and Ahmed, S and Abramson, JS and Perales, MA and Ahmed, N and Mirza, AS and Isufi, I and Frigault, MJ and Crombie, JL and Miklos, DB and Vasconcelos, A and Crotta, A and Bernasconi, D and Roy, D and Bleickardt, E and Pasquini, MC and Kamdar, M}, title = {CRS or ICANS Are Rare Beyond 2 Weeks After Lisocabtagene Maraleucel Infusion: Data From Clinical Trials and the Real-World Setting.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {2}, pages = {171.e1-171.e12}, pmid = {41235976}, issn = {2666-6367}, support = {U01 AI184132/AI/NIAID NIH HHS/United States ; R01 CA231838/CA/NCI NIH HHS/United States ; R21 AG077024/AG/NIA NIH HHS/United States ; U24 HL157560/HL/NHLBI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; OT3 HL147741/HL/NHLBI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; R01 AI150999/AI/NIAID NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; R01 HL171117/HL/NHLBI NIH HHS/United States ; R01 AI128775/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; P01 CA111412/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Immunotherapy, Adoptive/adverse effects/methods ; *Cytokine Release Syndrome/etiology ; Adult ; Aged ; *Neurotoxicity Syndromes/etiology ; Clinical Trials as Topic ; Receptors, Chimeric Antigen ; }, abstract = {Improved understanding of the timing of cytokine release syndrome (CRS) and immune effector cell-mediated neurotoxicity syndrome (ICANS)/neurological events (NE) after chimeric antigen receptor (CAR) T-cell therapy infusion can inform patient safety monitoring. To report CRS and ICANS/NE outcomes, including incidence, onset, and resolution, in patients treated with lisocabtagene maraleucel (liso-cel) in clinical trials and the real-world setting. This analysis included patients treated with liso-cel in 5 clinical trials across different B-cell non-Hodgkin lymphoma indications (n = 702) and in the real-world setting for large B-cell lymphoma, as captured in the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry (n = 877). All outcomes are reported descriptively. Among 702 patients in clinical trials, 54% had any-grade CRS (grade ≥3 at onset, 1%), with 98% of events occurring ≤day 15 after infusion; median time to resolution was 5 days. Any-grade NEs occurred in 31% of patients (grade ≥3 at onset, 5%), with 88% of events occurring ≤day 15 after infusion; median time to resolution was 7 days. Among 877 patients in the real-world setting, 49% had any-grade CRS (maximum grade ≥3, 3%), with 97% of events occurring ≤day 15 after infusion; median time to resolution was 4 days. Any-grade ICANS occurred in 27% of patients (maximum grade ≥3, 10%). Of 150 patients with reported onset date, 95% had onset ≤day 15 after infusion; median time to resolution was 5.5 days. The vast majority of CRS or ICANS/NEs occurred ≤day 15 after liso-cel infusion. These results support the recently updated United States Food and Drug Administration monitoring requirements aimed to improve treatment access while maintaining patient safety.}, }
@article {pmid41236449, year = {2026}, author = {Kim, NJ and Li, M and Vutien, P and Mecham, B and Borgerding, J and Swarts, K and Atuluru, P and Michel, MC and Barnard Giustini, A and Mezzacappa, C and Berry, K and VoPham, T and Marsh, TL and Feng, Z and Johnson, KM and Beste, LA and Kaplan, DE and Taddei, TH and Ioannou, GN}, title = {Changes in Liver Disease Etiology Support a Lower Alpha-Fetoprotein Threshold for Hepatocellular Carcinoma Screening.}, journal = {Gastroenterology}, volume = {170}, number = {3}, pages = {606-618}, doi = {10.1053/j.gastro.2025.08.021}, pmid = {41236449}, issn = {1528-0012}, mesh = {Humans ; *Carcinoma, Hepatocellular/diagnosis/blood/etiology/epidemiology ; *Liver Neoplasms/diagnosis/blood/etiology/epidemiology ; *alpha-Fetoproteins/analysis ; Male ; *Early Detection of Cancer/methods ; Middle Aged ; Female ; United States/epidemiology ; Aged ; Liver Cirrhosis/blood/diagnosis ; *Biomarkers, Tumor/blood ; Predictive Value of Tests ; Hepatitis C/complications ; Liver Diseases, Alcoholic/blood/complications/diagnosis ; Retrospective Studies ; Sensitivity and Specificity ; }, abstract = {BACKGROUND &amp; AIMS: Serum alpha-fetoprotein (AFP) is a key component of hepatocellular carcinoma (HCC) screening, but its test characteristics are uncertain as alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD) rates increase.<br><br>METHODS: We evaluated AFP trends at HCC diagnosis and estimated its test performance for HCC screening in cirrhosis using Veterans Health Administration (VHA) and United Network for Organ Sharing data.<br><br>RESULTS: Among the 40,399 VHA patients diagnosed with HCC between 2001 and 2021, median AFP at HCC diagnosis declined over time and was highest in active-hepatitis C (HCV) (32.7 vs cured-HCV 8.3, ALD 9.0, MASLD 7.7 ng/mL). Among the 28,170 VHA patients with cirrhosis receiving care in 2019 (9.6% active-HCV, 43% cured-HCV, 24% ALD, 14% MASLD), 1,029 developed HCC in 2019. At AFP thresholds &#x2265;20 and &#x2265;10 ng/mL, the overall sensitivity/specificity for HCC screening was 31.7%/98.5% and 41.9%/94.1%, respectively. Lowering the AFP threshold to &#x2265;10 ng/mL increased sensitivity with minimal reductions in specificity across all liver disease etiologies: active-HCV (sensitivity/specificity: 43.7% to 60.7%/92.6% to 83.0%), cured-HCV (32.5% to 41.5%/99.0% to 94.7%), ALD (22.8% to 32.3%/99.2% to 95.1%), and MASLD (21.7% to 29.9%/99.4% to 96.7%). Analysis of United Network for Organ Sharing (26,213 patients with HCC) resulted in similar increases in test sensitivity as the AFP threshold declined from &#x2265;20 to &#x2265;10 ng/mL (overall: 31.8% to 48.7%; active-HCV: 36.7% to 58.6%, cured-HCV: 21.4% to 36.4%, MASLD: 19.1% to 33.4%, and ALD: 15.9% to 27.1%).<br><br>CONCLUSIONS: For HCC screening in MASLD, ALD, and cured-HCV cirrhosis, reducing the AFP threshold to &#x2265;10 ng/mL would substantially increase sensitivity while maintaining very high specificity.}, }
@article {pmid41237309, year = {2025}, author = {Kanellopoulou, A and Bouras, E and Chan, AT and Marchand, LL and Wolk, A and Wu, AH and Gunter, MJ and Nimptsch, K and Haycock, P and Lewis, SJ and Martin, RM and Zuber, V and Phipps, AI and Peters, U and Van Duijnhoven, FJB and Tsilidis, KK}, title = {Investigating the association between anthropometry and colorectal cancer survival: a two-sample Mendelian randomization analysis.}, journal = {International journal of epidemiology}, volume = {54}, number = {6}, pages = {}, pmid = {41237309}, issn = {1464-3685}, support = {C18281/A29019//Cancer Research UK programme grant, the Integrative Cancer Epidemiology Programme/ ; NIHR202411//Cancer Research UK programme grant, the Integrative Cancer Epidemiology Programme/ ; //NIHR Bristol Biomedical Research Centre/ ; }, mesh = {Humans ; Mendelian Randomization Analysis ; *Colorectal Neoplasms/mortality/genetics ; Male ; Female ; Body Mass Index ; Middle Aged ; Waist Circumference/genetics ; Waist-Hip Ratio ; Aged ; *Anthropometry ; Birth Weight/genetics ; Body Height/genetics ; Proportional Hazards Models ; }, abstract = {BACKGROUND: Observational epidemiologic studies on the association of anthropometric traits and colorectal cancer (CRC) survival provide inconsistent results, and potential limitations prohibit the investigation of causality. We examined the associations between seven genetically predicted anthropometric traits [height, body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-hip circumference ratio, birth weight and body fat percentage] and CRC-specific mortality among CRC cases using two-sample Mendelian randomization (MR).<br><br>METHODS: Analyses were performed using 16&#xa0;964 CRC cases, out of which 4010 died due to their disease, from the Genetics and Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry. We further conducted stratified analyses by anatomical site and stage. We applied the inverse variance weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions and adjust for collider bias.<br><br>RESULTS: One standard deviation (SD 13.4&#x2009;cm) higher genetically predicted levels of WC were associated with worse CRC survival [hazard ratio (HR); 1.22, 95% confidence interval (CI); 1.02-1.47]. Positive associations were further observed for a SD higher genetically predicted BMI (SD; 4.8&#x2009;kg/m2, HR; 1.5, 95% CI; 1.15-1.95) and HC (SD; 9.2&#x2009;cm, HR; 1.32, 95% CI; 1.02-1.73) and CRC-specific mortality in cases of stages II/III. The latter associations were generally robust to sensitivity analyses. Positive but imprecisely estimated associations were found for most other anthropometric traits.<br><br>CONCLUSIONS: Despite the limitations of cancer survival research, our findings support that CRC cases should avoid obesity. Further research should inform the development of recommendations targeting overweight/obesity management during cancer surveillance.}, }
@article {pmid41237667, year = {2025}, author = {Voillet, V and van Duijn, J and Vanshylla, K and Dintwe, OB and Pattacini, L and Omar, FL and Khuzwayo, S and Euler, Z and Schwedhelm, K and MacMillan, HR and Gilbert, PB and Fiore-Gartland, A and Newell, EW and Hendriks, J and McElrath, MJ and Stieh, DJ and De Rosa, SC and Andersen-Nissen, E}, title = {Unbiased cell clustering analysis of vaccine-induced T cell responses in the Imbokodo HIV-1 vaccine trial.}, journal = {EBioMedicine}, volume = {122}, number = {}, pages = {106017}, pmid = {41237667}, issn = {2352-3964}, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage ; *HIV-1/immunology ; *HIV Infections/immunology/prevention &amp; control/virology ; Cluster Analysis ; Female ; Male ; Adult ; *T-Lymphocytes/immunology/metabolism ; CD8-Positive T-Lymphocytes/immunology/metabolism ; CD4-Positive T-Lymphocytes/immunology/metabolism ; Vaccination ; T-Lymphocyte Subsets/immunology/metabolism ; Middle Aged ; Immunophenotyping ; }, abstract = {BACKGROUND: HIV-1 T cell responses are associated with viral control and may be protective in a prophylactic vaccination setting. Traditional methods for analysing these responses might be biased towards specific functionalities or epitopes. This study presents an unsupervised and unbiased clustering analysis workflow, using the Leiden algorithm followed by selection of antigen-specific clusters using MIMOSA positivity calls, for high-dimensional flow cytometry data to identify distinct T cell populations associated with protection in the HVTN 705/HPX2008/Imbokodo HIV-1 vaccine efficacy trial.<br><br>METHODS: Participants were vaccinated with Ad26.Mos4.HIV (M0, M3) and Ad26.Mos4.HIV + Clade C gp140 (M6, M12), and a validated 28-colour intracellular cytokine staining assay was performed on PBMC isolated at M7, M13 and M24 in a pilot immunogenicity (n = 60) and case-control cohort (n = 283). 28-colour phenotyping assays were also performed on PBMC from the case-control cohort (n = 334).<br><br>FINDINGS: Our clustering analysis workflow allowed identification of vaccine-induced subpopulations of both CD4+ and CD8+ T cells expressing combinations of the 28 markers. Durable HIV-1 antigen-specific CD4+ and CD8+ T cell responses were observed for up to 2 years, comprising mainly clusters of polyfunctional T cells expressing anti-viral cytokines and activation markers. Eight CD4+ and six CD8+ HIV-1 antigen-specific T cell clusters were induced by vaccination; only one CD4+ T cell cluster specific for Gag was mildly elevated in cases (acquiring HIV) compared to controls.<br><br>INTERPRETATION: Our study introduces an innovative analysis approach to identify vaccine-induced T cell subpopulations in vaccine trials. Comparison of T cell clusters between cases and controls holds promise for improving the efficacy of future HIV-1 vaccination strategies.<br><br>FUNDING: This work was funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the Division of AIDS (DAIDS), both of the US National Institutes of Health (NIH) [NIAID grants to the HIV Vaccine Trials Network (HVTN) (Fred Hutchinson Cancer Center): UM1AI068618 (HVTN LC to M.J.M.) and UM1AI068635 (HVTN SDMC to P.B.G.)] and by Janssen Vaccines &amp; Prevention B.V. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or Janssen.}, }
@article {pmid41239501, year = {2025}, author = {Terashima, M and Nakayama, K and Shirai, S and Ugai, S and Lee, HY and Matsui, H and Mizuno, H and Tanaka, S and Song, M and Sasamoto, N and Kawachi, I and Giovannucci, EL and Ugai, T}, title = {Diverging global incidence trends of early-onset cancers: comparisons with incidence trends of later-onset cancers and mortality trends of early-onset cancers.}, journal = {Military Medical Research}, volume = {12}, number = {1}, pages = {79}, pmid = {41239501}, issn = {2054-9369}, support = {R50 CA274122/NH/NIH HHS/United States ; 23K20052//Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; Incidence ; Female ; *Neoplasms/epidemiology/mortality ; Male ; Adult ; Middle Aged ; *Age of Onset ; Global Health/statistics &amp; numerical data ; *Mortality/trends ; }, abstract = {BACKGROUND: The global increase in the incidence of early-onset cancers (defined as cancers diagnosed at 20-49 years old) is a serious public health problem. We investigated 1) whether the incidence trend of early-onset cancers differs from that of later-onset cancers and 2) whether both the incidence and mortality of early-onset cancers have increased concurrently.<br><br>METHODS: We utilized age-standardized incidence and mortality rates for early-onset and later-onset cancers diagnosed between 2000 and 2017 from the Cancer Incidence in Five Continents and World Health Organization (WHO) mortality databases. The national obesity prevalence among adults aged 20-49&#xa0;years was obtained from the National Clinical Database. Using joinpoint regression models, we calculated average annual percentage changes (AAPCs) for cancer incidence and mortality by cancer types and countries. We additionally conducted human development index (HDI)-stratified analyses and assessed the correlation between the obesity prevalence in younger populations and early-onset cancer incidence by country. To investigate the more recent trend of early-onset cancer mortality, we extended our mortality analysis after 2017 for cancer types and countries with statistically significant positive AAPCs in both incidence and mortality of early-onset cancers between 2000 and 2017.<br><br>RESULTS: Our analysis showed that 10 early-onset cancer types (thyroid cancer, breast cancer, melanoma, uterine cancer, colorectal cancer, kidney cancer, cervical cancer, pancreatic cancer, multiple myeloma, Hodgkin lymphoma) in females and 7 early-onset cancer types (thyroid cancer, kidney cancer, testis cancer, prostate cancer, colorectal cancer, melanoma, leukemia) in males had statistically significant positive AAPCs in at least 10 countries. Among these, the following early-onset cancer types had significantly higher AAPCs than later-onset cancer types in females: colorectal cancer (6 countries; AAPC range: 1.8-3.8%), cervical cancer (6 countries; AAPC range: 1.2-3.3%), pancreatic cancer (5 countries; AAPC range: 2.3-13.0%), and multiple myeloma (5 countries; AAPC range: 3.1-9.8%); in males: prostate cancer (12 countries; AAPC range: 3.9-18.4%), colorectal cancer (8 countries; AAPC range: 1.8-3.2%), and kidney cancer (6 countries; AAPC range: 2.0-6.0%). We observed statistically significant positive AAPCs in both the incidence and mortality of the following early-onset cancer types: uterine cancer (5 countries) and colorectal cancer (3 countries in females and 5 countries in males). The steeper increases in early-onset cancers compared with later-onset cancers were mainly observed in the very high-HDI country group, including early-onset colorectal cancer (AAPC&#x2009;=&#x2009;2.4%, 95% CI 2.1-2.6 in females; AAPC&#x2009;=&#x2009;2.0%, 95% CI 1.7-2.4 in males) to later-onset colorectal cancer (AAPC = -0.1%, 95% CI -0.2 to 0 in females; AAPC = -0.2%, 95% CI -0.3 to 0 in males). We observed strong positive correlations between the increasing obesity prevalence and the rising incidence of early-onset obesity-related cancers in several countries, including Australia (7 cancer types), United Kingdom (7 cancer types), Canada (7 cancer types), Republic of Korea (7 cancer types), and USA (6 cancer types) in females and United Kingdom (7 cancer types), Canada (6 cancer types), Australia (5 cancer types), Sweden (5 cancer types), and Republic of Korea (4 cancer types) in males. Although we did not observe an apparent spike after 2017 in many countries, we observed continued increases in the mortality of certain cancer types, such as uterine cancer (Japan, Republic of Korea, United Kingdom, USA, and Ecuador) in females and colorectal cancer (Argentina, Canada, United Kingdom, and USA) in males.<br><br>CONCLUSIONS: The increase in many early-onset cancer types was significantly higher than that of later-onset cancers, and the incidence and mortality of certain early-onset cancer types (such as colorectal cancer) increased simultaneously. Our study highlights global differences in cancer incidence and mortality trends of early-onset and later-onset cancers.}, }
@article {pmid41243521, year = {2025}, author = {Hirsch, J and Cadet, T and Wells, K and Thompson, B and Bullock, K and Nedjat-Haiem, FR}, title = {Perspectives of Advance Care Planning for Latinos During COVID-19.}, journal = {The American journal of hospice &amp; palliative care}, volume = {}, number = {}, pages = {10499091251396828}, pmid = {41243521}, issn = {1938-2715}, support = {K23 AG062795/AG/NIA NIH HHS/United States ; S21 MD010690/MD/NIMHD NIH HHS/United States ; U54 MD012397/MD/NIMHD NIH HHS/United States ; }, abstract = {Latinos face challenges in accessing care for serious illness and lack preparedness for healthcare crises which were exacerbated by the COVID-19 pandemic. Following a social ecological model, this study explored perceptions of advanced care planning (ACP) for Latinos from key informants including community members and health care providers. A total of 12 focus groups including 25 community members and 24 providers were completed in both English and Spanish from April to July of 2020. Using a grounded theory approach and constant comparison, we identified 4 primary themes: underlying vulnerabilities and barriers to ACP, the pandemic context, unique Latino pandemic experience, and urgency to do ACP because of COVID. The Latino experience reflects a complex interplay between 2 macro systems, a unique Latino experience and the pandemic, which included significant communication gaps, isolation, mistrust, and anxiety. The pandemic was an eye-opening experience for many Latinos which has made ACP more relevant as awareness and knowledge of death and dying shifted.}, }
@article {pmid41248759, year = {2025}, author = {Thonglert, K and Apisarnthanarax, S and Yeap, BY and Havard, ME and Schaub, SK and Nyflot, MJ and Bowen, SR and He, Y and Tsai, J and De, BS and Chamseddine, I and Pursley, J and Roberts, H and Wo, J and Prayongrat, A and Alisanant, P and Amornwichet, N and Khorprasert, C and Hong, T and Koay, EJ and Grassberger, C}, title = {Establishing Albumin-Bilirubin Score Changes as Predictors of Radiation-Induced Liver Disease in Hepatocellular Carcinoma Patients Post-External Beam Radiation Therapy.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2025.11.009}, pmid = {41248759}, issn = {1879-355X}, support = {P01 CA261669/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: To determine albumin-bilirubin (ALBI) score change thresholds that indicate hepatotoxicity and predict poorer overall survival (OS) in hepatocellular carcinoma patients post-external beam radiation therapy (EBRT).<br><br>METHODS AND MATERIALS: The development cohort consisted of 329 hepatocellular carcinoma patients treated with liver-targeted EBRT across 2 centers from 2008 to 2023, with 71% classified as Child-Pugh (CP) A and 29% as CP-B/C. Recursive partitioning analysis identified thresholds associated with OS, which were evaluated using Cox regression, compared to a 2-point increase in CP score (CP2+) and externally validated using data from 2 independent centers (n = 248). The primary outcome was to establish ALBI score change thresholds associated with poorer OS. Secondary outcomes included comparing the prognostic accuracy of ALBI score change thresholds with the CP2+ criterion, analyzing the predictive value across different baseline liver functions, and examining the association between radiation dose to the normal liver and ALBI score changes.<br><br>RESULTS: ALBI changes of >0.25 (ALBI change grade 1) and >0.5 (ALBI change grade 2) were identified as optimal thresholds. CP2+ showed superior discriminative performance in the overall cohort; however, when stratifying by baseline liver status, ALBI change grade 1 outperformed CP2+ in CP-B/C patients (hazard ratio, 4.4; 95% CI, 2.4-7.8). Overall, these findings were confirmed in the external validation cohort. Multivariable Cox models, including CP2+ or ALBI changes and baseline liver status, demonstrated higher or similar concordance for ALBI score changes across all data sets. Mean liver dose correlated more strongly with ALBI score changes (logistic regression odds ratio = 1.09/1.07 for grade 1/2) than with CP2+ (odds ratio = 1.04).<br><br>CONCLUSIONS: ALBI score changes of >0.25 and >0.5 are alternatives to CP2+ to evaluate radiation-induced hepatotoxicity, with the potential for more accurate assessment based on baseline liver function. Their objectivity and stronger correlation with normal liver dose make ALBI score changes more suitable for dose-response models aimed at minimizing the risk of liver complications following EBRT.}, }
@article {pmid41249067, year = {2026}, author = {Leichter, SM and Ahmad, K and Henikoff, S}, title = {Polycomb misregulation in enterocytes drives tissue decline in the aging Drosophila intestine.}, journal = {Genome research}, volume = {36}, number = {1}, pages = {102-114}, pmid = {41249067}, issn = {1549-5469}, support = {F32 GM153148/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Enterocytes/metabolism ; *Polycomb-Group Proteins/genetics/metabolism ; *Aging/genetics ; *Drosophila Proteins/genetics/metabolism ; Intestines/cytology ; Histones/metabolism/genetics ; Stem Cells/metabolism ; Cell Proliferation ; Drosophila melanogaster/genetics ; RNA Polymerase II/metabolism/genetics ; Chromatin/metabolism/genetics ; Cell Differentiation ; Intestinal Mucosa/metabolism ; Drosophila/genetics ; }, abstract = {Aging compromises intestinal integrity, yet the chromatin changes driving this decline remain unclear. Polycomb-mediated repression is essential for silencing developmental genes, but this regulatory mechanism becomes dysregulated with age. Although shifts in Polycomb regulation within intestinal stem cells have been linked to gut aging, the Polycomb landscape of differentiated cell types remains unexplored. Differentiated cells comprise the majority of the gut epithelium and directly impact both tissue and whole organismal aging. Using single-cell chromatin profiling of the Drosophila intestine, we identify cell type-specific chromatin landscape changes during aging. We find that old enterocytes aberrantly repress genes essential for transmembrane transport and chitin metabolism, contributing to intestinal barrier decline, an example of antagonistic pleiotropy in a regenerative tissue. Barrier decline leads to derepression of JAK/STAT ligands in all cell types and increased proliferation of aging stem cells, with elevated RNA polymerase II (RNAPII) at S-phase-dependent histone genes. Specific upregulation of histone genes during aging stem cell proliferation resembles RNAPII hypertranscription of histone genes in aggressive human cancers. Our work reveals that misregulation of the Polycomb-mediated H3K27me3 histone modification in differentiated cells during aging not only underlies tissue decline but also mirrors transcriptional changes in cancer, suggesting a common mechanism linking aging and cancer progression.}, }
@article {pmid41252152, year = {2025}, author = {Sergeeva, OA and Jin, G and Sarkar, M and Zeiger, J and Dhindwal, S and Chin, SS and Abulizi, A and Lai, Z and Brown, C and DeMaria, WG and Ryan, D and An, X and Karp, HJ and Teran, E and Yuan, C and Klaskin, D and Reeve, TA and Yu, GK and Tam, EM and Kaech, SM and Preyer, M and Matis, L and Fine, JS and Martomo, SA and Myers, JS}, title = {EVOLVE platform, a trispecific T cell engager with integrated CD2 costimulation, for the treatment of solid and hematologic tumors.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {47}, pages = {e2510829122}, pmid = {41252152}, issn = {1091-6490}, mesh = {Humans ; Animals ; Mice ; *T-Lymphocytes/immunology ; *CD2 Antigens/immunology ; *Antibodies, Bispecific/immunology/pharmacology ; CD3 Complex/immunology ; Cell Line, Tumor ; Lymphocyte Activation/immunology ; *Hematologic Neoplasms/immunology/therapy/drug therapy ; *Neoplasms/immunology/therapy ; Xenograft Model Antitumor Assays ; CD58 Antigens/immunology ; Female ; }, abstract = {Ten CD3 T cell engagers (TCEs) have received regulatory approval for the treatment of hematologic and solid tumors. However, limited costimulatory signaling essential for sustained T cell effector activity may limit CD3 TCE clinical efficacy and response duration. The CD2 receptor is an attractive costimulation target owing to its association with T cell receptor signaling and favorable expression profile. We show that CD2 costimulation is superior in maintaining T cell viability and effector function relative to other pathways in in vitro chronic stimulation assays. The extracellular domain of CD58, the predominant CD2 ligand, is functional as an antibody fusion, improving bispecific potency. We observe that higher CD3 affinity molecules have the potential for superagonism in the context of an integrated CD2 agonist. Evaluation of TCEs with integrated CD2 costimulation and attenuated CD3 binding identified optimal CD3 affinity agonists that avoid target-independent T cell activation and demonstrated an increased therapeutic index relative to nonattenuated CD3 agonists. This platform shows increased tumor-killing efficacy as compared to CD3 affinity-matched bispecifics for known tumor targets such as HER2, CD20, B7-H4, and UL16-binding protein 2 (ULBP2). We demonstrate that ULBP2-targeted trispecifics with integrated CD2 costimulation and optimized CD3 affinity are superior to higher-affinity CD3 molecules in in vivo mouse efficacy studies. This integrated CD2 costimulation platform, which we termed EVOLVE, represents a next-generation TCE platform to increase T cell effector function in the tumor microenvironment and has the potential to address unmet patient needs by improving the depth and durability of clinical antitumor T cell responses.}, }
@article {pmid41252205, year = {2026}, author = {MacLean, F and Zemek, RM and Tsegaye, AT and Graham, JB and Swarts, JL and Vick, SC and Potchen, NB and Cruz Talavera, I and Warrier, L and Dubrulle, J and Schroeder, LK and Elz, A and Sowerby, D and Saito, A and Thomas, KK and Mack, M and Schiffer, JT and McClelland, RS and Jerome, KR and Chohan, BH and Ngure, K and Mugo, NR and Newell, EW and Lingappa, JR and Lund, JM and , }, title = {Genital herpes shedding episodes associate with altered spatial organization and activation of mucosal immune cells.}, journal = {JCI insight}, volume = {11}, number = {1}, pages = {}, pmid = {41252205}, issn = {2379-3708}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; R01 AI131914/AI/NIAID NIH HHS/United States ; R01 AI141435/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; R01 HD114505/HD/NICHD NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R01 AI129715/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *Herpes Genitalis/immunology/virology ; *Herpesvirus 2, Human/immunology ; *Virus Shedding/immunology ; Adult ; Vagina/immunology/virology/pathology ; Mucous Membrane/immunology/virology ; *Immunity, Mucosal/immunology ; Cervix Uteri/immunology/virology ; Middle Aged ; T-Lymphocytes/immunology ; Young Adult ; Transcriptome ; Macrophages/immunology ; }, abstract = {Herpes Simplex Virus 2 (HSV-2) infection results in variable rates of local viral shedding in anogenital skin. The effect of episodic viral exposures on immune cells in adjacent mucosal tissues, including the genital tract, is unknown. However, any immune responses at this site could affect protective mucosal immunity, tissue homeostasis, and adverse health outcomes. To investigate the effect of HSV-2 on cervicovaginal tract immunity, we applied flow cytometry, immunofluorescence imaging, analysis of soluble immune factors, and spatial transcriptomics to cervicovaginal tissue and blood samples provided by a total of 232 HSV-2-seropositive and seronegative participants, with genital HSV-2 shedding evaluated at the time of biopsy. This unique dataset was used to define and spatially map immune cell subsets and localized gene expression via spatial transcriptomics. HSV-2 seropositivity alone was associated with minimal differences in cervicovaginal and circulating T cell phenotypes. However, the vaginal mucosa during active HSV-2 shedding was associated with alterations in T cell, macrophage, and DC localization and gene expression, consistent with increased immune surveillance, with immune activating and suppressing signals potentially reinforcing mucosal tissue homeostasis.}, }
@article {pmid41252670, year = {2026}, author = {Drevdahl, DJ and Canales, MK and Dorcy, KS}, title = {Contesting Professional Nursing Values.}, journal = {Nursing inquiry}, volume = {33}, number = {1}, pages = {e70064}, doi = {10.1111/nin.70064}, pmid = {41252670}, issn = {1440-1800}, support = {//The authors received no specific funding for this work./ ; }, mesh = {Humans ; *Ethics, Nursing/history ; United States ; *Codes of Ethics/history ; *Professionalism ; *Social Values ; History, 20th Century ; }, abstract = {A code of ethics, as proof of nursing professionalism, is used to promote nursing's core values. In the United States, the American Nurses Association's (ANA) Code of Ethics is accepted as the primary source for professional nursing values. Particular processes are used within nursing to embed professional values into nursing discourse. A historical review of the ANA Code of Ethics, a review of published articles about professional nursing values, and an examination of the development and globalization of the Nurses Professional Values Scale informed our examination of nursing's efforts to delineate, instill, and measure professional nursing values. The analysis was informed theoretically by Bourdieu and his concept of "playing the game." Constructing and reinforcing professional nursing values reveals difficulties about what constitutes core nursing values and what they mean, particularly with respect to values that comprise the good nurse; the inability to measure and evaluate said values; and the colonization of Western values globally. The inordinate amount of time and energy spent on nursing values surfaced the vexing nature of such efforts. The concept of profession and its accompanying values must be regarded with suspicion.}, }
@article {pmid41253492, year = {2025}, author = {Kimble, EL and Wright, JH and Torkelson, A and Kirchmeier, DR and Braathen, K and Ruff, RO and Shimp, KR and Seaton, BW and Gauthier, J and Kolokythas, O and Boiani, NE and Jellyman, D and Yeung, CC and Tam, E and Price, JP and Hirayama, A and Turtle, CJ}, title = {Novel antibodies for identification, selection, and manipulation of T cells expressing Whitlow linker-containing CARs.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {11}, pages = {}, pmid = {41253492}, issn = {2051-1426}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Receptors, Chimeric Antigen/immunology/metabolism/genetics ; Mice ; *T-Lymphocytes/immunology/metabolism ; *Antibodies, Monoclonal/immunology ; *Single-Chain Antibodies/immunology ; *Immunotherapy, Adoptive/methods ; *Receptors, Antigen, T-Cell/immunology/metabolism ; }, abstract = {BACKGROUND: The translational study of chimeric antigen receptor (CAR) T-cell function, persistence, immunophenotype, and spatial localization after infusion is crucial for understanding factors that influence clinical outcomes. However, research has been limited by a lack of optimized tools to reliably detect CAR-engineered cells. To address this, we developed a novel platform to generate monoclonal antibodies (mAbs) targeting a linker peptide incorporated in single-chain variable fragments (scFvs) of most CAR constructs.<br><br>METHODS: Using recombinant proteins and scFv linker peptides as immunogens, we generated murine mAbs against the Whitlow linker peptide, capable of binding cells expressing Whitlow linker-containing CARs in both fresh and formalin-fixed paraffin-embedded (FFPE) tissues. We evaluated these antibodies in multiple in vitro translational applications relevant to CAR T-cell research and manufacturing.<br><br>RESULTS: We identified five unique mAbs reactive against the Whitlow linker and characterized their binding properties and three-dimensional structural conformation. One clone was evaluated in depth, demonstrating comparable capacity to identify CAR T cells in peripheral blood relative to other methods using anti-idiotype antibodies or recombinant CAR-target proteins. In contrast to these reagents, the anti-Whitlow mAb detects cells expressing Whitlow linker-containing CARs with different antigen specificities, including those harboring the widely employed anti-CD19 FMC63-derived scFv as well as other scFvs, such as those targeting B-cell maturation antigen (BCMA) or CD33. Importantly, the anti-Whitlow mAb identified CAR T cells in situ in archival FFPE tissues, and a DNA-barcoded format enabled their spatial characterization and immunophenotyping in highly multiplexed immunohistochemistry. We also assessed the functional consequences of antibody binding on CAR T cells in vitro and demonstrated the feasibility of anti-Whitlow mAb-mediated selective enrichment of CAR-expressing T cells for potential utility in manufacturing workflows.<br><br>CONCLUSIONS: Anti-Whitlow mAb clones exhibited distinct structural and functional properties that can be leveraged for multiple applications, providing versatile tools for detection, selection and manipulation of a broad range of clinical and preclinical CAR T-cell products.}, }
@article {pmid41254197, year = {2025}, author = {Yi, JC and Henrikson, NB and Panattoni, L and Liao, Y and Jones, SMW}, title = {Relationships between financial distress and anxiety and depression in cancer survivors.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {12}, pages = {1084}, pmid = {41254197}, issn = {1433-7339}, support = {U24AT011310//Emotional Well-Being and Economic Burden Research Network (EMOT-ECON;)/ ; }, mesh = {Humans ; Female ; Male ; *Cancer Survivors/psychology ; Middle Aged ; *Depression/epidemiology/etiology/psychology ; *Financial Stress/psychology/epidemiology ; Adult ; *Anxiety/epidemiology/etiology/psychology ; Aged ; *Neoplasms/psychology/economics ; Surveys and Questionnaires ; Age Factors ; }, abstract = {PURPOSE: Many cancer survivors experience financial distress. This distress can be associated with anxiety and depressive symptoms in cancer survivors. The aim of the study was to examine how much unique variance in anxiety and depressive symptoms is accounted for by financial distress using a measure developed specifically for financial distress using item response theory.<br><br>METHODS: Participants were recruited either through a cancer survivorship program or through the Prolific survey panel. Measures included patient reports of demographic and clinical variables. Financial related anxiety/worry and depression were assessed. The Generalized Anxiety Disorder-7 (GAD-7) and the Patient Health Questionnaire-8 (PHQ-8) were used for general measures of anxiety and depression, respectively. Separate hierarchical regressions were performed with the GAD-7 and PHQ-8 as outcome variables.<br><br>RESULTS: A total of N&#x2009;=&#x2009;459 cancer survivors completed the survey. The sample average age was 51.5&#xa0;years (SD&#x2009;=&#x2009;15.0), 67.5% female, 85.6% White, 7.4% Hispanic, and 6.5% Asian race. The most common cancer diagnosis was breast (27.9%). Age, income, education, and financial anxiety were associated with anxiety, and the overall model accounted for 31% of the variance. For depression, only female sex and financial depression were significantly associated and accounted for 46% of the variance.<br><br>CONCLUSION: Financial distress in combination with demographic and clinical variables operated differently in models of anxiety and depression in cancer survivors. More demographic variables were associated with anxiety symptoms than with depressive symptoms. Interventions such as financial navigation could reduce overall distress.}, }
@article {pmid41254224, year = {2026}, author = {Masopust, D and Awasthi, A and Bosselut, R and Brooks, DG and Buggert, M and Chamoto, K and Cui, W and Dong, C and Farber, DL and Gebhardt, T and Gerlach, C and Goldrath, A and Greenberg, PD and Hale, JS and Hayday, A and Homann, D and Iannacone, M and Jameson, SC and Jenkins, MK and Joshi, NS and Kaech, SM and Kallies, A and Kamphorst, AO and Kaplan, MH and Klenerman, P and Künzli, M and Lanzavecchia, A and Lauer, GM and Lugli, E and Luster, AD and Mackay, LK and McElrath, MJ and Mueller, SN and Ndhlovu, Z and Ndung'u, T and Ohashi, PS and Oxenius, A and Pantaleo, G and Pepper, M and Picker, LJ and Quarnstrom, CF and Reyes-Terán, G and Roederer, M and Rosato, PC and de Oca, GS and Sallusto, F and Schumacher, TN and Schwartz, DM and Shin, EC and Soerens, AG and Thommen, DS and Vezys, V and Viola, JPB and Walker, BD and Watts, TH and Weaver, CT and Wherry, EJ and Xue, HH and Youngblood, B and Ahmed, R}, title = {Guidelines for T cell nomenclature.}, journal = {Nature reviews. Immunology}, volume = {26}, number = {4}, pages = {298-313}, pmid = {41254224}, issn = {1474-1741}, mesh = {*Terminology as Topic ; Humans ; *T-Lymphocyte Subsets/immunology/classification ; Animals ; *Guidelines as Topic ; *T-Lymphocytes/immunology/classification ; }, abstract = {Advances in T cell biology have revealed heterogeneity among T cell populations that is not captured by existing general nomenclature. This issue has caused an ad hoc broadening of core T cell subset definitions and the invention of new subset designations that have not been uniformly delineated. To address this issue, in this Consensus Statement, we propose guidelines that serve three goals. First, they advocate that primary research reports define the experimental basis by which relevant subsets are designated in the methods section of each study. Second, they provide standardized definitions for existing subset designations in popular use, and common experimental criteria for defining each subset are noted. Last, they present an alternative 'modular nomenclature' paradigm. The newly proposed modular nomenclature eschews conceptualization of antigen-experienced T cells as belonging to a few idealized subsets, and the nomenclature instead simply indicates individual biological properties present in a T cell population with brief descriptors. Collectively, these guidelines intend to enhance transparency in the literature while facilitating clearer communication of findings and concepts to researchers, students and clinicians.}, }
@article {pmid41255967, year = {2025}, author = {Garsed, D and Zwimpfer, T and Fereday, S and Pandey, A and Ariyaratne, D and Jayawardana, M and Twomey, L and Laumont, C and Kennedy, C and Bolithon, A and Meagher, N and Milne, K and Hamilton, P and Alsop, J and Antoniou, A and Au-Yeung, G and Beckmann, M and de Gonzalez, AB and Bisinotto, C and Blome, F and Bodelon, C and Boros, J and Brand, A and Carney, M and Cazorla-Jimenez, A and Chiu, D and Christie, E and Chudecka-Glaz, A and Coulson, P and Cushing-Haugen, K and Cybulski, C and Darcy, K and David, C and Davidson, T and Ekici, A and Elishaev, E and Emons, J and Engler, T and Farrell, R and Fischer, A and Garcia-Closas, M and Gentry-Maharaj, A and Ghatage, P and Glasspool, R and Harter, P and Hartkopf, A and Hartmann, A and Heikaus, S and Hernandez, B and Hettiaratchi, A and Heublein, S and Huntsman, D and Jimenez-Linan, M and Jones, M and Kang, E and Kaznowska, E and Kluz, T and Kommoss, F and Konecny, GE and Kruitwagen, R and Kwon, J and Lambrechts, D and Lee, CH and Lester, J and Leung, S and Leung, Y and Linder, A and Lissowska, J and Loverix, L and Lubiński, J and Mateoiu, C and McNeish, L and Moubarak, M and Nelson, G and Nevins, N and Olawaiye, A and Olbrecht, S and Orsulic, S and Osorio, A and Quinn, C and Mohan, GR and Ray-Coquard, I and Rodriguez-Antona, C and Roxburgh, P and Rübner, M and Salfinger, S and Samra, S and Schoemaker, M and Sinn, HP and Sonke, G and Steele, L and Stewart, C and Talhouk, A and Tan, A and Tarney, C and Taylor, S and Van de Vijver, K and der Aa, MA and Van Gorp, T and Van Nieuwenhuysen, E and van Wagensveld, L and Wahner-Hendrickson, A and Walter, C and Wang, C and Welz, J and Wentzensen, N and Wilkens, L and Winham, S and Winterhoff, B and Anglesio, M and Berchuck, A and do Reis, FC and Cohen, P and Conrads, T and Crowe, P and Doherty, J and Fasching, P and Fortner, R and Garcia, M and Gayther, S and Goodman, M and Gronwald, J and Harris, H and Heitz, F and Horlings, H and Karlan, B and Kelemen, L and Maxwell, G and Menon, U and Modugno, F and Neuhausen, S and Schildkraut, J and Staebler, A and Sundfeldt, K and Swedlow, A and Vergote, I and Wu, A and Brenton, J and Pharoah, P and Pearce, C and Pike, M and Goode, E and Ramus, S and Köbel, M and Nelson, B and DeFazio, A and Friedlander, M and Bowtell, D}, title = {Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41255967}, issn = {2693-5015}, support = {R21 CA267050/CA/NCI NIH HHS/United States ; R01 CA172404/CA/NCI NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA248288/CA/NCI NIH HHS/United States ; M01 RR000056/RR/NCRR NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; R01 CA168758/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.}, }
@article {pmid41256175, year = {2025}, author = {Cheng, S and Suger, AH and Goss, LB and Zhang, J and Fuller, H and Guo, B and Lindström, S and Darst, BF}, title = {Validation and context-dependent effects of a prostate cancer polygenic risk score in the All of Us Research Program.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41256175}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; U01 CA261339/CA/NCI NIH HHS/United States ; R00 CA246063/CA/NCI NIH HHS/United States ; R03 CA287235/CA/NCI NIH HHS/United States ; }, abstract = {Polygenic risk scores (PRSs) have demonstrated strong potential for improving prostate cancer risk stratification. However, it is unknown whether the clinical utility of prostate cancer PRS vary by demographic, lifestyle, and socioeconomic factors. We validated a previously developed multi-ancestry PRS of 451 prostate cancer risk variants and evaluated context-dependent effects using genetic and clinical data from the diverse All of Us Research Program, including 7,577 cases and 90,608 controls across six genetic ancestry groups. In ancestry-stratified testing, the PRS showed strong associations with prostate cancer risk, with odds ratios (ORs) per standard deviation (SD) increase ranging from 1.61 (95% CI=1.02-2.64, P=0.05) in Middle Eastern to 2.19 (95% CI=1.98-2.42, P=2.2×10[-51]) in American populations. Age-stratified analyses showed an overall reduced PRS effect with increasing age. Across modifiable lifestyle and healthcare access factors, PRS effects were larger in those with higher body mass index (OR ranging from 1.71-2.17 in underweight to obese individuals, P=0.02), in never or former smokers vs. current smokers (OR=2.06, 2.37, and 1.93, respectively, P=0.06), and in those recently accessing healthcare (OR=2.21 vs. 1.88, P=0.05), highlighting important context-specific modifiers. We did not observe context-dependent effects by other socioeconomic factors, such as income, education, and insurance. In a phenome-wide association study (PheWAS), the PRS was associated with 14 clinical outcomes, including known prostate cancer-related conditions. These findings confirm the predictive strength of the multi-ancestry prostate cancer PRS across diverse populations and underscore the importance of accounting for demographic, lifestyle, and healthcare-related contexts when applying PRS in clinical and public health settings.}, }
@article {pmid41256406, year = {2025}, author = {Soysa, R and Abideen, S and Reyes, VZ and Headley, MB}, title = {Ontogeny and functional potential of founding dendritic cells in the developing lung.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41256406}, issn = {2692-8205}, support = {R21 AI173825/AI/NIAID NIH HHS/United States ; }, abstract = {Lung development begins in utero and reaches full maturity post birth. Dendritic cells (DC) play a key role in immune regulation in lungs. However, comprehensive exploration of DCs in these immature lungs has not been performed. Here we explored DCs from fetal to newborn mouse lungs phenotypically, ontogenetically, transcriptomically and functionally and found two DC subsets, resembling adult cDC1 and cDC2, but with key differences. Phenotypically, fetal-cDC1 lacks the classical-DC1 (cDC1) marker XCR1, while the fetal-cDC2 express both cDCassociated genes as well as monocyte-derived DC genes. Both DC subsets wane as lungs enter the alveolar stage, giving way to the more familiar adult cDC1 and cDC2. Both fetal-cDC1 and fetal-cDC2 derive from ED14.5 fetal liver Macrophage Dendritic Progenitors, not from monocytes or classic Precursor-cDC (Pre-cDC), indicating a unique ontogeny of first DCs in developing mouse lungs. Together we provide the first in depth exploration of first DCs in developing lungs.}, }
@article {pmid41256432, year = {2025}, author = {Favor, A and Quijano, R and Chernova, E and Kubaney, A and Weidle, C and Esler, MA and McHugh, L and Carr, A and Hsia, Y and Juergens, D and Carr, KD and Kim, PT and Politanska, Y and Sehgal, E and Kwon, PS and Pecoraro, RJ and Glasscock, C and Borst, AJ and DiMaio, F and Stoddard, BL and Baker, D}, title = {De novo design of RNA and nucleoprotein complexes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41256432}, issn = {2692-8205}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; S10 OD028581/OD/NIH HHS/United States ; }, abstract = {Nucleic acids fold into sequence-dependent tertiary structures and carry out diverse biological functions, much like proteins. However, while considerable advances have been made in the de novo design of protein structure and function, the same has not yet been achieved for RNA tertiary structures of similar intricacy. Here, we describe a generative diffusion framework, RFDpoly, for generalized de novo biopolymer (RNA, DNA and protein) design, and use it to create diverse and designable RNA structures. We design RNA structures with novel folds and experimentally validate them using a combination of chemical footprinting (SHAPE-seq) and electron microscopy. We further use this approach to design protein-nucleic acid assemblies; the crystal structure of one such design is nearly identical to the design model. This work demonstrates that the principles of structure-based de novo protein design can be extended to nucleic acids, opening the door to creating a wide range of new RNA structures and protein-nucleic acid complexes.}, }
@article {pmid41256528, year = {2025}, author = {Chun, J and Tripathi, P and Flores-Garcia, Y and Madan, B and Lee, GA and Fahad, AS and Lei, H and Teng, IT and Hurlburt, NK and Flynn, BJ and Pancera, M and Miura, K and Zhou, T and Idris, AH and Zavala, F and Seder, RA and Kwong, PD and DeKosky, BJ}, title = {Anti-Malaria Antibody Engineering Broadens Recognition Motifs and Reveals New Homotypic Interactions that Enhance Protective Breadth.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41256528}, issn = {2692-8205}, support = {DP5 OD023118/OD/NIH HHS/United States ; R01 AI181684/AI/NIAID NIH HHS/United States ; R01 AI192975/AI/NIAID NIH HHS/United States ; }, abstract = {The monoclonal antibody L9 mediates high-level protection against malaria in children for up to 6 months in Africa. L9 preferentially binds with high affinity to the NVDP minor repeat on the P. falciparum circumsporozoite protein (PfCSP). Here, we sought to improve the affinity of L9 to enhance protection against rare strains with two spatially separated minor repeats or a single minor repeat. Site saturation mutagenesis and yeast display-screening identified a panel of affinity-improved variants. In vivo challenge showed one variant, L9_yd19, to be modestly more potent against a chimeric transgenic Plasmodium encoding PfCSP with two widely spaced minor repeats from a Kenyan parasite strain, with no loss in potency against the benchmark 3D7 strain with its standard complement of minor repeats. L9_yd19 also had high affinity against NANP major repeats and was protective against transgenic Plasmodium with PfCSP containing only NANP major repeats (NANP12). Cryo-EM studies revealed L9_yd19 to recognize PfCSP with two distinct homotypic interfaces, which combined to yield two trimeric layers of antibodies comprising asymmetric trimers that dimerized in a head-to-head fashion. These data reveal a new antibody mechanism that utilizes interfaces involving dual homotypic symmetry elements, a 2-fold and an asymmetric 3-fold, for potentially improved malaria prevention.}, }
@article {pmid41256718, year = {2025}, author = {Ukogu, OA and Montague, Z and Altan-Bonnet, G and Nourmohammad, A}, title = {Design principles of the cytotoxic CD8[+] T-cell response.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41256718}, issn = {2692-8205}, support = {R35 GM142795/GM/NIGMS NIH HHS/United States ; ZIA BC012007/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Cytotoxic T lymphocytes eliminate infected or malignant cells, safeguarding surrounding tissues. Although experimental and systems-immunology studies have cataloged many molecular and cellular actors involved in an immune response, the design principles governing how the speed and magnitude of T-cell responses emerge from cellular decision-making remain elusive. Here, we recast the T-cell response as a feedback-controlled program, wherein the rates of activation, proliferation, differentiation and death are regulated through antigenic, pro- and anti-inflammatory cues. By exploring a broad class of feedback-controller designs as potential immune programs, we demonstrate how the speed and magnitude of T-cell responses emerge from optimizing signal-feedback to protect against diverse infection settings. We recover an inherent trade-off: infection clearance at the cost of immunopathology. We show how this trade-off is encoded into the logic of T-cell responses by hierarchical sensitivity to different immune signals. Notably, we find that designs that balance harm from acute infections and autoimmunity produce immune responses consistent with experimentally observed patterns of T-cell effector expansion in mice. Extending our model to immune-based T-cell therapies for cancer tumors, we identify a trade-off between the affinity for tumor antigens ("quality") and the abundance ("quantity") of infused T-cells necessary for effective treatment. Finally, we show how therapeutic efficacy can be improved by targeted genetic perturbations to T-cells. Our findings offer a unified control-logic for cytotoxic T-cell responses and point to specific regulatory programs that can be engineered for more robust T-cell therapies.}, }
@article {pmid41257223, year = {2025}, author = {Sawyer, L and Suchy-Dicey, AM and Nelson, LA and Sarche, M and Reese, JA and Cole, S and Sitlani, CM and Umans, JG and Fretts, AM}, title = {Association of Social Support With Glycemic Control Among American Indians With Type 2 Diabetes: The Strong Heart Family Study.}, journal = {Diabetes spectrum : a publication of the American Diabetes Association}, volume = {38}, number = {4}, pages = {455-460}, pmid = {41257223}, issn = {1040-9165}, support = {U01 HL041642/HL/NHLBI NIH HHS/United States ; U01 HL041654/HL/NHLBI NIH HHS/United States ; R01 HL109315/HL/NHLBI NIH HHS/United States ; 75N92019D00030/HL/NHLBI NIH HHS/United States ; 75N92019D00028/HL/NHLBI NIH HHS/United States ; R01 HL109284/HL/NHLBI NIH HHS/United States ; U01 HL065521/HL/NHLBI NIH HHS/United States ; 75N92019D00027/HL/NHLBI NIH HHS/United States ; R01 HL109301/HL/NHLBI NIH HHS/United States ; R01 HL109282/HL/NHLBI NIH HHS/United States ; U01 HL065520/HL/NHLBI NIH HHS/United States ; U01 HL041652/HL/NHLBI NIH HHS/United States ; 75N92019D00029/HL/NHLBI NIH HHS/United States ; R01 HL109319/HL/NHLBI NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; }, abstract = {Few studies have examined associations of social support with blood glucose control in American Indians (AIs), a population with a high burden of type 2 diabetes and related complications. This study examined the association of perceived social support with A1C among AIs in the Strong Heart Study. This cross-sectional study included 431 AI participants. Social support was measured using questions adapted from the National Comorbidity Survey and validated for use in AIs. A1C was measured using high-performance liquid chromatography. Generalized estimating equations were used to examine the association of social support with A1C. Participants who reported greater levels of social support had lower A1C levels. After adjustment for potential confounders, for every 1-SD increase in social support (6.8 points), A1C was 0.21% lower (β = -0.21%, 95% CI -0.40 to -0.01, P = 0.04). These data suggest that higher levels of social support are associated with better control of blood glucose. Further studies are needed to determine the mechanism by which perceived social support affects A1C.}, }
@article {pmid41257522, year = {2025}, author = {Sanderson, JB and Lin, YH and Su, K and Wang, Y and Portuguese, A and Gauthier, J and Durbin, M and Banerjee, R}, title = {Treatment-Emergent Parkinsonism in Four Patients Treated with Chimeric Antigen Receptor T-Cell Therapy.}, journal = {Movement disorders clinical practice}, volume = {}, number = {}, pages = {}, doi = {10.1002/mdc3.70452}, pmid = {41257522}, issn = {2330-1619}, abstract = {BACKGROUND: Treatment-emergent motor and neurocognitive adverse events (MNTs) are rare but increasingly well-documented complications of chimeric antigen receptor T-cell (CAR-T) therapy. Here, we describe the development of parkinsonism in four patients who received CAR-T therapy with either B-cell maturation antigen (BCMA)-targeting ciltacabtagene autoleucel for multiple myeloma (n = 3) or CD-19-targeting axicabtagene autoleucel for lymphoma (n = 1).<br><br>CASES: We report four cases of parkinsonism in patients who received CAR-T therapy. Two patients had evidence of underlying neurodegenerative parkinsonism, either clinically or through subsequent workup for their movement disorder. All patients received some combination of symptom-directed and immunomodulatory therapies.<br><br>CONCLUSION: This report describes features of CAR-T treatment-emergent parkinsonism, introduces parkinsonism as a potential effect of CD-19-targeted CAR-T therapy, and suggests utility of screening for underlying clinical or biomarker signs of pre-existing neurodegenerative parkinsonism prior to CAR-T infusion.}, }
@article {pmid41259068, year = {2026}, author = {Hathaway, CL and Brown, ER and Cherne, S and Sepulveda, AL and Chirenje, ZM and Jeenarain, N and Naidoo, L and Siva, S and Singh, N and Woeber, K and Gaffoor, Z and Mirembe, BG and Kiweewa, FM and Mansoor, LE and Chinula, L and Dadabhai, S and Mugo, NR and Palanee-Phillips, T and Barnabas, RV}, title = {Association of human papillomavirus on risk of HIV acquisition in African women: analyses from MTN-020/ASPIRE.}, journal = {Journal of the National Cancer Institute}, volume = {118}, number = {3}, pages = {485-491}, pmid = {41259068}, issn = {1460-2105}, support = {UM1AI106707//National Institute of Allergy and Infectious Diseases/ ; /MH/NIMH NIH HHS/United States ; 1200-GR0244780//Bill and Melinda Gates Foundation/ ; UM1AI068615//National Institute of Allergy and Infectious Diseases/ ; UM1AI068633//National Institute of Allergy and Infectious Diseases/ ; UM1 AI069518/AI/NIAID NIH HHS/United States ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; /NH/NIH HHS/United States ; //Microbicide Trials Network/ ; }, mesh = {Humans ; Female ; *Papillomavirus Infections/epidemiology/virology/complications/immunology ; *HIV Infections/epidemiology/virology/immunology ; Adult ; *Papillomaviridae/isolation &amp; purification/genetics ; South Africa/epidemiology ; Young Adult ; Risk Factors ; Zimbabwe/epidemiology ; Adolescent ; DNA, Viral/isolation &amp; purification ; Uganda/epidemiology ; Malawi/epidemiology ; Cervix Uteri/virology ; Human Papillomavirus Viruses ; }, abstract = {BACKGROUND: Observational data on the synergy between human papillomavirus (HPV) infection and risk for HIV acquisition are needed. HPV clearance, associated with an influx of cells targeted by HIV, may increase HIV risk. This study examined the association between HPV and HIV acquisition using endocervical swabs collected in MTN-020/ASPIRE.<br><br>METHODS: Healthy, sexually active women without HIV participating in the ASPIRE dapivirine ring study in Malawi, South Africa, Uganda, and Zimbabwe provided endocervical swabs monthly, which were tested for HPV-DNA. HPV status was classified into prevalent, persistent (HPV+ for at least 4&#x2009;months), HPV clearance (HPV+ followed by HPV-), HPV acquisition (HPV- followed by HPV+), and remaining HPV positive (2 subsequent HPV+). Cox time-varying regression models were used to assess associations between HPV states and HIV acquisition.<br><br>RESULTS: Among 91 HIV acquisition endpoints, HPV clearance increased HIV risk for high-risk types (16/18/31/33/35/45/52/58) (HR = 2.40, 95% CI = 1.59 to 3.62). Remaining HPV+ also showed a moderately increased risk (HR = 1.59, 95% CI = 1.07 to 2.35), while prevalent, persistent, and HPV acquisition events showed non-significant associations. Elevated HIV risk was also observed for clearance of HPV16/18, other high-risk types, low-risk types, and HPV6/11. There was also a dose-response relationship, with HIV risk increasing by 1.75-fold (95% CI = 1.55 to 1.96) for each additional HPV type cleared.<br><br>CONCLUSIONS: HPV clearance-related immune activation is strongly linked to HIV acquisition, likely due to increased CD4+ T cells and inflammation. These findings support HPV vaccination as a potential HIV prevention strategy and highlight the need to integrate HIV prevention into cervical cancer programs.}, }
@article {pmid41259538, year = {2025}, author = {Slein, MD and Backes, IM and Jiménez, LM and Kelkar, NS and Garland, CR and Khanwalkar, US and Sholukh, AM and Johnston, C and Leib, DA and Ackerman, ME}, title = {Eliminating interactions with the viral Fc receptor improves antibody-mediated protection against neonatal HSV infection in mice.}, journal = {Science translational medicine}, volume = {17}, number = {825}, pages = {eadu8579}, doi = {10.1126/scitranslmed.adu8579}, pmid = {41259538}, issn = {1946-6242}, mesh = {Animals ; *Receptors, Fc/metabolism/immunology ; *Herpes Simplex/immunology/prevention &amp; control/virology ; Humans ; Antibodies, Monoclonal/immunology ; Mice ; Herpesvirus 1, Human/immunology ; *Antibodies, Viral/immunology ; Immunoglobulin G/immunology ; Antibodies, Neutralizing/immunology ; Viral Envelope Proteins/immunology/metabolism ; Female ; Protein Binding ; Animals, Newborn ; Pregnancy Complications, Infectious ; }, abstract = {Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules. For example, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG, promoting evasion of humoral immune responses. Although monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of vFcR activity on mAb-mediated protection is unknown. Using HSV-1 with intact and ablated gE-mediated Fc binding, as well as Fc-engineered mAbs with modified ability to interact with gE/gI, we investigated the role of the vFcR in mAb-mediated protection from nHSV. HSV-specific mAbs modified to lack binding to gE exhibited enhanced neutralization in vitro and superior protection in vivo compared with their native IgG1 forms. Improved protection was dependent on the presence of vFcR activity and was observed for mAbs specific for both glycoprotein D and glycoprotein B, as well as for a nonneutralizing mAb, and for both laboratory-adapted and clinical isolates of HSV-1 and HSV-2. Further, human IgG3 allotypes, including those lacking vFcR binding, also exhibited enhanced antiviral activity in vivo, identifying a unique viral susceptibility to this subclass. In summary, this study demonstrates that rendering mAbs insensitive to the vFcR can improve protection against HSV, offering prospects for antibody-based interventions.}, }
@article {pmid41259899, year = {2025}, author = {Maiorano, BA and Cigliola, A and Tateo, V and Mercinelli, C and Pastorino, GL and Dizman, N and Ebrahimi, H and Pal, SK and Gupta, S and Grivas, P and Kamat, AM and Spiess, PE and Agarwal, N and Necchi, A}, title = {Outcomes of immune checkpoint inhibitor rechallenge in advanced urothelial carcinoma: results from a global real-world evidence study.}, journal = {ESMO open}, volume = {10}, number = {12}, pages = {105862}, pmid = {41259899}, issn = {2059-7029}, mesh = {Humans ; *Immune Checkpoint Inhibitors/therapeutic use/administration &amp; dosage/pharmacology ; Male ; Female ; Retrospective Studies ; Aged ; Middle Aged ; *Urologic Neoplasms/drug therapy/mortality/pathology ; *Carcinoma, Transitional Cell/drug therapy/mortality/pathology ; Treatment Outcome ; Aged, 80 and over ; *Urinary Bladder Neoplasms/drug therapy ; }, abstract = {BACKGROUND: Several immune checkpoint inhibitors (ICIs) are approved for urothelial carcinoma (UC), but limited information is currently available regarding the efficacy of rechallenging ICIs in patients with previous ICI exposure.<br><br>PATIENTS AND METHODS: A retrospective study was carried out using the TriNetX&#xae; database for a large-scale search of patients with advanced UC (aUC) who had received two separate courses of ICIs (either alone or in combinations). Kaplan-Meier analysis was used to estimate progression-free and overall survival (PFS, OS) of ICI rechallenge. Propensity score matching analysis was run to balance and compare groups based on the duration of ICI rechallenge and stage at diagnosis.<br><br>RESULTS: Out of 35 789 patients, a cohort of 292 (0.81%) treated with &#x2265;2 ICI-including lines between 2014 and 2024 was identified. There were 86% bladder versus 14% upper tract UC. At initial diagnosis, 49% had stage IV, whereas 51% had stage I-III disease. The median time on prior ICI treatment was 19.5 months; the median time from the end of ICI to the start of ICI rechallenge was 9.4 months. After a median follow-up of 21.7 months, the median OS of ICI rechallenge was 20.5 months, the median PFS was 10.3 months. Previous use of an ICI in a nonmetastatic setting was associated with longer median OS than both lines given in aUC (P < 0.001). Among those who received a previous ICI in a metastatic setting, a cut-off of 12 months for the ICI rechallenge was associated with a longer median OS (P = 0.027). The longest duration of rechallenge treatment was achieved with anti-programmed cell death protein 1 given after anti-programmed death-ligand 1 therapy (18.2 months, P < 0.001).<br><br>CONCLUSIONS: Although it is an uncommon and not standard strategy, previous ICI in nonmetastatic UC and a period of &#x2265;12 months after previous ICI in the metastatic setting were associated with better outcomes after ICI rechallenge in patients with aUC.}, }
@article {pmid41260224, year = {2026}, author = {Roy, V and Kellman, BP and Hsu, WL and Nziza, N and Parker, L and Germosen, D and Bonifer, R and Pfeiffer, RM and Yu, KJ and Michels, B and Chen, TC and Chen, CJ and Goldstein, AM and Waterboer, T and Wang, CP and Kumar, N and Jain, A and Newell, EW and Streeck, H and Alter, G and Hildesheim, A and Liu, Z and Julg, B}, title = {Epstein-Barr-virus-specific functional antibody signatures in the context of nasopharyngeal carcinoma development.}, journal = {Med (New York, N.Y.)}, volume = {7}, number = {1}, pages = {100925}, pmid = {41260224}, issn = {2666-6340}, support = {R01 AI080289/AI/NIAID NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Male ; *Nasopharyngeal Carcinoma/immunology/virology ; Female ; *Herpesvirus 4, Human/immunology ; *Epstein-Barr Virus Infections/immunology/complications ; Middle Aged ; *Antibodies, Viral/blood/immunology ; *Nasopharyngeal Neoplasms/immunology/virology ; Immunoglobulin G/blood/immunology ; Adult ; Receptors, IgG/immunology ; Taiwan ; Aged ; Immunoglobulin M/immunology/blood ; Singapore ; Immunoglobulin A/immunology/blood ; Case-Control Studies ; Phagocytosis ; }, abstract = {BACKGROUND: Nasopharyngeal carcinoma (NPC) in endemic areas is strongly linked to Epstein-Barr virus (EBV) infection. EBV-specific immunoglobulin (Ig)A and IgG titers have been used for diagnosis and prognosis, but their full potential for prediction and protection remains unclear.<br><br>METHODS: We analyzed samples from 353 individuals, including patients with NPC at diagnosis or patients with NPC years prior to diagnosis, matched controls, and family members from NPC multiplex families from Taiwan, along with 50 patients with NPC from Singapore with survival data. We used systems serology, a comprehensive approach to assess antibody subclass, isotype, and fragment crystallizable gamma receptor (Fc&#x3b3;R) binding, along with effector functions such as complement deposition, cellular phagocytosis, and natural killer (NK) cell activation.<br><br>FINDINGS: Patients with NPC showed a broad expansion of antibody levels, Fc&#x3b3;R binding, and Fc effector functions, especially neutrophil phagocytosis and complement deposition, compared to controls. Prior to NPC onset, individuals exhibited elevated EBV-specific IgM levels and higher Fc&#x3b3;RIIA and Fc&#x3b3;RIIIB binding, suggesting an early immune response to viral activity. IgMs appeared as potential correlative markers for NPC. In contrast, controls showed increased IgG2 levels and Fc&#x3b3;RIIB binding, indicating lower inflammatory responses. On a per-antibody level, controls exhibited stronger Fc effector functions, suggesting a protective role in preventing NPC. Additionally, we identified a multivariate antibody signature associated with survival after treatment.<br><br>CONCLUSIONS: This study provides valuable insights into EBV-specific antibodies as predictive biomarkers of NPC progression, offering opportunities for improved disease management.<br><br>FUNDING: This work was supported by the Ragon Institute of Mass General, MIT, and Harvard with support from the National Cancer Institute (CA264646 to E.W.N.).}, }
@article {pmid41260262, year = {2026}, author = {Saura, C and Cortés, J and Modi, S and Kim, SB and Hamilton, E and Hurvitz, SA and Krop, IE and Curigliano, G and Iwata, H and Im, SA and Herbolsheimer, P and Karnoub, M and Boran, A and Kuwahara, Y and Egorov, A and André, F}, title = {Pooled analysis by best confirmed response to trastuzumab deruxtecan and related biomarkers in patients with HER2-positive metastatic breast cancer from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {37}, number = {3}, pages = {353-363}, doi = {10.1016/j.annonc.2025.11.007}, pmid = {41260262}, issn = {1569-8041}, mesh = {Humans ; *Breast Neoplasms/drug therapy/pathology/genetics/mortality ; Female ; *Erb-b2 Receptor Tyrosine Kinases/metabolism/genetics ; *Trastuzumab/administration &amp; dosage/therapeutic use/adverse effects ; *Biomarkers, Tumor/genetics/metabolism ; Middle Aged ; Adult ; *Camptothecin/analogs &amp; derivatives/administration &amp; dosage/therapeutic use/adverse effects ; *Immunoconjugates/therapeutic use/administration &amp; dosage/adverse effects ; Aged ; Progression-Free Survival ; Antineoplastic Agents, Immunological/therapeutic use ; }, abstract = {BACKGROUND: Objective response rates in the DESTINY-Breast01/02/03 trials, which evaluated trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC), were 62%/70%/79%, respectively.<br><br>PATIENTS AND METHODS: This exploratory pooled analysis investigated associations between best confirmed response to T-DXd and baseline characteristics/long-term outcomes in patients who received T-DXd 5.4 mg/kg in DESTINY-Breast01/02/03. Endpoints included best confirmed response per (blinded) independent central review [(B)ICR] using RECIST v1.1, progression-free survival (PFS) by (B)ICR, overall survival (OS), safety, and biomarker analyses of expression levels/alterations of genes relevant to HER2-positive mBC or T-DXd activity.<br><br>RESULTS: A total of 834 patients who received T-DXd in DESTINY-Breast01/02/03 were assessable for response; 125 (15.0%) experienced complete response (CR), 477 (57.2%) experienced partial response (PR), and 232 (27.8%) were considered non-responders (stable disease/progressive disease). The median number of prior regimens in the metastatic setting was two for patients with CR versus three for patients with PR and non-responders; visceral disease and baseline brain or bone metastases were less frequently observed in patients with CR. The 24-month PFS rates in patients with CR, PR, and no response, respectively, were 77.8%, 46.3%, and 20.6%, and 36-month OS rates were 88.6%, 54.0%, and 35.9%. Rates of serious adverse events, T-DXd discontinuation, and interstitial lung disease/pneumonitis were numerically lower in patients with CR. In exploratory biomarker analyses, responders had tumors with numerically higher HER2 plasma copy number, lower ESR1 gene expression and ESR1 mutation frequency, and lower circulating tumor DNA levels at baseline.<br><br>CONCLUSIONS: Patients with objective response to T-DXd, particularly those with CR, showed prolonged median PFS and OS. These results support T-DXd use across broad patient groups with HER2-positive mBC, including those with lower disease burden. Patients whose disease does not respond to T-DXd represent an unmet medical need, and research into more effective treatment approaches for these patients is warranted.}, }
@article {pmid41260264, year = {2026}, author = {Hurvitz, SA and Loi, S and O'Shaughnessy, J and Okines, AFC and Tolaney, SM and Sohn, J and Saura, C and Zhu, X and Cameron, D and Bachelot, T and Hamilton, E and Curigliano, G and Wolff, AC and Harbeck, N and Masuda, N and Vahdat, L and Zaman, K and Valdes-Albini, F and Block, M and Pluard, T and Tan, TJ and Gawryletz, C and Chan, A and Bedard, PL and Yerushalmi, R and Xu, B and Schmitt, M and Xie, D and Borges, VF and , }, title = {Tucatinib and trastuzumab emtansine for patients with previously treated HER2-positive locally advanced and metastatic breast cancer: primary analysis of the randomized phase III trial HER2CLIMB-02.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {37}, number = {3}, pages = {341-352}, doi = {10.1016/j.annonc.2025.11.005}, pmid = {41260264}, issn = {1569-8041}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology/mortality ; *Erb-b2 Receptor Tyrosine Kinases/metabolism ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Middle Aged ; *Ado-Trastuzumab Emtansine/administration &amp; dosage/adverse effects ; Adult ; Aged ; Quinazolines/administration &amp; dosage/adverse effects ; Oxazoles/administration &amp; dosage/adverse effects ; Pyridines/administration &amp; dosage/adverse effects ; *Brain Neoplasms/drug therapy/secondary ; Progression-Free Survival ; }, abstract = {BACKGROUND: Trastuzumab emtansine (T-DM1) is a standard treatment option in patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (LA/MBC). Here, we report the efficacy and safety of tucatinib in combination with T-DM1 compared with T-DM1 alone from the phase III HER2CLIMB-02 study (NCT03975647).<br><br>PATIENTS AND METHODS: Eligible patients had HER2-positive LA/MBC that had been previously treated with trastuzumab and a taxane in any setting; these included patients with brain metastases (BMs). Patients were randomly assigned 1 : 1 to receive T-DM1 (3.6 mg/kg intravenously every 21 days) combined with either tucatinib (300 mg orally twice daily) in the tucatinib arm or placebo (orally twice daily) in the control arm.<br><br>RESULTS: In total, 463 patients were randomly assigned. After a median follow-up duration of 24.4 months, the median progression-free survival (PFS) was 9.5 months in the tucatinib arm and 7.4 months in the control arm [hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.61-0.95, P = 0.0163]. A PFS benefit was observed across all prespecified subgroups, including in patients with BMs. Interim overall survival analysis results were immature. The median OS was not reached in the tucatinib arm and was 38.0 months in the control arm (HR 1.23, 95% CI 0.87-1.74). The incidences of treatment-emergent adverse events (TEAEs) associated with any treatment discontinuation and of grade &#x2265;3 TEAEs were higher in the tucatinib arm than in the control arm (22.1% versus 11.6% and 68.8% versus 41.2%, respectively). The most common grade &#x2265;3 TEAEs in the tucatinib arm were elevated alanine aminotransferase (16.5%) and aspartate aminotransferase levels (16.5%) (versus 2.6% for both in the control arm).<br><br>CONCLUSION: The addition of tucatinib to T-DM1 improved PFS in patients with previously treated HER2-positive LA/MBC, including patients with BMs, and exhibited a manageable safety profile.}, }
@article {pmid41260765, year = {2026}, author = {Rojanasopondist, P and Kaz, A and Yu, M and Grady, WM}, title = {Emerging Biomarkers for Managing Barrett's Esophagus.}, journal = {Gastrointestinal endoscopy clinics of North America}, volume = {36}, number = {1}, pages = {149-170}, doi = {10.1016/j.giec.2025.05.005}, pmid = {41260765}, issn = {1558-1950}, mesh = {Humans ; *Barrett Esophagus/genetics/metabolism/diagnosis/pathology/therapy ; *Adenocarcinoma/genetics/metabolism/diagnosis ; *Esophageal Neoplasms/genetics/diagnosis/metabolism ; *Biomarkers, Tumor/metabolism/genetics ; DNA Methylation ; Biomarkers ; MicroRNAs ; }, abstract = {Comparative analyses of normal esophageal tissue, Barrett's Esophagus (BE), and esophageal adenocarcinoma have identified distinctive molecular alterations in genomic DNA, epigenetics, non-coding RNA, and proteins that have shown promise as disease-specific biomarkers. Some of the best characterized and promising biomarkers for managing BE are multi-target esophageal cytology DNA assays based on methylated-DNA and immunohistochemical staining of Trefoil factor 3. Additional biomarkers including microRNA, measures of genomic instability, mixed-method panels, and other novel biomarkers (e.g. volatile organic compounds and saliva microbiome) remain in early development and will need further validation in large, prospective studies prior to clinical use.}, }
@article {pmid41260881, year = {2026}, author = {Valieris, R and Rosa, L and Martins, L and Defelicibus, A and Carraro, DM and Nunes, DN and Dias-Neto, E and Rosales, R and da Silva, IT}, title = {Regulators of homologous recombination deficiency identified by machine learning using somatic multi-omics data.}, journal = {Life science alliance}, volume = {9}, number = {2}, pages = {}, pmid = {41260881}, issn = {2575-1077}, mesh = {Humans ; *Machine Learning ; DNA Copy Number Variations/genetics ; DNA Methylation/genetics ; *Neoplasms/genetics ; *Homologous Recombination/genetics ; Genomics/methods ; Polymorphism, Single Nucleotide/genetics ; Mutation ; Biomarkers, Tumor/genetics ; Gene Expression Regulation, Neoplastic ; Multiomics ; }, abstract = {Homologous recombination deficiency (HRD) is a critical biomarker for guiding targeted therapies, yet the full range of somatic alterations driving HRD across cancers remains incompletely characterized. Here, we present a tumor-agnostic machine learning framework that integrates somatic multi-omics data, including copy-number variations, single-nucleotide variants, DNA methylation, and gene expression from over 8,000 patients in The Cancer Genome Atlas. Using a genome-wide mutational signature-based HRD score as ground truth, our model achieved high predictive performance and leveraged SHAP-based explainability to uncover HRD regulators beyond BRCA1/2 Cross-tumor analysis revealed both shared and cancer type-specific molecular determinants, whereas functional enrichment highlighted key molecular and cellular processes. These findings expand the known repertoire of HRD-associated alterations, provide a resource for mechanistic investigation, and demonstrate the potential of integrative AI approaches to improve patient stratification for HR-targeted therapies across diverse malignancies.}, }
@article {pmid41261512, year = {2025}, author = {Greenlee, H and Crew, KD and Maurer, M and Kalinsky, K and Cremers, S and Naini, A and Tsai, WY and Shi, Z and Brogan, F and Hershman, DL}, title = {Phase I Randomized, Placebo-Controlled, Cross-Over Dose-Finding Study of Coenzyme Q10 on Doxorubicin Pharmacokinetics during Breast Cancer Treatment.}, journal = {Integrative cancer therapies}, volume = {24}, number = {}, pages = {15347354251388014}, pmid = {41261512}, issn = {1552-695X}, support = {K23 CA141052/CA/NCI NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; *Ubiquinone/analogs &amp; derivatives/administration &amp; dosage/blood/pharmacology ; *Doxorubicin/pharmacokinetics/administration &amp; dosage/adverse effects/therapeutic use ; *Breast Neoplasms/drug therapy ; Middle Aged ; Cross-Over Studies ; Adult ; Aged ; Dose-Response Relationship, Drug ; Cyclophosphamide/administration &amp; dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics/therapeutic use ; Maximum Tolerated Dose ; Antibiotics, Antineoplastic/pharmacokinetics/administration &amp; dosage ; }, abstract = {AIM: To determine effects of Coenzyme Q10 (CoQ10) supplementation in breast cancer patients receiving doxorubicin treatment.<br><br>METHODS: Phase I randomized, placebo-controlled, cross-over, dose-finding study among women with stage I-III breast cancer receiving 4 cycles of doxorubicin plus cyclophosphamide. The study was designed to test effects on doxorubicin pharmacokinetic parameters when administering up to the maximum tolerated dose of CoQ10 of 1200&#x2009;mg/day. Eligible patients were randomized to Arm A (CoQ10 after Cycle 3, followed by placebo after Cycle 4) or Arm B (placebo after Cycle 3, followed by CoQ10 after Cycle 4). CoQ10 concentrations and total antioxidant capacity (TAC) were measured before and after chemotherapy cycles. Non-compartmental pharmacokinetic parameters of doxorubicin and its active metabolites were measured with and without CoQ10. Paired t-tests assessed intra-patient differences in pharmacokinetic parameters, serum CoQ10 concentrations, TAC, and adverse events.<br><br>RESULTS: Six patients received 300&#x2009;mg/day of CoQ10 (Arm A [n&#x2009;=&#x2009;3], Arm B [n&#x2009;=&#x2009;3]). One patient received 600&#x2009;mg/day of CoQ10 but was discontinued due to non-adherence. Serum CoQ10 concentrations were increased in patients receiving 300&#x2009;mg/day (mean&#x2009;&#xb1;&#x2009;SD change: CoQ10, 1.6&#x2009;&#xb1;&#x2009;0.9&#x2009;&#xb5;g/mL; placebo, -0.01&#x2009;&#xb1;&#x2009;0.3&#x2009;&#xb5;g/mL; P&#x2009;=&#x2009;.01). There were no clinically significant pharmacokinetic interactions between 300&#x2009;mg/day CoQ10 and doxorubicin and no differences in TAC or adverse events during treatment and nontreatment periods. The trial was closed early due to slow accrual.<br><br>CONCLUSION: 300&#x2009;mg/day of CoQ10 with doxorubicin did not change doxorubicin pharmacokinetics and was not associated with treatment-related adverse events. Future studies should evaluate the long-term effects of CoQ10 at 300&#x2009;mg/day and safety studies should examine higher doses.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT00976131.}, }
@article {pmid41261829, year = {2025}, author = {Wu, HV and Oeffinger, KC and Chou, JF and Henderson, TO and Hudson, MM and Diller, LR and McDonald, AJ and Ford, J and Mubdi, NZ and Rinehart, D and Vukadinovich, C and Elkin, EB and Leisenring, WM and Armstrong, GT and Ford, JS and Moskowitz, CS}, title = {Assessing delivery of and attitudes toward a randomized intervention to increase mammography uptake among childhood cancer survivors: A report from the Childhood Cancer Survivor Study.}, journal = {Journal of psychosocial oncology}, volume = {}, number = {}, pages = {1-16}, pmid = {41261829}, issn = {1540-7586}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; T32 CA275764/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA134722/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: This study characterizes utilization of, and attitudes toward, a two-part intervention of (1) mailed materials, including educational laminated cards for patients and healthcare providers, and (2) telephone counseling, that aimed to increase screening mammography uptake among adult female survivors of childhood cancer compared to attention controls.<br><br>METHODS: Participants (n&#x2009;=&#x2009;136, median age 35&#x2009;years, range 25-49&#x2009;years) were diagnosed with cancer between 1976 and 1999 before age 21&#x2009;years and had been treated with chest radiation. At study end, participants completed a questionnaire asking about their use of and attitudes toward the intervention components. Fisher's exact tests assessed associations.<br><br>RESULTS: Among 130 survivors who completed the survey, 45 (35%) received a mammogram. Eighty-five (65%) survivors recalled receiving both intervention components; about half (n&#x2009;=&#x2009;73, 56%) found the laminated cards helpful and/or described the telephone counseling as positive or activating (n&#x2009;=&#x2009;81, 62%). Of the 96 women who provided responses, approximately two-thirds (n&#x2009;=&#x2009;64, 67%) reported little to no fear/anxiety regarding the intervention. Women were more likely to obtain a mammogram if they remembered receiving both intervention components compared to women who reported receiving one or no components (45% vs. 24%, p&#x2009;=&#x2009;0.050), reported using the laminated card to discuss screening with a healthcare provider (72% vs. 51%, p&#x2009;=&#x2009;0.086), or found the telephone counseling motivational (61% vs. 30%, p&#x2009;=&#x2009;0.003).<br><br>CONCLUSIONS: In summary, the two-part intervention was well-received and elicited minimal fear/anxiety. Receiving intervention messaging in multiple forms and sharing it with a healthcare provider was associated with intervention efficacy.}, }
@article {pmid41261961, year = {2026}, author = {Chen, JY and Francis, P and Martinez, A and Marre, E and Thornton, S and Loggers, ET and Shinohara, MM}, title = {Exploring sexual health in patients with cutaneous T-cell lymphoma: a mixed-methods study.}, journal = {The British journal of dermatology}, volume = {194}, number = {3}, pages = {583-584}, doi = {10.1093/bjd/ljaf466}, pmid = {41261961}, issn = {1365-2133}, support = {//Michael Piepkorn Endowed Chair in Dermatology Research/ ; }, }
@article {pmid41262227, year = {2025}, author = {Banerjee, R and Das, MK and Smith, KD}, title = {Amyloid Deposits in a Bone Marrow Biopsy Alongside a Presumed Causative Clone.}, journal = {EJHaem}, volume = {6}, number = {6}, pages = {e70180}, pmid = {41262227}, issn = {2688-6146}, }
@article {pmid41266372, year = {2025}, author = {Barnes, DR and Tyrer, JP and Dennis, J and Leslie, G and Bolla, MK and Lush, M and Aeilts, AM and Aittomäki, K and Andrieu, N and Andrulis, IL and Anton-Culver, H and Arason, A and Arun, BK and Balmaña, J and Bandera, EV and Barkardottir, RB and Berger, LPV and Berrington de Gonzalez, A and Berthet, P and Białkowska, K and Bjørge, L and Blanco, AM and Blok, MJ and Bobolis, KA and Bogdanova, NV and Brenton, JD and Butz, H and Buys, SS and Caligo, MA and Campbell, I and Castillo, C and Claes, KBM and Colonna, SV and Cook, LS and Daly, MB and Dansonka-Mieszkowska, A and de la Hoya, M and deFazio, A and DePersia, A and Ding, YC and Doherty, JA and Domchek, SM and Dörk, T and Einbeigi, Z and Engel, C and Evans, DG and Foretova, L and Fortner, RT and Fostira, F and Foti, MC and Friedman, E and Frone, MN and Ganz, PA and Gentry-Maharaj, A and Glendon, G and Godwin, AK and González-Neira, A and Greene, MH and Gronwald, J and Guerrieri-Gonzaga, A and Hamann, U and Hansen, TVO and Harris, HR and Hauke, J and Heitz, F and Hogervorst, FBL and Hooning, MJ and Hopper, JL and Huff, CD and Huntsman, DG and Imyanitov, EN and Izatt, L and Jakubowska, A and James, PA and Janavicius, R and John, EM and Kar, S and Karlan, BY and Kennedy, CJ and Kiemeney, LALM and Konstantopoulou, I and Kupryjanczyk, J and Laitman, Y and Lavie, O and Lawrenson, K and Lester, J and Lesueur, F and Lopez-Pleguezuelos, C and Mai, PL and Manoukian, S and May, T and McNeish, IA and Menon, U and Milne, RL and Modugno, F and Mongiovi, JM and Montagna, M and Moysich, KB and Neuhausen, SL and Nielsen, FC and Noguès, C and Oláh, E and Olopade, OI and Osorio, A and Papi, L and Pathak, H and Pearce, CL and Pedersen, IS and Peixoto, A and Pejovic, T and Peng, PC and Peshkin, BN and Peterlongo, P and Powell, CB and Prokofyeva, D and Pujana, MA and Radice, P and Rashid, MU and Rennert, G and Richenberg, G and Sandler, DP and Sasamoto, N and Setiawan, VW and Sharma, P and Sieh, W and Singer, CF and Snape, K and Sokolenko, AP and Soucy, P and Southey, MC and Stoppa-Lyonnet, D and Sutphen, R and Sutter, C and Tan, YY and Teixeira, MR and Terry, KL and Thomsen, LCV and Tischkowitz, M and Toland, AE and Van Gorp, T and Vega, A and Velez Edwards, DR and Webb, PM and Weitzel, JN and Wentzensen, N and Whittemore, AS and Winham, SJ and Wu, AH and Yadav, S and Yu, Y and Ziogas, A and Berchuck, A and Couch, FJ and Goode, EL and Goodman, MT and Monteiro, AN and Offit, K and Ramus, SJ and Risch, HA and Schildkraut, JM and Thomassen, M and Simard, J and Easton, DF and Jones, MR and Chenevix-Trench, G and Gayther, SA and Antoniou, AC and Pharoah, PDP}, title = {Genome-wide association study of 398,238 women unveils seven loci associated with high-grade serous ovarian cancer.}, journal = {NPJ genomic medicine}, volume = {10}, number = {1}, pages = {73}, pmid = {41266372}, issn = {2056-7944}, support = {R01 CA074850/CA/NCI NIH HHS/United States ; P50 CA105009/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; P50 CA116201/CA/NCI NIH HHS/United States ; R01 CA126841/CA/NCI NIH HHS/United States ; U10 CA180868/CA/NCI NIH HHS/United States ; U01 CA069417/CA/NCI NIH HHS/United States ; R03 CA130065/CA/NCI NIH HHS/United States ; R01 CA140323/CA/NCI NIH HHS/United States ; UM1 CA164973/CA/NCI NIH HHS/United States ; R01 CA260132/CA/NCI NIH HHS/United States ; R01 CA176785/CA/NCI NIH HHS/United States ; N01 PC067010/PC/NCI NIH HHS/United States ; P50 CA159981/CA/NCI NIH HHS/United States ; RC4 CA153828/CA/NCI NIH HHS/United States ; P30 CA016056/CA/NCI NIH HHS/United States ; R01 CA087538/CA/NCI NIH HHS/United States ; R01 CA142996/CA/NCI NIH HHS/United States ; P50 CA125183/CA/NCI NIH HHS/United States ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; R01 CA106414/CA/NCI NIH HHS/United States ; P30 CA072720/CA/NCI NIH HHS/United States ; R01 CA095023/CA/NCI NIH HHS/United States ; PPRPGM-Nov20\100002//Cancer Research UK (CRUK)/ ; P30 CA168524/CA/NCI NIH HHS/United States ; U01 CA161032/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; R03 CA113148/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; K22 CA138563/CA/NCI NIH HHS/United States ; R01 CA058860/CA/NCI NIH HHS/United States ; Z01 ES049033/ImNIH/Intramural NIH HHS/United States ; R01 CA080742/CA/NCI NIH HHS/United States ; S10 RR025141/RR/NCRR NIH HHS/United States ; U10 CA027469/CA/NCI NIH HHS/United States ; R01 CA063678/CA/NCI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; K07 CA080668/CA/NCI NIH HHS/United States ; U01 CA116167/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA214545/CA/NCI NIH HHS/United States ; R01 CA128978/CA/NCI NIH HHS/United States ; N02 CP011019/CP/NCI NIH HHS/United States ; N02 CP065504/CP/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; U19 CA148537/CA/NCI NIH HHS/United States ; P30 CA051008/CA/NCI NIH HHS/United States ; R01 CA116167/CA/NCI NIH HHS/United States ; R01 CA083918/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; R03 CA115195/CA/NCI NIH HHS/United States ; PRCPJT-May21\100006//Cancer Research UK (CRUK)/ ; U10 CA037517/CA/NCI NIH HHS/United States ; P20 GM130423/GM/NIGMS NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R25 CA112486/CA/NCI NIH HHS/United States ; R01 CA054419/CA/NCI NIH HHS/United States ; R01 CA122443/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA076016/CA/NCI NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; U01 CA063464/CA/NCI NIH HHS/United States ; P30 CA016520/CA/NCI NIH HHS/United States ; R01 CA160669/CA/NCI NIH HHS/United States ; U01 CA058860/CA/NCI NIH HHS/United States ; R01 CA248288/CA/NCI NIH HHS/United States ; U01 CA164920/CA/NCI NIH HHS/United States ; R35 CA253187/CA/NCI NIH HHS/United States ; U19 CA148112/CA/NCI NIH HHS/United States ; R01 CA149429/CA/NCI NIH HHS/United States ; P01 CA017054/CA/NCI NIH HHS/United States ; N01 CN025403/CA/NCI NIH HHS/United States ; R01 CA142081/CA/NCI NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 CA049449/CA/NCI NIH HHS/United States ; R01 CA063682/CA/NCI NIH HHS/United States ; R01 CA192393/CA/NCI NIH HHS/United States ; K07 CA095666/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; R01 CA112523/CA/NCI NIH HHS/United States ; U10 CA180822/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We meta-analyzed >22 million variants for 398,238 women from the Ovarian Cancer Association Consortium (OCAC), UK Biobank (UKBB) and Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) to identify novel HGSOC susceptibility loci. Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was TP53 3'-UTR SNP rs78378222-T's association with HGSOC (per-T-allele relative risk (RR) = 1.44, 95% CI:1.28-1.62, P = 1.76 × 10[-9]). Polygenic scores (PGS) were developed using OCAC and CIMBA data and trained on FinnGen data. The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95% CI:1.37-1.54) per standard deviation when validated in the UKBB. This study represents the largest HGSOC GWAS to date - demonstrating that improvements in imputation reference panels and increased sample sizes help to identify HGSOC associated variants that previously went undetected, ultimately improving PGS which can improve personalized HGSOC risk prediction.}, }
@article {pmid41266432, year = {2025}, author = {Day, PM and Thompson, CD and Scherer, EM and Carter, JJ and Galloway, DA and Lowy, DR and Schiller, JT}, title = {Post-attachment neutralization of HPV16 by antibodies derived from Gardasil-vaccinated women.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {239}, pmid = {41266432}, issn = {2059-0105}, abstract = {HPV vaccines exhibit high type-specific and antibody-mediated protection against anogenital infection, even after a single dose. Complete and long-term "sterilizing" immunity against incident infection appears to be established in most HPV vaccinees, suggesting that not only are persistent levels of virus-inhibiting antibodies routinely generated but that they are also exceptionally potent at preventing infection. The process of HPV infection is unusually protracted at several steps, including slow internalization after the virions bind to the cell surface. This observation prompted us to comprehensively evaluate the ability of neutralizing antibodies to prevent infection subsequent to HPV pseudovirion attachment to cells. Using sera and memory B cell-derived monoclonal antibodies from Gardasil-vaccinated women, we observed almost complete post-attachment neutralization of HPV16 pseudovirion infection of HaCaT cells three hours after attachment, even when vaccinees' sera were diluted 250-fold, with a gradual loss of activity up to 18 h. Unexpectedly, three distinct mechanisms of post-attachment neutralization were discovered, capsid shedding from the cell surface, capsid retention on the cell surface, and rapid capsid degradation after internalization.}, }
@article {pmid41268055, year = {2025}, author = {Salerno, S and Li, Y}, title = {A Pseudo-Value Approach to Causal Deep Learning of Semi-Competing Risks.}, journal = {Arabian journal of mathematics}, volume = {}, number = {}, pages = {}, pmid = {41268055}, issn = {2193-5351}, support = {R01 CA249096/CA/NCI NIH HHS/United States ; R01 CA269398/CA/NCI NIH HHS/United States ; }, abstract = {While mortality is often the main focus of cancer studies, non-fatal events, such as disease progression, can vitally impact patient outcomes. For example, recurrence after curative treatment is a crucial endpoint in lung cancer, affecting available second-line treatments and personalized care. Estimating the de-confounded effect of interventions on disease recurrence is a key aspect of assessing cancer treatments. However, semi-competing risks complicate causal inference when death prevents disease recurrence. Existing approaches for estimating causal quantities in semi-competing survival functions rely on complex objective functions with strong assumptions and are challenging to estimate accurately. To address these challenges, we propose a deep learning approach for estimating the causal effect of treatment on non-fatal outcomes in the presence of dependent censoring and complex covariate relationships. Our three-stage approach involves estimating the marginal survival function using an Archimedean copula representation, and a jackknife pseudo-value approach that estimates pseudo-survival probabilities at fixed time points. These pseudo-survival probabilities serve as target values for developing causal estimators that are consistent and do not rely on assumptions like proportional hazards across all time points. In the final stage, we employ a deep neural network to link pseudo-outcomes, the causal variable, and additional confounders. This enables us to estimate survival average causal effects through direct standardization. We evaluate our approach through numerical studies and apply it to the Boston Lung Cancer Study, specifically examining the effect of surgical tumor resection in patients with early-stage non-small cell lung cancer.}, }
@article {pmid41268646, year = {2025}, author = {Heng, F and Sun, Y and Xu, J and Gilbert, PB}, title = {Generalized nonparametric temporal modeling of recurrent events with application to a malaria vaccine trial.}, journal = {Biometrics}, volume = {81}, number = {4}, pages = {}, pmid = {41268646}, issn = {1541-0420}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; DMS-1915829//National Science Foundation/ ; R37 AI054165/NH/NIH HHS/United States ; }, mesh = {*Malaria Vaccines/therapeutic use ; Humans ; *Models, Statistical ; *Malaria/prevention &amp; control/epidemiology ; Computer Simulation ; Algorithms ; Statistics, Nonparametric ; Likelihood Functions ; Recurrence ; Biometry/methods ; }, abstract = {Motivated by a malaria vaccine efficacy trial, this paper investigates generalized nonparametric temporal models of intensity processes with multiple time scales. Through the choice of link functions, the proposed models encompass a wide range of models such as the multiplicative temporal intensity model and the additive temporal intensity model. A maximum likelihood estimation procedure is developed to estimate the effects of two time-scales via the local linear smoothing with double kernels. Computational algorithms are developed to facilitate applications of the proposed method. An adaptive algorithm is developed to overcome the challenges of overlapping covariates. A cross-validation bandwidth selection procedure based on the logarithm of likelihood criteria is discussed. The asymptotic properties of the proposed estimators are investigated. Our simulation study shows that the proposed methods have satisfactory finite sample performance for both the multiplicative temporal intensity model and additive temporal intensity model. The proposed methods are applied to analyze the MAL-094/MAL-095 malaria vaccine efficacy trial data to investigate how the new malaria infection risk changes over time and how a prior infection or vaccination changes the future infection risk. The proposed method provides new insight into the protective effects of the malaria vaccine against new malaria infections and how the vaccine efficacy is modified by the history of prior malaria infection over time.}, }
@article {pmid41269777, year = {2026}, author = {Phillips, T and Di, M and Miller, TA and Wang, J and Pierre, A and Maglinte, GA and Seymour, EK and Wang, Y}, title = {Real-world comparative effectiveness of Bruton tyrosine kinase inhibitors in relapsed/refractory mantle cell lymphoma.}, journal = {Blood advances}, volume = {10}, number = {5}, pages = {1457-1468}, pmid = {41269777}, issn = {2473-9537}, mesh = {Humans ; *Lymphoma, Mantle-Cell/drug therapy/mortality/pathology ; *Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; Female ; Male ; *Protein Kinase Inhibitors/therapeutic use ; Aged ; Middle Aged ; Retrospective Studies ; Piperidines/therapeutic use ; Adenine/analogs &amp; derivatives/therapeutic use ; Treatment Outcome ; Pyrazines/therapeutic use ; Aged, 80 and over ; Pyrazoles/therapeutic use ; Pyrimidines/therapeutic use ; Benzamides/therapeutic use ; Recurrence ; Tyrosine Kinase Inhibitors ; }, abstract = {This real-world retrospective cohort study evaluated utilization and comparative effectiveness of covalent Bruton tyrosine kinase inhibitor (cBTKi) monotherapies in relapsed/refractory mantle cell lymphoma (R/R MCL) from electronic health records in the United States. Adults with R/R MCL who received second- or third-line (2L/3L) zanubrutinib, acalabrutinib, or ibrutinib monotherapy, on or after 1 January 2018, were included. Inverse probability of treatment weighting was used in adjusted Cox models to compare real-world time-to-next treatment (rwTTNT) and overall survival (rwOS). Among 698 patients who received 2L/3L cBTKi monotherapy, 49%, 32%, and 19% received acalabrutinib, ibrutinib, and zanubrutinib, respectively. Unadjusted analyses showed median rwTTNT for 2L zanubrutinib, acalabrutinib, and ibrutinib was 14.5 (95% confidence interval [CI], 11.0-23.2), 12.8 (95% CI, 10.5-15.6), and 10.3 (95% CI, 7.6-13.7) months, and median rwOS was 26.4 (95% CI, 23.2 to not reached [NR]), 29.2 (95% CI, 22.9-38.1), and 29.3 (95% CI, 21.8-41.6) months, respectively. Median rwTTNT for 3L zanubrutinib, acalabrutinib, and ibrutinib was 21.1 (95% CI, 3.9 to NR), 9.2 (95% CI, 6.8-14.7), and 9.6 (95% CI, 4.8-18.0) months, and median rwOS was NR (95% CI, 27.3 to NR), 27.4 (95% CI, 15.1-42.2), and 27.0 (95% CI, 15.6 to NR) months, respectively. Adjusted models in the 2L/3L cohorts combined showed numerically longer rwTTNT and statistically significantly longer rwOS for zanubrutinib vs ibrutinib (hazard ratio, 0.63; 95% CI, 0.42-0.96), and trends for improved rwTTNT and rwOS for zanubrutinib over acalabrutinib. Toxicity was a frequent reason for changing to another cBTKi. These findings suggest potential improvements in rwTTNT and rwOS with the use of second- and next-generation cBTKis for R/R MCL from 2018 and beyond.}, }
@article {pmid41269781, year = {2026}, author = {Artz, AS and Logan, B and Saber, W and Geller, N and Bellach, A and Kou, J and Wood, WA and McCarty, JM and Knight, TG and Runaas, L and Johnston, L and Walston, J and Nakamura, R and Mishra, A and Uberti, J and Dahi, PB and Saultz, JN and McCurdy, SR and Morris, L and Imus, P and Hogan, WJ and Nadiminti, K and Bhatt, VR and Olin, R and Maakaron, J and Sobecks, R and Wall, S and Mattila, D and Protz, B and Devine, SM and Horowitz, MM and Sorror, ML}, title = {CHARM is prognostic of geriatric morbidity and toxicity after allogeneic transplant for older adults: BMT CTN 1704 study.}, journal = {Blood advances}, volume = {10}, number = {5}, pages = {1657-1669}, pmid = {41269781}, issn = {2473-9537}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; UG1 HL069246/HL/NHLBI NIH HHS/United States ; UG1 HL108987/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; Prognosis ; Transplantation, Homologous/adverse effects ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Geriatric Assessment ; Middle Aged ; *Bone Marrow Transplantation/adverse effects ; Activities of Daily Living ; Risk Assessment ; Frailty ; Prospective Studies ; Morbidity ; Aged, 80 and over ; }, abstract = {Despite concerns about the toxicity of allogeneic hematopoietic cell transplantation (alloHCT) in older patients, prospective data characterizing prevalence or risk stratification for geriatric morbidity such as disability or frailty are limited. We prospectively assessed the prognostic impact of the novel composite health assessment risk model (CHARM), a score established to predict 1-year nonrelapse mortality (NRM), among 1105 patients aged ≥60 years enrolled on the Bone Marrow Transplant Clinical Trials Network Study 1704. Secondary end points were assessed post-alloHCT at day 100 (D100), D180, and D365 in multivariable models adjusted with predetermined clinical variables. Among alloHCT survivors, the prevalence of disability by instrumental activities of daily living (IADL), frailty by the Physical Frailty Phenotype, and physical function impairment by Patient Reported Measurement Information System (PROMIS) was highest at D100 and lower on D180 and D365. Higher CHARM scores were independently associated with greater disability (coefficient, -0.64; 95% confidence interval [CI], -0.85 to -0.43; P< .001), increased frailty (coefficient, 0.19; CI, 0.081-0.31; P< .001), worse PROMIS physical function, greater PROMIS depression, increased serious organ toxicity by D100, more cognitive decline at D100, and higher mortality after acute graft-versus-host disease (GVHD) but not significantly associated with PROMIS anxiety or acute GVHD. Higher CHARM scores predicted worse disability-free survival (odds ratio [OR], 2.03; CI, 1.66-2.48; P< .001) and lower frailty-free survival (OR, 2.00; CI, 1.61-2.49). In summary, CHARM is an independent prognostic scoring system not only for NRM but also for geriatric morbidity and functional limitation-free survival through 1 year after alloHCT. Pre-alloHCT CHARM is a novel tool to aid shared decision-making for older patients. This trial was registered at www.clinicaltrials.gov as #NCT03992352.}, }
@article {pmid41271741, year = {2025}, author = {Huppert, LA and Gliwa, AS and Tait, M and Quintal, L and Starzinski, S and Cheung, A and Moasser, M and Majure, M and Melisko, M and Munster, P and Rugo, HS and Campbell, M and Fong, L and Chien, AJ}, title = {Phase Ib study of intratumoral talimogene laherparepvec (T-VEC) in combination with chemotherapy or endocrine therapy in patients with advanced HER2-negative breast cancer.}, journal = {NPJ breast cancer}, volume = {11}, number = {1}, pages = {130}, pmid = {41271741}, issn = {2374-4677}, abstract = {Talimogene laherparepvec (T-VEC) is an oncolytic virus that is hypothesized to enhance responses to systemic therapy. This Phase 1b trial evaluated the safety and efficacy of intratumoral T-VEC plus chemotherapy (CT) or endocrine therapy (ET) for patients with hormone receptor positive (HR +)/HER2- and triple negative (TN) advanced breast cancer (ABC) with injectable locoregional/chest wall disease. The primary endpoint was safety/tolerability. Secondary endpoints were objective response rate by irRECIST 1.1 and clinical assessment of local response. 19 patients enrolled (9 HR + /HER2-; 10 TN; median two lines of prior CT). Intratumoral T-VEC was administered with the following partners: gemcitabine/carboplatin (n = 8), nab-paclitaxel (n = 7), paclitaxel (n = 2), or ET (n = 2). Eight patients in the T-VEC + gemcitabine/carboplatin arm were formally evaluated for dose limiting toxicities (DLTs) based on pre-specified protocol criteria, and one DLT (grade 3 neutropenia leading to carboplatin dose reduction) was identified. Response per irRECIST 1.1 was evaluated in 16 patients: partial response (n = 2, 12.5%), stable disease (n = 7, 43.8%), progressive disease (n = 7, 43.8%). Patients with higher pre-treatment tumor infiltrating lymphocytes (TILs) were more likely to respond, and clinical responders had induction of Ki-67 in multiple peripheral myeloid populations. In conclusion, the addition of intratumoral T-VEC to CT or ET was safe in patients with ABC and injectable locoregional disease, supporting the continued investigation of direct intratumoral immunomodulatory strategies that can enhance local and systemic immune responses. NCT03554044.}, }
@article {pmid41271835, year = {2025}, author = {Chamberlin, S and Graham, J and Jeng, S and Swarts, J and Ferris, M and Heise, M and Baric, RS and McWeeney, S and Lund, J and Mooney, M}, title = {Adaptive immune response to West Nile virus infection in the Collaborative Cross mouse model: A database of cellular phenotypes and Quantitative Trait Loci.}, journal = {Scientific data}, volume = {12}, number = {1}, pages = {2029}, pmid = {41271835}, issn = {2052-4463}, support = {U19 AI100625/AI/NIAID NIH HHS/United States ; U19AI100625//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Animals ; *West Nile Fever/immunology/genetics ; *Quantitative Trait Loci ; Mice ; Collaborative Cross Mice ; Phenotype ; Disease Models, Animal ; *Adaptive Immunity/genetics ; West Nile virus ; }, abstract = {West Nile virus (WNV) infection can lead to a wide range of clinical outcomes, from asymptomatic to self-limiting febrile and serious neuro-invasive disease. Knowledge of the genetic factors contributing to the heterogeneity of this disease can inform pathogenic mechanisms, help guidethe development of cell based therapeutics, vaccines and inform lifestyle choices. Yet this knowledge is incomplete in humans. Here we present data from a large-scale experiment aimed at identifying quantitative trait loci (QTL) associated with adaptive immune cellular phenotypes observed in response to infection with WNV. This data was generated using the Collaborative Cross (CC) mouse model, previously demonstrated as a representative model for human WNV infection and homeostatic immune states. In addition, due to challenges of QTL mapping with the large number of intermediate, highly coordinated immune and virologic phenotypes, we also provide a computational pipeline for the prioritization of gene candidates designed to leverage those characteristics for downstream mechanistic studies.}, }
@article {pmid41272850, year = {2025}, author = {Mariapun, S and Eriksson, M and Tai, MC and Mohd Taib, NA and Yip, CH and Rahmat, K and Vachon, CM and Lindstrom, S and Li, J and Hartman, M and Hall, P and Easton, DF and Ho, WK and Teo, SH}, title = {Genome-wide association study of Asian women identifies putative mammographic density-associated loci.}, journal = {Breast cancer research : BCR}, volume = {27}, number = {1}, pages = {207}, pmid = {41272850}, issn = {1465-542X}, support = {/WT_/Wellcome Trust/United Kingdom ; UM.C/HIR/MOHE/06//Malaysian Ministry of Higher Education High Impact Research Grant/ ; MR/P012930/1//Newton - Ungku Omar Fund/ ; v203477/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; Female ; *Genome-Wide Association Study ; *Breast Density/genetics ; *Breast Neoplasms/genetics/diagnostic imaging/pathology ; *Asian People/genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; Genetic Predisposition to Disease ; Mammography ; Aged ; Adult ; *Genetic Loci ; White People/genetics ; Risk Factors ; }, abstract = {BACKGROUND: Mammographic density (MD) is a strong, heritable risk factor for breast cancer. To date, 55 independent MD-associated genetic loci have been identified through genome-wide association studies (GWASs) in women of European ancestry; however, no studies have been reported in Asian women.<br><br>METHODS: To identify novel loci, we conducted genome-wide association studies (GWASs) of absolute dense, absolute nondense, and percentage area and volumetric densities, adjusting for age, body mass index (BMI), and ancestry-informative principal components, in a multi-ethnic cohort of 2,951 Asian women attending opportunistic mammography screening. We selected 175 novel loci that were associated with at least one MD phenotype at P&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10[-&#x2009;6] for (a) replication in an independent set of 401 Asian breast cancer cases, using density measurements from the unaffected breasts, (b) evaluation in a GWAS meta-analysis of MD in 27,900 women of European ancestry and (c) evaluation with breast cancer risk in Asian women.<br><br>RESULTS: Four of the 175 loci were replicated in women of Asian ancestry at P&#x2009;<&#x2009;0.05, with directions of association that were consistent with those observed in the GWAS. The rs7018644 SNP at the 9p13.1 locus was the only loci replicated in both Asian and European cohorts. In addition, eight SNPs were also associated with breast cancer risk (P&#x2009;<&#x2009;0.05) in a GWAS meta-analysis of Asian women.<br><br>CONCLUSION: This study identifies potential novel MD-associated loci in Asian women. Replication in a larger Asian study is needed to confirm these findings.}, }
@article {pmid41273917, year = {2025}, author = {Leger, KJ and Stratton, KL and Sachdeva, R and Armenian, SH and Bhat, AH and Boyle, PM and Edwards, LA and Meacham, LR and Narasimhan, S and Nathan, PC and Sadak, KT and Sharma, S and Border, WL and Leisenring, WM and Chow, EJ}, title = {Enhancing Prediction of Cancer Therapy-Related Cardiomyopathy From Surveillance Echocardiograms: A Children's Oncology Group Study.}, journal = {JACC. Advances}, volume = {4}, number = {12 Pt 2}, pages = {102363}, pmid = {41273917}, issn = {2772-963X}, support = {R01 CA211996/CA/NCI NIH HHS/United States ; U10 CA095861/CA/NCI NIH HHS/United States ; R21 CA277746/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Early echocardiographic indicators of cardiac remodeling may enhance cardiomyopathy risk prediction in childhood cancer survivors (CCS).<br><br>OBJECTIVES: The objective of the study was to assess whether influential echocardiographic measures can be combined to develop a robust cardiomyopathy risk prediction model in CCS.<br><br>METHODS: Multicenter retrospective study of &#x2265;1-year CCS with digitally archived surveillance echocardiograms, enrolled cardiomyopathy cases (left ventricular [LV] fractional shortening &#x2264;28% or LV ejection fraction &#x2264;50% on &#x2265;2 occasions) and noncases (&#x2265;5-year CCS who maintained fractional shortening &#x2265; 30% and ejection fraction &#x2265;55% without initiation of cardiac medications). Echocardiograms were centrally quantitated in a blinded fashion. Least absolute shrinkage and selection operator regression identified the most influential 2-year predictors of cardiomyopathy among 27 echocardiographic parameters. Logistic regression was used to generate ORs with 95% CIs. Estimates were applied to the training and test data sets to generate area under the receiver operating characteristic curves (AUC).<br><br>RESULTS: Data from 146 CCS (52 cases; 94 noncases) with a median follow-up of 9.3 years post-cancer diagnosis and a total of 281 echocardiograms were included. A set of 7 echocardiographic measures were identified as the most influential predictors, with AUC of 0.82 (95% CI: 0.74-0.89) and 0.85 (95% CI: 0.74-0.95) in the training and test data sets, respectively. LV end-systolic dimension (ORmm: 1.2; 95% CI: 1.1-1.4), apical 4-chamber longitudinal strain (OR%: 1.2; 95% CI: 1.0-1.3), and septal A' velocity (ORcm/s: 1.3; 95% CI: 1.1-1.6) were strongly predictive of cardiomyopathy. AUCs were similar if cancer treatment exposures were included.<br><br>CONCLUSIONS: Early abnormalities in echocardiographic parameters of structure and function predict subsequent cardiomyopathy in CCS and can identify high-risk survivors who warrant early intervention.}, }
@article {pmid41274869, year = {2025}, author = {Liu, C and Joehanes, R and Ma, J and Xie, J and Yang, J and Wang, M and Huan, T and Hwang, SJ and Wen, J and Sun, Q and Demirkale, CY and Heard-Costa, NL and Orchard, P and Carson, AP and Haessler, JW and Raffield, LM and Reiner, AP and Franceschini, N and Auer, PL and Kooperberg, C and Li, Y and O'Connor, G and Murabito, JM and Munson, P and Levy, D}, title = {Integrating whole genome and transcriptome sequencing to characterize the genetic architecture of isoform variation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {10615}, pmid = {41274869}, issn = {2041-1723}, support = {HHSN268201100037C/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; HHSN268201600032C/ES/NIEHS NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; R01 AG075884/AG/NIA NIH HHS/United States ; R01 HL163972/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 HL155569/HL/NHLBI NIH HHS/United States ; K26 DK138425/DK/NIDDK NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; R01 HL175681/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL129132/HL/NHLBI NIH HHS/United States ; R01 AA028263/AA/NIAAA NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; HHSN268201600038C/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01 HL146500/HL/NHLBI NIH HHS/United States ; R01 HG013163/HG/NHGRI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; R01 AG086303/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Quantitative Trait Loci/genetics ; Protein Isoforms/genetics ; Genome-Wide Association Study ; Female ; *Transcriptome/genetics ; Whole Genome Sequencing ; Polymorphism, Single Nucleotide ; Male ; Middle Aged ; Gene Expression Profiling ; Genome, Human ; Gene Frequency ; }, abstract = {We present a whole-blood isoform ratio QTL (irQTL) resource by analyzing genome-wide isoform-to-gene expression ratios using sequencing data. In Framingham Heart Study (FHS, n = 2622) discovery, we identify over 1.1 million cis-irQTLs (minor allele frequency [MAF] ≥ 0.01, ±1 Mb of 10,883 isoform transcripts, P < 5 × 10[-8]) across 4,971 genes. Among 11,425 sentinel cis-irQTLs, 72% replicate (P < 1 × 10[-4]) in the Women's Health Initiative (WHI; n = 2005). Notably, 20% of cis-irQTLs have no significant association with overall gene expression, indicating isoform-specific regulation. These variants are enriched at splice donor/acceptor sites and genome-wide association study loci (P < 1 × 10[-10]). We also identify 1870 sentinel trans-irQTLs (MAF ≥ 0.01, P < 1.5 × 10[-13]) for 1,084 isoforms across 590 genes, and 2327 rare cis-irQTLs (0.003 < MAF < 0.01) for 2467 isoforms of 1428 genes in FHS, with external replication rates of 61% and 41% in WHI, respectively. We highlight rs12898397 in ULK3, which alters splice site usage and reduces expression of a full-length isoform. Mendelian randomization supports a causal role between this isoform shift and reduced diastolic blood pressure. These findings highlight the power of irQTL mapping to uncover transcript-specific regulatory mechanisms underlying complex traits.}, }
@article {pmid41275868, year = {2026}, author = {Silhol, R and Booton, RD and Mitchell, KM and Stannah, J and Stevens, O and Dimitrov, D and Bershteyn, A and Johnson, LF and Kelly, SL and Kim, HY and Maheu-Giroux, M and Martin-Hughes, R and Mishra, S and Stone, J and Stuart, R and Stover, J and Vickerman, P and Wilson, DP and Baral, S and Donnell, D and Imai-Eaton, JW and Boily, MC}, title = {Identifying priority populations for HIV interventions using acquisition and transmission indicators: a combined analysis of 15 mathematical models from ten African countries.}, journal = {The lancet. HIV}, volume = {13}, number = {1}, pages = {e30-e39}, doi = {10.1016/S2352-3018(25)00199-7}, pmid = {41275868}, issn = {2352-3018}, mesh = {Humans ; *HIV Infections/transmission/epidemiology/prevention &amp; control ; Male ; Female ; Africa/epidemiology ; Sex Workers/statistics &amp; numerical data ; *Models, Theoretical ; Adult ; Young Adult ; Adolescent ; Middle Aged ; Homosexuality, Male ; }, abstract = {BACKGROUND: Characterising disparities in HIV infection across populations by gender, age, and HIV risk is key information to guide intervention priorities. We aimed to assess how indicators measuring HIV acquisitions, transmissions, or potential long-term infections influence estimates of the contribution of different populations to new infections, including key populations (including female sex workers, their clients, men who have sex with men).<br><br>METHODS: In this mathematical model comparison analysis, we evaluated four indicators using nine models representing 15 different settings across Africa. The acquisition indicator (I1) measured the annual proportion of all new infections acquired by a specific population, the direct transmission indicator (I2) measured the annual proportion of all new infections directly transmitted by a specific population, and the 1-year transmission population-attributable fractions (tPAFs; I3) and 10-year tPAFs (I4) measured the proportion of new infections averted if transmission involving a specific population was blocked over a specific time period. We compared estimates of the four indicators across seven populations and 15 settings and assessed if the contribution of specific populations ranked differently across indicators for ten settings.<br><br>FINDINGS: Different indicators identified distinct priority populations as the largest contributors: I1 identified women aged 25 years and older outside key populations as contributing the most to acquired infections in eight of ten settings in 2020, but to direct transmissions (I2) in only two settings. In six of ten settings, I4 identified non-key population men aged 25 years and older and clients of female sex workers as the largest contributors to HIV transmission. Notably, non-key population women aged 15-24 years acquired (I1) more infections in 2020 (median of 1&#xb7;7 times higher across models) than they directly transmitted (I2), whereas more infections were transmitted than acquired in non-key population men aged 25 years and older (median 1&#xb7;4 times more) and clients of female sex workers (1&#xb7;6 times more) in all but one model. Estimates of the 10-year tPAFs accounting for transmission in the long-term were substantially larger than the direct transmission indicator for all populations, especially for female sex workers (2&#xb7;0 times higher).<br><br>INTERPRETATION: Indicators that reflect HIV acquisitions and transmissions in the short and long term can be used to capture the complexity of HIV epidemics across different populations and timeframes. The added nuance would improve the effectiveness of the HIV prevention response across all populations at risk.<br><br>FUNDING: US National Institutes of Health and UK Medical Research Council.<br><br>TRANSLATION: For the French translation of the abstract see Supplementary Materials section.}, }
@article {pmid41276459, year = {2026}, author = {Yang, E and Salerno, S and Dahlerus, C and Hirth, RA and Xu, T and Eckard, A and Agbenyikey, W and Horton, GM and Clark, S and Messana, JM and Li, Y}, title = {The Impact of Transplant Waitlisting Measures on Dialysis Facilities' Star Ratings.}, journal = {Health services research}, volume = {61}, number = {1}, pages = {e70071}, pmid = {41276459}, issn = {1475-6773}, support = {75FCMC18D0041-75FCMC18F0001//Centers for Medicare and Medicaid Services/ ; HHSM-500-2013-13017I-HHSM-500-T001//Centers for Medicare and Medicaid Services/ ; }, mesh = {Humans ; *Waiting Lists ; Cross-Sectional Studies ; United States ; *Kidney Transplantation/statistics &amp; numerical data ; *Renal Dialysis/statistics &amp; numerical data ; Female ; Male ; Middle Aged ; *Ambulatory Care Facilities/standards/statistics &amp; numerical data ; Aged ; Centers for Medicare and Medicaid Services, U.S. ; }, abstract = {OBJECTIVE: To evaluate how adding kidney transplantation waitlisting measures-the Standardized First Kidney Transplant Waitlist Ratio for Incident Dialysis Patients (SWR) and Percentage of Prevalent Patients Waitlisted (PPPW)-affects Dialysis Facility Care Compare Star Ratings.<br><br>STUDY SETTING AND DESIGN: In this observational, cross-sectional study, we calculated the difference between facilities' published (with waitlisting measures) and counterfactual (without waitlisting measures) Star Ratings. We used multinomial regression to examine associations between Star Rating changes after waitlisting measure inclusion and facility characteristics and calculated corresponding average risk differences.<br><br>We used comprehensive clinical and administrative data from the Centers for Medicare/Medicaid Services from 2021 to investigate the impact of waitlisting measure addition on Star Ratings. Facility characteristics included demographic and patient mix, area deprivation index (ADI), dialysis organization affiliation, and urbanicity.<br><br>PRINCIPAL FINDINGS: 36.5% of facilities' ratings changed after waitlisting measures were added. Facility characteristics associated with a higher average risk of Star increase included location in low-ADI (0.091; 95% CI: 0.072, 0.109) or urban areas (0.061; 95% CI: 0.034, 0.087), independent/small dialysis organization affiliation (0.062; 95% CI: 0.041, 0.083), and having more PD patients (0.115; 95% CI: 0.093, 0.138). Characteristics associated with a higher average risk of Star decrease included high-ADI (0.075; 95% CI: 0.054, 0.095) or rural (0.056; 95% CI: 0.028, 0.083) location, large dialysis organization affiliation (0.058; 95% CI: 0.039, 0.078), having more patients with dual Medicare/Medicaid eligibility (0.052; 95% CI: 0.032, 0.071), and having fewer peritoneal dialysis patients (0.100; 95% CI: 0.081, 0.120).<br><br>CONCLUSIONS: Including waitlisting measures significantly impacts the Star Ratings and captures a new dimension of care quality. Worse socioeconomic status-related facility characteristics were strongly associated with worse Star Rating outcomes. These findings can inform future discussions about risk adjustment among the developers of the SWR and PPPW measures.}, }
@article {pmid41277126, year = {2025}, author = {Powles, T and Tagawa, ST and Vulsteke, C and Gross-Goupil, M and Park, SH and Necchi, A and De Santis, M and Duran, I and Morales-Barrera, R and Guo, J and Sternberg, CN and Bellmunt, J and Goebell, PJ and Kovalenko, M and Boateng, F and Sierecki, M and Wang, L and Sima, CS and Waldes, J and Bangs, R and Loriot, Y and Grivas, P}, title = {A plain language summary of the TROPiCS-04 study: sacituzumab govitecan use after platinum-based chemotherapy and immunotherapy in people with locally advanced or metastatic cancer of the bladder, urethra, or upper urinary tract.}, journal = {Future oncology (London, England)}, volume = {21}, number = {28}, pages = {3593-3610}, doi = {10.1080/14796694.2025.2579003}, pmid = {41277126}, issn = {1744-8301}, }
@article {pmid41278697, year = {2025}, author = {Chang, CH and Handler, T and Fuda, N and Pascua, D and Mouton, T and Larracuente, AM}, title = {Pervasive suppressors halt the spread of selfish Segregation Distorter in a natural population.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41278697}, issn = {2692-8205}, support = {R35 GM119515/GM/NIGMS NIH HHS/United States ; }, abstract = {Meiotic drivers are selfish genetic elements that subvert Mendelian inheritance to increase their own transmission, yet they are typically found at low frequencies across natural populations. The factors that limit their spread remain unclear. To investigate this paradox, we studied the Segregation Distorter (SD) system, a selfish coadapted gene complex in Drosophila melanogaster. SD biases its transmission by killing sperm carrying a homologous chromosome bearing a target locus, Responder (Rsp), which appear as satellite repeats. Such selfish killing impairs male fertility and imposes selective pressure on the host genome to evolve resistance, either by deleting Rsp copies or acquiring unlinked suppressors. To characterize the spectrum of Rsp alleles and the frequency of segregating suppressors, we surveyed 90 strains from the Drosophila Genome Reference Panel. Rather than loss of Rsp, we found that over half of the strains (52/90) harbor suppressors located on the X chromosome or autosomes, but not the Y chromosome. The widespread presence of strong suppressors limited the resolution of our genome-wide association mapping; however, recombination analysis identified a strong X-linked suppressor to a ~300 kb interval on the chromosome. Together, our findings suggest that pervasive, multilocus suppression constrains the spread of SD in natural populations.}, }
@article {pmid41279072, year = {2025}, author = {Williamson, C and Curry, L and Mkhize, NN and Giorgi, EE and Magaret, CA and Lambson, BE and Hons, SB and Kaldine, H and Moyo-Gwete, T and Rolland, M and Rossenkhan, R and Garcia, NMG and Moodley, C and Yssel, A and Huang, Y and Marsden, AA and Reeves, DB and Mayer, BT and Bumgarner, RE and Beaume, N and Westfall, DH and Juraska, M and DeCamp, AC and Murrell, H and Bai, H and Deng, W and Pankow, AP and Bhattacharya, T and York, T and Ndabambi, N and Chen, L and Zhao, H and Gwashu-Nyangiri, A and Thebus, R and Cohen, P and Murrell, B and Karuna, S and Hural, J and Mgodi, N and Edupuganti, S and Morris, L and Montefiori, D and McElrath, MJ and Cohen, MS and Corey, L and Edlefsen, PT and Gilbert, PB and Moore, PL and Mullins, JI}, title = {VRC01 Selects Rare HIV Escape Mutations After Acquisition in Antibody-Mediated Prevention Trials.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279072}, issn = {2692-8205}, support = {K25 AI155224/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; R01 AI152115/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; R01 AI157854/AI/NIAID NIH HHS/United States ; INV-016189/GATES/Gates Foundation/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; R01 AI186721/AI/NIAID NIH HHS/United States ; }, abstract = {Broadly neutralizing antibodies (bnAbs) show promise in HIV prevention, yet viral escape remains a challenge. In the Antibody Mediated Prevention (AMP) trials, the CD4 binding site (CD4bs) bNAb VRC01 blocked acquisition by VRC01-sensitive strains. However, its influence on viral evolution post-acquisition is not fully understood. Here we analyzed >12,000 HIV env sequences from 47 participants from the AMP trials, identifying VRC01-mediated de novo escape mutations in 8 of 26 VRC01-treated participants but none in 21 placebo participants. These mutations were found at very low frequency (<1%) in global viruses. Escape mutations, primarily located in the Loop-D and β23/V5 regions of Env, conferred cross-resistance to several CD4bs bnAbs, while more potent CD4bs bnAbs like N6 and 1-18 largely retained their activity. Our findings demonstrate that prophylactic VRC01 can select for viral escape after infection, underscoring the need for next-generation bnAbs with improved breadth and potency to enhance durability and efficacy of antibody-based HIV prevention.}, }
@article {pmid41279209, year = {2025}, author = {Awany, D and Ariefdien, DT and Mendelsohn, SC and Rozot, V and Mulenga, H and Nyangu, S and Tameris, M and Moloantoa, T and Katona, A and Maruri, F and Noor, F and Panchia, R and Hlongwane, K and Stanley, K and van der Heijden, YF and Hadley, K and Gartland, AF and Innes, C and Brumskine, W and Dheda, K and Jaumdally, S and Perumal, T and Martinson, N and Leslie, A and Fourie, B and Hiemstra, A and Malherbe, ST and Walzl, G and Naidoo, K and Churchyard, G and Chegou, NN and Sterling, TR and Hatherill, M and Scriba, TJ}, title = {Inflammatory Biomarkers of Asymptomatic and Symptomatic Tuberculosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279209}, issn = {2692-8205}, support = {U01 AI152075/AI/NIAID NIH HHS/United States ; }, abstract = {A large proportion of individuals with tuberculosis (TB) are asymptomatic. The biological and inflammatory underpinnings of asymptomatic TB are unknown and may differ from symptomatic TB. We characterised blood transcriptomic and proteomic profiles in South African community screening vs. health facility-based triage cohorts. Asymptomatic TB shared core transcriptomic and proteomic features with symptomatic TB, including upregulation of innate, interferon and inflammatory pathways and downregulation of T and B cell pathways. Integration of transcriptomic and proteomic data from asymptomatic TB individuals identified two distinct sub-clusters characterized by higher or lower bacterial burden, blood IFN-γ responses, BMI, and chest radiographic abnormalities, suggesting different disease severity. We identified a new blood transcriptomic signature of asymptomatic TB. However, diagnostic performance of transcriptomic and proteomic markers was weaker for asymptomatic TB than symptomatic TB, suggesting that policy development for community-based, asymptomatic TB screening should not adopt biomarkers developed for symptomatic TB triage without further optimization.}, }
@article {pmid41279355, year = {2025}, author = {Khan, SA and Faerber, D and Kirkey, D and Raffel, S and Hadland, B and Deininger, M and Buettner, F and Zhao, HG}, title = {Cross-Species Morphology Learning Enables Nucleic Acid-Independent Detection of Live Mutant Blood Cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279355}, issn = {2692-8205}, support = {R01 HL168110/HL/NHLBI NIH HHS/United States ; }, abstract = {In hematology/oncology clinics, molecular diagnostics based on nucleic acid sequencing or hybridization are routinely employed to detect malignancy-associated genetic mutations and are instrumental in therapeutic stratification and prognostication. However, their limited cost-efficiency constrains their use in pre-malignant screening-specifically, the detection of rare circulating mutant blood cells in asymptomatic individuals. In both neonates and adults, the presence of malignancy-associated mutations in peripheral blood correlates with an elevated risk of future neoplastic transformation, with certain mutations, such as KMT2A rearrangements, exhibiting near-complete penetrance. If feasible, pre-malignant screening could enable early intervention and even disease prevention. Here, we introduce a high-throughput, single-cell computer vision platform capable of identifying mutant peripheral blood cells by recognizing mutation-specific morphological features. The morphology recognition module was developed through cross-species learning from murine to human datasets, enabling a generalizable and cost-effective approach for detecting mutations in live blood cells. The platform holds promise for translation into pre-malignant screening applications in asymptomatic neonates and adults as well as measurable residual disease monitoring in malignancies. Furthermore, it provides a novel single-cell morphological data modality that complements existing molecular layers, including genomics, epigenomics, transcriptomics, and proteomics.}, }
@article {pmid41279420, year = {2025}, author = {Matsen, FA and Dumm, W and Sung, K and Johnson, MM and Rich, D and Starr, T and Song, YS and Fukuyama, J and Haddox, HK}, title = {Separating selection from mutation in antibody language models.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279420}, issn = {2692-8205}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; DP2 AI177890/AI/NIAID NIH HHS/United States ; R56 HG013117/HG/NHGRI NIH HHS/United States ; R01 HG013117/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Antibodies are encoded by nucleotide sequences that are generated by V(D)J recombination and evolve according to mutation and selection processes. Existing antibody language models, however, focus exclusively on antibodies as strings of amino acids and are fitted using standard language modeling objectives such as masked or autoregressive prediction. In this paper, we first show that fitting models using this objective implicitly incorporates nucleotide-level mutation processes as part of the protein language model, which degrades performance when predicting effects of mutations on functional properties of antibodies. To address this limitation, we devise a new framework: a Deep Amino acid Selection Model (DASM) that learns the selection effects of amino-acid mutations while explicitly factoring out the nucleotide-level mutation process. By fitting selection as a separate term from the mutation process, the DASM exclusively quantifies functional effects: effects that change some aspect of the function of the antibody. This factorization leads to substantially improved performance on standard functional benchmarks. Moreover, our model is an order of magnitude smaller and multiple orders of magnitude faster to evaluate than existing approaches, as well as being readily interpretable.}, }
@article {pmid41279479, year = {2026}, author = {Larsen, BB and Harari, S and Gen, R and Stewart, C and Veesler, D and Bloom, JD}, title = {Functional and antigenic constraints on the Nipah virus fusion protein.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279479}, issn = {2692-8205}, support = {DP1 AI158186/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; 75N93022C00036/AI/NIAID NIH HHS/United States ; U19 AI181881/AI/NIAID NIH HHS/United States ; }, abstract = {Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and host membranes. Here, we use non-replicative pseudoviruses to safely measure the effects of all F single amino-acid residue mutations on its cell entry function and neutralization by monoclonal antibodies. We compare mutational tolerance in F with previous experimental measurements for RBP and show that F is much more functionally constrained than the RBP. We also identify mutationally intolerant sites on the F trimer surface and core that are critical for proper function, and describe mutations that are candidates for stabilizing F in the prefusion conformation for vaccine design. We quantify how F mutations affect neutralization by six monoclonal antibodies, and show that the magnitude of mutational effects on neutralization varies among antibodies. Our measurements of mutational effects on Nipah virus F predict the ability of the antibodies to neutralize the related Hendra virus. Overall, our work defines the functional and antigenic constraints on the F protein from an important zoonotic virus.}, }
@article {pmid41279534, year = {2025}, author = {McCrone, JT and Baele, G and Omah, IF and Kinganda-Lusamaki, E and Brew, JA and Carvalho, LM and Dudas, G and Mbala-Kingebeni, P and Suchard, MA and Rambaut, A}, title = {Evidence of latency reshapes our understanding of Ebola virus reservoir dynamics.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279534}, issn = {2692-8205}, support = {/WT_/Wellcome Trust/United Kingdom ; R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; }, abstract = {Ebola virus (EBOV) has caused severe outbreaks of haemorrhagic fever in Central and West Africa since the first observed zoonotic epidemic in the late 1970s. While recent outbreaks have revealed much about the epidemiological dynamics that sustain human-to-human transmission, the mechanisms by which the virus persists between outbreaks are unknown. Previously, phylogenetic approaches have been used to characterise the EBOV reservoir from the evolutionary relationships among observed human outbreaks. We here employ a novel phylogenetic latency model - inspired by recent observations of extreme EBOV evolutionary rate heterogeneity in humans - to characterise the natural history of EBOV and by extension its reservoir. We find the prevailing model of EBOV reservoir dynamics is deficient, and the long-term EBOV evolutionary rate is slower than previously believed. The hypothesis that EBOV diversity dates back to a bottleneck event just prior to the first human outbreak is not supported by the data. Further, our results suggest that EBOV undergoes extended periods of quiescence in the reservoir, similar to that observed in a small fraction of human infections. These findings have significant implications for understanding the source of EBOV outbreaks, characterising the EBOV reservoir, and uncovering the factors that contribute to EBOV outbreaks in humans.}, }
@article {pmid41279560, year = {2025}, author = {Sohn, MH and Dubocanin, D and Vollger, MR and Kwon, Y and Minkina, A and Munson, KM and Hart, SF and Ranchalis, JE and Parmalee, NL and Sedeño-Cortés, AE and Ou, J and Au, NY and Bohaczuk, S and Carroll, B and Frazar, CD and Harvey, WT and Hoekzema, K and Huang, MF and Jacques, CN and Jensen, DM and Kolar, JT and Lee, R and Lin, J and Loy, K and Mack, T and Mao, Y and Pham, MM and Ryke, E and Smith, JD and Sutherlin, L and Swanson, EG and Weiss, JM and Wg, SA and Carvalho, C and Coorens, TH and Harris, K and Wei, CL and Eichler, EE and Altemose, N and Bennett, JT and Stergachis, AB}, title = {A telomere-to-telomere map of somatic mutation burden and functional impact in cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279560}, issn = {2692-8205}, support = {UG3 NS132128/NS/NINDS NIH HHS/United States ; T32 HG000035/HG/NHGRI NIH HHS/United States ; UG3 NS132061/NS/NINDS NIH HHS/United States ; DP5 OD029630/OD/NIH HHS/United States ; UG3 NS132136/NS/NINDS NIH HHS/United States ; UM1 DA058236/DA/NIDA NIH HHS/United States ; UM1 DA058235/DA/NIDA NIH HHS/United States ; UG3 NS132144/NS/NINDS NIH HHS/United States ; UG3 NS132132/NS/NINDS NIH HHS/United States ; UM1 DA058219/DA/NIDA NIH HHS/United States ; UG3 NS132084/NS/NINDS NIH HHS/United States ; UG3 NS132105/NS/NINDS NIH HHS/United States ; UM1 DA058229/DA/NIDA NIH HHS/United States ; UM1 DA058220/DA/NIDA NIH HHS/United States ; UG3 NS132135/NS/NINDS NIH HHS/United States ; UG3 NS132146/NS/NINDS NIH HHS/United States ; U24 NS132103/NS/NINDS NIH HHS/United States ; T32 GM007454/GM/NIGMS NIH HHS/United States ; UG3 NS132139/NS/NINDS NIH HHS/United States ; UG3 NS132134/NS/NINDS NIH HHS/United States ; U01 HG013744/HG/NHGRI NIH HHS/United States ; UM1 DA058230/DA/NIDA NIH HHS/United States ; U24 MH133204/MH/NIMH NIH HHS/United States ; K99 GM155552/GM/NIGMS NIH HHS/United States ; UG3 NS132024/NS/NINDS NIH HHS/United States ; T32 GM141828/GM/NIGMS NIH HHS/United States ; UG3 NS132138/NS/NINDS NIH HHS/United States ; UG3 NS132127/NS/NINDS NIH HHS/United States ; }, abstract = {Oncogenesis involves widespread genetic and epigenetic alterations, yet the full spectrum of somatic variation genome-wide remains unresolved. We generated a near-telomere-to-telomere (T2T) diploid assembly of a donor paired with deep short- and long-read sequencing of their melanoma. This revealed that 16% of somatic variants occur in sequences absent from GRCh38, with satellite repeats acting as hotspots for UV-induced damage due to sequence-intrinsic mutability and inefficient repair. Centromere kinetochore domains emerged as focal sites of structural, genetic, and epigenetic variation, leading to remodeling of centromere kinetochore binding domains during tumor evolution. Single-molecule telomere reconstructions uncovered cycles of attrition, deletion, and telomerase-mediated extension that shape cancer telomeres. Finally, diploid chromatin maps exposed that copy number alterations and epimutations, rather than point mutations, predominate in rewiring cancer regulatory programs. These findings define the full landscape of a cancer's somatic variation and their functional impact, establishing a blueprint for T2T studies of mosaicism.}, }
@article {pmid41279611, year = {2025}, author = {Mullins, JI and Deng, W and Giorgi, EE and Magaret, CA and Rolland, M and Bhattacharya, T and Westfall, DH and Yssel, AEJ and Bumgarner, RE and Murrell, B and Ndung'u, T and Robb, ML and Rossenkhan, R and Edlefsen, PT and Dong, KL and Chen, L and Gwashu-Nyangiri, A and Zhao, H and Thebus, R and Sawe, F and Nitayaphan, S and York, T and Matten, D and Murrell, H and Pankow, AP and Juraska, M and Ludwig, J and Hural, J and Cohen, MS and Corey, L and McElrath, MJ and Gilbert, PB and Williamson, C}, title = {Long-Read Deep Sequencing Reveals High Rates of Multilineage Transmission and Rapid Viral Population Changes in Acute HIV Infection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279611}, issn = {2692-8205}, support = {INV-033558/GATES/Gates Foundation/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P30 AI060354/AI/NIAID NIH HHS/United States ; INV-016189/GATES/Gates Foundation/United States ; }, abstract = {Understanding the selective forces acting upon HIV early in infection is crucial to design prevention strategies. By leveraging deep sequencing and the short diagnostic intervals of the FRESH and RV217 cohorts (median 4 days) between the last-negative and first-positive RNA tests, we captured a precise and early snapshot of acute HIV infection. The frequency of multiple transmitted viruses of 38% in these as well as placebo recipients from the AMP trials was higher than previously published, with the true frequency likely to be higher. The relative abundance of lineages fluctuated substantially over time in two-thirds of the multilineage infections, generating uncertainty in identifying the specific viruses that were transmitted and founding the infection. Viral populations exhibited diversity and selection on the Gag and Env proteins at the earliest times examined, with sites inferred to be undergoing negative selection most evident. These data may help explain vaccination failures and provide new targets for prevention.}, }
@article {pmid41279707, year = {2025}, author = {Barker, M and Milanov, O and Dumm, W and Rich, D and Turakhia, Y and Matsen, FA}, title = {larch: mapping the parsimony-optimal landscape of trees for directed exploration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279707}, issn = {2692-8205}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Phylogenetic inference algorithms for large data sets typically return a single tree. However, there are often many optimal trees, especially when sequence data is closely related. We develop a compact representation of large collections of maximally parsimonious histories-trees with mutations mapped onto tree edges. Our C++ implementation, larch, leverages this representation for a highly parallel search algorithm. The storage component uses our history DAG structure to compactly represent large families of optimal trees. The search algorithm integrates this storage with matOptimize for rapid tree optimization; the DAG structure allows us to accept thousands of conflicting tree rearrangements in parallel. The integration enables a new type of tree search: one that systematically maps out the collection of good trees, enabling moves that are directed away from the current set of optimal trees to cross valleys and increase the diversity of the set of optimal trees. It is able to identify more parsimonious trees than are found by other methods. We find diverse optimality landscapes for viral datasets, including many distinct plateaux. We also find that our implementation produces similar results whether using a variety of single starting trees or an ensemble of starting trees, indicating effective global optimization.}, }
@article {pmid41279816, year = {2025}, author = {Giorgi, EE and Gillespie, K and Domin, E and Fouda, G and Permar, SR and Montefiori, DC and Janes, H}, title = {Differences in neutralization susceptibility between clade C HIV viruses from breastmilk versus contemporaneous circulating viruses from sexually acquired infections.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279816}, issn = {2692-8205}, support = {INV-036842/GATES/Gates Foundation/United States ; INV-007368/GATES/Gates Foundation/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; R01 AI162245/AI/NIAID NIH HHS/United States ; P01 AI117915/AI/NIAID NIH HHS/United States ; }, abstract = {HIV viruses that establish infection possess phenotypic and genotypic characteristics that have been selected for and that differ across transmission routes, including their susceptibility to broadly neutralizing antibodies (bnAbs). While sexually transmitted viruses have been well characterized, studies of vertically transmitted viruses are sparse and from cohorts that are often small in size and more than a decade old. To investigate whether viruses transmitted vertically during lactation possess distinct neutralization profiles compared to viruses transmitted sexually, we compared the neutralization sensitivity of 25 clade C breastmilk viruses to that of 99 contemporaneous clade C viruses from sera of adults with sexual acquisition against three bnAbs in clinical development. Three out of 7 breastmilk donors (43%) had one or more viruses resistant to 2 or more bnAbs, compared to 8 out of 99 (8%) contemporaneous adult viruses (p=0.02). Breastmilk viruses were more resistant to PGT121 and VRC07.523 (median IC80 >50 compared to 1.16 for PGT121, and 12.75 vs. 0.38 for VRC07.523; p=0.013 and <0.001 respectively), and more breastmilk viruses than adult viruses were resistant to VRC07.523 (94% vs. 43%, p=0.001). Interestingly, the breastmilk viruses most resistant to VRC07.523 had on average one or more glycans in V3 compared to adult transmitted viruses (median 3 vs. 2 glycosylation sites, including flanking position 295; p=0.009), and the number of V3 glycans was negatively correlated with VRC07.523 sensitivity (p=0.007). These findings highlight potential differences in bnAb susceptibility of vertically transmitted viruses and emphasize the need to increase sequencing efforts and screening of infant viruses to better inform the efficacy of candidate bnAbs to prevent vertical transmission of HIV.}, }
@article {pmid41279840, year = {2025}, author = {Billato, I and Pages, H and Carey, V and Waldron, L and Sales, G and Romualdi, C and Risso, D}, title = {Benchmarking large-scale single-cell RNA-seq analysis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279840}, issn = {2692-8205}, support = {U24 CA289073/CA/NCI NIH HHS/United States ; U24 HG004059/HG/NHGRI NIH HHS/United States ; }, abstract = {The increasing size of single-cell RNA sequencing (scRNA-seq) datasets poses major computational challenges. This work benchmarks the scalability, efficiency, and accuracy of five widely used analysis frameworks (Seurat, OSCA, scrapper, Scanpy, and rapids_singlecell), focusing on the impact of algorithmic and infrastructural choices on performance. We performed a systematic comparison of these workflows using representative datasets, including a 1.3 million mouse brain cell dataset for scalability and three smaller datasets (BE1, scMixology, and cord blood CITE-seq) with ground truth labels to assess clustering accuracy. Principal Component Analysis (PCA) was used as a paradigmatic step to evaluate the computational performance of six SVD algorithms (exact, ARPACK, IRLBA, randomized, Jacobi, and incremental PCA) across multiple data representations (dense, sparse, HDF5) and hardware configurations (CPU vs GPU). All methods showed high concordance in PCA results, with negligible loss of accuracy in truncated approaches. GPU-based computation using rapids_singlecell provided a 15× speed-up over the best CPU methods, with moderate memory usage. On CPU, ARPACK and IRLBA were the most efficient for sparse matrices, while randomized SVD performed best for HDF5-backed data. Among full pipelines, rapids_singlecell was the fastest, whereas OSCA and scrapper achieved the highest clustering accuracy (ARI up to 0.97) in datasets with known cell identities. Performance differences were largely driven by the choice of highly variable genes (HVGs) and PCA implementation. The study highlights that scalability in scRNA-seq analysis depends critically on both algorithmic and infrastructural factors. GPU acceleration and optimized BLAS/LAPACK configurations markedly enhance performance, while Bioconductor-based pipelines remain robust in accuracy. The provided benchmarks offer practical guidelines for efficient and reliable analysis of large-scale single-cell datasets.}, }
@article {pmid41279922, year = {2025}, author = {Mihalas, AB and Mitchell, K and Arora, S and O'Connor, SA and Patel, AP and Plaisier, CL and Paddison, PJ}, title = {Characterization of quiescent subpopulations and proliferative compartments in glioblastoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41279922}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA295090/CA/NCI NIH HHS/United States ; R01 NS119650/NS/NINDS NIH HHS/United States ; S10 OD026919/OD/NIH HHS/United States ; }, abstract = {Glioblastoma (GBM) quiescent (Q) cell populations are hypothesized to contain cancer stem-like cells (CSC) that drive tumor growth, cellular heterogeneity, and recurrence. However, GBM tumors do not neatly resolve into developmental hierarchies and Q stem-like activities are difficult to assess. Here, we evaluated tumor Q subpopulations in patient-derived GBM xenograft tumors using live cell reporters, DNA label retention assays, and single cell genomics. Compared to adult neural stems cells (NSCs), GBM Q populations contain hybrid transcriptional states composed of networks found in both dormant and activated adult NSCs, resulting in constitutive expression of key Q egress transcription factors and their targets (e.g., AP-1 and CCND1/2). As a result, even the longest Q-residing cells (~12 days) in xenograft tumors continuously cycle and fail to enter dormant Q states. We provide evidence and hypothesize that transient Q states in primary tumors arise as part of distinct proliferative compartments rather than deterministic developmental hierarchies driven by CSC activity. We further speculate that increases in basal translation rates drive Q instability in GBM tumors.}, }
@article {pmid41280050, year = {2025}, author = {Langley, CA and Lilly, M and Malik, HS and Emerman, M}, title = {Fitness Landscapes of APOBEC3G Antagonism by HIV-1 Vif proteins.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41280050}, issn = {2692-8205}, support = {T32 GM007270/GM/NIGMS NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {Host immune factors shape viral evolution. The HIV-1 Vif protein counteracts viral hypermutation caused by the host cytidine deaminase APOBEC3G (A3G), ensuring productive infection. Using deep mutational scanning (DMS) across two divergent HIV-1 clade B Vif proteins, we systematically mapped the mutational landscape governing their antagonism of A3G. These high-resolution fitness maps define conserved and adaptable regions of Vif, illuminating core principles of host-virus coevolution. Most missense mutations were strongly deleterious, reflecting pervasive purifying selection. Yet several highly conserved residues at binding interfaces with A3G, RNA, and CBFβ exhibited unexpected mutational tolerance, revealing structural flexibility at these sites. Comparative analysis revealed shared constraints and striking differences between HIV-1 strains, shaped by epistatic interactions and additional selective pressures, including Vif antagonism of A3H and PP2A. By pinpointing evolutionary vulnerabilities and adaptive mechanisms, this study provides a framework for understanding viral plasticity and developing targeted strategies to disrupt Vif-mediated immune evasion.}, }
@article {pmid41281197, year = {2025}, author = {Jennings-Shaffer, C and Chen, C and Palacios, JA and Matsen Iv, FA}, title = {Generalizing matrix representations to fully heterochronous ranked tree shapes.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {41281197}, issn = {2331-8422}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; R35 GM148338/GM/NIGMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Phylogenetic tree shapes capture fundamental signatures of evolution. We consider "ranked" tree shapes, which are equipped with a total order on the internal nodes compatible with the tree graph. Recent work has established an elegant bijection of ranked tree shapes and a class of integer matrices, called F -matrices, defined by simple inequalities. This formulation is for isochronous ranked tree shapes, where all leaves share the same sampling time, such as in the study of ancient human demography from present-day individuals. Another important style of phylogenetics concerns trees where the "timing" of events is by branch length rather than calendar time. This style of tree, called a rooted phylogram, is output by popular maximum-likelihood methods. These trees are broadly relevant, such as to study the affinity maturation of B cells in the immune system. Discretizing time in a rooted phylogram gives a fully heterochronous ranked tree shape, where leaves are part of the total order. Here we extend the F -matrix framework to such fully heterochronous ranked tree shapes. We establish an explicit bijection between a class of F -matrices and the space of such tree shapes. The matrix representation has the key feature that values at any entry are highly constrained via four previous entries, enabling straightforward enumeration of all valid tree shapes. We also use this framework to develop probabilistic models on ranked tree shapes. Our work extends understanding of combinatorial objects that have a rich history in the literature.}, }
@article {pmid41281241, year = {2025}, author = {Ukogu, OA and Montague, Z and Altan-Bonnet, G and Nourmohammad, A}, title = {Design principles of the cytotoxic CD8[+] T-cell response.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {41281241}, issn = {2331-8422}, support = {R35 GM142795/GM/NIGMS NIH HHS/United States ; ZIA BC012007/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Cytotoxic T lymphocytes eliminate infected or malignant cells, safeguarding surrounding tissues. Although experimental and systems-immunology studies have cataloged many molecular and cellular actors involved in an immune response, the design principles governing how the speed and magnitude of T-cell responses emerge from cellular decision-making remain elusive. Here, we recast the T-cell response as a feedback-controlled program, wherein the rates of activation, proliferation, differentiation and death are regulated through antigenic, pro- and anti-inflammatory cues. By exploring a broad class of feedback-controller designs as potential immune programs, we demonstrate how the speed and magnitude of T-cell responses emerge from optimizing signal-feedback to protect against diverse infection settings. We recover an inherent trade-off: infection clearance at the cost of immunopathology. We show how this trade-off is encoded into the logic of T-cell responses by hierarchical sensitivity to different immune signals. Notably, we find that designs that balance harm from acute infections and autoimmunity produce immune responses consistent with experimentally observed patterns of T-cell effector expansion in mice. Extending our model to immune-based T-cell therapies for cancer tumors, we identify a trade-off between the affinity for tumor antigens ("quality") and the abundance ("quantity") of infused T-cells necessary for effective treatment. Finally, we show how therapeutic efficacy can be improved by targeted genetic perturbations to T-cells. Our findings offer a unified control-logic for cytotoxic T-cell responses and point to specific regulatory programs that can be engineered for more robust T-cell therapies.}, }
@article {pmid41281626, year = {2026}, author = {Sarria, GR and Torales, S and Rossi, F and Ricagni, L and Baldeon, D and Felix, A and Li, B and Gkika, E and Ferraris, G and Sarria, GJ}, title = {Radiotherapy access in Latin America: Socio-economic determinants and equity challenges socio-economic determinants in Latin America for radiotherapy.}, journal = {Clinical and translational radiation oncology}, volume = {56}, number = {}, pages = {101062}, pmid = {41281626}, issn = {2405-6308}, abstract = {INTRODUCTION: Radiotherapy (RT) is essential for cancer treatment, yet access in Latin America remains highly unequal due to socio-economic and systemic disparities. This study aims to identify and analyze the key socio-economic determinants influencing RT access, infrastructure, and workforce distribution across 11 Latin American countries.<br><br>METHODS: A comprehensive database was created using 29 demographic, economic, and healthcare-related variables from public sources and expert input. Countries included were Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Paraguay, Peru, Uruguay, and Venezuela. Variables were categorized under access, demand, and supply of RT services. Correlation analyses and linear/exponential regression models were applied in an exploratory way to evaluate relationships between socio-economic indicators and RT availability.<br><br>RESULTS: Higher GDP per capita and adjusted GDP (PPP) correlated significantly with better RT infrastructure, including EBRT and megavoltage units (r&#xa0;>&#xa0;0.68, p&#xa0;<&#xa0;0.05). Urban population percentage strongly correlated with RT access (r&#xa0;=&#xa0;-0.77, p&#xa0;=&#xa0;0.005), while social security coverage was linked to lower inhabitants per RT center (r&#xa0;=&#xa0;-0.67, p&#xa0;=&#xa0;0.025). Notably, the number of radiation oncologists correlated perfectly with patients requiring EBRT (r&#xa0;=&#xa0;1.0, p&#xa0;<&#xa0;0.001), but showed no correlation with poverty or urbanization, highlighting workforce capacity constraints. Rural areas were underserved due to infrastructure centralization in urban zones. High out-of-pocket expenditure and low public health investment would be associated with limited access to these treatments.<br><br>CONCLUSION: Socio-economic disparities-particularly GDP, healthcare coverage, and urbanization-are strongly associated with RT access inequities in Latin America. For the medical community and public policymakers, confirming these assumptions requires a different scope about discussions regarding access to these highly complex services, when they are not associated with the population's health needs but rather with the countries' mere organizational and financial capabilities. Some possible formats require the definition of new clinical and financial management models. Our findings underscore the need for targeted health policies, investment in infrastructure and workforce, and decentralized care models. Expanding RT services beyond urban centers and improving funding models are critical to ensuring equitable cancer treatment across the region.}, }
@article {pmid41282795, year = {2025}, author = {Wu, X and Kim, A and Breeze, CE and O'Mara, TA and Ramachandran, D and Dörk, T and Koutros, S and Rothman, N and Prokunina-Olsson, L and Mancuso, N and Lindström, S and Kraft, P}, title = {Prioritizing context-specific genetic risk mechanisms in 11 solid cancers.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282795}, support = {U01 CA194393/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: While genome-wide association studies (GWAS) have identified hundreds of cancer-associated genetic variants, the specific biological contexts where these variants exert their effects remain largely unknown. We aimed to prioritize context-specific genetic risk mechanisms for 11 solid cancers at both genome-wide and single-variant resolutions.<br><br>METHODS: We integrated cancer GWAS summary statistics from European ancestry samples (avg. n cases=47,856) with ~1,500 context-specific annotations representing candidate cis-regulatory elements. For genome-wide analysis, we applied CT-FM, a method that leverages heritability enrichment estimates and an annotation correlation matrix to select likely disease-relevant biological contexts. After identifying putative causal SNPs (PIP&#x2265;0.5) via functionally informed fine-mapping, we used CT-FM-SNP to identify relevant contexts for individual variants. A combined SNP-to-gene framework was applied to construct putative {regulatory SNP-context-gene-cancer} quadruplets.<br><br>RESULTS: Stratified LD score regression analysis identified 52 annotations with significant heritability enrichment (Bonferroni-corrected P&#x2264;0.05). CT-FM prioritized four high-confidence (PIP&#x2265;0.5) biological contexts: mammary luminal epithelial cells for breast cancer, a prostate cancer epithelial cell line (VCaP) for prostate cancer, and bulk tumor tissue contexts for colorectal and renal cancers. Variant-level analysis of hundreds of putatively causal SNPs corroborated these findings and identified additional high-confidence contexts for other malignancies, including estrogen receptor-negative breast cancer and bladder cancer. A total of 489 putative regulatory quadruplets were constructed, proposing specific molecular mechanisms underlying the observed GWAS signals.<br><br>CONCLUSION: These findings advance our understanding of genetic susceptibility to different cancers. Future work in larger, more diverse GWAS, coupled with more comprehensive annotation atlases, is essential to expand upon and validate our results.}, }
@article {pmid41282799, year = {2025}, author = {Ellis, AL and Stauss, M and Tiburcio, PB and Emmen, IE and Edlefsen, PT and Kosmider, E and Barlow, S and Goss, M and Temte, JL and Stachler, E and McMahon, K and Sabeti, P and O'Connor, DH and O'Connor, SL}, title = {Adaptation of the multiplexed CRISPR-Cas13 CARMEN RVP assay for longitudinal detection of respiratory pathogens from air samples.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282799}, support = {R01 AI170737/AI/NIAID NIH HHS/United States ; U01 CK000542/CK/NCEZID CDC HHS/United States ; U01 CK000630/CK/NCEZID CDC HHS/United States ; }, abstract = {Air sampling is a non-invasive alternative to individual testing for respiratory pathogens. Alternative methods to the "gold standard" quantitative RT-PCR (qRT-PCR) are required to enable higher throughput, lower cost, and more multiplexed detection of pathogens. The multiplexed CRISPR-Cas13 CARMEN Respiratory Viral Panel (RVP) was described previously for high-throughput detection of nine respiratory pathogens from nasal swab samples. Here, we modified and optimized the CARMEN RVP assay to overcome the unique challenges of air samples, including low biomass and environmental inhibitors. We monitored for SARS-CoV-2 and influenza A (Flu A) via qRT-PCR in air samples from 15 schools within Dane County, Wisconsin (USA) during the 2023-2024 school year. SARS-CoV-2 was detectable throughout the entire sampling period, while Flu A detection was seasonal from November 2023 to March 2024. We then analyzed a subset of samples from seven schools using an optimized CARMEN RVP assay for air surveillance (RVP_air) and compared results to qRT-PCR. The RVP_air assay detected several additional pathogens beyond our primary targets. The frequencies and patterns of SARS-CoV-2 positivity, but not Flu A, were similar between qRT-PCR and RVP_air across the 2023-2024 sampling period. We developed a secondary panel (RVP_air_flu) to better detect both H1N1 and H3N2 subtypes. Finally, we compared air sample results to clinical nasal swabs collected from the same school district. For several pathogens (SARS-CoV-2, HCoV-OC43, Flu A), positive air detections coincided with positive nasal swabs. These findings demonstrate that the RVP_air assay can effectively detect airborne pathogens from infected individuals within indoor spaces.}, }
@article {pmid41282846, year = {2025}, author = {Haack, AJ and Brown, LG and Zeng, Y and Khan, T and Robertson, IH and Kennedy, DS and Adams, KN and MacDonald, JW and Bammler, TK and Stefanovic, F and Moloney, K and Stolarczuk, JE and Takezawa, MG and Alizai, MY and Hassan, GW and Lim, FY and Chaussabel, D and Walker, EG and Errett, NA and Berthier, E and Theberge, AB}, title = {A Flexible and Responsive Remote Study Design to Assess Gene Expression Changes During Wildfire Smoke Exposure with homeRNA, an At-home Blood Sampling Kit.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282846}, support = {R21 ES034338/ES/NIEHS NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R35 GM128648/GM/NIGMS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {Transcriptomic responses to wildfire smoke are difficult to study given the unpredictability of wildfires and the challenges of collecting blood during active disasters. To overcome these challenges, we developed a flexible study design leveraging homeRNA, our at-home blood collection and RNA stabilization kit. Between June 2021 and April 2022, 58 participants across 10 U.S. states collected 635 blood samples before, during, and after wildfire events. This responsive approach captured three exposure groups: high exposure in Okanogan County, Washington, medium exposure from transported smoke, and low exposure. During the 10-month study, 93% of participants (n=54/58) returned at least 6 samples. In a preliminary exploratory analysis, we analyzed 770 genes with a Nanostring panel from nine participants (6 high, 3 low-medium exposure) using the BloodGen3 framework. In the high exposure participants, we observed trends toward overexpression of inflammation (inflammation aggregates A33 and A35, and modules M13.1 and M13.12), with concurrent underexpression of adaptive immune responses (lymphocytic aggregates A1 and A6, B cell module M13.18, T cell modules M16.24 and M15.38). This study establishes that homeRNA enables flexible, responsive sampling during disasters, overcoming traditional logistical barriers to capture time-sensitive biological data across dispersed populations.}, }
@article {pmid41282907, year = {2025}, author = {Reed, JC and Downs, C and McAllister, K and Mauer, C and McClurkan, CL and Wilson, D and Holzhauer, K and Dickerson, JA and Cannon, CA and Babu, TM and Golden, MR and Koelle, DM and Greninger, AL}, title = {Differentiating Mpox Infection and Vaccination Using a Validated Multiplex Orthopoxvirus IgG Serology Assay.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41282907}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; }, abstract = {The resurgence of monkeypox virus (MPXV) outbreaks has increased demand for validated serological assays to assess exposure and immunity. Cross-reactivity among orthopoxivuses, stemming from high sequence conservation, complicates distinguishing antibody responses from natural MPXV infection versus vaccination or other orthopoxvirus exposures. We validated the Meso Scale Discovery (MSD) V-PLEX Orthopoxvirus Panel 1 (IgG) Kit, which quantifies antibody levels to five MPXV antigens and their vaccina virus (VACV) orthologs, following Good Clinical Laboratory Practice (GCLP) guidelines. We assessed assay performance using serum from 26 individuals with prior mpox, 52 JYNNEOS vaccine recipients, and 179 unexposed controls. The assay reliably detected antibody responses in all exposed cohorts with peak levels observed 2-months post-vaccination. Antibody levels to specific antigens also correlated with Modified Vaccinia Ankara (MVA) neutralization titer, particularly for MPXV B6R/VACV B5R, MPXV E8L/VACV D8L, and MPXV M1R/VACV L1. Receiver operating characteristic (ROC) analysis showed that some individual antigens achieved high sensitivity and specificity for exposure detection (AUC > 0.96 for VACV D8L, MPXV B6R, VACV B5R); however, individual antigens performed poorly in distinguishing infection from vaccination. In contrast, antibody level ratios between some MPXV and VACV orthologs effectively differentiated MPXV infection from vaccinia vaccination with high sensitivity and specificity (e.g. MPXV A35R/VACV A33R ortholog ratio, AUC = 0.97, sensitivity = 0.97, specificity = 0.96). Our findings validate the MSD assay for clinical research and serosurveillance to assess MPXV immunity and support the utility of ortholog pair ratio analysis as a strategy to discriminate vaccinated and infected individuals.}, }
@article {pmid41284631, year = {2026}, author = {Banerjee, R and Khouderchah, C and Akhtar, OS and Liang, EC and Gauthier, J and Dhodapkar, MV and Portuguese, AJ}, title = {Prior transplantation and idecabtagene vicleucel in multiple myeloma: a secondary analysis of CIBMTR data.}, journal = {Blood}, volume = {147}, number = {3}, pages = {312-315}, doi = {10.1182/blood.2025031426}, pmid = {41284631}, issn = {1528-0020}, mesh = {Humans ; *Multiple Myeloma/therapy/mortality ; *Immunotherapy, Adoptive/methods ; Male ; *Antigens, CD19/therapeutic use ; Female ; *Hematopoietic Stem Cell Transplantation ; Middle Aged ; Registries ; Transplantation, Autologous ; Aged ; Receptors, Chimeric Antigen ; }, abstract = {Recent analyses have suggested a possible negative impact of prior autologous stem cell transplantation on outcomes with idecabtagene vicleucel (ide-cel) chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma. Our registry-based analysis of >800 ide-cel recipients did not identify any such association.}, }
@article {pmid41285296, year = {2026}, author = {Harper, K and Adintori, PA and Heimgartner, J and Schmidt, E and Carpenter, PA and Ullrich, C}, title = {Best Practice Considerations in Nutritional Care for Adult Patients Undergoing Hematopoietic Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {3}, pages = {234-249}, doi = {10.1016/j.jtct.2025.11.021}, pmid = {41285296}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Adult ; Nutrition Assessment ; *Nutrition Therapy/methods ; Nutritional Status ; Practice Guidelines as Topic ; }, abstract = {The American Society of Transplantation and Cellular Therapy partnered with established registered dietitian experts in hematopoietic cell transplantation (HCT). Committee members and the expert dietitians developed frequently asked questions (FAQs) asked by HCT providers. The expert dietitians drafted a list of these FAQs, which were then reviewed by the Practice Guidelines Committee and organized by the representatives assigned as partners for this article. The FAQs are organized by phase in the peri-HCT period. The FAQs cover pre-HCT and early post-HCT nutrition assessment (FAQs 1 to 4), early post-HCT nutrition interventions (FAQs 5 to 11), and chronic post-HCT nutrition interventions (FAQs 13 to 16). Finally, emerging topics in nutritional care with HCT recipients are highlighted as future directions with opportunities for further research (FAQ 17-19).}, }
@article {pmid41285650, year = {2026}, author = {Ho, C and Kennedy, N and Di, M and Gopal, AK and Lynch, RC and Ng, K and Wu, QV and Poh, C and Raghunathan, V and Rasmussen, H and Shadman, M and Till, BG and Ujjani, CS and Smith, SD}, title = {Barriers to Investigator-Initiated Clinical Trial Enrollment in Frontline Large B-Cell Lymphoma.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {26}, number = {3}, pages = {e367-e375}, doi = {10.1016/j.clml.2025.11.002}, pmid = {41285650}, issn = {2152-2669}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Lymphoma, Large B-Cell, Diffuse/therapy ; *Clinical Trials as Topic ; Retrospective Studies ; Aged ; *Patient Selection ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Frontline therapy fails to cure ∼ 25% of patients with large B-cell lymphoma (LBCL), underscoring the need for clinical trials to improve outcomes. However, enrollment remains limited by logistical and structural barriers. Investigator-initiated trials (IITs) at our center enroll patients 5 to 10 times faster than industry-sponsored trials, yet the influence of geography and socioeconomic status on participation remains poorly understood.<br><br>METHODS: We retrospectively reviewed adults with newly diagnosed large B-cell lymphoma (LBCL) referred to Fred Hutchinson Cancer Center (FHCC) between October 2022 and June 2024. Patients were prescreened by a clinical research nurse and investigators for frontline IIT eligibility. Demographic, geographic, and socioeconomic data were collected, including sex, race, ethnicity, distance from FHCC, area deprivation index, insurance, and interpreter need. Logistic and elastic net regression were used to evaluate predictors of trial enrollment. Trial-ineligible patients were analyzed descriptively.<br><br>RESULTS: Of 153 patients, 68 (44%) were trial-eligible; 24 (35%) enrolled. Enrolled patients lived closer to FHCC (median 15 vs. 50 miles; P = .00015) and had lower ADI scores (median 8 vs. 21; P = .006) than non-enrolled eligible patients. In univariate analysis, both distance and ADI were associated with enrollment; in multivariable stepwise regression, only distance remained significant. Elastic net regression identified both distance and ADI as frequently selected predictors. Among 85 trial-ineligible patients, 61% had already initiated treatment; these patients also lived farther away and in more deprived areas.<br><br>CONCLUSION: Geographic distance and neighborhood deprivation significantly influenced trial enrollment, even in investigator-initiated trials (IITs). Decentralized trial models, telemedicine triage, and system-level interventions are needed to reduce these inequities.}, }
@article {pmid41285840, year = {2025}, author = {Jackson, LA and Coler, RN and Deye, GA and Carter, D and Gray, SA and Pecor, T and Davis, J and Larsen, SE and Posavad, CM and Cox, C and Watanabe, A and Lundeen, JS and Gill, R and Kalyanasundaram, A and Siddiqui, AA}, title = {Safety and immunogenicity of the Sm-p80 GLA-SE schistosomiasis vaccine.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {247}, pmid = {41285840}, issn = {2059-0105}, support = {UM1 AI148684/AI/NIAID NIH HHS/United States ; UM1AI148684//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {Schistosomiasis is a neglected tropical disease with the greatest burden in sub-Saharan Africa. An efficacious and safe vaccine would have a major global public health impact. The investigational SchistoShield® (Sm-p80 [antigen] + GLA-SE [adjuvant]) vaccine targets the Sm-p80 surface membrane antigen of Schistosoma mansoni and in nonhuman primate challenge studies was shown to be highly effective in killing pathogenic female worms and reducing host organ pathology and egg excretion. In this Phase 1 first-in-human, dose-escalation trial with sequential assignment, we evaluated the safety and immunogenicity of the vaccine in healthy adults in the United States. The vaccine formulations, given as a three dose intramuscular series, were well tolerated and adjuvanted formulations induced robust IgG ELISA responses against the Sm-p80 antigen. The vaccine has been advanced to a Phase 1b trial among adults in endemic areas of Africa.Clinicaltrials.gov registration: NCT05292391 https://Clinicaltrials.gov/study/NCT05292391 .}, }
@article {pmid41286102, year = {2025}, author = {Smith, JL and Adebamowo, CA and Adebamowo, SN and Darst, BF and Fullerton, SM and Gogarten, SM and Hamed, ME and Hirbo, JB and Hysong, MR and Johar, AS and Khan, AT and Kullo, IJ and Konigsberg, IR and Kraft, P and Lange, LA and Li, Y and Martin, AR and Nelson, SC and Choudhury, A and Ramsay, M and Cobran, EK and Schaid, DJ and Sharma, J and Wang, Y and Wojcik, GL and ,  and Sun, Q}, title = {Recommendations for responsible use of population descriptors in polygenic risk score development.}, journal = {Nature genetics}, volume = {57}, number = {12}, pages = {2962-2971}, pmid = {41286102}, issn = {1546-1718}, support = {U01HG011719//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01 HG011717/HG/NHGRI NIH HHS/United States ; U01CA261339//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01 CA261339/CA/NCI NIH HHS/United States ; U01HG011720//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01 HG011723/HG/NHGRI NIH HHS/United States ; U01 HG011715/HG/NHGRI NIH HHS/United States ; U01 HG011697/HG/NHGRI NIH HHS/United States ; U01HG011697//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01 HG011719/HG/NHGRI NIH HHS/United States ; U01HG011717//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; T32 HL007111/HL/NHLBI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; U01HG011723//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01 HG011710/HG/NHGRI NIH HHS/United States ; U01HG011710//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; HL07111-45//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01HG011715//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; }, mesh = {Humans ; *Multifactorial Inheritance/genetics ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study/methods ; Risk Assessment ; *Genomics/methods ; Risk Factors ; Genetic Risk Score ; }, abstract = {The recent report from the National Academies of Sciences, Engineering and Medicine emphasizes the importance of detailed and tailored use of population descriptors in genomic analyses, but specific guidance for genomic data analysts is still lacking. In this Perspective, we focus on polygenic risk score (PRS) development and demonstrate that population descriptors are explicitly or implicitly involved in every step of the process. Attention to this matter is both an analytical concern and an ethical concern, as each decision has an impact on PRS results and performance across diverse populations. Drawing from the experience of the Polygenic Risk Methods Development (PRIMED) Consortium, we offer recommendations for applying population descriptors throughout the entire process of PRS development, validation and application. We urge the research community, particularly data analysts, to critically evaluate and justify their choices when using these descriptors to ensure both scientific rigor and research integrity.}, }
@article {pmid41286306, year = {2025}, author = {Li, Y and Zhou, Z and Zhang, Y and Jia, D and Wang, D and Reiger, MC and Creighton, CJ and Nelson, PS and Corey, E and Morrissey, C and Xin, L}, title = {Targeting FZD6 creates therapeutically actionable vulnerabilities for advanced prostate cancer.}, journal = {Oncogene}, volume = {44}, number = {50}, pages = {4868-4877}, pmid = {41286306}, issn = {1476-5594}, support = {R21 CA277368/CA/NCI NIH HHS/United States ; R01CA271457//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P50 CA097186/CA/NCI NIH HHS/United States ; W81XWH-22-1-0752//U.S. Department of Defense (United States Department of Defense)/ ; R21CA277368//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA125123/CA/NCI NIH HHS/United States ; R01 CA190378/CA/NCI NIH HHS/United States ; R01 CA271457/CA/NCI NIH HHS/United States ; P50CA97186//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 19CHAL11//Prostate Cancer Foundation (PCF)/ ; }, mesh = {Male ; Humans ; *Prostatic Neoplasms/genetics/pathology/drug therapy/metabolism ; *Frizzled Receptors/genetics/metabolism/antagonists &amp; inhibitors ; Animals ; Mice ; Cell Line, Tumor ; Cell Proliferation ; Wnt Signaling Pathway ; Xenograft Model Antitumor Assays ; Polo-Like Kinase 1 ; DNA Repair ; Cell Cycle Proteins/genetics/metabolism ; Proto-Oncogene Proteins/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Protein Serine-Threonine Kinases/metabolism/genetics ; Protein-Tyrosine Kinases/genetics/metabolism ; DNA Breaks, Double-Stranded ; }, abstract = {Wnt signaling is a complex pathway consisting of numerous ligands and frizzled (FZD) receptors. These signaling components are widely expressed in human prostate tissues and often undergo upregulation or mutation in advanced prostate cancers. Enhanced Wnt signaling promotes prostate cancer cell proliferation, metastasis, and resistance to therapy. However, targeting pan-Wnt signaling poses challenges due to tissue toxicity. We show that FZD6 is the most highly expressed and frequently amplified Wnt receptor in advanced human prostate cancers. Knockdown of FZD6 suppresses both in vitro and in vivo growth of various prostate cancer cell lines and patient-derived xenograft models. FZD6 knockdown impairs DNA double-strand break (DSB) repair, as determined by both resolution of γH2AX foci and DNA DSB repair reporter assays. Mechanistically, FZD6 knockdown-induced growth suppression is linked to reduced activities of SRC kinase and STAT3, while DNA damage repair deficiency is mediated through WEE1 downregulation via PLK1. Knockdown of FZD6 enhances the therapeutic efficacy of genotoxic agents for prostate cancer cells. A kinome-wide CRISPR-Cas9 knockout screen reveals that FZD6 inhibition sensitizes prostate cancer cells to the inhibition of PKMYT1, a WEE kinase family member. Collectively, we demonstrate that targeting a single FZD receptor highly expressed in prostate cancers can yield significant therapeutic efficacy, and uncover therapeutic vulnerabilities associated with FZD6 inhibition.}, }
@article {pmid41286512, year = {2026}, author = {Al-Ali, RW and Gui, G and Ravindra, N and Andrew, G and Mukherjee, D and Wong, ZC and Huang, Y and Gerhold, J and Holman, M and Jacobsen, A and D'Angelo, J and Miller, J and Elias, K and Auletta, JJ and El Chaer, F and Devine, SM and Jimenez, AMJ and De Lima, MJG and Litzow, MR and Kebriaei, P and Saber, W and Spellman, SR and Zeger, SL and Page, KM and Radich, JP and Lindsley, RC and Dillon, LW and Hourigan, CS}, title = {Measurable residual mutated NPM1 before allogeneic transplant for acute myeloid leukemia.}, journal = {Bone marrow transplantation}, volume = {61}, number = {2}, pages = {222-224}, pmid = {41286512}, issn = {1476-5365}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; 1-ZIA-HL006163//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, }
@article {pmid41287255, year = {2026}, author = {Follmann, D and Dang, L and Chu, E and Fintzi, J and Janes, H and Gilbert, PB and Andrews, LIB and Serebryannyy, L and Carroll, R and Lin, B and Koup, R and Toma, J and Deng, W and Priddy, F and Dixit, A and Zhou, H and Baden, L and El Sahly, HM}, title = {A Test-Negative Design for Immune Correlates Approximates a Traditional Exposure-Proximal Design but Requires Far Fewer Blood Samples.}, journal = {The Journal of infectious diseases}, volume = {233}, number = {3}, pages = {e646-e650}, pmid = {41287255}, issn = {1537-6613}, support = {HHSN261201500003I/NH/NIH HHS/United States ; 75N91019D00024/NH/NIH HHS/United States ; //Biostatistics Research Branch/ ; //Vaccine Research Center/ ; //Intramural Research Program/ ; //National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *COVID-19/immunology/prevention &amp; control ; *Antibodies, Neutralizing/blood ; *SARS-CoV-2/immunology ; *Antibodies, Viral/blood ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Male ; Research Design ; Female ; }, abstract = {Traditional vaccine clinical trials sample blood from all participants. In contrast, the test-negative immune correlates (TNIC) design only samples blood from participants who develop symptoms. We compared traditional to test-negative immune correlates methods in the mRNA-1273 severe acute respiratory syndrome coronavirus 2 vaccine efficacy clinical trial. Using a neutralizing antibody assay, hazard ratios were 0.48 (95% confidence interval [CI], .29-.73) and 0.55 (95% CI, .28-1.06) for traditional and test-negative methods, respectively. Analogous ratios for binding antibody assay were 0.69 (95% CI, .52-.94) and 0.78 (95% CI, .50-1.20). The results support use of the logistically simpler TNIC design.}, }
@article {pmid41287634, year = {2025}, author = {Kikawa, C and Huddleston, J and Loes, AN and Turner, SA and Lee, J and Barr, IG and Cowling, BJ and Englund, JA and Greninger, AL and Harvey, R and Hasegawa, H and Ho, F and Lacombe, K and Leung, NHL and Lewis, NS and Peck, H and Watanabe, S and Smith, DJ and Bedford, T and Bloom, JD}, title = {Near real-time data on the human neutralizing antibody landscape to influenza virus to inform vaccine-strain selection in September 2025.}, journal = {Virus evolution}, volume = {11}, number = {1}, pages = {veaf086}, pmid = {41287634}, issn = {2057-1577}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI165818/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; 75N93021C00014/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; F30 AI186284/AI/NIAID NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {The hemagglutinin of human influenza virus evolves rapidly to erode neutralizing antibody immunity. Twice per year, new vaccine strains are selected with the goal of providing maximum protection against the viruses that will be circulating when the vaccine is administered ~8-12 months in the future. To help inform this selection, here we quantify how the antibodies in recently collected human sera neutralize viruses with hemagglutinins from contemporary influenza strains. Specifically, we use a high-throughput sequencing-based neutralization assay to measure how 188 human sera collected from Oct 2024 to April 2025 neutralize 140 viruses representative of the H3N2 and H1N1 strains circulating in humans as of the summer of 2025. This data set, which encompasses 26 148 neutralization titre measurements, provides a detailed portrait of the current human neutralizing antibody landscape to influenza A virus. The full data set and accompanying visualizations are available for use in vaccine development and viral forecasting.}, }
@article {pmid41288462, year = {2026}, author = {Dotson, EH and Elmariah, SB and Bergerat, AM and James, K and Luo, T and Reed, SD and Guthrie, KA and Mitchell, CM}, title = {A pilot study of vaginal nerve fiber and blood vessel density in postmenopausal women with genitourinary syndrome of menopause.}, journal = {Menopause (New York, N.Y.)}, volume = {33}, number = {4}, pages = {413-419}, pmid = {41288462}, issn = {1530-0374}, support = {R01AG048209//National Institute of Aging/ ; }, mesh = {Humans ; Female ; Pilot Projects ; *Vagina/innervation/blood supply/pathology ; *Postmenopause/physiology ; Middle Aged ; *Nerve Fibers/pathology ; Estradiol/administration &amp; dosage ; Administration, Intravaginal ; Syndrome ; *Female Urogenital Diseases/pathology/drug therapy ; *Blood Vessels/pathology ; Estrogens/administration &amp; dosage ; Vaginal Diseases/drug therapy ; Vaginal Creams, Foams, and Jellies/administration &amp; dosage ; }, abstract = {OBJECTIVE: Menopause is accompanied by decreased circulating estrogen for all people; however, only some develop genitourinary syndrome of menopause, the cause of which is unknown. In this pilot study, we measured vaginal blood vessel and nerve fiber density, as well as vaginal fluid immune markers to identify a potential cause of vaginal symptoms.<br><br>METHODS: This is a secondary analysis of samples from a randomized trial of vaginal estradiol or moisturizer versus placebo for moderate-severe postmenopausal vaginal discomfort. Fourteen participants were selected from the placebo tablet/vaginal moisturizer or dual placebo arms of the original study: eight with a &#x2265;2-point reduction in most bothersome symptom severity (responders) and six with a <2-point reduction in symptom severity (nonresponders). At 0, 4, and 12 weeks, we characterized vaginal protein gene product 9.5-positive nerve fiber and CD31+ vessel length and density from vaginal wall biopsies (immunofluorescent staining) and vaginal fluid immune markers (MesoScale Discovery). We compared responders versus nonresponders at baseline and across visits using linear mixed models to evaluate associations between symptoms, nerve/vessel length and density, and immune markers.<br><br>RESULTS: There were no significant differences in baseline characteristics between responders and nonresponders. Mean CD31+ vessel length at 12 weeks was higher in responders than nonresponders (P = 0.034), while all other measurements were similar between the two groups. No clear patterns were observed across proinflammatory or chemoattractant cytokine concentrations with biopsy measures.<br><br>CONCLUSIONS: Vaginal blood supply and extent of vascularization may contribute to vaginal discomfort symptoms in postmenopausal people; however, the results of this small study need to be confirmed with a larger sample size.}, }
@article {pmid41288979, year = {2025}, author = {Li, A and Jafari, O and Lam, BD and Jiang, JY and Kim, RB and Ma, S and Zhou, E and Tiong, JW and Chiang, EC and Ryu, J and Amos, CI and La, J and Fillmore, NR}, title = {Validation of a Risk Score for Cancer-Associated Thrombosis Using Nationwide EHR Data.}, journal = {JAMA network open}, volume = {8}, number = {11}, pages = {e2544428}, pmid = {41288979}, issn = {2574-3805}, mesh = {Humans ; Female ; *Neoplasms/complications/epidemiology ; Male ; *Electronic Health Records/statistics &amp; numerical data ; Middle Aged ; Risk Assessment/methods ; Aged ; *Venous Thromboembolism/epidemiology/etiology ; Risk Factors ; *Thrombosis/etiology/epidemiology ; }, abstract = {IMPORTANCE: Venous thromboembolism (VTE) is associated with increased mortality and morbidity in patients with cancer. Existing risk prediction models are typically validated within individual sites, a fragmented approach that limits clinical adoption.<br><br>OBJECTIVE: To validate the electronic health record cancer-associated thrombosis (EHR-CAT) score compared with the benchmark Khorana score in a contemporary cohort of patients with cancer across the nation, before and after treatment, excluding those at high risk of bleeding.<br><br>This prognostic study included patients in a nationwide longitudinal EHR database from January 2018 to December 2023 with follow-up continuing to April 2025. Patients with newly diagnosed, invasive, solid, or hematologic malignant neoplasms (defined using validated International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] algorithms) receiving systemic therapy (defined using the first antineoplastic medication) were included. Those with recent history of acute VTE diagnosis or anticoagulant prescription were excluded.<br><br>EXPOSURES: Demographics, risk model variables, and common anticoagulant trial exclusion criteria (as a proxy for identifying people at high risk of bleeding) were extracted on or before index therapy initiation date.<br><br>MAIN OUTCOMES: Incident VTE and bleeding outcomes at 6 months were defined using validated ICD-10-CM algorithms.<br><br>RESULTS: A total of 732&#x202f;594 patients (median [IQR] age, 65.0 [56.9-73.0] years; 425&#x202f;124 female [58.0%]; 25&#x202f;634 Asian [3.5%], 94&#x202f;269 Black [12.9%], 48&#x202f;266 Hispanic [6.6%], 583&#x202f;047 White [76.9%]) with active cancer receiving systemic therapy between 2018 and 2023 from 184 health systems were identified. With a median (IQR) follow-up of 676 (340-1151) days, the incidence of 6-month VTE, bleeding, and mortality was 4.7% (34&#x202f;499 patients), 3.7% (26&#x202f;993 patients), and 8.4% (60&#x202f;239 patients), respectively. Bleeding risk was higher in the 26.0% of patients (190&#x202f;413) meeting anticoagulant trial exclusion criteria (7.2% vs 2.4%; hazard ratio, 2.5 [95% CI, 2.5-2.5]). The EHR-CAT score stratified patients into discriminative risk groups (C statistic, 0.70-0.71) both before and after exclusion for bleeding risk. When compared with the benchmark Khorana score (C statistic, 0.63), EHR-CAT reclassified 20% of patients into revised categories with improved prediction accuracy. Furthermore, EHR-CAT had consistent calibration in subgroups by age, sex, race, ethnicity, and individual health system sites.<br><br>CONCLUSIONS: This prognostic study of the EHR-CAT risk score demonstrated the external validity and feasibility of using readily available structured EHR data to estimate VTE risk in patients with cancer.}, }
@article {pmid41289158, year = {2026}, author = {Rayes, A and Logan, BR and Liu, X and Dara, J and Buckley, RH and Oved, JH and Kapoor, N and Kapadia, M and Chandra, S and Martinez, CA and Bunin, NJ and Chandrakasan, S and Chen, K and Bednarski, JJ and Haines, HL and Eissa, H and Talano, JM and Keller, MD and Ebens, CL and Chaudhury, S and Shereck, EB and Aquino, VM and Knutsen, AP and Alexander, JL and Gillio, AP and Chellapandian, D and Shah, AJ and Miller, HK and Vander Lugt, MT and Seroogy, CM and Dorsey, MJ and Mousallem, T and Parrott, RE and O'Reilly, RJ and Aguayo-Hiraldo, PI and Prockop, SE and Dávila Saldaña, BJ and Thakar, MS and Burroughs, LM and Torgerson, TR and Leiding, JW and Marsh, RA and Griffith, LM and Pulsipher, MA and Kohn, DB and Notarangelo, L and Cowan, MJ and Puck, JM and Cuvelier, GDE and Heimall, J and Haddad, E and Pai, SY and Dvorak, CC}, title = {Outcomes following matched sibling donor transplantation for severe combined immunodeficiency: a report from the PIDTC.}, journal = {Blood advances}, volume = {10}, number = {3}, pages = {887-900}, pmid = {41289158}, issn = {2473-9537}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R24 AI184316/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U54 AI082973/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Severe Combined Immunodeficiency/therapy/mortality ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Siblings ; Female ; Male ; Graft vs Host Disease/etiology/prevention &amp; control ; Infant ; Child, Preschool ; Transplantation Conditioning/methods ; Treatment Outcome ; Retrospective Studies ; Child ; Tissue Donors ; Adolescent ; Adult ; }, abstract = {The Primary Immune Deficiency Treatment Consortium performed a retrospective analysis of 133 patients with severe combined immunodeficiency (SCID) receiving matched sibling donor (MSD) hematopoietic cell transplantation (HCT) between 1980 and 2023 at 30 North American institutions. In this largest cohort of MSD outcomes in patients with SCID to date, we examined the impact of conditioning regimen and graft-versus-host disease (GVHD) prophylaxis on survival and immune recovery. Outcomes after MSD HCT for SCID were excellent. Patients without an active infection or failure to thrive (FTT) at the time of HCT had 5-year overall survival superior to those with infection or FTT. Acute and chronic GVHD outcomes were independent of GVHD prophylaxis, conditioning regimen, SCID type, or presence of maternal engraftment. Patients without active infection at the time of HCT had superior chronic GVHD-free event-free survival vs those with infection. T-cell reconstitution at 6 months was less likely achieved with use of GVHD prophylaxis or serotherapy, and in patients with leaky SCID or Omenn syndrome. At 6 months, 1 year, and 2-5 years, T-cell reconstitution was less likely with ADA, DCLRE1C, or RAG genotype. B-cell reconstitution at 1 year and 2-5 years was negatively affected by development of grade 2 to 4 or 3 to 4 acute GVHD. Conditioning did not affect T- or B-cell reconstitution. Our data suggest omitting conditioning and GVHD prophylaxis for patients with typical SCID did not negatively affect 5-year outcomes after MSD HCT, but the data are insufficient to recommend this approach for best long-term outcomes. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.}, }
@article {pmid41290584, year = {2025}, author = {Elias, S and Brown, S and Egini, O and Walji, M and Homsy, S and Velayati, A and Devlin, S and Ponce, DM and Kennedy, V and Bharadwaj, S and Shiraz, P and Jakubowski, AA and Papadopoulos, EB and Muffly, L and Perales, MA and Giralt, SA and Smith, M and Gyurkocza, B}, title = {Allogeneic hematopoietic cell transplantation in acute myeloid leukemia not in complete remission: outcomes and prognostic factors in a contemporary cohort.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {208}, pmid = {41290584}, issn = {2044-5385}, support = {K08 HL156082/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; }, }
@article {pmid41291065, year = {2025}, author = {Chan, M and Gujral, TS}, title = {Beyond genomics: 3D microtumor assays for rapid, clinically relevant functional drug testing.}, journal = {Oncogene}, volume = {44}, number = {50}, pages = {4910-4915}, pmid = {41291065}, issn = {1476-5594}, support = {R01CA273081//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U01FD007925//U.S. Department of Health &amp; Human Services | U.S. Food and Drug Administration (U.S. Food &amp; Drug Administration)/ ; }, mesh = {Humans ; *Genomics/methods ; *Neoplasms/drug therapy/genetics/pathology ; Precision Medicine/methods ; Drug Screening Assays, Antitumor/methods ; Tumor Microenvironment/drug effects ; *Antineoplastic Agents/pharmacology ; Animals ; }, abstract = {Precision oncology is increasingly moving beyond genomics alone to approaches that directly test how patient tumors respond to therapy. This shift reflects a central challenge in oncology, where sequencing alone often fails to identify effective therapies for rare, treatment-resistant, or genomically ambiguous tumors. Here, we highlight three-dimensional (3D) microtumor models as a powerful functional platform that preserves the architecture, cell types, and microenvironment of intact tumors for drug screening. By capturing biology that 2D models and genomics alone miss, this approach enables more accurate prediction of therapeutic vulnerabilities and expands the precision-oncology toolkit for patients who currently lack actionable options.}, }
@article {pmid41292664, year = {2025}, author = {Ercan, C and Pan, X and Paulson, TG and Stachler, MD and Akarca, FG and Grady, WM and Maley, CC and Yuan, Y}, title = {Histopathology-based Spatial Profiling of Immune and Molecular Features Predicts Cancer risk in Barrett's Esophagus.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41292664}, support = {R01 CA140657/CA/NCI NIH HHS/United States ; R01 CA285517/CA/NCI NIH HHS/United States ; R37 CA269649/CA/NCI NIH HHS/United States ; U2C CA271902/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Improved cancer risk stratification is needed to differentiate high-risk individuals with Barrett's esophagus (BE) from low-risk populations to reduce overtreatment and improve outcome. The evolution of BE towards adenocarcinoma is likely driven by a combination of genomic and microenvironmental factors, yet existing predictive models rarely integrate both using routine specimens.<br><br>METHOD: We developed BEACON (Barrett Esophagus DNA content Abnormality and immune ecology for Cancer Outcome), a spatially aware framework predicting DNA content abnormalities and characterizing immune spatial ecology from routine histopathology. First, using 777 BE biopsies with flow cytometry-based DNA content data scanned at two institutions, we trained and tested DACOR (DNA content abnormality recognition), a multi-instance learning model that predicts DNA content abnormalities from histopathology. Next, complementary models for cell classification and tissue segmentation enabled spatial immune ecology metric computations. Lastly, a logistic regression model integrated molecular immune ecological features and epithelial morphology for cancer risk stratification.<br><br>RESULTS: DACOR achieved 0.825 AUC in the test cohort for DNA content abnormality prediction. DNA content abnormal regions exhibited increased lymphoplasma cellular inflammation versus normal regions (p=0.006). Patients classified as DNA content abnormal by DACOR demonstrated increased cancer progression (p=0.0001). Among patients with DNA content abnormality, cancer progressors exhibited increased plasma cell clustering adjacent to abnormal epithelium compared to non-progressors. The integrated risk classification model stratified DNA content abnormal patients into high- and low-risk groups with 0.817 AUC.<br><br>CONCLUSION: BEACON spatially integrates molecular abnormality with immune spatial ecology to stratify BE patients by cancer progression risk using routine pathology images. This scalable, explainable approach could improve clinical decision-making and reduce unnecessary surveillance in low-risk patients.}, }
@article {pmid41292719, year = {2026}, author = {Masaki, N and Bedford, T}, title = {Hidden Markov models detect recombination and ancestry of SARS-CoV-2.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292719}, issn = {2692-8205}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; }, abstract = {When individuals are co-infected with distinct SARS-CoV-2 lineages, homologous recombination can generate mosaic genomes carrying mutations from both parental lineages. A variety of methods exist to detect recombinant sequences and their parental lineages in surveillance-scale datasets comprised of millions of SARS-CoV-2 genomes. However, these methods often rely on user-specified parameters, such as the probability a recombination breakpoint occurs between adjacent positions on the query sequence. In this study, we devise a hidden Markov model that detects recombinant SARS-CoV-2 sequences and identifies their parental lineages within a test set of sequences. Our method does not depend on user-specified parameters and can accommodate de novo mutations on the query sequence that are not present in the predicted parental lineages. To achieve this, we use maximum likelihood to estimate parameters that characterize the transition and emission probabilities in our hidden Markov model. Applying our method to 440,307 SARS-CoV-2 sequences sampled in England between September 2020 and March 2024, we detect 7,619 recombinant sequences corresponding to 1.73% (95% CI: [1.69%, 1.77%]) of all sampled sequences. We observe a positive association between the proportion of query sequences detected as recombinant in each week and community SARS-CoV-2 prevalence. This is consistent with higher prevalence increasing the risk of co-infection by distinct lineages and promoting the emergence of recombinant sequences. Finally, we observe localized clusters of recombination breakpoints within spike and in intergenic regions.}, }
@article {pmid41292772, year = {2025}, author = {Rajendran, A and Haldipur, P and Arora, S and Grama, K and Subramanian, SS and Galan, LM and Johnson, D and Aldinger, KA and Shendure, J and Millen, KJ and Gennari, JH and Pattwell, SS}, title = {Elucidating Neurodevelopmental Trajectories in Cancer with Topic Modeling: Revealing Persistent External Granule Layer Lineages in Medulloblastoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292772}, issn = {2692-8205}, support = {T15 LM007442/LM/NLM NIH HHS/United States ; K22 CA258953/CA/NCI NIH HHS/United States ; R21 NS138661/NS/NINDS NIH HHS/United States ; R21 NS142543/NS/NINDS NIH HHS/United States ; R37 NS095733/NS/NINDS NIH HHS/United States ; R21 NS133390/NS/NINDS NIH HHS/United States ; R01 CA270785/CA/NCI NIH HHS/United States ; }, abstract = {The cerebellar rhombic lip generates cerebellar progenitors and neurons that ultimately differentiate to comprise over half of all neurons in the adult human brain. Standard clustering approaches often fragment or miss rhombic lip progenitor populations entirely due to their transient nature, small size, and rapid state transitions, leaving fundamental questions unanswered about normal cerebellar development and how such processes may be hijacked in pediatric brain cancer. Medulloblastoma, the most common malignant pediatric brain tumor, affects approximately 500 children annually in the United States with overall survival rates varying dramatically by subgroup. Sonic hedgehog (SHH) medulloblastoma, comprising 25-30% of cases, arises from rhombic lip-derived granule neuron precursors (GNP) within the external granule layer (EGL) and has particularly poor outcomes in several subtypes (5-year survival ~41%). Using our topic modeling framework on over one million fetal cerebellar nuclei, we identify proliferative rhombic lip and EGL states that bifurcate into distinct glial and neuronal lineages through intermediate progenitors and capture a portion of the developmental spectrum form outer EGL (oEGL) proliferation through inner EGL (iEGL) differentiation. These developmental signatures (topics) persist in medulloblastoma, validating GNP origins of SHH tumors and revealing age-specific molecular programs that correspond to distinct stages of EGL development within SHH subtypes. Our transferable framework enables systematic comparison of developmental and disease states across technologies without data integration, solving a fundamental challenge as genomic atlases expand.}, }
@article {pmid41292945, year = {2025}, author = {Salisbury, NJH and Patil-Amonkar, S and Roman, A and Galloway, DA}, title = {E2F1-3 activate Merkel cell polyomavirus early transcription and replication.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292945}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; S10 OD030225/OD/NIH HHS/United States ; }, abstract = {Merkel cell polyomavirus (MCPyV) is a DNA virus that establishes a persistent asymptomatic infection during childhood and can cause Merkel cell carcinoma (MCC) later in life. Its Large and Small Tumor antigens (LT, ST), splice variants of a common viral early transcript, drive viral replication and tumorigenesis by binding to and perturbing the function of host proteins. LT binds and inhibits RB1, deregulating E2F activity and host cell cycle control to permit viral replication during S phase. While the functions of LT and ST are relatively well characterized, how their expression is controlled is poorly defined. Here, we discovered that E2F1-3/DP1 dimers bind the MCPyV Non-Coding Control Region (NCCR) via a consensus E2 site close to the LT/ST transcriptional start site. Inhibiting E2F-NCCR binding, either by deleting the E2 site or treatment with a E2F small molecule inhibitor, downregulated LT/ST mRNA and protein expression in MCC cells and in 293A cells transfected with MCPyV. Our findings reveal an E2F/LT/RB1 positive feedback loop that appears to have evolved to support viral replication and is hijacked in MCC cells to promote cellular proliferation. Furthermore, we identified E2 sites in the NCCRs of PyVs closely related to MCPyV, including murine PyV, which mediate E2F/DP binding and potentiate viral early transcription. E2F/DP also bound weakly to the SV40 and BKPyV NCCRs, despite lacking an E2 site. Our findings challenge the prevailing model that PyV LT expression drives S phase entry and suggest, in contrast, that S phase entry stimulates PyV early transcription and replication.}, }
@article {pmid41292998, year = {2025}, author = {Kuppers, DA and Arora, S and Wladyka, CL and Ge, R and Liu, S and Peng, Y and Su, R and Wilhite, A and Chen, J and He, C and Hsieh, AC and Paddison, PJ}, title = {N6-methyladenosine regulation of mRNA translation is essential for early human erythropoiesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41292998}, issn = {2692-8205}, support = {R01 GM135362/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA280389/CA/NCI NIH HHS/United States ; R01 DK119270/DK/NIDDK NIH HHS/United States ; P30 DK056465/DK/NIDDK NIH HHS/United States ; R37 CA230617/CA/NCI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; R01 CA276308/CA/NCI NIH HHS/United States ; }, abstract = {N6-methyladenosine (m[6]A) is an abundant modification of mRNA with important regulatory roles in normal and malignant hematopoiesis. We previously reported that in human erythroid leukemia (HEL) cells, m[6]A mRNA marking selectively regulates translation of essential erythropoiesis genes required for in vitro differentiation and human erythroid colony formation. Here, we further investigated the timing and nature of requirement for m[6]A-methyltransferase (MTase) activity during human erythropoiesis, using a standardized in vitro erythroid differentiation assay for hHSPCs. We identified two critical m[6]A regulated developmental windows in BFU-E and during the transition from CFU-E to proerythroblasts. These windows of m[6]A-MTase requirement coincide with rising global m[6]A levels, which peak in proerythroblasts. After proerythroblast formation, however, m[6]A -MTase activity is dispensable for differentiation, proliferation, and survival. In BFU-E, m[6]A-MTase promotes proliferation but is dispensable for differentiation, while, in CFU-E, both m[6]A -MTase and the YTHDF family of m[6]A readers are essential for differentiation to proerythroblasts. Mechanistically, in CFU-E, m[6]A - MTase activity enhances translation of ribosomal and oxidative phosphorylation (OXPHOS) genes, thereby elevating global protein synthesis rates and enabling efficient erythroblast formation. We propose that this form of translational regulation by m[6]A emerged as an evolutionary adaptation to meet the high translational demands of human erythropoiesis.}, }
@article {pmid41294288, year = {2025}, author = {Furlong, J and Goya, S and Nawrocki, EP and Calhoun, V and Hatcher, E and Yankie, L and Greninger, AL}, title = {Automated annotation and validation of human respiratory virus sequences using VADR.}, journal = {Database : the journal of biological databases and curation}, volume = {2025}, number = {}, pages = {}, pmid = {41294288}, issn = {1758-0463}, support = {NU50CK000630//National Center for Zoonotic, Vector-borne, and Enteric Diseases/ ; U01 CK000630/CK/NCEZID CDC HHS/United States ; 1R03LM014965-01/LM/NLM NIH HHS/United States ; /NH/NIH HHS/United States ; R03 LM014965/LM/NLM NIH HHS/United States ; }, mesh = {Humans ; *Molecular Sequence Annotation/methods ; *Genome, Viral/genetics ; Phylogeny ; }, abstract = {Accurate annotation of viral genomes is essential for reliable downstream analysis and public data sharing. While National Center for Biotechnology Information's (NCBI's) Viral Annotation DefineR (VADR) pipeline provides standardized annotation and quality control, it only supports six viral groups to date. Here, we developed and validated 12 new reference sequence-based VADR models targeting key human respiratory viruses: measles virus, mumps virus, rubella virus, human metapneumovirus, human parainfluenza virus types 1-4, and seasonal coronaviruses (229E, NL63, OC43, and HKU1). Model construction was guided by a comprehensive analysis of intra-species genomic and phylogenetic diversity, enabling the development of genotype-specific models associated with reference genomes that defined expected genome structure and annotation. Models were trained on 5327 publicly available complete viral genomes and tested on 372 viral genomes not yet submitted to GenBank. VADR passed 96.3% of publicly available viral genomes and 98.1% of viral genomes not in the training set, correctly identifying overlapping ORFs, mature peptides, and transcriptional slippage as well as genome misassemblies. VADR detected novel viral biology including the first reported HCoV-OC43 NS2 knockout in a human infection and novel G and SH coding sequence lengths in human metapneumovirus. These VADR models are publicly available and are used by NCBI curators as part of the GenBank submission pipeline, supporting high-quality, scalable viral genome annotation for research and public health.}, }
@article {pmid41296783, year = {2025}, author = {Xu, S and Hudson, A and Janes, HE and Tomaras, GD and Ackerman, ME}, title = {Candidate correlates of protection in the HVTN505 HIV-1 vaccine efficacy trial identified by positive-unlabeled learning.}, journal = {PLoS computational biology}, volume = {21}, number = {11}, pages = {e1013705}, pmid = {41296783}, issn = {1553-7358}, support = {P01 AI162242/AI/NIAID NIH HHS/United States ; R56 AI165448/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; }, mesh = {*AIDS Vaccines/immunology/therapeutic use ; Humans ; *HIV Infections/prevention &amp; control/immunology ; *HIV-1/immunology ; *Machine Learning ; HIV Antibodies/immunology ; *Vaccine Efficacy ; Computational Biology ; }, abstract = {With a goal of unveiling mechanisms by which vaccines can provide protection against HIV-1 acquisition, several studies have explored correlates of risk of HIV-1 acquisition in HVTN 505, which was a phase IIb trial conducted to assess the safety and efficacy of a DNA plasmid and recombinant adenovirus serotype 5-vectored HIV vaccine regimen among individuals in the United States who were vulnerable to acquiring HIV. While this trial failed to meet its predetermined efficacy criteria, both immunological and virological correlates of reduced risk of acquisition have been reported, suggesting that at least some vaccine recipients were protected from some viruses. In this work, we describe application of a novel Positive-Unlabeled machine learning-based approach to infer protection status among vaccine recipients that did not acquire HIV, resulting in improved power to detect potential correlates of immunity. Having established the analytical robustness of protection status predictions using cross-validation and permutation testing strategies, we report increased confidence in previously identified correlates of risk, such as vaccine-elicited anti-HIV-1 Env glycoprotein IgG3 antibodies and antibody-dependent phagocytosis, and the new observation of an inverse correlation between inferred vaccine-mediated protection and virus-specific IgA responses. Though its biological validity is not established, this inference approach offers a new means to use case-control datasets to identify candidate markers of effective immune responses in the context of low vaccine efficacy.}, }
@article {pmid41296990, year = {2025}, author = {Liao, R and Fay, M and Mian, OY}, title = {Reply to: Toward Clinical Readiness: Critical Reflections on PATHOMIQ_PRAD and Artificial Intelligence Histologic Classifiers in Prostate Cancer.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500261}, doi = {10.1200/CCI-25-00261}, pmid = {41296990}, issn = {2473-4276}, }
@article {pmid41297101, year = {2026}, author = {Ronco, L and Tapscott, S and Voermans, NC and , }, title = {Meeting report: The FSHD society 2025 international research congress.}, journal = {Neuromuscular disorders : NMD}, volume = {58}, number = {}, pages = {106262}, doi = {10.1016/j.nmd.2025.106262}, pmid = {41297101}, issn = {1873-2364}, mesh = {*Muscular Dystrophy, Facioscapulohumeral/therapy/genetics ; Humans ; *Biomedical Research ; Congresses as Topic ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder marked by progressive muscle weakness and disability throughout life. Affecting about one million people worldwide, FSHD is among the most common forms of muscular dystrophy. To advance global collaboration, the FSHD Society hosted the 32nd International Research Congress (IRC) on June 12-13, 2025, in Amsterdam, the Netherlands. More than 250 researchers, clinicians, patients, and industry representatives attended, highlighting key developments in FSHD research. The Congress comprised six scientific sessions: (1) Population Genetics &amp; Modifiers, (2) Measures of Disease Activity &amp; Progression, (3) Novel Clinical Outcome Measures, (4) Mechanisms of Disease &amp; Interventional Strategies, (5) Clinical Care &amp; Related Issues, and (6) Clinical Studies &amp; Trial Design. Keynote presentations were delivered by Leendert Trouw (Leiden University Medical Center, Netherlands) and Karen Chen (SMA Foundation, USA), who shared perspectives from their respective research domains. Preceding the IRC, the Industry Collaborative (IC) for Therapeutic Development united experts in clinical science, biomarkers, and industry to identify knowledge gaps and strengthen strategies for developing effective FSHD therapies. Following the IRC, the inaugural FSHD Connect Europe meeting brought together patients and families from across Europe to exchange experiences and gain updates on emerging clinical and scientific advances. The FSHD Society continues to foster research and community engagement to accelerate treatment breakthroughs. The next International Research Congress will be held in Chicago, Illinois, on June 25-26, 2026.}, }
@article {pmid41298252, year = {2025}, author = {Shook-Sa, BE and Zivich, PN and Cole, SR and Rosenberg, NE and Hudgens, MG and Donnell, DJ and Moyo, S and Zuma, K and Ayles, H and Bock, P and Eron, JJ and Hayes, RJ and Edwards, JK}, title = {Examining the effect of universal testing and treatment strategies for HIV prevention in Zambia and South Africa: generalizing the results of the HPTN 071 (PopART) trial.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {12}, pages = {e70062}, pmid = {41298252}, issn = {1758-2652}, support = {R37AI029168/NH/NIH HHS/United States ; K01AI177102/NH/NIH HHS/United States ; PRCRPG-Nov21&#x2216;100001/CRUK_/Cancer Research UK/United Kingdom ; P30AI50410/NH/NIH HHS/United States ; K01AI182506/NH/NIH HHS/United States ; R01AI157758/NH/NIH HHS/United States ; K01 AI182506/AI/NIAID NIH HHS/United States ; R21MH134750/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/diagnosis/drug therapy/epidemiology ; Male ; Zambia/epidemiology ; South Africa/epidemiology ; Adult ; Female ; Young Adult ; Adolescent ; *HIV Testing/methods ; Incidence ; Anti-HIV Agents/therapeutic use ; }, abstract = {INTRODUCTION: HIV Prevention Trials Network (HPTN) 071 (PopART) was a cluster-randomized trial to evaluate universal testing and treatment (UTT) strategies for HIV prevention. HPTN071 compared three arms: (A) combination prevention with UTT; (B) combination prevention with universal testing and antiretroviral therapy initiation according to local guidelines; and (C) standard of care (SOC). Interventions were implemented in entire randomized communities, with impacts on HIV incidence measured in "population cohorts," that is the HPTN071 sample. Unexpectedly, a significantly lower incidence was not observed in arm A relative to SOC. Importantly, rates of participation in the HPTN071 sample differed among population subgroups, for example men were underrepresented.<br><br>METHODS: To correct for underrepresented subgroups, PopART intervention effects are estimated in a population of interest, adults aged 18-44 in trial provinces, characterized with two nationally representative HIV-focused surveys. The HPTN071 sample is weighted to match the population of interest by demographics and HIV risk factors. Risk of HIV acquisition is compared across arms, both in the trial population (unweighted) and the population of interest (weighted). Both (1) the risk of HIV acquisition between 1 and 3 years and (2) the risk of HIV acquisition by 3 years are compared.<br><br>RESULTS: In the trial population, estimated risk in arm A is, counterintuitively, slightly higher than SOC (Year 1-3 Risk Difference [RD]: 0.10%; 95% CI: -1.15%, 1.25%). After weighting, risk in arm A is lower than SOC in the population of interest (RD: -0.34%; 95% CI: -2.04%, 0.96%). Weighting also strengthened the estimated effect in arm B relative to SOC (unweighted RD: -0.66%, 95% CI: -1.88%, 0.46%; weighted RD: -1.18%, 95% CI: -2.85%, 0.15%). Weighted year 3 risk difference estimates indicated even stronger possible intervention effects: A versus SOC -0.83% (95% CI: -2.94%, 0.99%), B versus SOC -1.86% (95% CI: -3.80%, -0.09%).<br><br>CONCLUSIONS: PopART interventions are estimated to be more protective in the population of interest than observed in the HPTN071 sample. These results partially explain the unexpected finding in arm A, providing further support for UTT strategies for HIV prevention. This analysis also highlights the importance of considering heterogeneous treatment effects among population subgroups when measuring the overall efficacy of HIV interventions.}, }
@article {pmid41299640, year = {2025}, author = {Ekwunife, OI and Kuo, AP and Banerjee, P and Zhang, S and Kiptinness, C and Omollo, V and Chen, Y and Roche, SD and Odoyo, J and Bukusi, E and Ngure, K and Sharma, M and Ortblad, KF}, title = {Understanding the cost of pharmacy-delivered HIV pre- and post-exposure prophylaxis service delivery in Kenya: findings from pilot studies.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {1536}, pmid = {41299640}, issn = {1472-6963}, support = {INV-033052/GATES/Gates Foundation/United States ; R34 MH120106/MH/NIMH NIH HHS/United States ; R34 MH120106/NH/NIH HHS/United States ; INV-033052/GATES/Gates Foundation/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Kenya ; Pilot Projects ; *HIV Infections/prevention &amp; control ; *Pre-Exposure Prophylaxis/economics ; Male ; *Post-Exposure Prophylaxis/economics ; Female ; Adult ; *Pharmacies/economics ; Anti-HIV Agents/economics/therapeutic use ; }, abstract = {BACKGROUND: Private pharmacies are a primary access point for health services in many African countries. Leveraging private-sector pharmacies to deliver HIV prevention services, including pre- and post-exposure prophylaxis (PrEP/PEP), may expand the reach of these services. Understanding delivery costs is necessary to inform scale-up.<br><br>METHODS: We used data from two pilot studies conducted in Kisumu County, Kenya. In the first pilot, pharmacy providers at 12 pharmacies delivered free PrEP/PEP to eligible clients (&#x2265;&#x2009;18 years) using a prescribing checklist with remote clinician oversight; PrEP/PEP drugs were donated from government stock. Using microcosting, we estimated the economic and financial costs from the provider's perspective for: (1) subsidized delivery (donated commodities excluded), and (2) non-subsidized delivery (donated commodities included). We also assessed client willingness to pay for PrEP services at pharmacies using PrEP client survey data. In the second pilot, pharmacy providers at 20 pharmacies delivered HIV testing services. We assessed providers' anticipated willingness to deliver PrEP services using provider survey data.<br><br>RESULT: From February to July 2022, pharmacies in the first pilot recorded 1,564 PrEP/PEP visits, and initiated 691 clients on PrEP. Among clients eligible to continue PrEP at the pharmacy, 69% (479/691) refilled at least once. We collected 694 surveys from PrEP clients. From March to June 2022, 40 providers in the second pilot completed surveys. The estimated economic (financial) costs per client-month on PrEP were $3.66 ($2.17) USD for subsidized and $13.23 ($11.74) USD for non-subsidized delivery, and for PEP were $3.66 ($2.15) USD for subsidized and $10.75 ($9.24) USD for non-subsidized delivery. Most PrEP clients (83%, 575/691) expressed willingness to pay for pharmacy-delivered PrEP services; the median amount they were willing to pay per visit was $3.30 USD (IQR $1.60-$4.10 USD), which exceeded the median maximum amount providers said they would charge per visit ($2.40 USD, IQR $1.60-$4.10 USD).<br><br>CONCLUSIONS: When subsidized with drugs from government stock, pharmacies are a low-cost platform for delivering PrEP and PEP services in Kenya. Client out-of-pocket payments could help sustain pharmacy PrEP/PEP delivery at scale, enabling broader coverage of HIV prevention services.}, }
@article {pmid41299744, year = {2025}, author = {Saini, J and Stacey, A and Egan, A and Regmi, R and Bloch, C and Schwarz, M and Rengan, R and Chen, J and Halasz, L}, title = {Implementing ocular treatment with pencil beam scanning: the FHCC experience.}, journal = {Radiation oncology (London, England)}, volume = {20}, number = {1}, pages = {178}, pmid = {41299744}, issn = {1748-717X}, mesh = {Humans ; *Radiotherapy Planning, Computer-Assisted/methods ; *Proton Therapy/methods ; Radiotherapy Dosage ; Middle Aged ; *Eye Neoplasms/radiotherapy ; Male ; Female ; Aged ; Organs at Risk/radiation effects ; Monte Carlo Method ; Aged, 80 and over ; }, abstract = {BACKGROUND: The Fred Hutchinson Cancer Center (FHCC) has developed a novel in-house method for ocular proton therapy by adapting a pencil beam scanning (PBS) beamline and using a commercial treatment planning system. This manuscript outlines the workflow from simulation to treatment delivery and presents our experiences with the initial 40 patients.<br><br>METHODS: Key innovations of our treatment approach include in-house developed treatment chair and gaze localization systems, CT imaging for planning, and a Monte Carlo algorithm for dose calculation. We gathered data on patient characteristics, dose volume statistics, and total treatment time. Additionally, we examined the distances patients traveled to access ocular proton therapy. An example illustrating our treatment technique is also presented.<br><br>RESULTS: The average patient age at the time of treatment was 63.9 years. Tumor apical height ranged from 0.7 to 11.9&#xa0;mm, and the largest basal diameter from 2.8 to 15.5&#xa0;mm. GTV volumes ranged from 0.02 to 0.89&#xa0;cc, while PTV volumes ranged from 0.17 to 2.27&#xa0;cc. The D99% dose to GTV ranged from 5041 to 5242&#xa0;cGy (RBE). The median mean dose to the lacrimal gland was 1570&#xa0;cGy (RBE), while the median D2% doses to the optic nerve, macula, and optic disc were 4188&#xa0;cGy (RBE), 5024&#xa0;cGy (RBE), and 5133&#xa0;cGy (RBE), respectively. Out of the 40 patients, 16 successfully met all treatment planning goals. The remaining patients did not meet some goals due to the target either abutting or being close (<&#x2009;2&#xa0;mm) laterally or distally to the OARs. The total treatment duration per fraction was approximately 25&#xa0;min. Nearly one-third of the patients traveled around 900 miles to receive ocular treatment.<br><br>CONCLUSIONS: The approach at FHCC demonstrates that ocular proton therapy can be effectively delivered using a general-purpose PBS beamline, providing a solution for centers without dedicated ocular beamlines.}, }
@article {pmid41299886, year = {2026}, author = {Tu, DS and Olson, AK and Waggie, KS and Garcia, NM and Hoglund, VJ and Walter, SI and Rosinski, JR and Sadeeshkumar, H and Patel, R and Sayar, E and Haffner, MC and Maves, L and Neefjes, J and Sarthy, JF and Lawlor, ER and Ganapathi, SS}, title = {Determining Preclinical Safety of Aclarubicin in Pediatric Malignancies.}, journal = {Pediatric blood &amp; cancer}, volume = {73}, number = {2}, pages = {e32169}, pmid = {41299886}, issn = {1545-5017}, support = {//Sam Day Foundation/ ; T32 CA009351/CA/NCI NIH HHS/United States ; K12 CA076930/CA/NCI NIH HHS/United States ; //Sunbeam Foundation/ ; //Andy Hill CARE Fund/ ; L40 CA264716/CA/NCI NIH HHS/United States ; R21 CA280139/CA/NCI NIH HHS/United States ; //Burroughs Wellcome Fund/ ; //CURE Childhood Cancer/ ; }, mesh = {Animals ; Mice ; Humans ; *Aclarubicin/pharmacology ; Child ; *Neoplasms/drug therapy/pathology ; Female ; Xenograft Model Antitumor Assays ; DNA Damage/drug effects ; Doxorubicin ; }, abstract = {BACKGROUND: Anthracyclines are among the most effective chemotherapeutic agents used to treat pediatric malignancies. However, their clinical use is limited by dose-dependent toxicities, particularly cardiotoxicity and secondary malignancies. Aclarubicin (Acla) is an anthracycline derivative that induces chromatin damage while sparing DNA damage, offering potential therapeutic benefit with reduced long-term toxicity.<br><br>METHODS: We evaluated the anti-tumor efficacy and safety profile of Acla in multiple in vitro pediatric cancer models and in vivo mouse models designed to mimic anthracycline re-treatment following prior doxorubicin (Doxo) exposure. Tumor growth, genotoxic stress, survival, and organ toxicity were assessed.<br><br>RESULTS: Acla demonstrated robust anti-tumor activity comparable to Doxo across diverse pediatric in vitro models. Unlike Doxo, Acla treatment did not induce significant genotoxic stress. In vivo, mice receiving Acla after Doxo exposure showed no evidence of cumulative cardiotoxicity or end-organ damage. In contrast, a second course of Doxo led to significant toxic mortality but was surprisingly not attributable to classic cardiac injury.<br><br>CONCLUSION: Our study highlights Acla as a promising anthracycline derivative for pediatric cancers, with potent anti-tumor efficacy and a superior safety profile, even following prior anthracycline exposure. These results support continued investigation of chromatin-damaging anthracyclines that can kill pediatric cancer cells without inducing genotoxic stress. In addition, our studies underscore the need to refine preclinical models to better understand both acute and chronic anthracycline toxicities in pediatric and adolescent populations.}, }
@article {pmid41301035, year = {2025}, author = {Lange, KR and de Blank, P and Xing, M and Mirzaei, S and Srivastava, DK and Oeffinger, K and Neglia, J and Krull, K and Nathan, PC and Howell, R and Ness, KK and Turcotte, LM and Leisenring, W and Armstrong, GT and Brinkman, T and Bowers, DC and Okcu, MF}, title = {Late Morbidity and Mortality in Survivors of Childhood Ependymoma: A Report from the Childhood Cancer Survivor Study (CCSS).}, journal = {Cancers}, volume = {17}, number = {22}, pages = {}, pmid = {41301035}, issn = {2072-6694}, support = {NA//American Lebanese-Syrian Associated Charities/ ; CA55727, GT Armstrong PI/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; CA21765, C. Roberts, Principal Investigator//Cancer Center Support Grant/ ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND/OBJECTIVES: Treatment of childhood ependymoma evolved from 1970 to 1999 by reducing radiation volumes and incorporating chemotherapy. The impact of these changes on long-term health outcomes remains unknown. In this report, we evaluated temporal changes in all-cause and cause-specific late mortality, chronic health conditions (CHCs), and subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort of adult survivors of pediatric ependymoma, diagnosed between 1970 and 1999.<br><br>METHODS: A total of 404 five-year survivors of ependymoma (47.5% female, 80.7% non-Hispanic White, median 6 (range 0-20) years at diagnosis, 22 (5-49) years from diagnosis) diagnosed between 1970 and 1999 and enrolled in the Childhood Cancer Survivor Study were evaluated for late (>5 years from diagnosis) mortality, SNs, and CHCs. Outcomes were analyzed by diagnosis decade, radiotherapy, and chemotherapy exposure. Gray's test compared cumulative incidences. Multivariable piecewise exponential models estimated relative risks (RRs).<br><br>RESULTS: Whole-brain radiation exposure decreased over time (42.9% (1970s) to 2.7% (1990s)), while focal radiation (21.4% to 68.9%), and chemotherapy (29.5% to 50.2%) use increased. Fifteen-year all-cause late mortality (incidence, 95% CI) remained similar across decades: 1970s (9.3%, 3.4-18.8%), 1980s (14.7%, 9.4-21.2%), 1990s (10.3%, 6.7-14.9%). All-cause late mortality was higher after treatment with whole-brain radiation (22.5%, 11.2-36.5%) compared to focal radiation (11.4%, 7.5-16.1%) or no brain radiation (3.5%, 0.9-9.1%) (p < 0.001), and with chemotherapy (14.4%, 9.6-20.0%) versus without (6.8%, 3.8-11.0%) (p = 0.004). Compared to no brain radiation, the RR (95% CI) of grade 3-4 CHCs increased among survivors treated with focal (2.6, 1.3-5.4) and whole-brain radiation (3.5, 1.5-8.1), while chemotherapy was not associated with CHCs or SNs.<br><br>CONCLUSIONS: Despite reduced radiation volumes and increased use of chemotherapy, late mortality and morbidity among pediatric ependymoma survivors remained largely unchanged across treatment decades.}, }
@article {pmid41301877, year = {2025}, author = {Bastin, N and Mezzanotte-Sharpe, J and Alvarez, R and Partridge, SC and Dintzis, SM and Stanton, SE and Gadi, VK and Kennedy, LC}, title = {Exploratory Analysis of the Impact of a Single Dose of Trastuzumab on the Immune Microenvironment in HER2-Positive Early-Stage Breast Cancer.}, journal = {Biomedicines}, volume = {13}, number = {11}, pages = {}, pmid = {41301877}, issn = {2227-9059}, support = {5K12CA090625-25/NH/NIH HHS/United States ; 1R01CA248192-20/NH/NIH HHS/United States ; K12 CA090625/CA/NCI NIH HHS/United States ; 1P30CA015704-20/NH/NIH HHS/United States ; Hayden Family Foundation Young Investigator Award//ASCO/CCF/ ; N/A//Safeway Foundation/ ; 1T32CA009515-20/NH/NIH HHS/United States ; 2T32CA217834-07/NH/NIH HHS/United States ; }, abstract = {Background: How the tumor microenvironment (TME) influences treatment response in HER2+ breast cancer following HER2-directed therapy is crucial for individualizing therapies and is currently understudied. The purpose of this exploratory analysis was to elucidate changes in the TME following treatment with trastuzumab. Methods: Fourteen HER2+ early-stage breast cancer patients underwent tissue biopsies before and after a dose of trastuzumab. Samples were evaluated for stromal tumor-infiltrating lymphocytes (TILs) and RNA-based cell and gene expression signatures. Tumor inflammation signature scores were generated to measure whether an adaptive immune response developed to trastuzumab within the tumor. Patients were also stratified as immune responders or non-responders based on changes in TILs. Results: Of the 14 enrolled patients, 13 had samples available for analysis, and 7 had an immune response as assessed by changes in TILs compared to 6 non-responders. Trastuzumab treatment decreased PD-L1 and TGF-Beta signatures and increased CTLA4 gene signatures, although results were not statistically significant, and increased DUSP1 expression. In the TIL responder group, there was increased expression of dendritic cells as well as MARCO expression. Conclusions: These findings, although exploratory in nature, highlight trastuzumab's ability to induce an immune response and suggest that some patients may be more primed to mount an immune response following treatment than others. Patients without a robust response in TILs may benefit from additional agents to favorably modulate the TME for optimized responses to HER2-directed therapy, an area of research which warrants further study.}, }
@article {pmid41305521, year = {2025}, author = {Swan, DA and Krantz, EM and Byrne, CM and Okuku, F and Nankoma, J and Mutyaba, I and Phipps, W and Schiffer, JT}, title = {Human Herpes Virus-8 Oral Shedding Heterogeneity Is Due to Varying Rates of Reactivation from Latency and Immune Containment.}, journal = {Viruses}, volume = {17}, number = {11}, pages = {}, pmid = {41305521}, issn = {1999-4915}, support = {K23 CA150931/CA/NCI NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 CA239593/CA/NCI NIH HHS/United States ; 5R01CA239593-25/NH/NIH HHS/United States ; }, mesh = {Humans ; *Virus Shedding ; *Herpesvirus 8, Human/physiology/immunology ; *Virus Latency ; *Virus Activation ; Viral Load ; Uganda/epidemiology ; Longitudinal Studies ; *Herpesviridae Infections/virology/immunology ; Male ; HIV Infections/virology/complications/immunology ; Female ; Adult ; *Mouth Mucosa/virology ; Sarcoma, Kaposi/virology/immunology ; Models, Theoretical ; }, abstract = {Human herpesvirus-8 (HHV-8) is a gamma herpesvirus linked to the development of Kaposi sarcoma (KS). KS is more common in persons living with HIV (PLWH), but endemic KS in HIV-negative individuals is also common in sub-Saharan Africa. HHV-8 shedding occurs in the oral mucosa and is likely responsible for transmission. The mechanistic drivers of different HHV-8 shedding patterns in infected individuals are unknown. We applied stochastic mathematical models to a longitudinal study of HHV-8 oral shedding in 295 individuals in Uganda who were monitored daily with oral swabs. Participants were divided into four groups based on whether they were HIV-negative or -positive, as well as KS-negative or -positive. In all groups, we observed a wide variance of shedding patterns, including no shedding, brief episodic low viral load shedding, prolonged episodic medium viral load shedding, and persistent high viral load shedding. Our model closely replicates patterns in individual data and attributes higher shedding rates to increased rates of viral reactivation and lower median viral load values to more rapid and effective engagement of cytolytic immune responses. Our model provides a framework for understanding different shedding patterns observed in individuals with HHV-8 infection.}, }
@article {pmid41305628, year = {2025}, author = {Garfias-Avila, N and Wang, CY and Lampe, JW and Mendoza, JA and Tapsoba, JD and Alcalá, NJ and Levy, L and Neuhouser, ML}, title = {Implications for Dietary Guideline Policy of a Cultural Adaptation of the US Dietary Guidelines for Women of Mexican Descent: A Pilot Study.}, journal = {Nutrients}, volume = {17}, number = {22}, pages = {}, pmid = {41305628}, issn = {2072-6643}, support = {1P50CA148143-16S1/NH/NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Middle Aged ; Biomarkers/blood ; Diet ; *Diet, Healthy/ethnology ; *Mexican Americans ; *Nutrition Policy ; Pilot Projects ; United States ; Washington ; }, abstract = {Background/Objectives: This study aims to evaluate whether the Dietary Guidelines for Americans (DGA) are effective for maintaining a healthy diet among Mexican-descent populations in the US or if a more culturally tailored policy approach is warranted. Methods: As a first outcome, 20 healthy women of Mexican descent from the Seattle area participated in a pilot randomized controlled trial. They were randomly assigned (10 participants each) to either a group receiving instruction on the standard 2015 DGA or a group receiving an adaptation of the DGA focused on traditional Mexican cuisine and culture. In this 12-week study (with follow-ups at 3 and 6 months), participants' acceptability of the cultural adaptation of the DGA was compared with that of the standard DGA with end-of-study surveys. Ten blood-based metabolic biomarkers were assessed at baseline and 3 months. Dietary changes at 3 months were assessed with a Food Frequency Questionnaire (FFQ) that was translated into Spanish but not culturally adapted. The secondary outcome was dietary change at 6 months. Results: The primary findings at 3 months showed that serum free fatty acids were reduced for the standard DGA arm. Carbohydrate consumption was reduced in the standard DGA arm only. The end-of-study survey results suggested that both interventions were well received by participants. Conclusions: The preliminary findings from this small sample size suggest that depending on a person's priorities, either intervention could be offered, with each arm showing slightly different dietary and biomarker outcomes.}, }
@article {pmid41307276, year = {2025}, author = {Robins, LI and Gafken, P and Lin, C and Jones, L and Hooper, SE}, title = {Dissecting HOCl Action in Chronic Wound Biofilms: Proteomic Insights From a Host-Relevant Model of Pseudomonas aeruginosa.}, journal = {MicrobiologyOpen}, volume = {14}, number = {6}, pages = {e70181}, pmid = {41307276}, issn = {2045-8827}, support = {//The authors received no specific funding for this work./ ; }, mesh = {*Pseudomonas aeruginosa/drug effects/physiology ; *Biofilms/drug effects/growth &amp; development ; *Hypochlorous Acid/pharmacology/metabolism ; Proteomics ; *Proteome/analysis ; *Bacterial Proteins/analysis/metabolism ; Microbial Viability/drug effects ; Pseudomonas Infections/microbiology ; Humans ; }, abstract = {Pseudomonas aeruginosa is found in 48%-52% of chronic wound biofilms, where its resistance to antimicrobials and host immunity presents a major clinical challenge. Although hypochlorous acid (HOCl) is known to be an effective antimicrobial, its mechanism of action remains unclear because standard experimental conditions often produce a mixture of HOCl and hypochlorite (OCl[-]), making it difficult to isolate the effects of HOCl. Here, we use proteomic profiling to investigate the effects of a pure, stable HOCl gel on P. aeruginosa biofilms in a physiologically relevant chronic wound model. We applied HOCl gel (5.7 mM, pH 6) to mature P. aeruginosa biofilms established in a wound-mimicking flow model. Proteins were analyzed using tandem mass tag (TMT)-based quantitative proteomics, identifying 1,878 proteins. HOCl treatment significantly reduced biofilm viability and altered the abundance of 330 proteins. We observed substantial depletion of proteins involved in biosynthesis, virulence, antibiotic resistance, and biofilm formation, alongside enrichment of stress response proteins. These findings indicate a shift toward survival phenotypes and weakened pathogenicity. Our data reveal that HOCl disrupts multiple pathways essential for P. aeruginosa survival and virulence. Crucially, our experimental design eliminates confounding factors that can lead to unintentional testing of mixed HOCl and OCl[-] species, allowing us to assess the specific effects of HOCl. These findings call for a re-evaluation of HOCl research methodologies and reiterate the importance of realistic infection models in antimicrobial testing.}, }
@article {pmid41307621, year = {2025}, author = {Lopez, K and Silva, M and Briant, KJ and Fox, B and Dee, C and Ceballos, RM and Thompson, B}, title = {Involving Latinas in Understanding Barriers, Facilitators, and Appropriate Outreach for Mammography in Tacoma, Washington, USA.}, journal = {Journal of community health}, volume = {}, number = {}, pages = {}, pmid = {41307621}, issn = {1573-3610}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Breast cancer screening rates are lower for Hispanic females (Latinas) than their non-Hispanic White counterparts. This discrepancy is partly due to health disparities, such as limited access to care, inability to take time off work, lack of health insurance, and cultural and emotional barriers. In response to a health department request, the Carol Milgard Breast Center conducted a qualitative assessment, as part of a community grant pilot award from Fred Hutchinson Cancer Center, to better understand the barriers and facilitators influencing Latinas' participation in mammography screening. The objective was to identify key characteristics of an intervention aimed at encouraging mammogram uptake among Latinas. Forty women were recruited and consented to participate in structured interviews, which included questions on their perceptions of mammography. The interviews explored structural barriers (e.g., lack of insurance), cultural issues (e.g., prioritizing family over individual health), and emotional concerns (e.g., fear of embarrassment). By detailing lessons learned and community identified outreach strategies, this work advances the evidence base on community engagement with Latinas for cancer education and outreach. Findings underscore the need for linguistically and culturally tailored resources, trusted messengers, and outreach approaches that meet Latinas where they are. The identified strategies can inform interventions to improve mammography uptake in similar communities and guide larger-scale implementation efforts.}, }
@article {pmid41308031, year = {2025}, author = {Gardner, JA and Nusapan, R and Tan, J and Levy, B and Tang, G and Fang, M and Velagaleti, GV and Cao, Y and Astbury, C and Mixon, JC and J Souers, R and Peterson, JF and Zou, YS}, title = {Current and Future Utilization of Optical Genome Mapping: Insights From the 2024 College of American Pathologists Supplemental Questionnaire.}, journal = {Archives of pathology &amp; laboratory medicine}, volume = {}, number = {}, pages = {}, doi = {10.5858/arpa.2025-0472-CP}, pmid = {41308031}, issn = {1543-2165}, abstract = {CONTEXT.&#x2014;: Optical genome mapping (OGM) represents a promising cytogenomic technology that detects structural variants, including fusions, rearrangements, copy number variants, and loss of heterozygosity, in a single assay. Unlike karyotyping, fluorescence in situ hybridization, or chromosomal microarray, OGM leverages long-molecule imaging to map the whole genome with high resolution. This positions OGM as a novel tool for constitutional and somatic/cancer genomics. However, its current and planned utilization in clinical and research settings remains unknown, necessitating further investigation.<br><br>OBJECTIVE.&#x2014;: To investigate the current utilization of OGM in clinical and research laboratories, assess its applications, and evaluate future utilization strategies.<br><br>DESIGN.&#x2014;: In 2024, a supplemental questionnaire was incorporated into 6 College of American Pathologists proficiency testing programs to evaluate OGM's utilization.<br><br>RESULTS.&#x2014;: Of 921 returned questionnaires, 712 were analyzed after duplicates were removed. Sixty-seven (9.4%) currently offered OGM testing: 5.2% (37) for research only, 1.8% (13) for only clinical use, and 2.4% (17) for both. Future adoption plans showed 7.6% (53 of 700 laboratories) and 7.9% (55 of 700 laboratories) aiming to implement OGM clinically within 12 and 24 months, respectively. The most common applications included hematologic malignancies and constitutional/germline postnatal disorders, followed by prenatal testing. International laboratories demonstrated statistically higher utilization rates than domestic laboratories (P = .001).<br><br>CONCLUSIONS.&#x2014;: This first survey on OGM clinical utilization reveals its status as a niche technology, with 67 laboratories currently using it. Its primary clinical applications are in constitutional/germline analysis and hematologic malignancies. Although international laboratories led in 2024, 108 laboratories (domestic and international) plan clinical adoption within 24 months, signaling OGM's potential for broader integration.}, }
@article {pmid41308080, year = {2025}, author = {Gee-Rodriguez, K and Yun, J and Duong, A and Indorf, A}, title = {Comparing relative dose intensity of weekly nab-paclitaxel regimens in early breast cancer: A retrospective study at a large academic outpatient cancer center.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251399901}, doi = {10.1177/10781552251399901}, pmid = {41308080}, issn = {1477-092X}, abstract = {IntroductionNational guidelines for breast cancer support substitution with nab-paclitaxel for paclitaxel or docetaxel due to medical necessity.[1] This study aimed to assess for correlation between weekly nab-paclitaxel dose and relative dose intensity (RDI) amongst early breast cancer patients.MethodsThis single-center, retrospective cohort study included adult patients with early breast cancer who switched from weekly paclitaxel to nab-paclitaxel after hypersensitivity reaction. The primary outcome of RDI was assessed in patients receiving nab-paclitaxel 80 mg/m[2] (NB80) or 100 mg/m[2] (NB100) intravenously (IV) weekly. Secondary outcomes included adverse effects, incidence of nab-paclitaxel alterations, and growth factor (GCSF) administration for secondary prophylaxis.ResultsAmongst 26 patients, the median age was 43 years (range 33 to 71), with the majority (54%) having stage II or later disease. Median RDI with NB80 was 91% (range 69 to 100%) versus 86% (55 to 100%) with NB100. Fifty percent of all patients underwent dose reductions. Dose delays occurred in a higher proportion of patients on 50% with NB80 vs 33% with NB100. Early nab-paclitaxel discontinuations occurred more on NB100 (33% vs 10%). Incidence of chemotherapy-induced peripheral neuropathy (CIPN) was 80% vs 83% with NB80 and NB100, respectively, while grade 2 CIPN was more common on NB100 (50% vs 35%). A lower rate of neutropenia resulted from NB80 (60 vs 67% with NB100).ConclusionNab-paclitaxel dosed at 80 mg/m[2] IV weekly, after switching due to paclitaxel hypersensitivity, may promote improved RDI and safety compared to nab-paclitaxel 100 mg/m[2] weekly amongst early breast cancer patients.}, }
@article {pmid41308477, year = {2026}, author = {Hoggard, NK and Elshafae, SM and Daniels, NA and Young, JA and Premanandan, C and Echols, JB and Chandrashekar, DS and Hildreth, BE and Haffner, MC and Rosol, TJ}, title = {Comparative histologic survey and transcriptomic investigation into canine prostate carcinoma.}, journal = {Research in veterinary science}, volume = {198}, number = {}, pages = {105981}, doi = {10.1016/j.rvsc.2025.105981}, pmid = {41308477}, issn = {1532-2661}, mesh = {Dogs ; Animals ; Male ; *Dog Diseases/pathology/genetics ; *Prostatic Neoplasms/veterinary/pathology/genetics ; *Transcriptome ; Retrospective Studies ; Prostate/pathology ; Urinary Bladder Neoplasms/pathology/veterinary ; Prostatic Intraepithelial Neoplasia/pathology/veterinary/genetics ; Humans ; }, abstract = {Dogs share features in prostate gland anatomy, physiology, and pathology with men. However, human and canine prostate carcinoma (PC) have histologic and molecular differences. Particularly, the histogenesis of canine PC (cPC) is unclear. This study investigated the origin of cPC using histopathology and transcriptomics with comparison to men. Prostate glands retrospectively and prospectively collected from 445 dogs (approximately 95 % autopsy samples) were surveyed for early carcinomas and preneoplastic lesions, particularly high-grade prostatic intraepithelial neoplasia (HGPIN) due to its role in the pathogenesis of PC in men. Lineage gene signatures defining prostate luminal epithelium and urothelium were identified for inter- and intraspecies RNA-sequencing comparisons, including between cPC and canine urinary bladder urothelial carcinoma (UC). Postmortem prostate lesion frequencies were similar to previously reported canine studies. Intraductal/intra-acinar growth (31/35; 88.6 %) was common in representative samples of cPC. Prostate epithelial changes consistent with HGPIN in men were not observed. Proliferative lesions and early carcinomas were rare (7/445; 1.6 %). Patterns in prostate and urothelium marker gene expression signatures differed between human and canine PC. Compared to non-neoplastic prostate gland, cPC had significantly decreased prostate-specific and increased urothelium gene signatures. The results suggest many cases diagnosed as cPC are UC or have urothelial differentiation and thus differ from PC in men, with important implications for canine tumor classification and translational studies.}, }
@article {pmid41308682, year = {2025}, author = {Necchi, A and Stitou, H and Bhanvadia, S and Psutka, SP}, title = {SunRISe-4 perioperative safety and TURBT stratification - Authors' reply.}, journal = {The Lancet. Oncology}, volume = {26}, number = {12}, pages = {e621}, doi = {10.1016/S1470-2045(25)00671-0}, pmid = {41308682}, issn = {1474-5488}, }
@article {pmid41309676, year = {2025}, author = {Yu, Z and Vromman, A and Nguyen, NQH and Schuermans, A and Li, L and Rentz, T and Nakao, T and Vellarikkal, SK and Uddin, MM and Niroula, A and Griffin, G and Honigberg, MC and Lin, AE and Gibson, CJ and Katz, DH and Tahir, UA and Fang, S and Dron, JS and Pan, M and Haidermota, S and Ganesh, S and Antoine, T and Weinstock, J and Austin, TR and Vasan, RS and Peloso, GM and Hornsby, W and Ganz, P and Manson, JE and Haring, B and Kooperberg, C and Reiner, AP and Bis, JC and Psaty, BM and Min, YI and Correa, A and Lange, LA and Post, WS and Rotter, JI and Rich, SS and Wilson, JG and Ebert, BL and Yu, B and Ballantyne, CM and Coresh, J and Sankaran, VG and Bick, AG and Jaiswal, S and Gerszten, RE and ,  and Libby, P and Gupta, RM and Natarajan, P}, title = {Human plasma proteomic profile of clonal hematopoiesis.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {11688}, pmid = {41309676}, issn = {2041-1723}, support = {RC2 HL102419/HL/NHLBI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; R01DK125782//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; N01 HC085080/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; 75N98025D00028/OD/NIH HHS/United States ; 25SFRNCCKMS1443062/AHA/American Heart Association-American Stroke Association/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; DP5 OD029586/OD/NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; 75N98025D00024/OD/NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; R01HL173028, R01HL148565//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01 DK108809/DK/NIDDK NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; R01 MH104964/MH/NIMH NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; Harold M. English Fellowship Fund//Harvard Medical School/ ; R01 HL153499/HL/NHLBI NIH HHS/United States ; R01 HL151283/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; R01 HL163099/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; N01 HC085082/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; R01 DK125782/DK/NIDDK NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; K08 HL161445/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01 HC085086/HL/NHLBI NIH HHS/United States ; N01 HC085083/HL/NHLBI NIH HHS/United States ; R01 MH104964 and R01 MH123451//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; 75N98025D00025/OD/NIH HHS/United States ; R01 HL134892/HL/NHLBI NIH HHS/United States ; 25SFRNPCKMS1463898/AHA/American Heart Association-American Stroke Association/United States ; R01 HL173028/HL/NHLBI NIH HHS/United States ; K08HL161445//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01 HC095167/HL/NHLBI NIH HHS/United States ; Burroughs Wellcome Foundation Career Award for Medical Scientists//Burroughs Wellcome Fund (BWF)/ ; R01 HL127564/HL/NHLBI NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; K99 HL165024/HL/NHLBI NIH HHS/United States ; R01HL142711, R01HL127564, R01HL148050, R01HL151283, R01HL148565, R01HL135242, and R01HL151152//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1R01HL134892 and 1R01HL163099-01//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; R01 HL142711/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; 1R01 HL159081, R01 HL153499//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; N01 HC055222/HL/NHLBI NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 HL159081/HL/NHLBI NIH HHS/United States ; N01 HC085079/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; R01 HL172803/HL/NHLBI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; 75N98025D00022/OD/NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; R00 HG012956/HG/NHGRI NIH HHS/United States ; 5U01DK108809//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; DP2 HL157540/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; R01 MH123451/MH/NIMH NIH HHS/United States ; TNE-18CVD04//Fondation Leducq/ ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; 75N98025D00027/OD/NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; R00HG012956//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; KAW 2020.0239//Science for Life Laboratory (SciLifeLab)/ ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; Paul and Phyllis Fireman Endowed Chair in Vascular Medicine//Massachusetts General Hospital (MGH)/ ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL135242/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; K99HL165024//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01 HC095165/HL/NHLBI NIH HHS/United States ; R01 HL134320/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; 24RGRSG1275749/AHA/American Heart Association-American Stroke Association/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; 24RGRSG1275749, 25SFRNCCKMS1443062, 25SFRNPCKMS1463898//American Heart Association (American Heart Association, Inc.)/ ; R01 HL148050/HL/NHLBI NIH HHS/United States ; N01 HC085081/HL/NHLBI NIH HHS/United States ; 75N98025D00026/OD/NIH HHS/United States ; R01HL148565//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; *Clonal Hematopoiesis/genetics ; Dioxygenases ; Animals ; *Proteomics/methods ; Mice ; Female ; DNA Methyltransferase 3A ; DNA-Binding Proteins/genetics/metabolism ; Male ; Proto-Oncogene Proteins/genetics/metabolism ; DNA (Cytosine-5-)-Methyltransferases/genetics ; Coronary Artery Disease/genetics/blood ; *Proteome/metabolism ; Repressor Proteins/genetics ; *Blood Proteins/metabolism/genetics ; Mice, Knockout ; Middle Aged ; Mutation ; Aged ; Mendelian Randomization Analysis ; }, abstract = {Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These associations show substantial heterogeneity by driver genes, sex, and race, and were enriched for immune response and inflammation pathways. Mendelian randomization in humans, coupled with ELISA in hematopoietic Tet2-/- vs wild-type mice validation, disentangle causal proteomic perturbations from TET2 CHIP. Lastly, we identify plasma proteins shared between CHIP and CAD.}, }
@article {pmid41310100, year = {2025}, author = {Hernandez, LE and Smitherman, AB and Santacroce, SJ and Liu, Y and Roy, MM and Ross, WL and Armstrong, H and Appel, B and Casillas, J and Hurtado-de-Mendoza, A and Demedis, J and Horwitz, LI and Mendoza, JA and Kadan-Lottick, NS}, title = {Childhood cancer survivors and their caregivers are amenable to survivorship surveillance with community-based primary care providers.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {41310100}, issn = {1932-2267}, support = {R01 CA261881/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: A minority of childhood cancer survivors (CCS) receive post-therapy survivorship surveillance at their oncology center (OC) within 5 years of diagnosis. Primary care providers (PCPs) could be a promising alternative. We determined CCS' preferences for the site of surveillance, associated factors, and rationale.<br><br>METHODS: CCS diagnosed with cancer at&#x2009;<&#x2009;21&#xa0;years at one of four participating hospitals, 2-4&#xa0;years post-therapy, and English- or Spanish-speaking (or their caregivers if CCS&#x2009;<&#x2009;18&#xa0;years) indicated their preference and reasons for site of survivorship surveillance (OC vs. PCP vs. no preference) at baseline prior to randomization into the BRIDGES trial (NCT05448560). Multivariable logistic regression models estimated prevalence ratios for site preference and examined associations with patient characteristics. Qualitative methods examined reasons for preference.<br><br>RESULTS: Of 235 participants, 92% (n&#x2009;=&#x2009;214; 48% female, 36% Hispanic, 46% public insurance, median age 12&#xa0;years at enrollment) indicated their preference. The majority (63%) were amenable to PCP-based surveillance (21% preferred PCP, 42% no preference). Preference for OC was associated with identifying as non-Hispanic "other" (Black, Asian, multi-racial) vs. non-Hispanic White (PR 4.7, p&#x2009;=&#x2009;0.005, 95% CI 1.68, 13.84) and older age (PR 1.1/year, p&#x2009;=&#x2009;0.02, 95% CI 1.01, 1.15), but not insurance or area-level social determinants of health (SDoH) indices. Reasons for preference comprised two themes: practical (facts, logistics) and psychological (emotions, beliefs). OCs were preferred for psychological reasons (46/60; 77%); PCPs were preferred for practical reasons (25/35; 74%).<br><br>CONCLUSIONS: Among diverse CCS, most were amenable to PCP-based survivorship surveillance, independent of SDoH factors.<br><br>Survivorship surveillance by PCPs may be a useful alternative for CCS.}, }
@article {pmid41310247, year = {2025}, author = {Alves, IM and Termini, CM}, title = {Blocking ferroptosis to expand human HSCs.}, journal = {Nature cell biology}, volume = {27}, number = {12}, pages = {2041-2042}, pmid = {41310247}, issn = {1476-4679}, support = {1K01DK126989-01A1//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; 23CDA1039196//American Heart Association (American Heart Association, Inc.)/ ; SPK-08-25//Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)/ ; }, }
@article {pmid41313144, year = {2025}, author = {Anderson, BO and Li, CI}, title = {Lobular carcinoma and endocrine biology: Lessons learned and future directions.}, journal = {Cancer}, volume = {131}, number = {23}, pages = {e70194}, doi = {10.1002/cncr.70194}, pmid = {41313144}, issn = {1097-0142}, }
@article {pmid41314597, year = {2026}, author = {Mosher, CE and Shinn, EH and Addington, EL and Wu, W and Bricker, JB and Helft, PR and Turk, AA and Vater, LB and Masood, A and Jalal, SI and Loehrer, PJ and Champion, VL and Johns, SA}, title = {Protocol of a randomized trial of acceptance and commitment therapy for patient fatigue interference and caregiver burden in advanced gastrointestinal cancer.}, journal = {Contemporary clinical trials}, volume = {160}, number = {}, pages = {108168}, pmid = {41314597}, issn = {1559-2030}, support = {R01 CA289486/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Fatigue/therapy/etiology/psychology ; *Acceptance and Commitment Therapy/methods ; *Gastrointestinal Neoplasms/psychology/complications ; *Caregivers/psychology ; Quality of Life ; Randomized Controlled Trials as Topic ; Telephone ; *Caregiver Burden/therapy/psychology ; Activities of Daily Living ; Female ; Male ; Clinical Trials, Phase II as Topic ; }, abstract = {Fatigue's interference with activities, mood, and cognition is one of the most prevalent and distressing problems of patients with advanced gastrointestinal cancer. As fatigue interferes with patient functioning, family caregivers often report feeling burdened by increasing demands. Evidence-based interventions for patient fatigue interference and caregiver burden are lacking in advanced gastrointestinal cancer. In a pilot trial, telephone-based Acceptance and Commitment Therapy (ACT) showed potential for reducing patient fatigue interference and caregiver burden in this population. The current Phase II trial seeks to determine the efficacy of this intervention for patients with advanced gastrointestinal cancer and moderate-to-severe fatigue interference and their family caregivers with significant caregiving burden. In this trial, 244 dyads are randomly assigned to either the ACT intervention or an education/support control. Participants in both conditions attend six weekly 50-min telephone sessions, four of which involve both dyad members, and a 30-min booster session. The primary aim is to test the effects of telephone-delivered ACT on patient fatigue interference and caregiver burden. Secondary outcomes include patient sleep interference and patient and caregiver engagement in daily activities and quality of life. Outcomes are assessed at baseline, 2 weeks post-intervention, and 3 months post-intervention. This trial also examines whether increased psychological flexibility, defined as mindful acceptance of present experiences, including challenges, while pursuing actions aligned with personal values, mediates ACT's effects on primary outcomes. Our ability to demonstrate ACT's efficacy will support its adoption in cancer care. Findings will also inform future ACT trials for dyads coping with other serious illnesses. Trial Registration ID: NCT06532877.}, }
@article {pmid41314741, year = {2025}, author = {Buchbinder, SP and Spinosa Guzman, S and Sanchez, J and Willems, W and Stieh, DJ and van Duijn, J and van Rosmalen, MGM and Hendriks, J and Nijs, S and Lavreys, L and Paez, CA and Grinzstejn, B and Hutter, J and Mann, P and Sierra Madero, JG and Cahn, P and Castagna, A and Truyers, C and Roels, S and Gilbert, PB and Carone, M and Luedtke, A and Corey, L and Pau, MG and Tomaka, F and , }, title = {Efficacy and safety of a mosaic HIV-1 vaccine regimen in men who have sex with men and transgender individuals (HVTN 706/HPX3002/Mosaico): a global, randomised, double-blind, placebo-controlled, phase 3 trial.}, journal = {The lancet. HIV}, volume = {12}, number = {12}, pages = {e823-e835}, doi = {10.1016/S2352-3018(25)00195-X}, pmid = {41314741}, issn = {2352-3018}, mesh = {Humans ; Male ; *HIV Infections/prevention &amp; control/immunology ; Adult ; *AIDS Vaccines/administration &amp; dosage/immunology/adverse effects ; Double-Blind Method ; *HIV-1/immunology ; *Transgender Persons ; Middle Aged ; *Homosexuality, Male ; Young Adult ; Vaccine Efficacy ; Female ; }, abstract = {BACKGROUND: There is a high unmet need for effective HIV prevention options, including vaccines, for individuals at high risk of HIV acquisition who choose not to use pre-exposure prophylaxis or other prevention strategies. This study evaluated the efficacy and safety of an HIV-1 vaccine regimen consisting of tetravalent mosaic adenovirus serotype 26-based vaccine (Ad26.Mos4.HIV) and bivalent clade C glycoprotein (gp) 140-mosaic gp140 vaccine, in a population with high seroincidence.<br><br>METHODS: This randomised, double-blind, phase 3 trial enrolled adult cisgender men and transgender individuals without HIV from 52 academic medical centres, health departments, and community-based clinics in Latin America, Europe, and the USA. Participants were randomly assigned (1:1) by use of a centrally prepared, computer-generated randomisation schedule to receive intramuscular injections of vaccine or saline placebo in stratified permuted blocks. Study participants, study site personnel (except for those with primary responsibility for study vaccine preparation and dispensing), and investigators were masked from vaccine allocation. The vaccine regimen consisted of Ad26.Mos4.HIV administered at months 0 and 3 followed by Ad26.Mos4.HIV administered concurrently with aluminium phosphate-adjuvanted clade C gp140-mosaic gp140 at months 6 and 12. The primary endpoint was vaccine efficacy in preventing HIV-1 acquisition between months 7 and 24 or between months 7 and 30 in the per-protocol population, which included all randomly assigned participants who received at least one study vaccination and who had not been diagnosed with HIV-1 4 weeks after the third vaccination, had received all planned vaccinations at the first three vaccination visits within the respective visit windows, and had no major protocol deviations linked to incorrect product administration. Safety outcomes were assessed in all randomised participants who received at least one study vaccination. The trial is registered with ClinicalTrials.gov (NCT03964415) and is complete.<br><br>FINDINGS: Between Nov 4, 2019, and Aug 13, 2021, 3900 participants were enrolled and randomly assigned; 3887 received at least one study vaccination (1942 assigned to vaccine, 1945 to placebo). 3870 (99&#xb7;6%) of 3887 participants were assigned male at birth, seven (0&#xb7;2%) were assigned female, and one participant's sex at birth was undifferentiated; 3557 (91&#xb7;5%) participants identified as male gender, 48 (1&#xb7;2%) as female gender, and 278 (7&#xb7;2%) as transgender or non-binary. The per-protocol population included 1525 participants in the vaccine group and 1494 in the placebo group. From month 7 to month 24 in the per-protocol population, HIV-1 incidence per 100 person-years was 3&#xb7;63 (95% CI 2&#xb7;77 to 4&#xb7;67) in the vaccine group and 3&#xb7;35 (2&#xb7;53 to 4&#xb7;36) in the placebo group, with an estimated vaccine efficacy (months 7-24) of -0&#xb7;7% (95% CI -50&#xb7;9 to 32&#xb7;8; p=0&#xb7;97). Vaccine efficacy (months 7-30) was -149&#xb7;1% (-737&#xb7;7 to 26&#xb7;0; p=0&#xb7;14). Most solicited local and systemic adverse events were mild or moderate and short-lived. Medically attended adverse events occurred in 999 (51&#xb7;4%) of 1942 participants given vaccine and 1002 (51&#xb7;5%) of 1945 participants given placebo; serious adverse events occurred in 82 (4&#xb7;2%) of 1942 participants given vaccine and 77 (4&#xb7;0%) of 1945 participants given placebo. No fatal adverse events considered related to the study vaccine occurred. Adverse events of special interest (thrombotic events or thrombocytopenia) occurred in four participants with vaccine and two with placebo; none had thrombosis with thrombocytopenia syndrome.<br><br>INTERPRETATION: The lack of efficacy in this and other HIV vaccine trials points to the importance of current efforts to develop vaccines that generate broadly neutralising antibodies.<br><br>FUNDING: Johnson &amp; Johnson; HIV Vaccine Trials Network; Division of AIDS, a division of National Institute of Allergy and Infectious Diseases; and US Army Medical Materiel Development Activity, a subordinate command of the US Army Medical Research and Development Command.}, }
@article {pmid41315206, year = {2025}, author = {Afrough, A and Dima, D and Razzo, B and Goel, U and Sannareddy, A and Pasvolsky, O and Vazquez-Martinez, MA and Ferreri, CJ and Banerjee, R and Khouri, J and Davis, JA and Gaballa, MR and Lieberman-Cribbin, A and Rana, MS and Julian, K and Anwer, F and Shune, L and DeJarnette, S and Grajales-Cruz, AF and Ouchveridze, E and De Avila, G and Susanibar-Adaniya, SP and Portuguese, AJ and Schrum, D and Eberwein, E and Hosoya, H and Mikkilineni, L and Kaur, G and McGuirk, JP and Rossi, A and Herr, MM and Castaneda, O and Locke, FL and Raza, S and Lin, Y and Atrash, S and Sborov, DW and Voorhees, PM and Richard, S and Garfall, AL and Sidana, S and Patel, KK and Hansen, DK and Cowan, AJ and Anderson, LD and Lee, HC}, title = {The impact of extramedullary and paraskeletal plasmacytomas on treatment outcomes in multiple myeloma treated with teclistamab: U.S. Myeloma Immunotherapy Consortium real-world experience.}, journal = {Blood cancer journal}, volume = {16}, number = {1}, pages = {12}, pmid = {41315206}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/pathology/mortality ; *Plasmacytoma/drug therapy/pathology/mortality ; Female ; Male ; Middle Aged ; Aged ; Adult ; Aged, 80 and over ; *Antibodies, Bispecific/therapeutic use ; Treatment Outcome ; Prognosis ; Retrospective Studies ; }, abstract = {Teclistamab, a bispecific antibody targeting B-cell maturation antigen (BCMA), is effective in relapsed or refractory multiple myeloma (RRMM), but its impact on patients with soft tissue plasmacytomas is unclear. We studied 385 RRMM patients treated with teclistamab at 13 U.S. centers through September 2023, with follow-up to April 2024. Soft tissue plasmacytomas were classified as true extramedullary disease (EMD; not contiguous with bone) or paraskeletal plasmacytomas (PSK; contiguous with bone). Patients with the simultaneous presence of both were classified as true-EMD, reflecting its adverse prognosis. Of those, 109 (28%) had true EMD, 33 (9%) had PSK, and 243 (63%) had no soft tissue plasmacytoma (No-STP). Median follow-up was 9.9 months. Overall response rates were 38% in true-EMD, 54.1% in PSK, and 62.4% in No-STP (p < 0.001). Median progression-free survival (PFS) was 1.4 months in true-EMD, 6.51 months in PSK, and 8.95 months in No-STP (p < 0.0001). Median overall survival (OS) was 9.54 months for true EMD, 13.1 months for PSK, and not reached in No-STP (p = 0.00012). In multivariable analysis, true-EMD was independently associated with inferior PFS and OS, while PSK showed numerically lower outcomes. These findings highlight the need for tailored strategies in patients with soft tissue plasmacytomas, particularly those with true-EMD.}, }
@article {pmid41319224, year = {2025}, author = {Chen, Z and Heng, S and Tapley, A and De Rosa, S and Zhang, B}, title = {Determining vaccine responders in the presence of baseline immunity using single-cell assays and paired control samples.}, journal = {Biostatistics (Oxford, England)}, volume = {26}, number = {1}, pages = {}, doi = {10.1093/biostatistics/kxaf045}, pmid = {41319224}, issn = {1468-4357}, mesh = {Humans ; *Single-Cell Analysis/methods ; *Immunogenicity, Vaccine/immunology ; *COVID-19 Vaccines/immunology ; B-Lymphocytes/immunology ; COVID-19/prevention &amp; control/immunology ; Cytokines/immunology ; Vaccination ; Immunity, Cellular ; }, abstract = {A key objective in vaccine studies is to evaluate vaccine-induced immunogenicity and determine whether participants have mounted a response to the vaccine. Cellular immune responses are essential for assessing vaccine-induced immunogenicity, and single-cell assays, such as intracellular cytokine staining (ICS) and B-cell phenotyping (BCP), are commonly employed to profile individual immune cell phenotypes and the cytokines they produce after stimulation. In this article, we introduce a novel statistical framework for identifying vaccine responders using ICS data collected before and after vaccination. This framework incorporates paired control data to account for potential unintended variations between assay runs, such as batch effects, that could lead to misclassification of participants as vaccine responders or non-responders. To formally integrate paired control data for accounting for assay variation across different time points (ie before and after vaccination), our proposed framework calculates and reports two $ P $-values, both adjusting for paired control data but in distinct ways: (i) the maximally adjusted $ P $-value, which applies the most conservative adjustment to the unadjusted $ P $-value, ensuring validity over all plausible batch effects consistent with the paired control samples' data, and (ii) the minimally adjusted $ P $-value, which imposes only the minimal adjustment to the unadjusted $ P $-value, such that the adjusted $ P $-value cannot be falsified by the paired control samples' data. Minimally and maximally adjusted $ P $-values offer a balanced approach to managing Type I error rates and statistical power in the presence of batch effects. We apply this framework to analyze ICS data collected at baseline and 4 wks post-vaccination from the COVID-19 Prevention Network (CoVPN) 3008 study. Our analysis helps address two clinical questions: (i) which participants exhibited evidence of an incident Omicron infection between baseline and 4 wks after receiving the final dose of the primary vaccination series, and (ii) which participants showed vaccine-induced T cell responses against the Omicron BA.4/5 Spike protein.}, }
@article {pmid41320342, year = {2025}, author = {Crown, J and Stroyakovskii, D and Yardley, DA and Huang, CS and Fasching, PA and Bardia, A and Chia, S and Im, SA and Martin, M and Xu, B and Barrios, CH and Untch, M and Moroose, R and Hurvitz, SA and Hortobagyi, GN and Slamon, DJ and Visco, F and Spera, G and Zarate, JP and Halligan, D and Li, Z and Loi, S}, title = {Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/HER2-negative early breast cancer: 5-year follow-up of NATALEE efficacy outcomes and updated overall survival.}, journal = {ESMO open}, volume = {10}, number = {11}, pages = {105858}, pmid = {41320342}, issn = {2059-7029}, mesh = {Humans ; *Aminopyridines/therapeutic use/administration &amp; dosage ; *Purines/therapeutic use/administration &amp; dosage ; Female ; *Aromatase Inhibitors/therapeutic use/administration &amp; dosage ; *Breast Neoplasms/drug therapy/mortality/pathology ; Middle Aged ; Male ; Follow-Up Studies ; Erb-b2 Receptor Tyrosine Kinases/metabolism ; Aged ; Adult ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Treatment Outcome ; Chemotherapy, Adjuvant/methods ; Receptors, Progesterone/metabolism ; Receptors, Estrogen/metabolism ; Letrozole/administration &amp; dosage/therapeutic use ; }, abstract = {BACKGROUND: At the primary efficacy analysis of the NATALEE phase III trial, ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) demonstrated a statistically significant improvement in invasive disease-free survival (iDFS) versus NSAI alone in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC). Continued follow-up of efficacy outcomes is important in assessing the durability of treatment benefit. We report 5-year estimates of efficacy outcomes, including an udpated analysis of overall survival (OS).<br><br>PATIENTS AND METHODS: Eligible patients included pre/postmenopausal women and men with HR-positive/HER2-negative EBC and anatomic stage IIA (N1 or N0 with high-risk factors), IIB, or III disease. Patients were randomized 1 : 1 to ribociclib 400 mg/day (3 weeks on/1 week off for 3 years) + NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 5 years) or NSAI alone. Premenopausal women and men received goserelin. The primary endpoint was iDFS, and secondary/exploratory endpoints included distant disease-free survival, recurrence-free survival, distant recurrence-free survival, and OS.<br><br>RESULTS: With a median iDFS follow-up of 55.4 months, ribociclib + NSAI demonstrated persistent iDFS benefit versus NSAI alone [hazard ratio 0.716, 95% confidence interval (CI) 0.618-0.829, nominal one-sided log-rank P < 0.0001]. Absolute iDFS improvement between treatment arms increased from the 3- (&#x394;2.7%) to the 5-year (&#x394;4.5%) time points. Persistent benefit over time was also observed across subgroups [including N0 patients (hazard ratio 0.606, 95% CI 0.372-0.986)] and secondary/exploratory endpoints. As OS continues to mature, numerical improvement in favor of ribociclib was observed (hazard ratio 0.800, 95% CI 0.637-1.003, nominal one-sided log-rank P = 0.026).<br><br>CONCLUSIONS: This prespecified 5-year follow-up of efficacy outcomes from NATALEE demonstrated that ribociclib + NSAI continued to reduce the risk of recurrence beyond the 3-year treatment window, supporting its use as adjuvant therapy in patients with HR-positive/HER2-negative EBC. An ongoing positive trend for improved OS in favor of ribociclib + NSAI was observed.}, }
@article {pmid41320687, year = {2025}, author = {Mileto, A and Inoue, A and Mohammadinejad, P and Coveler, AL and Lee, YS and Leng, S and Johnson, MP and Sun, Y and Thomas, JV and Yeh, BM and Bruining, DH and Fletcher, JG}, title = {Prospective pilot evaluation of dark borosilicate oral contrast media for the evaluation of the stomach and small bowel using CT.}, journal = {Abdominal radiology (New York)}, volume = {}, number = {}, pages = {}, pmid = {41320687}, issn = {2366-0058}, support = {R44 DK103495/DK/NIDDK NIH HHS/United States ; }, abstract = {PURPOSE: To evaluate the feasibility of use of dark borosilicate oral contrast media (DBOCM) in abdominopelvic CT in comparison with conventional oral contrast media (COCM) in a multi-institutional setting.<br><br>METHODS: Patients with known or suspected inflammatory bowel disease (IBD) (Site A) or suspected peritoneal carcinomatosis (Site B), who had undergone initial standard-of-care CT using COCM (positive, n&#x2009;=&#x2009;10; neutral n&#x2009;=&#x2009;22), underwent research CT with DBOCM. Attenuation differences between bowel wall and lumen using COCM and DBOCM were measured. Three radiologists independently examined all examinations with COCM and DBOCM. Patient tolerance and safety were recorded. Bowel wall visualization, distention, distended bowel length, and radiologist preference for bowel visualization were rated. Imaging findings using both oral contrast media were recorded, and a final consensus evaluation was performed to evaluate whether additional findings detected with DBOCM were visible with COCM.<br><br>RESULTS: Thirty-two patients (IBD, n&#x2009;=&#x2009;15; suspected peritoneal carcinomatosis, n&#x2009;=&#x2009;17) were included. No severe adverse effects were seen with DBOCM. Compared to COCM, DBOCM yielded significantly higher attenuation differences between bowel wall and lumen (P&#x2009;<&#x2009;.001). Bowel wall visualization, distention, and distended bowel length was significantly higher from the stomach to the ileum using DBOCM (P&#x2009;<&#x2009;.001). DBOCM was preferred by each reader over COCM for all intestinal segments, but significance was not achieved in pooled results. Additional imaging findings were found in seven patients (22% [7/32]; 95% CI 9-40%) using DBOCM.<br><br>CONCLUSION: Compared to COCM, DBOCM yielded improved bowel wall visualization and distention, also revealing additional imaging findings.}, }
@article {pmid41321225, year = {2026}, author = {Sekeres, MA and Mattison, R and Artz, A and Baer, MR and Chua, CC and Demichelis-Gómez, R and Egan, PC and Fletcher, L and Foucar, C and Garcia, JS and Gilberto, L and Gómez de León, A and Lancet, J and Loh, KP and Malcovati, L and Marini, B and Platzbecker, U and Sorror, ML and Tinsley-Vance, S and Treitz, J and Oliveros, MJ and Ibrahim, S and Roldan, Y and Guyatt, G and Brignardello-Petersen, R}, title = {American Society of Hematology 2025 guidelines for treating newly diagnosed acute myeloid leukemia in older adults.}, journal = {Blood advances}, volume = {10}, number = {6}, pages = {1897-1928}, pmid = {41321225}, issn = {2473-9537}, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/diagnosis ; Aged ; Disease Management ; Hematology ; United States ; Societies, Medical ; }, abstract = {BACKGROUND: Older adults with acute myeloid leukemia (AML) represent a cancer population in which disease-based risk factors, comorbidities, patient goals, and treatment risks and benefits influence treatment recommendations.<br><br>OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health professionals in their decisions about management of AML in older adults.<br><br>METHODS: ASH formed a multidisciplinary guideline panel, including patient representatives, that minimized bias from conflicts of interest. Clarity Research Group at McMaster University supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development and evaluation approach, including evidence-to-decision frameworks, to assess evidence and make recommendations.<br><br>RESULTS: The panel agreed on 9 critical clinical recommendations for managing AML in older adults, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management; traditional induction and postremission therapy vs hypomethylating agent or low-dose cytarabine, or combinations with venetoclax; the role and duration of postremission therapy; combinations with venetoclax vs monotherapy; the use of targeted therapy, including isocitrate dehydrogenase and FMS-like tyrosine kinase 3 (FLT3) inhibitors, in appropriate patients; the role of hematopoietic stem cell transplantation in nonfavorable prognosis AML; and the role of transfusion support for patients no longer receiving antileukemic therapy.<br><br>CONCLUSIONS: Key recommendations of these guidelines include treatment over best supportive care; venetoclax-based regimens over monotherapies; and incorporation of FLT3 inhibitors into traditional induction and postremission therapy.}, }
@article {pmid41321622, year = {2025}, author = {Nukaya, M and Carney, PR and Cafferty, C and Zahed, K and Yun, I and Al-Adra, DP and Kazim, NA and Farghli, AR and Chan, M and Stram, A and Kratz, JD and Berres, ME and Yen, A and Gujral, TS and Sethupathy, P and Bradfield, CA and Ronnekleiv-Kelly, SM}, title = {CDK7 is a novel therapeutic target in fibrolamellar carcinoma.}, journal = {iScience}, volume = {28}, number = {12}, pages = {113925}, pmid = {41321622}, issn = {2589-0042}, support = {IK2 BX006146/BX/BLRD VA/United States ; }, abstract = {Fibrolamellar Carcinoma (FLC) is a rare and deadly cancer that arises in young, otherwise healthy patients. For patients that cannot be treated with surgery, only 30%-45% survive to 5 years with current treatment options. These poor survival odds highlight the need for new therapeutic targets. Using patient samples, we identified that abnormal function of cyclin-dependent kinase 7 (CDK7) is a key component of pathways that are essential for FLC cancer cell identity and survival. Consequently, drug inhibitors of CDK7 suppressed these abnormal pathways and also caused cancer cell death in a dose-dependent manner. This held true in several patient-derived models of FLC. We then found that inhibition of CDK7 can combine with other drug candidates to increase the therapeutic response in FLC cells. Taken together, this suggests CDK7 is a promising target for future treatment in human FLC.}, }
@article {pmid41323153, year = {2025}, author = {Ojee, E and Odiyo, J and Adhiambo, J and Mabele, E and Omondi, V and Begnel, ER and Chohan, BH and Kinuthia, J and Gantt, S and Lehman, DA and Aluvaala, J and Were, F and Were, V and Wamalwa, D and Slyker, J}, title = {A cost analysis of postpartum home visit programming in Kenya: estimates to aid policymakers.}, journal = {Frontiers in health services}, volume = {5}, number = {}, pages = {1644078}, pmid = {41323153}, issn = {2813-0146}, abstract = {INTRODUCTION: The World Health Organization (WHO) and UNICEF recommend at least two postnatal home visits by a health provider within the first two weeks of life to improve newborn survival. Kenya's Universal Health Coverage (UHC) initiative includes a home-visit strategy to advance Sustainable Development Goal (SDG) 3.2, which targets reducing neonatal mortality to below 12 per 1,000 live births. We estimated the costs of starting a postnatal home-visit program in a level three health facility in Kenya, based on recommendations from Kenya's Ministry of Health policymakers.<br><br>METHODS: An ingredients-based costing method was used to determine the actual costs of home visits incurred during a research project conducted in 2019, and to estimate program costs from the government's perspective as the payer. Per-visit costs were calculated for three staffing approaches: Community Health Promoter (CHP), Registered Nurse (RN), and a Combined model where two providers (RN + CHP) visited each home together.<br><br>RESULTS: Staff salaries and transportation costs were the main drivers of recurrent program expenses. The CHP approach had the lowest total cost at $27,302 ($24.46 per visit), followed by the RN-only approach at $36.45 per visit, while the Combined model (RN+CHP) was the most expensive at $52.10 per visit. Discussions with policymakers noted that the RN+CHP approach was least feasible and scalable. They proposed an alternative "Hybrid" model in line with current programs being scaled up: weekly RN visits during the first month of life (neonatal period), and quarterly CHP visits thereafter.<br><br>DISCUSSION: This study presents a costing tool and generalizable formula that policymakers can use to estimate program costs based on different facility characteristics and staffing needs. The findings can support Kenya's efforts to scale up postnatal home-visit programs to improve maternal and newborn health outcomes within the UHC framework.}, }
@article {pmid41323215, year = {2025}, author = {Bobić, M and Bushe, DH and Lee, H and Winey, BA and Efstathiou, JA and Paganetti, H and Pursley, J and Peters, N and Nenoff, L}, title = {Comparison of cone beam computed tomography post-processing methods for online adaptive proton therapy of prostate cancer.}, journal = {Physics and imaging in radiation oncology}, volume = {36}, number = {}, pages = {100858}, pmid = {41323215}, issn = {2405-6316}, abstract = {BACKGROUND AND PURPOSE: Although cone beam computed tomography (CBCT) enables online adaptive radiotherapy, its CT number accuracy may be insufficient for online adaptive proton therapy (OAPT). We compared proton dose distributions calculated directly on CBCT with calculations using additional CBCT image-processing methods in prostate cancer.<br><br>MATERIALS AND METHODS: Retrospective proton plans were created for 10 prostate patients originally treated with 5-fraction online adaptive photon radiotherapy using CBCT. These plans were forward-calculated on each CBCT with four different approaches: (1) the clinical CBCT with a dedicated CT number calibration, (2) CBCT with histogram correction, (3) CT deformed to the CBCT, and (4) deformed CT with an air-cavity correction. Additionally, adaptive treatment using an OAPT workflow was simulated for each fraction and compared among the four CBCT-based methods. Dose-volume histograms (DVH) and related parameters were compared between the four methods for both non-adaptive and online adaptive treatment simulations.<br><br>RESULTS: Proton dose distributions were comparable across all CBCT-based strategies, with median differences of up to 1% for all DVH metrics compared to a reference method. Larger differences were observed for doses calculated directly on the CBCT for patient geometries deviating from the CBCT-specific calibration. Despite these differences, all four methods indicated the dosimetric benefits of OAPT over non-adaptive treatment.<br><br>CONCLUSION: An advanced CBCT system enables proton dose calculations performed directly on the CBCT, demonstrating sufficient accuracy for integration into an OAPT workflow. Additional CBCT-based post-processing techniques are recommended to maximize the dosimetric benefit of plan adaptation in all patient populations.}, }
@article {pmid41324241, year = {2026}, author = {Sadowska-Klasa, A and Lim, FY and Xie, H and Zamora, D and Stevens-Ayers, T and Leisenring, WM and Edmison, BC and De Rosa, SC and Mielcarek, M and Boeckh, M}, title = {New Insights Into Factors Shaping CMV-Specific T-Cell Polyfunctionality After Hematopoietic Cell Transplantation.}, journal = {American journal of hematology}, volume = {101}, number = {2}, pages = {255-268}, pmid = {41324241}, issn = {1096-8652}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; K23 AI163343/AI/NIAID NIH HHS/United States ; CA15704/NH/NIH HHS/United States ; K23AI163343/NH/NIH HHS/United States ; //Fred Hutchinson Cancer Research Center/ ; //Gda&#x144;ski Uniwersytet Medyczny/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation ; *Cytomegalovirus/immunology ; Male ; Female ; Middle Aged ; *Immunosuppressive Agents/administration &amp; dosage/therapeutic use ; Adult ; *Cytomegalovirus Infections/immunology/drug therapy ; *CD8-Positive T-Lymphocytes/immunology ; *CD4-Positive T-Lymphocytes/immunology ; Aged ; Mycophenolic Acid/administration &amp; dosage ; Adrenal Cortex Hormones/administration &amp; dosage ; Cyclophosphamide/administration &amp; dosage ; Cyclosporine/administration &amp; dosage ; }, abstract = {Polyfunctional cytomegalovirus (CMV)-specific T cells are critical for antiviral immunity in allogeneic hematopoietic cell transplantation (HCT) recipients. However, gaps remain in managing refractory CMV and optimizing virus-specific cellular therapy (VST). We conducted a comparative analysis of how timing and dosing of immunosuppressive agents, including post-transplant cyclophosphamide (PT-Cy), corticosteroids, mycophenolate mofetil (MMF), and calcineurin inhibitors (CNIs), shape CMV-specific T-cell polyfunctionality. CD4[+] and CD8[+] T-cell responses (IFN-γ plus ≥ 1 functional marker) were assessed following pp65 stimulation within 100 days post-HCT in the pre- and post-letermovir era. Among 243 patients, 31% exhibited polyfunctional CD4[+] and CD8[+] responses. PT-Cy did not significantly impair T-cell functionality. Cyclosporine was associated with higher frequencies of polyfunctional T cells compared to tacrolimus, even at concentrations above the therapeutic range. Intermediate (≥ 0.5 mg/kg) and high-dose (≥ 1 mg/kg) corticosteroids, especially within 2-4 weeks before testing, significantly suppressed T-cell responses, though rapid tapering preserved function. Prolonged administration of MMF (≥ 2000 mg) diminished T-cell polyfunctionality. These findings provide novel insights into the importance of timing and dosing of the immunosuppressive effects of PT-Cy, corticosteroids, MMF and CNIs on CMV-specific immunity. Adjusting immunosuppression in specific time windows may improve the management of refractory CMV infections and optimize VST in HCT recipients.}, }
@article {pmid41324575, year = {2026}, author = {Coronado, GD and Hoffman, RM and Llavona-Ortiz, J and Rutter, CM}, title = {The Centers for Medicare and Medicaid Services and others misunderstand stool testing for colorectal cancer.}, journal = {Journal of the National Cancer Institute}, volume = {118}, number = {3}, pages = {386-391}, pmid = {41324575}, issn = {1460-2105}, support = {T32 CA272303/CA/NCI NIH HHS/United States ; NCI T32 CA272303 02/BC/NCI NIH HHS/United States ; R01 MD018253/MD/NIMHD NIH HHS/United States ; 1R01MD 018253-01//National Institute of Minority Health and Health Disparities/ ; /NH/NIH HHS/United States ; R01 CA265020-01/BC/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/economics ; United States ; *Centers for Medicare and Medicaid Services, U.S. ; *Early Detection of Cancer/economics/methods/standards ; *Feces/chemistry ; Colonoscopy/economics ; Biomarkers, Tumor/analysis ; Occult Blood ; Sensitivity and Specificity ; Mass Screening/economics/methods ; }, abstract = {The May 2021 Centers for Medicare and Medicaid Services (CMS) coverage determination allowed reimbursement for blood-based biomarker tests and other tests for colorectal cancer screening that meet minimum 74% sensitivity and 90% specificity thresholds. However, these performance benchmarks fail to account for the importance of detecting precancerous lesions and the impact of the recommended testing interval on the effectiveness of screening. We review the limitations of the CMS criteria, summarize supporting evidence for stool-based testing and colonoscopy as effective and cost-efficient screening modalities, and offer recommendations to strengthen CMS coverage decisions to better align with public health goals in colorectal cancer prevention.}, }
@article {pmid41324589, year = {2026}, author = {Murray, J and Einhaus, T and Radtke, S and Bar, KJ and Peterson, CW and Kiem, HP}, title = {Engraftment of gene-edited hematopoietic stem cells after antibody-drug conjugate conditioning in nonhuman primates.}, journal = {Blood advances}, volume = {10}, number = {4}, pages = {1094-1105}, pmid = {41324589}, issn = {2473-9537}, support = {P51 OD010425/OD/NIH HHS/United States ; P51 OD011092/OD/NIH HHS/United States ; }, mesh = {Animals ; *Hematopoietic Stem Cell Transplantation/methods ; *Hematopoietic Stem Cells/metabolism/cytology/drug effects ; *Immunoconjugates/pharmacology ; *Transplantation Conditioning/methods ; Macaca mulatta ; *Gene Editing ; Receptors, CCR5/genetics ; Humans ; }, abstract = {Hematopoietic stem cell (HSC) gene therapies provide lifelong benefit in numerous hematological diseases and disorders, but safety and toxicity remain a critical barrier for routine application. In the setting of immunodeficiency syndromes and infectious diseases such as HIV infection, conditioning regimens may exacerbate immune dysfunction, blunting, or impairing overall efficacy. Here, we conduct a head-to-head comparison of 2 novel antibody-drug conjugates (ADCs) with a pyrrolobenzodiazepine payload for autologous transplant in rhesus macaques. These ADCs target either CD117 or CD45 and are benchmarked against the clinical standard busulfan. We quantified the extent of myeloablation and immunosuppression, time to hematopoietic recovery, long-term engraftment of CCR5 CRISPR-edited autologous HSCs, and resistance to infection when challenged with increasing concentrations of an HIV-like virus. Both ADCs enabled engraftment of CRISPR-edited HSCs, although with lower levels of long-term editing compared with busulfan. We observed myeloablation with similar times to hematopoietic recovery and preserved lymphocyte counts with all 3 conditioning regimens, but neither ADC conditioning nor busulfan enabled sufficient CCR5 editing for viral immunity. Although these results only apply to the specific ADC-conditioning protocols tested here, they are a step toward developing targeted strategies to engraft cells with therapeutic edits and highlight the need for further refinement of antibody-based selection.}, }
@article {pmid41325059, year = {2025}, author = {Zhang, Y and Walker, RW and Kaplan, RC and Qi, Q}, title = {Added sugars, gut microbiota, and host health.}, journal = {Gut microbes}, volume = {17}, number = {1}, pages = {2592431}, pmid = {41325059}, issn = {1949-0984}, support = {R01 DK126698/DK/NIDDK NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; R01 AG085320/AG/NIA NIH HHS/United States ; R01 DK137968/DK/NIDDK NIH HHS/United States ; P30 ES023515/ES/NIEHS NIH HHS/United States ; R01 DK134672/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome/drug effects ; Animals ; Bacteria/classification/metabolism/genetics/isolation &amp; purification ; *Dietary Sugars/adverse effects/metabolism ; Fatty Acids, Volatile/metabolism ; Obesity/microbiology ; }, abstract = {Excessive intake of added sugars is a global public health concern, given its established links with cardiometabolic disease and other chronic conditions. Emerging evidence suggests that the gut microbiota might mediate the harms of high sugar intake. In this review, we summarize evidence from animal and human studies regarding the impact of added sugar intake on gut microbiota diversity and composition, and discuss potential mechanisms linking sugar-induced microbial changes to health outcomes. Added sugars, including glucose, fructose, and sucrose, can alter gut microbial diversity, enrich sugar-utilizing taxa, and deplete short-chain fatty acid-producing bacteria. These microbial changes may impair gut barrier integrity, increase luminal oxygen and alternative electron acceptors under inflammatory conditions, reduce short-chain fatty acid production, alter bile acid and amino acid metabolism, and promote translocation of endotoxin across the gut barrier into the bloodstream. Collectively, these pathways may link added sugar intake to irritable bowel syndrome, obesity, liver steatosis, diabetes, and cardiovascular diseases. However, inconsistent results on alterations in the gut microbiota related to added sugar intake were observed across studies, which may be due to differences in sugar dose and form (liquid vs. solid), as well as population variation in background diet, host genetics, and gut microbial ecology. Future research should focus on mechanistic investigations, characterization of inter-individual variability in response to added sugar intake, and clinical studies to assess whether dietary or therapeutic interventions can reverse sugar-induced gut microbial changes and improve host health outcomes.}, }
@article {pmid41325432, year = {2025}, author = {Müller, NF and Wick, RR and Judd, LM and Williamson, DA and Bedford, T and Howden, BP and Duchêne, S and Ingle, DJ}, title = {Quantifying plasmid movement in drug-resistant Shigella species using phylodynamic inference.}, journal = {PLoS pathogens}, volume = {21}, number = {12}, pages = {e1013621}, pmid = {41325432}, issn = {1553-7374}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; }, mesh = {*Plasmids/genetics ; Phylogeny ; *Shigella/genetics/drug effects ; *Drug Resistance, Bacterial/genetics ; Humans ; Gene Transfer, Horizontal ; Evolution, Molecular ; Anti-Bacterial Agents/pharmacology ; Dysentery, Bacillary/microbiology ; Bayes Theorem ; }, abstract = {The 'silent pandemic' of antimicrobial resistance (AMR) represents a significant global public health threat. AMR genes in bacteria are often carried on mobile elements, such as plasmids. The horizontal movement of plasmids allows AMR genes and resistance to key therapeutics to disseminate in a population. However, the quantification of the movement of plasmids remains challenging with existing computational approaches. Here, we introduce a novel method that allows us to reconstruct and quantify the movement of plasmids in bacterial populations over time. To do so, we model chromosomal and plasmid DNA co-evolution using a joint coalescent and plasmid transfer process in a Bayesian phylogenetic network approach. This approach reconstructs differences in the evolutionary history of plasmids and chromosomes to reconstruct instances where plasmids likely move between bacterial lineages while accounting for parameter uncertainty. We apply this new approach to a five-year dataset of Shigella, exploring the plasmid transfer rates of five different plasmids with different AMR and virulence profiles. In doing so, we reconstruct the co-evolution of the large Shigella virulence plasmid with the chromosome DNA. We quantify higher plasmid transfer rates of three small plasmids that move between lineages of Shigella sonnei. Finally, we determine the recent dissemination of a multidrug-resistant plasmid between S. sonnei and S. flexneri lineages in multiple independent events and through steady growth in prevalence since 2010. This approach has a strong potential to improve our understanding of the evolutionary dynamics of AMR-carrying plasmids as they are introduced, circulate, and are maintained in bacterial populations.}, }
@article {pmid41325480, year = {2025}, author = {Johnson, MM and Sung, K and Haddox, HK and Vora, AA and Araki, T and Victora, GD and Song, YS and Fukuyama, J and Matsen Iv, FA}, title = {Nucleotide context models outperform protein language models for predicting antibody affinity maturation.}, journal = {PLoS computational biology}, volume = {21}, number = {12}, pages = {e1013758}, pmid = {41325480}, issn = {1553-7358}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; R01 HG013117/HG/NHGRI NIH HHS/United States ; R56 HG013117/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {Animals ; Humans ; Mice ; Receptors, Antigen, B-Cell/genetics/immunology ; *Antibody Affinity/genetics/immunology ; Computational Biology ; B-Lymphocytes/immunology ; Evolution, Molecular ; Somatic Hypermutation, Immunoglobulin/genetics ; *Nucleotides/genetics ; Phylogeny ; }, abstract = {Antibodies play a crucial role in adaptive immunity. They develop as B cell receptors (BCRs): membrane-bound forms of antibodies that are expressed on the surfaces of B cells. BCRs are refined through affinity maturation, a process of somatic hypermutation (SHM) and natural selection, to improve binding to an antigen. Computational models of affinity maturation have developed from two main perspectives: molecular evolution and language modeling. The molecular evolution perspective focuses on nucleotide sequence context to describe mutation and selection; the language modeling perspective involves learning patterns from large data sets of protein sequences. In this paper, we compared models from both perspectives on their ability to predict the course of antibody affinity maturation along phylogenetic trees of BCR sequences. This included models of SHM, models of SHM combined with an estimate of selection, and protein language models. We evaluated these models for large human BCR repertoire data sets, as well as an antigen-specific mouse experiment with a pre-rearranged cognate naive antibody. We demonstrated that precise modeling of SHM, which requires the nucleotide context, provides a substantial amount of predictive power for predicting the course of affinity maturation. Notably, a simple nucleotide-based convolutional neural network modeling SHM outperformed state-of-the-art protein language models, including one trained exclusively on antibody sequences. Furthermore, incorporating estimates of selection based on a custom deep mutational scanning experiment brought only modest improvement in predictive power. To support further research, we introduce EPAM (Evaluating Predictions of Affinity Maturation), a benchmarking framework to integrate evolutionary principles with advances in language modeling, offering a road map for understanding antibody evolution and improving predictive models.}, }
@article {pmid41325571, year = {2026}, author = {Tomasini, P and Wang, Y and Li, Y and Felip, E and Wu, L and Cui, J and Besse, B and Spira, AI and Neal, JW and Goto, K and Baik, CS and Marmarelis, ME and Ichihara, E and Zhang, Y and Lee, JS and Lee, SH and Yang, JC and Michels, S and Anastasiou, Z and Curtin, JC and Lyu, X and Mahoney, J and Demirdjian, L and Meyer, CS and Zhang, Y and Leconte, I and Lorenzini, P and Knoblauch, RE and Trani, L and Baig, M and Bauml, JM and Cho, BC and , }, title = {Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non-Small Cell Lung Cancer: Results From CHRYSALIS-2.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {1}, pages = {54-65}, pmid = {41325571}, issn = {1527-7755}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology ; *Lung Neoplasms/drug therapy/genetics/pathology/enzymology ; Female ; Male ; Middle Aged ; Aged ; ErbB Receptors/genetics/antagonists &amp; inhibitors ; *Mutation ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Adult ; *Quinolines/administration &amp; dosage/adverse effects/therapeutic use ; Aged, 80 and over ; Protein Kinase Inhibitors/adverse effects/therapeutic use ; Antibodies, Bispecific ; }, abstract = {PURPOSE: For patients with advanced non-small cell lung cancer (NSCLC) harboring atypical epidermal growth factor receptor (EGFR) mutations (eg, S768I, L861Q, G719X), efficacy of current treatment options is limited.<br><br>PATIENTS AND METHODS: CHRYSALIS-2 Cohort C enrolled participants with NSCLC harboring atypical EGFR mutations (G719X, S768I, L861Q, etc) and &#x2264;2 previous lines of therapy. Participants were treatment-na&#xef;ve or previously received first- or second-generation EGFR tyrosine kinase inhibitors. Coexisting exon 20 insertions, exon 19 deletions, or exon 21 L858R mutations were exclusionary. Participants received 1,050 mg (1,400 mg if &#x2265;80 kg) intravenous amivantamab once weekly for the first 4 weeks and then once every 2 weeks plus 240 mg oral lazertinib once daily. The primary end point was investigator-assessed objective response rate (ORR).<br><br>RESULTS: As of January 12, 2024, 105 participants received amivantamab-lazertinib. Most common atypical mutations were G719X (56%), L861X (26%), and S768I (23%), including single and compound mutations. In the overall population (median follow-up: 16.1 months), the ORR was 52% (95% CI, 42 to 62). The median duration of response (mDoR) was 14.1 months (95% CI, 9.5 to 26.2). The median progression-free survival (mPFS) was 11.1 months (95% CI, 7.8 to 17.8); median overall survival (mOS) was not estimable (NE; 95% CI, 22.8 to NE). Adverse events were consistent with previous studies and primarily grade 1 and 2. Among treatment-na&#xef;ve participants, the ORR was 57% (95% CI, 42 to 71). The mPFS was 19.5 months (95% CI, 11.2 to NE), the mDoR was 20.7 months (95% CI, 9.9 to NE), and mOS was NE (95% CI, 26.3 to NE). Solitary or compound EGFR mutations had no major impact on ORR. The ORR in participants with P-loop and &#x3b1;C-helix compressing, classical-like, and T790M-like mutations was 45% (n = 38), 64% (n = 14), and 67% (n = 3), respectively.<br><br>CONCLUSION: In participants with atypical EGFR-mutated advanced NSCLC, amivantamab-lazertinib demonstrated clinically meaningful antitumor activity with no new safety signals.}, }
@article {pmid41325737, year = {2026}, author = {Rillamas-Sun, E and Huang, Y and Langley, BO and Donzella, SM and Cobos, S and Guthrie, KA and Davidson, NE and Di, C and Greenlee, H}, title = {Comparisons of Physical Activity and Sedentary Behavior Measurements From the ActiGraph, International Physical Activity Questionnaire, and Fitbit in Women With History of Breast Cancer.}, journal = {Journal of physical activity &amp; health}, volume = {23}, number = {3}, pages = {425-433}, doi = {10.1123/jpah.2025-0009}, pmid = {41325737}, issn = {1543-5474}, mesh = {Humans ; Female ; *Breast Neoplasms ; *Sedentary Behavior ; *Exercise ; Middle Aged ; Surveys and Questionnaires ; *Actigraphy/instrumentation ; *Fitness Trackers ; Cancer Survivors ; Aged ; Self Report ; Adult ; }, abstract = {BACKGROUND: Self-reported and wearable device derived data on physical activity (PA) differ in burden, transparency, and validity, underscoring the need for comparison in cancer survivorship research. Physical activity and sedentary behavior measured from the ActiGraph, International Physical Activity Questionnaire (IPAQ), and Fitbit Inspire device in women with early-stage breast cancer were compared.<br><br>METHODS: Breast cancer survivors participating in a lifestyle intervention trial concurrently provided ActiGraph and IPAQ data at baseline and 6&#xa0;months. Fitbit devices were used for PA self-monitoring after randomization and data were available at follow-up only. Comparisons of PA measurements were estimated via Pearson correlation coefficients and visualized using Bland-Altman plots. Prevalence of meeting moderate to vigorous PA guidelines of &#x2265;150&#xa0;minutes per week were also calculated.<br><br>RESULTS: At baseline (n = 73), mean vigorous PA was 2 and 5&#xa0;minutes per day for ActiGraph and IPAQ, respectively (r = .22, P = .06), while mean sedentary hours per day were 11.4 and 6.2 for ActiGraph and IPAQ, respectively (r = .29, P = .01). Correlations between ActiGraph and IPAQ at 6-month follow-up (n = 50) were not statistically significant. Six-month comparisons of PA measures between ActiGraph and Fitbit (n = 30) were higher than those between IPAQ and Fitbit (n = 30). Prevalence of meeting moderate to vigorous PA guidelines at baseline was 40% for ActiGraph and 59% for IPAQ (P = .01). At 6&#xa0;months, proportions meeting moderate to vigorous PA guidelines were 50%, 73%, and 67% for ActiGraph, IPAQ, and Fitbit, respectively.<br><br>CONCLUSION: Correlations of PA comparing self-report from IPAQ and activity devices from ActiGraph and Fitbit were weak. Strengths and limitations of PA measurement methods should be weighed accordingly in studies of lifestyle interventions for breast cancer survivors.}, }
@article {pmid41325870, year = {2026}, author = {Khouderchah, C and Lynch, R and Holmberg, L}, title = {Impact of Post-Autologous Peripheral Blood Stem Cell Transplant (ASCT)- Granulocyte Colony Stimulating Factor (G-CSF) on Toxicity Profiles in Hodgkin Lymphoma (HL) Patients Receiving Pre-ASCT Immune Checkpoint Inhibitors (ICI).}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {4}, pages = {428.e1-428.e4}, doi = {10.1016/j.jtct.2025.11.035}, pmid = {41325870}, issn = {2666-6367}, }
@article {pmid41326606, year = {2026}, author = {Yu, TC and Kikawa, C and Dadonaite, B and Loes, AN and Englund, JA and Bloom, JD}, title = {Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza haemagglutinin.}, journal = {Nature ecology &amp; evolution}, volume = {10}, number = {3}, pages = {452-466}, pmid = {41326606}, issn = {2397-334X}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; DGE-2140004//National Science Foundation (NSF)/ ; T32 GM007270/GM/NIGMS NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; R01AI165821//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; S10 OD020069/OD/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; T32GM007270//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 75N93021C00015/AI/NIAID NIH HHS/United States ; }, mesh = {*Influenza A Virus, H3N2 Subtype/genetics/immunology ; *Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology ; Mutation ; *Evolution, Molecular ; Epistasis, Genetic ; Humans ; Influenza, Human/virology ; *Genetic Pleiotropy ; }, abstract = {The evolution of human influenza virus haemagglutinin (HA) involves simultaneous selection to acquire antigenic mutations that escape population immunity while preserving protein function and stability. Epistasis shapes this evolution, as an antigenic mutation that is deleterious in one genetic background may become tolerated in another. However, the extent to which epistasis can alleviate pleiotropic conflicts between immune escape and protein function/stability is unclear. Here we measure how all amino acid mutations in the HA of a recent human H3N2 influenza strain affect its cell entry function, acid stability and neutralization by human serum antibodies. We find that epistasis has entrenched certain mutations so that reverting to the ancestral amino acid identity in earlier strains is no longer tolerated. Epistasis has also enabled the emergence of antigenic mutations that were detrimental to the cell entry function of HA in earlier strains. However, epistasis appears insufficient to overcome the pleiotropic costs of antigenic mutations that impair the stability of HA, explaining why some mutations that strongly escape human antibodies never fix in nature. Our results refine our understanding of the mutational constraints that shape recent H3N2 influenza evolution: epistasis can enable antigenic change, but pleiotropic effects can restrict its trajectory.}, }
@article {pmid41326734, year = {2026}, author = {Gaebler, C and Kor, S and Allers, K and Perotti, M and Mwangi, D and Meixenberger, K and Hanke, K and Trenkner, T and Kraus, T and Sha, Y and Arentowicz, C and Odidika, S and Grahn, N and Scheck, R and Perkins, N and Pardons, M and Igbokwe, V and Corman, V and Burmeister, T and Blau, O and Sürücü, G and Pruß, A and Schneider, CG and Klausen, G and Sauter, J and Klein, F and Sander, LE and Hofmann, J and Vuong, L and Bullinger, L and Penter, L and Gruell, H and Reeves, DB and Schommers, P and Hoelzemer, A and Obermeier, M and Blau, IW and Schneider, T and Penack, O}, title = {Sustained HIV-1 remission after heterozygous CCR5Δ32 stem cell transplantation.}, journal = {Nature}, volume = {650}, number = {8102}, pages = {701-709}, pmid = {41326734}, issn = {1476-4687}, support = {R01 AI186721/AI/NIAID NIH HHS/United States ; K25 AI155224/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Receptors, CCR5/genetics ; *HIV Infections/virology/therapy/immunology/drug therapy/genetics ; Male ; *HIV-1/genetics/isolation &amp; purification/physiology/immunology ; *Heterozygote ; Remission Induction ; Leukemia, Myeloid, Acute/therapy ; *Stem Cell Transplantation ; *Mutation ; RNA, Viral/blood ; Adult ; Transplantation, Homologous ; *Hematopoietic Stem Cell Transplantation ; Middle Aged ; }, abstract = {HIV cure is exceptionally rare, with only six cases documented among the estimated 88 million individuals who have acquired HIV since the onset of the epidemic[1-6]. Successful cures, including that of the pioneering individual known as the Berlin patient, are limited to those who received allogeneic stem cell transplants (allo-SCTs) for haematological cancers. HIV resistance from stem cell donors with the rare homozygous CCR5Δ32 mutation was long considered the main mechanism for HIV remission without antiretroviral therapy. However, recent reports have highlighted CCR5-independent mechanisms as important contributors to HIV cure[6-8]. Here we provide new evidence for this conceptual shift, whereby long, treatment-free HIV remission was achieved after allo-SCT with functionally active CCR5. A man with heterozygous CCR5 wild-type/Δ32 living with HIV received allo-SCT from a HLA-matched unrelated heterozygous CCR5 wild-type/Δ32 donor as treatment for acute myeloid leukaemia. Three years after allo-SCT, the patient discontinued antiretroviral therapy. So far, HIV remission has been sustained for more than 6 years with undetectable plasma HIV RNA. Reservoir analysis revealed intact proviral HIV before transplantation, but no replication-competent virus in blood or intestinal tissues after allo-SCT. Declining or absent HIV-specific antibody and T cell responses support the absence of viral activity. High antibody-dependent cellular cytotoxicity activity at the time of transplantation may have contributed to HIV reservoir clearance. These results demonstrate that CCR5Δ32-mediated HIV resistance is not essential for durable remission, which underscores the importance of effective viral reservoir reductions in HIV cure strategies.}, }
@article {pmid41326736, year = {2026}, author = {Peluso, MJ and Sandel, DA and Deitchman, AN and Kim, SJ and Dalhuisen, T and Tummala, HP and Tibúrcio, R and Zemelko, L and Borgo, GM and Singh, SS and Schwartz, K and Deswal, M and Williams, MC and Hoh, R and Shimoda, M and Narpala, S and Serebryannyy, L and Khalili, M and Vendrame, E and SenGupta, D and Whitmore, LS and Tisoncik-Go, J and Gale, M and Koup, RA and Mullins, JI and Felber, BK and Pavlakis, GN and Reeves, JD and Petropoulos, CJ and Glidden, DV and Spitzer, MH and Gama, L and Caskey, M and Nussenzweig, MC and Chew, KW and Henrich, TJ and Yukl, SA and Cohn, LB and Deeks, SG and Rutishauser, RL}, title = {Correlates of HIV-1 control after combination immunotherapy.}, journal = {Nature}, volume = {650}, number = {8100}, pages = {187-195}, pmid = {41326736}, issn = {1476-4687}, support = {K23 AI162249/AI/NIAID NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; INV-002707/GATES/Gates Foundation/United States ; S10 OD018040/OD/NIH HHS/United States ; R01 AI170239/AI/NIAID NIH HHS/United States ; P30 AI152501/AI/NIAID NIH HHS/United States ; P01 AI169606/AI/NIAID NIH HHS/United States ; T32 GM136547/GM/NIGMS NIH HHS/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; K24 AA022523/AA/NIAAA NIH HHS/United States ; UL1 TR001872/TR/NCATS NIH HHS/United States ; R01 AI183666/AI/NIAID NIH HHS/United States ; R01 DE032033/DE/NIDCR NIH HHS/United States ; T32 AI060530/AI/NIAID NIH HHS/United States ; P01 AI178375/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/immunology/therapy/virology/drug therapy ; *HIV-1/immunology/drug effects/genetics ; Male ; Female ; Adult ; *Immunotherapy/methods ; Middle Aged ; CD8-Positive T-Lymphocytes/immunology/cytology ; *AIDS Vaccines/immunology/administration &amp; dosage ; Viral Load ; Antibodies, Neutralizing/immunology/administration &amp; dosage ; Proof of Concept Study ; Broadly Neutralizing Antibodies/immunology ; HIV Antibodies/immunology ; }, abstract = {The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority[1]. Combination immunotherapy including HIV vaccination, immune stimulation, latency reversal and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models[2-6], but few studies have translated such approaches into people. Here we performed a single-arm, proof-of-concept study in ten people living with HIV on ART, combining the following three approaches: (1) therapeutic vaccination with an HIV Gag conserved element-targeted DNA + IL-12 prime/modified vaccinia Ankara (MVA) boost regimen followed by (2) administration of two bNAbs (10-1074, VRC07-523LS) and a toll-like receptor 9 agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption (Clinicaltrials.gov: NCT04357821). Seven out of the ten participants exhibited post-intervention control after pausing ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8[+] T cells early in response to rebounding virus correlated with a lower median viral load after peak viraemia off ART. These data suggest that combination immunotherapy approaches might prove effective in inducing sustained control of HIV by slowing rebound and improving CD8[+] T cell responses, and that these approaches should continue to be optimized.}, }
@article {pmid41326929, year = {2025}, author = {Hinkel, RE and Kalima, M and Msadabwe, SC and Mwaba, CK and Ng'uni, FC and Fisa, R and Tambatamba, BC and Chuba, A and Trejo, MJ and Lishimpi, K and Soliman, AS}, title = {False-Positive Screening, Over-Referral, and Length of time between Cervical Cancer Early Detection and Confirmed Diagnosis Over Nine Years in Lusaka, Zambia.}, journal = {Journal of epidemiology and global health}, volume = {16}, number = {1}, pages = {3}, pmid = {41326929}, issn = {2210-6014}, support = {R25 CA112383/CA/NCI NIH HHS/United States ; U54 MD017979/MD/NIMHD NIH HHS/United States ; }, mesh = {Humans ; Female ; Zambia/epidemiology ; *Uterine Cervical Neoplasms/diagnosis/epidemiology ; *Early Detection of Cancer/statistics &amp; numerical data ; Adult ; *Referral and Consultation/statistics &amp; numerical data ; Middle Aged ; False Positive Reactions ; Time Factors ; *Mass Screening/statistics &amp; numerical data ; HIV Infections/epidemiology ; }, abstract = {PURPOSE: While Zambia has an efficient program for early detection of cervical cancer, most cases are diagnosed at advanced stages. This study examined the time between suspecting cancers at screening clinics and histopathologic confirmation of cervical cancer in the Lusaka Province of Zambia.<br><br>METHODS: This study included the records of 3,483 women with suspected cancerous lesions identified by visual inspection of the cervix (VIA) who were referred from Lusaka Province screening facilities from 2014 to 2022. The study linked screening records with corresponding histopathologic results of the lesions after examination at the University Teaching Hospital. Variables abstracted from the medical records included age, human immunodeficiency virus (HIV) status, district of residence and referral clinic, and dates of referral and confirmed diagnosis.<br><br>RESULTS: False-positive VIA results constituted about 90% of all referrals. Women living with HIV (WLWH) had longer wait times between screening referrals and receipt of histopathologic results, most notably women coming from rural settings (median of 146 days) compared to urban settings (median of 69 days) (p&#x2009;<&#x2009;0.05). Among women diagnosed with low-grade intraepithelial lesions, WLWH had a 63% higher risk of confirmed cancer diagnosis (CI: 1.16, 2.29) than women not living with HIV. For high-grade intraepithelial lesions, the adjusted HR showed WLWH having a 17% (CI: 0.89, 1.53) higher risk of confirmed cancer diagnosis compared to women not living with HIV.<br><br>CONCLUSION: The high rate of false-positives and long wait times call for expanded service infrastructure, particularly in rural settings, and continuing provider education/training to optimize screening sensitivity and shorten wait times in the Lusaka Province. Such measures may reduce the overload on the existing histopathology infrastructure and may provide lessons for other limited-resource countries facing similar cancer control and prevention challenges.}, }
@article {pmid41328526, year = {2025}, author = {Zhang, X and Vasan, S and Zheng, C and Prentice, RL and Navarro, SL and Tinker, L and Raftery, D and Gowda, GAN and Van Horn, L and Sun, Y and Tabung, FK and Pan, K and Lampe, JW and Neuhouser, ML}, title = {Calibrated Dietary Patterns and Cancer Risk in the Women's Health Initiative Cohorts.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwaf259}, pmid = {41328526}, issn = {1476-6256}, support = {K00 CA253745/CA/NCI NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; }, abstract = {We developed calibration equations using metabolomics from fasting blood and 24-hour urine for Healthy Eating Index 2010 (HEI-2010) and Alternative Healthy Eating Index 2010 (AHEI-2010) to address measurement error from self-reported diet. We examined associations between metabolomic-calibrated dietary patterns and cancer risk in the Women's Health Initiative (WHI, n=108,522). Metabolomic signatures were created from a WHI Feeding (n=153;2010-2014) and WHI Observational Study (n=450;2006-2009). Dietary patterns were regressed on metabolites using the feeding study food intake records. Metabolomic-based dietary patterns were estimated from 24-hour dietary recalls, FFQ and 4DFR in the Observational Study using a stepwise approach. Cox regression estimated cancer risk of metabolomic-calibrated dietary patterns with a median follow-up of 15.8 years. Adjusted R2 for HEI-2010 and AHEI-2010 calibration equations were 57.5% and 48.8% for FFQ, 61.6% and 62.6% for 4DFR, and 52.5% and 53.2% for dietary recalls. Without calibration, a 20% increment in HEI-2010 was associated with lower risk of colorectal (HR=0.94, 95% CI=0.90-0.99), lung (HR=0.90, 95% CI=0.86-0.94), bladder (HR=0.86, 95% CI=0.75-0.99), and total invasive cancers (HR=0.98, 95% CI=0.96-0.99). With metabolomic calibration, higher HEI-2010 was associated with lower risk of lung (HR=0.79, 95% CI=0.71-0.88) and total invasive cancers (HR=0.96, 95% CI=0.92-1.00). Metabolomic-calibrated dietary patterns might mitigate measurement errors and strengthen diet-cancer associations.}, }
@article {pmid41329166, year = {2026}, author = {Arends, T and Bennett, SR and Tapscott, SJ}, title = {DUX4-induced HSATII RNA accumulation drives protein aggregation, impacting RNA processing pathways.}, journal = {The Journal of cell biology}, volume = {225}, number = {2}, pages = {}, pmid = {41329166}, issn = {1540-8140}, support = {K99AR081926/NH/NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; K99 AR081926/AR/NIAMS NIH HHS/United States ; R01AR045203/NH/NIH HHS/United States ; //University of Washington/ ; R01 AR045203/AR/NIAMS NIH HHS/United States ; //Seattle Children's Cancer Consortium/ ; T32 CA009657/CA/NCI NIH HHS/United States ; P30 CA015704/NH/NIH HHS/United States ; T32CA009657/CA/NCI NIH HHS/United States ; //Fred Hutch/ ; }, mesh = {Humans ; *Homeodomain Proteins/metabolism ; *Cell Nucleus/metabolism ; *RNA, Untranslated ; *Protein Aggregation, Pathological ; *Muscular Dystrophy, Facioscapulohumeral/metabolism/pathology ; *RNA Processing, Post-Transcriptional ; RNA, Satellite/metabolism ; Azacitidine/metabolism ; Methyltransferases/metabolism ; Y-Box-Binding Protein 1/metabolism ; RNA, Double-Stranded/metabolism ; Cell Line ; Cell Nucleolus/metabolism ; }, abstract = {RNA-driven protein aggregation leads to cellular dysregulation and contributes to the development of diseases and tumorigenesis. Here, we show that double homeobox 4 (DUX4), an early embryonic transcription factor and causative gene of facioscapulohumeral muscular dystrophy (FSHD), induces the accumulation of stable intranuclear RNAs, including nucleolar RNA and human satellite II (HSATII) RNA that drive protein aggregation in muscle cells. Specifically, HSATII RNA sequesters RNA methylation factors. HSATII-YBX-1 ribonucleoprotein (RNP) complex formation is mediated by HSATII double-stranded RNA and RNA methylase NSUN2 activity. Aberrant HSATII-RNP complexes affect RNA processing pathways, including RNA splicing. Differential splicing of genes mediated by HSATII-RNP complexes is associated with pathways known to be dysregulated by DUX4 expression. These findings highlight the broader influence of DUX4 on nuclear RNA dynamics and suggest that HSATII RNA could be a critical mediator of RNA processing regulation. Understanding the impact of HSATII-RNP formation on RNA processing provides insight into the molecular mechanisms underlying FSHD.}, }
@article {pmid41330717, year = {2025}, author = {Park, YH and Cortes, J and Modi, S and Hurvitz, SA and Bianchini, G and Iwata, H and Shitara, K and Siena, S and Goto, Y and Ku, GY and Powell, CA and Swain, SM and Arunachalam, M and Janek, M and Cheng, Y and Chu, C and Verma, P and Kuptsova-Clarkson, N and Mathias, E and Goodman, E and Rugo, HS}, title = {Characterization of the safety profile of trastuzumab deruxtecan by dose: a pooled analysis across DESTINY studies.}, journal = {The oncologist}, volume = {31}, number = {1}, pages = {}, pmid = {41330717}, issn = {1549-490X}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; //Daiichi Sankyo, Inc/ ; }, mesh = {Humans ; *Trastuzumab/adverse effects/therapeutic use/administration &amp; dosage/pharmacology ; Female ; *Immunoconjugates/adverse effects/therapeutic use/administration &amp; dosage/pharmacology ; *Camptothecin/analogs &amp; derivatives/adverse effects/administration &amp; dosage/therapeutic use ; Male ; Middle Aged ; Aged ; Adult ; *Breast Neoplasms/drug therapy/pathology ; Nausea/chemically induced ; Erb-b2 Receptor Tyrosine Kinases/genetics ; *Antineoplastic Agents, Immunological/adverse effects ; *Neoplasms/drug therapy ; }, abstract = {BACKGROUND: Trastuzumab deruxtecan (T-DXd), an approved human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate, may cause treatment-emergent adverse events (TEAEs), most commonly gastrointestinal and hematologic TEAEs. This pooled analysis evaluated TEAEs across 2 doses of T-DXd in patients with different cancers to support safe and effective real-world use.<br><br>PATIENTS AND METHODS: Data were pooled from 9 phase I-III clinical trials (DS8201-A-J101; DESTINY-Breast01/02/03/04; DESTINY-Lung01/02; DESTINY-Gastric01/02) of T-DXd 5.4 or 6.4&#x2009;mg/kg every 3&#x2009;weeks in patients (N&#x2009;=&#x2009;1678) with metastatic breast, gastric, or lung cancer with varying HER2 expression or HER2 mutation status. Nausea, vomiting, neutropenia, fatigue, and interstitial lung disease (ILD) were evaluated for time to onset and dose-related outcomes. Antiemetic analysis was limited before a 2020 protocol change recommending prophylaxis.<br><br>RESULTS: Common TEAEs (in &#x2265;20%) were fatigue, nausea, vomiting, neutropenia, anemia, and thrombocytopenia; mostly grade 1 or 2. TEAEs leading to dose reduction, drug interruption, and discontinuation with T-DXd were 22.6%, 42.8%, and 17.7% (5.4&#x2009;mg/kg), and 29.7%, 47.6%, and 16.6% (6.4&#x2009;mg/kg), respectively. Neutropenia, nausea, and fatigue occurred in 34.6%, 74.6%, and 56.5% of patients (5.4&#x2009;mg/kg) and 49.3%, 65.5%, and 52.8% (6.4&#x2009;mg/kg). Adjudicated drug-related ILD occurred in 12.0% and 10.9%, respectively.<br><br>CONCLUSION: Gastrointestinal and hematologic TEAEs were most common, with nausea, neutropenia, and fatigue most commonly reported. ILD/pneumonitis occurred in &#x223c;11%-12% of patients, with severe cases infrequent. Most TEAEs were low grade, though dose modifications highlight the need for proactive TEAE management, particularly in older patients and those with renal impairment.}, }
@article {pmid41330919, year = {2025}, author = {Lai, M and Kim, K and Zheng, Y and Castellani, CA and Ratliff, SM and Wang, M and Liu, X and Haessler, J and Huan, T and Bonsu, K and Newcomb, C and McKessy, K and Bielak, LF and Zhao, W and Joehanes, R and Ma, J and Guo, X and Manson, JE and Grove, ML and Bressler, J and Taylor, KD and Lappalainen, T and Kasela, S and Blackwell, TW and Lake, NJ and Faul, JD and Ferrier, KR and Ekker, SC and Hou, L and Kooperberg, C and Reiner, AP and Zhang, K and Peyser, PA and Fornage, M and Boerwinkle, E and Raffield, LM and Carson, AP and Rich, SS and Liu, Y and Levy, D and Rotter, JI and Smith, JA and Arking, DE and Liu, C and , }, title = {Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {10962}, pmid = {41330919}, issn = {2041-1723}, support = {R01 HL105756/HL/NHLBI NIH HHS/United States ; R21 HL144877/HL/NHLBI NIH HHS/United States ; R01 AG059727/AG/NIA NIH HHS/United States ; R01 AG085753/AG/NIA NIH HHS/United States ; R01 HL155569/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *DNA Methylation/genetics ; *DNA, Mitochondrial/genetics ; Female ; Male ; CpG Islands/genetics ; Aged ; *Heteroplasmy/genetics ; Genome-Wide Association Study ; *Cell Nucleus/genetics ; HEK293 Cells ; Epigenesis, Genetic ; *Epigenome/genetics ; *Mitochondria/genetics ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; }, abstract = {We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.}, }
@article {pmid41332620, year = {2025}, author = {Crowell, HL and Dong, Y and Billato, I and Cai, P and Emons, M and Gunz, S and Guo, B and Li, M and Mahmoud, A and Manukyan, A and Pagès, H and Panwar, P and Rao, S and Sargeant, CJ and Kern, LS and Ramos, M and Sun, J and Totty, M and Carey, VJ and Chen, Y and Collado-Torres, L and Ghazanfar, S and Hansen, KD and Martinowich, K and Maynard, KR and Patrick, E and Righelli, D and Risso, D and Tiberi, S and Waldron, L and Gottardo, R and Robinson, MD and Hicks, SC and Weber, LM}, title = {Orchestrating Spatial Transcriptomics Analysis with Bioconductor.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332620}, issn = {2692-8205}, support = {U24 HG004059/HG/NHGRI NIH HHS/United States ; U01 MH122849/MH/NIMH NIH HHS/United States ; R35 GM150671/GM/NIGMS NIH HHS/United States ; R00 HG012229/HG/NHGRI NIH HHS/United States ; R01 MH126393/MH/NIMH NIH HHS/United States ; }, abstract = {Spatial transcriptomics technologies provide spatially-resolved measurements of gene expression through assays that can either target selected genes or capture transcriptome-wide expression profiles. The complexity and variability of these technologies and their associated data necessitate multi-step workflows integrating diverse computational methods and software packages. We provide a freely accessible, open-source, continuously updated and tested online book containing reproducible code examples, datasets, and discussion about data analysis workflows for spatial omics data using Bioconductor in R, including interoperability with Python.}, }
@article {pmid41332638, year = {2025}, author = {McCutcheon, KR and Wu, J and Ozdemir, YC and McKinney, BJ and Srinivasan, S and Itokawa, A and Newsom, OJ and Vigil, A and Fox, DB and Sullivan, LB and Alvarez, JV}, title = {Recurrent Breast Cancer Cells Depend on De novo Pyrimidine Biosynthesis to Suppress Ferroptosis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332638}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA285322/CA/NCI NIH HHS/United States ; R01 CA292658/CA/NCI NIH HHS/United States ; }, abstract = {Breast cancer recurrence remains a major clinical challenge, often associated with therapy resistance and altered metabolic states. To define metabolic vulnerabilities of recurrent disease, we performed a CRISPR knockout screen targeting 421 metabolic genes in paired primary and recurrent HER2-driven breast cancer cell lines. While both primary and recurrent tumors shared dependencies on core metabolic pathways, recurrent tumors exhibited selective essentiality for the de novo pyrimidine synthesis pathway, including Cad, Dhodh, and Ctps. Pharmacologic inhibition of the rate-limiting enzyme DHODH with BAY-2402234 selectively impaired the growth of recurrent tumor cells, while primary tumor cells were relatively resistant. BAY treatment robustly inhibited pyrimidine synthesis in all lines, but only recurrent cells underwent iron-dependent lipid peroxidation and ferroptotic cell death. Lipidomic profiling revealed enrichment of polyunsaturated ether phospholipids in recurrent cells, which may predispose them to ferroptosis. A sensitizer CRISPR screen in primary cells further identified nucleotide salvage and lipid metabolic pathways as modifiers of DHODH inhibitor sensitivity. Stable isotope tracing and nutrient depletion experiments showed that primary cells can compensate for DHODH inhibition through nucleotide salvage, whereas recurrent cells exhibit impaired salvage capacity, likely due to reduced expression of Slc28/Slc29 nucleoside transporters. Together, these findings reveal that breast cancer recurrence is associated with increased dependence on de novo pyrimidine synthesis to suppress ferroptosis, highlighting a therapeutically actionable metabolic vulnerability in recurrent disease.}, }
@article {pmid41332714, year = {2025}, author = {Isaac, KJ and Cox, KEL and Ho, KY and Humphries, EM and Kucher, N and Leek, JT and Mosher, S and Schatz, MC and Tan, FJ and Hoffman, AM}, title = {Insights into the Datasets, Tools, and Training Needs of the AnVIL Community: 2024.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332714}, issn = {2692-8205}, support = {U24 HG010263/HG/NHGRI NIH HHS/United States ; }, abstract = {The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) provides a secure cloud-based environment where research and education communities can analyze genomic and biomedical data. The platform supports a wide range of data analysis as well as the ability to safely store and access data in compliance with NIH policies. Work on the AnVIL platform can be easily shared to promote reproducible science and collaboration. The purpose of this study is to better understand the current user base of the AnVIL platform. The AnVIL Community Poll aimed to collect baseline information, identify development opportunities, guide the prioritization of user support strategies, and succinctly but comprehensively describe the current AnVIL Community. The AnVIL Team disseminated the inaugural AnVIL Community Poll by sharing it broadly on social media and through AnVIL and related consortia mailing lists. We categorized respondents as either returning or potential users of the AnVIL platform (based on their provided usage description) and examined user experiences: specifically user backgrounds, technological comfort, research interests, computational needs, and preferences for training and support. Our sample of the AnVIL community found opportunities for platform adoption beyond the current user base and identified areas where training should be enhanced, training preferences, and user computational needs. Specifically, while most respondents were involved in human genomics research, there may be potential for growth in adoption of the platform by prioritizing materials to support clinical researchers. All respondents felt availability of specific tools or datasets was a key feature of the platform. The broader community may also benefit from further development or showcasing of resources to facilitate cost management, finding and incorporating analysis tools, and data import. Our sample greatly preferred virtual training opportunities and returning users of the platform foresaw needing large amounts of storage. This poll provided an insightful snapshot of the current state of the AnVIL and demonstrated areas where the AnVIL Team can take specific steps to address barriers related to platform adoption and further support the existing and varied AnVIL Community. This work can be built upon through user interviews, community discussion, and coordinating a recurring poll.}, }
@article {pmid41332722, year = {2025}, author = {Motmaen, A and Jude, KM and Wang, N and Minervina, A and Feldman, D and Lichtenstein, MA and Ebenezer, A and Correnti, C and Thomas, PG and Garcia, KC and Baker, D and Bradley, P}, title = {Targeting peptide-MHC complexes with designed T cell receptors and antibodies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332722}, issn = {2692-8205}, support = {75N92020D00005/HL/NHLBI NIH HHS/United States ; 75N93022D00005/AI/NIAID NIH HHS/United States ; 75N93023D00005/AI/NIAID NIH HHS/United States ; 75N95020D00005/DA/NIDA NIH HHS/United States ; 75N99020D00005/OF/ORFDO NIH HHS/United States ; R01 AI103867/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; }, abstract = {Class I major histocompatibility complexes (MHCs), expressed on the surface of all nucleated cells, present peptides derived from intracellular proteins for surveillance by T cells. The precise recognition of foreign or mutated peptide-MHC (pMHC) complexes by T cell receptors (TCRs) is central to immune defense against pathogens and tumors. Although patient-derived TCRs specific for cancer-associated antigens have been used to engineer tumor-targeting therapies, their reactivity toward self- or near-self antigens may be constrained by negative selection in the thymus. Here, we introduce a structure-based deep learning framework, ADAPT (Antigen-receptor Design Against Peptide-MHC Targets), for the design of TCRs and antibodies that bind to pMHC targets of interest. We evaluate the ADAPT pipeline by designing and characterizing TCRs and antibodies against a diverse panel of pMHCs. Cryogenic electron microscopy structures of two designed antibodies bound to their respective pMHC targets demonstrate atomic-level accuracy at the recognition interface, supporting the robustness of our structure-based approach. Computationally designed TCRs and antibodies targeting pMHC complexes could enable a broad range of therapeutic applications, from cancer immunotherapy to autoimmune disease treatment, and insights gained from TCR-pMHC design should advance predictive understanding of TCR specificity with implications for basic immunology and clinical diagnostics.}, }
@article {pmid41332752, year = {2025}, author = {Hsieh, HC and Gao, G and Han, Q and Brenes, D and Baraznenok, E and Yan, R and Serafin, R and Bishop, KW and Wang, R and Konnick, EQ and Pritchard, CC and Figiel, S and Hamdy, FC and Mills, IG and Reder, NP and Reddi, DM and Paulson, TG and Grady, WM and Valk, JE and True, LD and Haffner, MC and Rao, SR and Woodcock, DJ and Liu, JTC}, title = {3D pathology-guided microdissection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332752}, issn = {2692-8205}, support = {R01 CA268207/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; U01 CA182940/CA/NCI NIH HHS/United States ; U2C CA271902/CA/NCI NIH HHS/United States ; R01 CA220004/CA/NCI NIH HHS/United States ; R01 DK138948/DK/NIDDK NIH HHS/United States ; U54 DK137328/DK/NIDDK NIH HHS/United States ; R01 EB031002/EB/NIBIB NIH HHS/United States ; U01 CA152756/CA/NCI NIH HHS/United States ; U54 CA163060/CA/NCI NIH HHS/United States ; }, abstract = {Traditional micro- and macro-dissection techniques enable the extraction of localized regions in thin tissue sections for molecular analysis. Despite the growing use of 3D microscopy, analogous methods for volumetric microdissection are lacking. We have developed a 3D microdissection method based on computer numerical controlled (CNC) milling integrated with open-top light-sheet microscopy. We demonstrate the ability to study tumor evolution along convoluted 3D branching architectures, which is inaccessible to 2D methods.}, }
@article {pmid41332789, year = {2025}, author = {Ruediger, CT and Styler, BS and Sawyer, EM and Spiri, S and King, G and Walsh, ME and Brar, GA and Jorgens, DM and Ünal, E}, title = {Tom70-mediated mitochondria-nuclear envelope contacts regulate nuclear pore complex inheritance during gametogenesis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41332789}, issn = {2692-8205}, support = {T32 GM132022/GM/NIGMS NIH HHS/United States ; R01 AG071869/AG/NIA NIH HHS/United States ; R35 GM134886/GM/NIGMS NIH HHS/United States ; T32 GM007127/GM/NIGMS NIH HHS/United States ; T32 GM007232/GM/NIGMS NIH HHS/United States ; R01 AG071801/AG/NIA NIH HHS/United States ; }, abstract = {Gametogenesis rejuvenates the cellular lineage and excludes senescence-associated factors from gametes. In Saccharomyces cerevisiae, this involves sequestration of nuclear constituents into the Gametogenesis-Uninherited Nuclear Compartment (GUNC), which is excluded from gametes. Here we identify the conserved mitochondrial import receptor Tom70 as a key regulator of GUNC-mediated exclusion. Loss of TOM70 disrupts the sequestration of nuclear pore complexes, but not senescence-associated aggregates and nucleolar components, into the GUNC. Tom70's role appears independent of its canonical function in mitochondrial import and instead reflects a meiosis-specific requirement for mitochondria-nuclear envelope tethering. During meiosis II, Tom70 concentrates around the GUNC, where it recruits the nuclear envelope tethering protein Cnm1. Loss of CNM1 partially phenocopies tom70∆, consistent with parallel tethering interactions. These findings uncover a previously unrecognized organelle contact-dependent pathway that remodels the nuclear envelope to support selective nuclear inheritance. More broadly, they highlight how organelle contacts integrate with nuclear quality control to safeguard gamete integrity.}, }
@article {pmid41333381, year = {2025}, author = {Vasavada, A and Palazzo, L and Luce, C and Sanchez, M and Triplette, M and Ralston, JD and Carter-Bawa, L and Green, BB and Gao, H and Li, CI and Anderson, ML and Su, YR and Rogers, K and Wernli, KJ}, title = {"It's coming whether we want it to or not": A qualitative exploration of older adults' comfort with and perceptions of technology and digital health.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41333381}, issn = {2693-5015}, support = {R01 CA262015/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Older adults bear a disproportionate cancer burden but remain underrepresented in digital health intervention trials compared to younger counterparts. Since the COVID-19 pandemic, engagement with telemedicine and patient portals through the electronic health record (EHR) has grown for all age groups, suggesting readiness to adopt digital health tools. This qualitative study primarily sought to understand how adults eligible for lung cancer screening (LCS) engage with technology and digital health in their daily lives. The secondary objective was to assess acceptability and compatibility of a video-based LCS health communication as a digital health tool.<br><br>METHODS: Semi-structured interviews were conducted with 15 participants aged 51-80 through videoconferencing or telephone. Transcripts were analyzed using a rapid team-based analysis approach. The Consolidated Framework for Implementation Research (CFIR) was used as a guiding framework from throughout the study, with constructs of interest informing interview guide questions in data collection, and CFIR-mapping to generate a code list in the analysis.<br><br>RESULTS: Our findings generated four CFIR-informed themes, with 8 subthemes: 1) Internal facilitators: comfort with technology, self-efficacy in troubleshooting; 2) External facilitators: leveraging internet for health information, use of wearable devices, patient portal functionalities; 3) Internal barriers: emotional response, social isolation; 4) External barriers: scamming and data privacy. When shown the LCS video-based health communication, participants described general approval of the content and delivery but expressed concerns about safety related to accessing the video due to its delivery via weblink.<br><br>CONCLUSIONS: Broadly, we found that older adults had high levels of technology use and leveraged various digital tools (such as wearable devices, mobile applications, and EHR patient portals) to manage their health care needs. Our findings underscore that older adults are active users of digital tools, yet persistent concerns about privacy, social isolation, and emotional burden must be addressed for digital health interventions to be acceptable and sustainable in this population.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT05747443; 2023-02-17.}, }
@article {pmid41333983, year = {2025}, author = {Hong, G and Walsh, J and Koshy, A and Hsu, JY and O'Dea, AL and Vesely, EM and Memon, W and Dezube, RH and Goss, CH and Goss, LB and Greene, A and Gross, JE and Wilson, A and Nichols, DP and Zhang, SX and Cramer, RA}, title = {Home sputum collection for Aspergillus fumigatus detection in adults with cystic fibrosis.}, journal = {ERJ open research}, volume = {11}, number = {6}, pages = {}, pmid = {41333983}, issn = {2312-0541}, abstract = {BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ETI) has impacted the ability for people with cystic fibrosis (PwCF) to spontaneously expectorate sputum, leading to lower respiratory sampling rates and infection detection challenges. Home sampling may permit a potential strategy for fungal detection in PwCF.<br><br>METHODS: We conducted a prospective decentralised cohort study of PwCF to test the feasibility of home sputum collection and ambient temperature transport for Aspergillus fumigatus (Af) detection. Participants collected and shipped weekly sputum samples from home to the laboratory for fungal culture and completed electronic questionnaires. Descriptive statistics were calculated for patient factors, sputum characteristics and Af-positive cultures. We used a generalised estimating equations model to determine the association between highly effective modulator therapy (HEMT) and sputum volume.<br><br>RESULTS: We enrolled 76 adults with cystic fibrosis (CF) with a median (interquartile range) forced expiratory volume in 1&#x2005;s (FEV1) % predicted of 72.5% (53.8-86.3). 60 (79%) were on ETI and 44 (58%) had a history of Aspergillus. 70 (92%) successfully collected and shipped three or more sputum samples. Of 284 samples received, 83% arrived within one day. Sputum collection was reported as easy in 83 (29%) and somewhat easy in 114 (40%) collection events. Sputum volume from PwCF on HEMT was 36% lower than those not on HEMT (36%, 95% CI 3-58; p=0.03), adjusting for covariates. Af was detected in 205 (73%) of home sputum samples.<br><br>CONCLUSION: Home sputum collection is feasible in adults with CF. Af was detected in remotely collected sputum samples. Further work to assess the validity of home sputum samples in PwCF is necessary to determine the value of remote specimens in clinical and research settings.}, }
@article {pmid41334110, year = {2026}, author = {Kim, Y and Yang, G and Oh, J and Gwak, SY and Kim, KH and Lee, J and Kim, JS and Lee, CG and Cho, J and Ky, B and Yoon, HI and Grassberger, C}, title = {Consolidation ICIs Alter cardiac subregion radiosensitivity in NSCLC patients treated with Chemo-Radiotherapy.}, journal = {Clinical and translational radiation oncology}, volume = {56}, number = {}, pages = {101069}, pmid = {41334110}, issn = {2405-6308}, abstract = {PURPOSE: he addition of immune checkpoint inhibitor (ICI) as consolidation therapy after chemoradiation (CRT) has improved survival rates in non-small cell lung cancer (NSCLC) patients. However, the cardiotoxicity of CRT combined with ICI remains underexplored. This study assesses if ICI exposure alters the critical cardiac subregion linked to radiation-induced heart disease (RIHD) following CRT.<br><br>METHODS: We conducted a retrospective analysis of 321 locally advanced NSCLC patients treated with definitive CRT from August 2008 to December 2019, including 67 who received consolidation ICI. Cardiac contours include the entire heart, chambers, major coronary arteries, and conduction nodes. The primary endpoint was RIHD, defined as a major adverse cardiac event and atrial fibrillation. We used Fine-Gray analysis to investigate associations between RIHD and mean doses to cardiac subregions.<br><br>RESULTS: In total, 53 patients (18.4&#xa0;%) developed RIHD, with no significant difference between CRT and CRT&#xa0;+&#xa0;ICI groups. Doses to cardiac subregions were similar between the groups. In the CRT group, multivariable analysis shows that dose to the base of the heart, especially the sinoatrial node (SAN), correlated with increased RIHD risk (HR&#xa0;=&#xa0;1.02 per 1&#xa0;Gy, 95&#xa0;%CI [1.01-1.03], p&#xa0;<&#xa0;0.001). In the CRT&#xa0;+&#xa0;IO group, the left ventricle (LV) dose was a significant predictor (1.06 [1.06-1.1], p&#xa0;=&#xa0;0.006).<br><br>CONCLUSIONS: Doses to the SAN and the base of the heart correlate with RIHD in CRT patients, while doses to LV in CRT&#xa0;+&#xa0;ICI patients. While the 2-6&#xa0;% increased risk per Gy seems modest, it is clinically significant as the subregions, being small structures, can potentially be completely spared with a carefully optimized plan.}, }
@article {pmid41334748, year = {2026}, author = {Fitzgerald, L and Ghosh, S and Khan, W and Bokun, A and Lax, A and Mu, F and Cook, EE and Chen, J and Chen, G and Wu, E and Lin, Y and Shi, L and Qureshi, ZP and Graf, SA}, title = {Real-world overall survival comparison between first-line Bruton tyrosine kinase inhibitors in treating chronic lymphocytic leukemia/small lymphocytic lymphoma: An analysis of Veterans Health Administration data.}, journal = {Journal of managed care &amp; specialty pharmacy}, volume = {32}, number = {2}, pages = {186-200}, pmid = {41334748}, issn = {2376-1032}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; Retrospective Studies ; Male ; Female ; Aged ; United States/epidemiology ; Piperidines/therapeutic use ; *Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; Middle Aged ; *Protein Kinase Inhibitors/therapeutic use ; United States Department of Veterans Affairs ; Benzamides/therapeutic use ; Adenine/analogs &amp; derivatives/therapeutic use ; Pyrazines/therapeutic use ; Pyrazoles/therapeutic use ; Pyrimidines/therapeutic use ; Aged, 80 and over ; Cohort Studies ; Tyrosine Kinase Inhibitors ; }, abstract = {BACKGROUND: Three covalent Bruton's tyrosine kinase inhibitors (BTKis) are approved first-line (1L) treatments for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). However, limited real-world data, especially in veterans, evaluate long-term outcomes associated with the different BTKis.<br><br>OBJECTIVE: To describe and compare real-world overall survival (rwOS) among patients with CLL/SLL treated with BTKis in the Veterans Health Administration electronic medical record database.<br><br>METHODS: This was a retrospective cohort study of patients with CLL/SLL who initiated 1L monotherapy of ibrutinib, acalabrutinib, or zanubrutinib between November 2019 and September 2023. Patients were grouped into 3 cohorts based on the BTKi initiated: (1) ibrutinib, (2) acalabrutinib, or (3) acalabrutinib or zanubrutinib (given small sample initiating zanubrutinib). Key inclusion criteria were 1L monotherapy treatment with a BTKi, at least 2 diagnoses of CLL/SLL, and continuous enrollment at least 12 months prior to and at least 28 days after the initiation of the BTKi. rwOS comparing the BTKi cohorts was analyzed using Kaplan-Meier methodology and adjusted Cox proportional hazards models. Sensitivity analyses adjusting for different sets of covariates were conducted.<br><br>RESULTS: The study included samples of 1,059, 504, and 612 patients treated with ibrutinib, acalabrutinib, and acalabrutinib or zanubrutinib (108 received zanubrutinib), respectively. Median rwOS was not reached in any cohort. In the main analysis comparing the ibrutinib and acalabrutinib cohorts, after adjustment for baseline characteristics, treatment with acalabrutinib was associated with an increased risk of death compared with ibrutinib (hazard ratio [HR], 1.33; 95% CI, 1.01-1.76; P&#x2009;=&#x2009;0.042). In the main analysis comparing the ibrutinib and acalabrutinib or zanubrutinib cohorts, the adjusted risk of death was numerically higher for acalabrutinib- or zanubrutinib-treated patients compared with ibrutinib (HR, 1.32; 95% CI, 1.00-1.74; P&#x2009;=&#x2009;0.050). For both comparisons, sensitivity analyses indicated similar trends in rwOS.<br><br>CONCLUSIONS: As new therapies emerge, this study highlights the comparative effectiveness of BTKis in the real world, potentially informing current clinical practice.}, }
@article {pmid41334909, year = {2026}, author = {Walter, M and Haick, AK and Massa, PA and Klouser, LM and Stensland, L and Santo, TK and Xie, H and Jerome, KR}, title = {Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport.}, journal = {Microbiology spectrum}, volume = {14}, number = {1}, pages = {e0195925}, pmid = {41334909}, issn = {2165-0497}, support = {R21 AI178255/AI/NIAID NIH HHS/United States ; R21AI178255//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {*Herpesvirus 1, Human/genetics/physiology ; Animals ; Mice ; Female ; *Herpes Simplex/virology/prevention &amp; control ; Mutation ; *Viral Structural Proteins/genetics/metabolism ; Virus Latency ; Disease Models, Animal ; Amino Acid Substitution ; Humans ; Vero Cells ; }, abstract = {UNLABELLED: Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions cause oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We show that this R2[17] virus is highly attenuated in mice and acts as a potent vaccine that protects mice against acute HSV-1 infection. However, we report that the R2[17] virus has residual retrograde transport. We show that R2[17] can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1.<br><br>IMPORTANCE: Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen without a cure or vaccine. HSV-1 travels through nerves between the oral and genital mucosa and the peripheral nervous system, where it establishes lifelong latency. Studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate the retrograde transport of HSV-1 strain F from the mucosa to the nervous system. Here, we present contradictory findings. We report that an HSV-1 virus from strain 17+ with the same R2 mutation has residual retrograde transport. This shows that the R2 mutation is not sufficient to fully prevent the retrograde transport of HSV-1 in all settings. This finding may be particularly relevant for assessing the safety of prospective live-attenuated vaccines that include the R2 mutation.}, }
@article {pmid41335105, year = {2026}, author = {Irinyi, L and Mintzes, B and Warning, J and Collie, L and Rush, A and Turtle, CJ and Byrne, JA}, title = {Long-Term Follow-Up of Patients Receiving Cell and Gene Therapy Products.}, journal = {Human gene therapy}, volume = {37}, number = {3-4}, pages = {78-92}, doi = {10.1177/10430342251403439}, pmid = {41335105}, issn = {1557-7422}, mesh = {Humans ; *Genetic Therapy/adverse effects/methods ; *Cell- and Tissue-Based Therapy/adverse effects/methods ; Follow-Up Studies ; Gene Therapy Agents ; }, abstract = {Cell and gene therapies present unique challenges for long-term follow-up as they may lead to adverse events that could emerge years after treatment. Long-term follow-up helps identify potential delayed adverse events, such as oncogenesis or immunogenicity, which might not manifest immediately after treatment. Current regulatory guidelines emphasize a risk-based approach, recommending follow-up durations based on the therapy's mechanism of action between 5 and 15 years. To facilitate long-term monitoring, regulatory authorities recommend the establishment of long-term follow-up protocols, often involving patient registries and supported by real-world data sources to systematically capture and track data from treated patients. These long-term follow-ups are instrumental in both post-approval safety studies and reimbursement decisions, where payers may link payments to treatment outcomes. As the field of cell and gene therapy evolves, regulatory frameworks continue to adapt, balancing the need for comprehensive long-term follow-up with the feasibility of implementation to ensure that therapies are adequately monitored, ensuring patient safety and therapeutic effectiveness over time. However, maintaining patient engagement over extended periods, ensuring high-quality data collection, and addressing privacy concerns present significant challenges. Innovative solutions such as decentralized data collection, digital health technologies, and data linkage with electronic health records aim to alleviate patient burden and improve data reliability.}, }
@article {pmid41335170, year = {2025}, author = {Le, H and Baek, G and Huang, I and Siu, C and Shadman, M}, title = {The Evolving Therapeutic Landscape of Richter Transformation.}, journal = {Current hematologic malignancy reports}, volume = {20}, number = {1}, pages = {21}, pmid = {41335170}, issn = {1558-822X}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/therapy/pathology ; Immunotherapy/methods ; Molecular Targeted Therapy ; Protein Kinase Inhibitors/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Lymphoma, Large B-Cell, Diffuse/therapy/pathology ; }, abstract = {PURPOSE OF REVIEW: Richter transformation (RT), the progression of chronic lymphocytic leukemia (CLL) to aggressive lymphomas, poses a significant therapeutic challenge with historically poor outcomes. Chemoimmunotherapy (CIT) regimens have demonstrated limited efficacy with short durations of response. This review aims to evaluate the evolving treatment landscape for RT, with a focus on recent advances in targeted therapies, immunotherapies, and cellular therapies that are redefining the current and future standards of care.<br><br>RECENT FINDINGS: The treatment paradigm for RT is rapidly shifting away from cytotoxic chemotherapy. The combination of the B-cell lymphoma 2 inhibitor venetoclax with CIT has emerged as a new first-line benchmark with promising response rates and overall survival. Covalent Bruton tyrosine kinase (BTK) inhibitors had modest activity as monotherapy but showed improved responses when given with an immune checkpoint inhibitor. Pirtobrutinib has demonstrated responses even in heavily pretreated patients. Furthermore, advancement in immunotherapy has expanded treatment options for this patient population with bispecific T-cell engagers achieving high response rates and chimeric antigen receptor T-cell therapy providing deep, durable responses and favorable median overall survival in the relapsed/refractory (R/R) setting. The therapeutic landscape for RT has broadened with the introduction of targeted agents and immunotherapy. Venetoclax-based regimens represent a new standard for chemotherapy-eligible patients, allowing for a more effective bridge to potentially curative consolidation with transplantation. For R/R disease, novel BTK inhibitors, bispecific antibodies, and cellular therapies are demonstrating substantial efficacy. Ongoing trials investigating combinations of these agents are poised to further transform RT management.}, }
@article {pmid41335420, year = {2026}, author = {Zhao, LP and Papadopoulos, GK and Skyler, JS and Parikh, HM and Kwok, WW and Lybrand, TP and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, &#xc5;}, title = {Profiling Associations Between IGHG-FCGR Ligand-Receptor Interactions and Disease Progression From Stage 1 and 2 to Stage 3 Type 1 Diabetes.}, journal = {Diabetes}, volume = {75}, number = {2}, pages = {379-388}, pmid = {41335420}, issn = {1939-327X}, support = {R01 DK132406/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 1/genetics/metabolism ; Disease Progression ; *Receptors, IgG/genetics/metabolism ; Male ; Female ; *Immunoglobulin G/genetics/metabolism ; Child ; Adolescent ; Ligands ; }, abstract = {UNLABELLED: The primary objective of this study was to investigate whether ligand-receptor interactions (LRIs) between IGHG and FCGR gene products are associated with progression to type 1 diabetes (T1D). Using two completed clinical trials (DPT-1 and TN07), we applied next-generation targeted sequencing to genotype IGHG and FCGR genes in a cohort of 1,214 individuals and assessed LRI associations with disease progression. A Cox regression model was used to quantify LRI associations. IGHG or FCGR alone was found to have weak and sporadic associations with progression. Multiple LRIs between IGHG and FCGR gene products were found to be associated with progression, especially LRIs of IGHG2 with multiple FCGR receptors that accelerate progression and those of IGHG4 with multiple FCGR receptors (some overlapping) that delay progression. Furthermore, as several crystal structures of FcγRs complexed with distinct IgG molecules are known, application of this knowledge here was hampered by the absence of any information on the subclass distribution of each of the several T1D-related autoantibodies. It cannot be excluded that their respective state of glycosylation may influence binding affinity to various FcγRs and the function of thus-formed complexes. Our findings suggest that LRIs of the IGHG and FCGR gene products probably influence progression, shedding new insights into some of the immunological mechanisms involved in progression to T1D. Our findings potentially facilitate the search for new immunotherapeutic treatment through intervening at key steps in the progression.<br><br>ARTICLE HIGHLIGHTS: This study investigated ligand-receptor interactions (LRIs) between IGHG and FCGR gene products in type 1 diabetes progression. Genes of 1,214 participants from the DPT-1 and TN07 trials were sequenced using next-generation targeted sequencing technology, and LRI associations with the progression time to type 1 diabetes were analyzed using Cox regression modeling. Weak associations were found for IGHG or FCGR variants individually, but multiple LRIs significantly impacted progression. Several IGHG2-FCGR interactions accelerated progression, while a few other IGHG4-FCGR interactions delayed it. The results may provide insights into certain immunogenetic mechanisms of T1D and suggest therapeutic potential of targeting specific LRIs.}, }
@article {pmid41337582, year = {2025}, author = {Dighe, K and Colak, O and Moitra, P and Alafeef, M and Skrodzki, D and Aditya, T and Saha, P and Gunaseelan, N and Hural, J and Pinto, C and Pan, D}, title = {Distinguishing active HIV-1 infection from vaccine-induced seropositivity in HIV vaccine trial participants.}, journal = {Science advances}, volume = {11}, number = {49}, pages = {eadz5639}, pmid = {41337582}, issn = {2375-2548}, mesh = {Humans ; *AIDS Vaccines/immunology/adverse effects ; *HIV-1/immunology ; *HIV Infections/diagnosis/immunology/blood/virology/prevention &amp; control ; HIV Antibodies/immunology/blood ; ROC Curve ; HIV Core Protein p24/immunology ; RNA, Viral/blood ; *HIV Seropositivity/diagnosis/immunology ; Male ; Sensitivity and Specificity ; Female ; }, abstract = {Vaccine-induced seropositivity (VISP) causes antibodies produced by HIV-1 vaccines to react with standard serological tests, complicating diagnosis and leading to false positives. To distinguish VISP from true HIV infections, we developed a rapid, multiplexed companion electrochemical assay that integrates a three-dimensional-printed device with screen-printed electrodes coated with antigen, antibody, and methylene blue-labeled antisense oligonucleotide probes. The test delivers quantitative results within 5 minutes with calculated analytical limits of detection of 5.88 picograms per milliliter for p24 antigen, 10.96 picograms per milliliter for anti-p24 antibody, and 1259 copies per milliliter for HIV-1 RNA, with minimal cross-reactivity. Clinical testing with 104 plasma samples obtained from vaccinated/unvaccinated, HIV-positive/negative individuals demonstrated 95% sensitivity and 98% specificity in distinguishing active HIV-1 infection from VISP cases. Receiver operating characteristic analysis produced area under the curve values of 0.9888 for HIV-1 RNA, 0.9705 for anti-p24 antibody, and 0.9356 for p24 antigen. These findings highlight the potential to reduce false-positive results caused by VISP by integrating this diagnostic test in clinical trials and large-scale vaccination programs.}, }
@article {pmid41337691, year = {2026}, author = {Necchi, A and Guerrero-Ramos, F and Crispen, PL and Herrera-Imbroda, B and Garje, R and Szabados, B and Peyton, CC and Pradere, B and Ku, JH and Shore, N and Bögemann, M and Preston, MA and Xylinas, E and Sanchez de Llano, C and Gong, C and Hasan, M and Urtishak, K and Battaglia, S and Stitou, H and Bhanvadia, S and Sweiti, H and Psutka, SP}, title = {Gemcitabine Intravesical System Plus Cetrelimab or Cetrelimab Alone as Neoadjuvant Therapy in Muscle-Invasive Bladder Cancer: SunRISe-4 Primary Analysis and Biomarker Results.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {7}, pages = {586-597}, pmid = {41337691}, issn = {1527-7755}, abstract = {PURPOSE: Standard of care for muscle-invasive bladder cancer (MIBC) is radical cystectomy (RC) with neoadjuvant cisplatin-based chemotherapy (NAC). However, many patients are ineligible for or refuse cisplatin. SunRISe-4 (ClinicalTrials.gov identifier: NCT04919512) is an open-label, multicenter, parallel-cohort phase II study assessing neoadjuvant gemcitabine intravesical system (TAR-200/gem-iDRS) plus cetrelimab or cetrelimab monotherapy in patients with MIBC.<br><br>METHODS: Adults with Eastern Cooperative Oncology Group performance status 0-1, cT2-T4a N0M0, ineligible/refusing NAC, and planned for RC were randomly assigned 5:3, stratified by transurethral resection of bladder tumor completeness (residual tumor &#x2264;3 cm permitted) and T stage, to receive TAR-200 plus cetrelimab (cohort 1) or cetrelimab monotherapy (cohort 2). The primary end point was pathologic complete response (pCR) at RC. Secondary end points included recurrence-free survival (RFS) and safety. Exploratory end points included pathologic overall response (pOR; &#x2264;ypT1N0) and circulating tumor (ct) and urinary tumor (ut) DNA molecular residual disease (MRD). Side-by-side descriptive efficacy summary was planned.<br><br>RESULTS: At the May 9, 2025, data cutoff, 159 patients were treated; 88 in cohort 1 and 46 in cohort 2 underwent RC. pCR, pOR, and 1-year RFS rates were 38%, 53%, and 77% in cohort 1 and 28%, 44%, and 64% in cohort 2, respectively. pCR rates were consistent across subgroups. No new safety signals were observed. Across cohorts, utDNA- status before RC (week 12) and utDNA clearance correlated with pCR (P < 10[-5] and < 10[-3], respectively). ctDNA- status at baseline and week 12 was associated with longer RFS compared with ctDNA+ status at the same time point (P = .04 and 0.01, respectively).<br><br>CONCLUSION: TAR-200 plus cetrelimab provided higher pCR, pOR, and 1-year RFS rates compared with cetrelimab monotherapy, supporting further investigation of the neoadjuvant combination in MIBC. utDNA and ctDNA MRD results support further investigation as biomarkers for residual local and nonlocal disease, respectively.}, }
@article {pmid41338217, year = {2026}, author = {Li, Q and Song, Q and Chen, Z and Choi, J and Moreno, V and Ping, J and Wen, W and Li, C and Shu, X and Yan, J and Shu, XO and Cai, Q and Long, J and Huyghe, JR and Pai, R and Gruber, SB and Yang, Y and Casey, G and Wang, X and Toriola, AT and Li, L and Singh, B and Lau, KS and Zhou, L and Zhang, Z and Wu, C and Peters, U and Zheng, W and Long, Q and Yin, Z and Guo, X}, title = {Large-scale integration of omics and electronic health records to identify potential risk protein biomarkers and therapeutic drugs for cancer prevention.}, journal = {American journal of human genetics}, volume = {113}, number = {1}, pages = {41-56}, pmid = {41338217}, issn = {1537-6605}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA297582/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers, Tumor/genetics/metabolism ; *Neoplasms/prevention &amp; control/genetics/drug therapy ; *Electronic Health Records ; Male ; Genome-Wide Association Study ; Female ; Proteomics/methods ; Quantitative Trait Loci/genetics ; Caffeine/therapeutic use ; }, abstract = {Identifying risk protein targets and their therapeutic drugs is crucial for effective cancer prevention. Here, we conduct integrative and fine-mapping analyses of large genome-wide association studies data for breast, colorectal, lung, ovarian, pancreatic, and prostate cancers and characterize 710 lead variants independently associated with cancer risk. Through mapping protein quantitative trait loci (pQTLs) for these variants using plasma proteomics data from over 75,000 participants, we identify 365 proteins associated with cancer risk. Subsequent colocalization analysis identifies 101 proteins, including 74 not reported in previous studies. We further characterize 36 potential druggable proteins for cancers or other disease indications. Analyzing >3.5 million electronic health records, we conducted analyses of emulated trials for 11 drugs across 290 comparisons and identified three drugs significantly associated with reduced colorectal cancer risk: caffeine vs. paroxetine (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.41-0.64), haloperidol vs. prochlorperazine (HR, 0.47; 95% CI, 0.33-0.68), and trazodone hydrochloride vs. paroxetine (HR, 0.49; 95% CI, 0.38-0.63). Conversely, caffeine was associated with increased cancer risk in comparison with finasteride (colorectal cancer) and fluoxetine (breast cancer). Meta-analysis identified six drugs significantly associated with cancer risk, including acetazolamide, which was associated with reduced colorectal cancer risk (HR, 0.79; 95% CI, 0.72-0.87). This study identifies previously unreported protein biomarkers and candidate drug targets across six major cancer types and highlights several approved drugs with potential chemopreventive effects.}, }
@article {pmid41338220, year = {2026}, author = {Shao, Y and Tran, Q and Feng, Y and Kolekar, P and Liu, Y and Liang, Z and Fan, L and McBride, A and Jones, T and Cameron, A and Mulder, H and Ji, L and Huang, BJ and Klco, JM and Meshinchi, S and Zhang, J and Carroll, WL and Loh, ML and Easton, J and Brown, PA and Ma, X}, title = {Analysis of error profiles of indels and structural variants in deep-sequencing data.}, journal = {Cell genomics}, volume = {6}, number = {2}, pages = {101082}, pmid = {41338220}, issn = {2666-979X}, support = {R01 CA293587/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; R01 CA273326/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *High-Throughput Nucleotide Sequencing/methods ; *INDEL Mutation/genetics ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {Despite extensive studies of the error profiles of SNVs, those of insertions/deletions (indels)/structural variants (SVs) remain elusive. Using ultra-deep sequencing, we show that the error rates of indel/SVs are >100-fold lower than those of SNVs, although repeat indels have high error rates of 1%. We validated this pattern in a cohort of 103 patients with relapsed B cell acute lymphoblastic leukemia (B-ALL). We analyzed repeat indels in 339 cancer driver genes and demonstrated that the number of repeat units is highly predictive of the error rate. We then analyzed minimal residual disease samples from 72 patients with relapsed B-ALL and demonstrated that our approach had positive detections in 61% of cases, outperforming clinical flow cytometry (51% detection). Overall, we established indel and SV error profiles in deep next-generation sequencing (NGS) data, enabling superior tumor detection at very low burdens, which has a significant impact on the clinical diagnosis and monitoring of human cancers and other diseases.}, }
@article {pmid41338709, year = {2025}, author = {Pandey, S and Anderson, N and Snidarich, M and Tsosie, U and Omernik, B and Brown, MC and Crothers, K and Walsh, C and Budak, JZ and Brooks, E and Echo-Hawk, A and Triplette, M}, title = {Common Determinants of Lung Cancer Screening Uptake in Three High-Risk and Underserved Communities.}, journal = {Journal of the American College of Radiology : JACR}, volume = {22}, number = {12}, pages = {1552-1566}, pmid = {41338709}, issn = {1558-349X}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/diagnostic imaging/diagnosis ; Male ; Female ; *Early Detection of Cancer/statistics &amp; numerical data ; Focus Groups ; Middle Aged ; Qualitative Research ; United States ; Aged ; *Vulnerable Populations ; Medically Underserved Area ; Adult ; Healthcare Disparities ; }, abstract = {OBJECTIVE: Though lung cancer screening (LCS) has significant mortality benefits and has been recommended by the US Preventive Services Task Force since 2013, uptake has been low, especially in most underserved populations. The objective of this study was to harmonize qualitative data from three parallel studies focused on communities with historically high rates of tobacco use and who face lung cancer disparities-people with human immunodeficiency virus; individuals that identify as lesbian, gay, bisexual, transgender, queer or questioning, and others; and urban-dwelling American Indian or Alaska Native individuals-to understand common barriers and facilitators to LCS to inform clinical programming.<br><br>METHODS: This qualitative study re-analyzed deidentified focus group transcripts from three recently conducted qualitative studies performed in partnership with these communities. Participants were all eligible, or near eligible, for LCS by US Preventive Services Task Force 2021 criteria. Transcripts were analyzed using inductive thematic analysis, with final themes mapped to the Health Equity Implementation Framework.<br><br>RESULTS: A total of 26 focus groups or interviews were analyzed, including a total of 109 participants (people with human immunodeficiency virus, n = 43; individuals that identify as lesbian, gay, bisexual, transgender, queer or questioning, and others, n = 21; American Indian or Alaska Native, n = 45). Fifteen themes emerged that represented common determinants of LCS behavior across the domains of the Health Equity Implementation Framework. Themes demonstrated broad interest in LCS and preventive health care but multilevel barriers to LCS engagement and completion. Participants endorsed facilitators such as community engagement, patient-provider information sharing, and patient navigation to enhance LCS uptake.<br><br>DISCUSSION: Despite several barriers to screening that contribute to low uptake, there are facilitators that could be used through multilevel interventions to support LCS in underserved high-risk populations.}, }
@article {pmid41338864, year = {2025}, author = {Scordo, M and Perales, MA and Mauguen, A and Lin, A and Kunvarjee, B and Paes Pena, M and Mcavoy, D and Nguyen, LK and Hogan, M and Chapman, N and Bieler, J and Cho, C and Gyurkocza, B and Harris, AC and Spitzer, B and O'Reilly, RJ and Jakubowski, AA and Lin, RJ and Papadopoulos, EB and Politikos, I and Ponce, DM and Shaffer, BC and Shah, GL and Tamari, R and Giralt, SA and Boelens, JJ and Curran, KJ}, title = {Model-based antithymocyte globulin dosing in ex vivo CD34+ selected allogeneic haematopoietic cell transplantation: a single-centre, single-arm, phase 2 study.}, journal = {The Lancet. Haematology}, volume = {12}, number = {12}, pages = {e956-e965}, doi = {10.1016/S2352-3026(25)00293-5}, pmid = {41338864}, issn = {2352-3026}, support = {P01 CA023766/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Antilymphocyte Serum/administration &amp; dosage/therapeutic use ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Male ; Female ; Middle Aged ; Adult ; Graft vs Host Disease/prevention &amp; control/etiology ; *Antigens, CD34/metabolism ; *Transplantation Conditioning/methods ; Transplantation, Homologous ; *Hematologic Neoplasms/therapy/mortality ; Aged ; Melphalan/administration &amp; dosage ; }, abstract = {BACKGROUND: Ex-vivo CD34+ selected allogeneic haematopoietic cell transplantation (HCT) provides favourable chronic graft-versus-host disease (GVHD)-free relapse-free survival but is limited by delayed immune reconstitution and early non-relapse mortality. High anti-thymocyte globulin (ATG) exposure after HCT has been associated with delayed CD4+ T-cell immune reconstitution, increased non-relapse mortality, and poor overall survival.<br><br>METHODS: We report the final analysis of a single-centre, phase 2 trial investigating pharmacokinetic model-based ATG (targeting <20 AU&#x2008;&#xd7;&#x2008;d/mL post-HCT exposure) in participants of any age undergoing ex vivo CD34+ selected allogeneic HCT after myeloablative conditioning for haematological malignancies. Two myeloablative conditioning regimens were used at the discretion of the treating physician: the chemotherapy-based regimen (target cumulative exposure of 65 mg&#x2008;&#xd7;&#x2008;h/L busulfan, 140 mg/m[2] melphalan, and 150 mg/m[2] fludarabine) and a high-dose total-body irradiation-based regimen (included total-body irradiation [1375 cGy], thiotepa [10 mg/kg], and cyclophosphamide [100 mg/kg]). The primary objective was an improvement in CD4+ immune reconstitution (>50 cells per &#x3bc;L at two consecutive timepoints by day +100) in at least 32% of the per protocol population. This study was registered with ClinicalTrials.gov (NCT04872595) and is completed.<br><br>FINDINGS: Between June 14, 2021, and Nov 28, 2023, we enrolled 59 participants with haematological malignancies. Among evaluable participants (n=56), the median age was 55 years (IQR 30-63), 34 (61%) were male, 22 (39%) were female, 44 (79%) had myeloid malignancies, and 44 (79%) had received chemotherapy-only myeloablative conditioning. The median estimated ATG exposure after HCT was 10 AU&#x2008;&#xd7;&#x2008;d/mL (IQR 9-11). CD4+ immune reconstitution was reached in 39 (70%) of 56 participants, meeting the study's primary endpoint. The most common grade 3 or worse adverse events were infections (103 [40%] of 259 events) and oral or gastrointestinal events (44 [17%] of 259 events). Grade 5 adverse events occurred in three participants including secondary graft failure (n=1) and multi-organ failure (n=2), with a total of four treatment-related deaths among participants.<br><br>INTERPRETATION: These results demonstrate that model-based ATG dosing promotes robust CD4+ immune reconstitution after ex vivo CD34+ selected allogeneic HCT, underscoring the potential of pharmacokinetically guided ATG as a strategy to optimise immune recovery in myeloablative, calcineurin inhibitor-free transplantation for haematological malignancies.<br><br>FUNDING: US National Cancer Institute, Memorial Sloan Kettering Cancer Center.}, }
@article {pmid41340045, year = {2025}, author = {Omame, A and Iyaniwura, SA and Ebenezer, A and Han, Q and Wang, X and Bragazzi, NL and Kong, JD and Woldegerima, WA}, title = {Pre-exposure vaccination in the high-risk population is crucial in controlling mpox resurgence in Canada.}, journal = {BMC infectious diseases}, volume = {26}, number = {1}, pages = {14}, pmid = {41340045}, issn = {1471-2334}, mesh = {Humans ; Canada/epidemiology ; Models, Theoretical ; *Vaccination ; *Pre-Exposure Prophylaxis ; Female ; Male ; *Influenza, Human/prevention &amp; control/epidemiology ; }, abstract = {As mpox spread continues across several endemic and non-endemic countries around the world, vaccination has become an integral part of the global response to control the epidemic. Some vaccines have been recommended for use against mpox by the World Health Organization (WHO). As the roll-out of mpox vaccines continue across the globe, it is imperative to develop mathematical models to support public health officials and governments agencies in optimizing vaccination strategies to curtail the resurgence of mpox. In this article, we develop a compartmental mathematical model to investigate the impact of vaccination in controlling a potential mpox resurgence in Canada. The model categorizes individuals into high- and low-risk groups and incorporates pre-exposure vaccination in the high-risk group and post-exposure vaccination in the high- and low-risk groups. The vaccine-free version of the model was calibrated to the daily reported cases of mpox in Canada from April to October 2022, from which we estimated key model parameters, including the sexual and non-sexual transmission rates. Furthermore, we calibrated the full model to the daily reported cases of mpox in Canada in 2024, to estimate the current mpox vaccination rates in Canada. Our results highlight the importance of pre-exposure vaccination in the high-risk group on controlling a potential resurgence of mpox in Canada, and the minimal effects of post-exposure vaccination in the high- and low-risk groups on the outbreak. In addition, our model predicts the possibility of mpox becoming endemic in Canada, in the absence of pre-exposure vaccination in the high-risk group. Overall, our modeling result suggests that pre-exposure vaccination in the high-risk group is crucial in controlling mpox outbreak in Canada. Stepping up this vaccination is sufficient to avert a potential mpox resurgence in Canada.Clinical trial number Not applicable.}, }
@article {pmid41342729, year = {2026}, author = {Perkins, RB and Wolf, AMD and Church, TR and Elkin, EB and Skates, SJ and Etzioni, RD and Guerra, CE and Herzig, A and Hoffman, RM and Oeffinger, KC and Raoof, S and Shih, YT and Walter, LC and Zeigler-Johnson, C and Manassaram-Baptiste, D and Smith, RA}, title = {Self-collected vaginal specimens for human papillomavirus testing and guidance on screening exit: An update to the American Cancer Society cervical cancer screening guideline.}, journal = {CA: a cancer journal for clinicians}, volume = {76}, number = {1}, pages = {e70041}, pmid = {41342729}, issn = {1542-4863}, mesh = {Humans ; Female ; *Uterine Cervical Neoplasms/diagnosis/virology ; *Papillomavirus Infections/diagnosis/virology ; *Early Detection of Cancer/methods/standards ; *Specimen Handling/methods/standards ; United States ; Adult ; Middle Aged ; *Vaginal Smears/methods ; Aged ; American Cancer Society ; *Papillomaviridae/isolation &amp; purification ; Mass Screening/methods/standards ; Vagina/virology ; Human Papillomavirus Viruses ; }, abstract = {This update expands the 2020 American Cancer Society (ACS) cervical cancer screening guideline for average-risk women and individuals with a cervix who are at average risk, to include self-collection for human papillomavirus (HPV) testing and revised guidance for exiting cervical cancer screening. Self-collected vaginal specimens, a method of primary HPV testing, align with the ACS cervical cancer screening guideline. When clinician-collected cervical specimens are used for HPV testing, repeat screening is recommended every 5 years for those with a negative test. For self-collected vaginal specimens, the ACS endorses the following recommendations of the Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee (of which it is a member): (1) primary HPV screening using clinician-collected cervical specimens is preferred, and self-collected vaginal specimens are acceptable for average-risk individuals aged 25-65 years; and (2) repeat testing in 3 years is recommended after a negative result on a self-collected HPV screening test. These recommendations apply only to combinations of collection devices and HPV assays approved by the US Food and Drug Administration for HPV testing in a clinical setting or at home. The rationale notes that the use of self-collected vaginal specimens can overcome barriers to screening for many patients, but most patients who test HPV-positive will require extra follow-up steps, and data on long-term, real-world effectiveness are limited. For certain high-risk individuals, clinician-collected samples are still recommended. Furthermore, in response to high rates of cervical cancer among individuals older than 65 years and with poor implementation of current exiting screening criteria, ACS has amended the 2020 guideline to recommend HPV testing at ages 60 and 65 years, with the last HPV test at an age no younger than 65 years as a requisite to exiting screening. The revised recommendation states: To qualify for discontinuation of screening, the ACS recommends an average-risk woman or an individual with a cervix at average risk have negative primary HPV tests (preferred) or negative co-testing using HPV tests and cytology (acceptable) at ages 60 and 65 years. If primary HPV tests or co-testing are not available, three consecutive negative cytology (Papanicolaou) tests at the recommended screening interval with the last test at age 65 years are acceptable. If self-collected vaginal specimens are used for HPV testing, the 3-year testing interval should be followed. Additional screening exit stipulations relate to women at higher risk because of prior abnormal test results or current immune suppression.}, }
@article {pmid41343299, year = {2025}, author = {Huddleston, J and Bedford, T}, title = {Timely vaccine strain selection and genomic surveillance improve evolutionary forecast accuracy of seasonal influenza A/H3N2.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {41343299}, issn = {2050-084X}, support = {R01 AI165821/AI/NIAID NIH HHS/United States ; R01 AI165821-01//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {*Influenza A Virus, H3N2 Subtype/genetics/immunology ; Humans ; *Influenza, Human/prevention &amp; control/virology/epidemiology ; *Influenza Vaccines/immunology ; *Evolution, Molecular ; Seasons ; Forecasting ; COVID-19/prevention &amp; control ; SARS-CoV-2 ; Genomics ; Pandemics ; }, abstract = {Evolutionary forecasting models inform seasonal influenza vaccine design by predicting which current genetic variants will dominate in the influenza season 12 months later. Forecasting models depend on hemagglutinin sequences from global public health networks to identify current genetic variants (clades) and estimate clade fitnesses. The lag between collection of a clinical sample and public availability of its sequence averages ∼3 months, complicating the 12-month forecasting problem by reducing our understanding of current clade frequencies. Despite continued methodological improvements to forecasting models, these constraints of a 12-month forecast horizon and 3-month submission lags impose an upper bound on any model's accuracy. The SARS-CoV-2 pandemic revealed that modern vaccine technology reduces forecast horizons to 6 months and expanded sequencing support reduces submission lags to 1 month on average. We quantified the potential effects of these public health policy changes on forecast accuracy for A/H3N2 populations. Reducing forecast horizons to 6 months reduced average absolute forecasting errors to 25% of the 12-month average, while reducing submission lags decreased uncertainty in current clade frequencies by 50%. These results show the potential to improve the accuracy of existing forecasting models through realistic changes to public health policy.}, }
@article {pmid41343677, year = {2025}, author = {Ersoy-Fazlioglu, B and Lingadahalli, S and Altintas, UB and Cingoz, A and Tekoglu, E and Lok Yu, IP and Dikbas, M and Missaghimamaghani, O and Yavuz, K and Adomat, H and Kulac, I and Morova, T and Xiao, K and Gleave, M and Fazli, L and Cejas, P and Cherkasov, A and Zwart, W and Haffner, MC and Long, HW and Collins, C and Bagci-Onder, T and Lack, NA}, title = {Distinct transcription factor interactions drive HOXB13 activity in different stages of prostate cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {49}, pages = {e2500327122}, pmid = {41343677}, issn = {1091-6490}, support = {PJT-173331//CIHR | Canadian Institutes of Health Research - Antimicrobial Resistance Research Initiative (AMR)/ ; NIH P50 CA097186//North Spore/ ; 221Z116//TUBITAK | Ulusal Metroloji Enstit&#xfc;s&#xfc;, T&#xfc;rkiye Bilimsel ve Teknolojik Ara&#x15f;tirma Kurumu (T&#xdc;B&#x130;TAK UME)/ ; PDF//Prostate Cancer Fight Foundation (PCFF)/ ; }, mesh = {Male ; *Homeodomain Proteins/metabolism/genetics ; Humans ; *Prostatic Neoplasms/metabolism/pathology/genetics ; Receptors, Androgen/metabolism/genetics ; Cell Proliferation ; Gene Expression Regulation, Neoplastic ; Cell Line, Tumor ; *Transcription Factors/metabolism/genetics ; Animals ; Mice ; }, abstract = {HOXB13 is a lineage-specific transcription factor that plays a critical role in initiation and progression of prostate cancer (PCa). While most research has focused on the role of HOXB13 on androgen receptor (AR) activity, here we demonstrate that HOXB13 is frequently expressed in AR-negative tumors and is essential for the proliferation of both AR-positive and -negative PCa models. Strikingly, HOXB13 is remarkably selective and has almost no effect on nonprostatic tissues. Despite this common essentiality in PCa, HOXB13 activity is markedly different in AR-negative stem cell-like tumors, where interactions with the AP-1 change the HOXB13 cistrome and interactome. Yet despite these distinct activities, HOXB13 activity is commonly mediated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction alters chromatin accessibility at HOXB13-binding sites, causing increased proliferation in AR-negative PCa. Overall, this work demonstrates a distinct mechanism of action for HOXB13 and highlights its critical role in AR-negative castration-resistant PCa.}, }
@article {pmid41344516, year = {2026}, author = {Alongi, F and Cuccia, F and Kotecha, R and Campione, M and Louie, AV and Ma, L and Minniti, G and Tree, AC and Dahele, M and Lo, S and Af Rosenschold, PM and Suh, JH and Niyazi, M and Sheehan, J and Guckenberger, M and Sahgal, A}, title = {ESTRO-ISRS clinical practice recommendations for re-irradiation of spinal metastases with Stereotactic Body Radiotherapy: Delphi consensus supported by a systematic review and meta-analysis.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {214}, number = {}, pages = {111304}, doi = {10.1016/j.radonc.2025.111304}, pmid = {41344516}, issn = {1879-0887}, mesh = {Humans ; *Spinal Neoplasms/radiotherapy/secondary ; *Radiosurgery/methods/adverse effects ; *Re-Irradiation/methods ; Delphi Technique ; Salvage Therapy/methods ; }, abstract = {BACKGROUND: Stereotactic body radiotherapy (SBRT) is an established treatment for previously unirradiated spinal metastases; however, the literature is limited with respect to SBRT as a re-irradiation salvage therapy. We performed a systematic review and meta-analysis as basis for joint ESTRO-ISRS clinical practice recommendations of salvage SBRT for spinal metastases.<br><br>METHODS: A systematic review and meta-analysis were performed using PRISMA methodology, including publications from January 2006 to September 2024, reporting on the clinical outcomes of&#xa0;&#x2265;&#xa0;5 patients treated with spine SBRT re-irradiation (&#x2265;5 Gy per fraction) for vertebral metastases. These data served as basis for joint ESTRO-ISRS clinical practice recommendations.<br><br>RESULTS: After the initial article screen, 20 studies (5 prospective, 15 retrospective) met the inclusion criteria for analysis. A total of 1538 spine metastases were treated in 1284 patients. The median re-irradiation dose was 24&#xa0;Gy in 2 fractions (range: 16-30&#xa0;Gy in 1-5 fractions) after a median 30&#xa0;Gy in 10 fractions of prior conventional radiotherapy. Vertebral compression fracture, nerve root damage, and myelopathy events were observed in a pooled proportion of 5.0&#xa0;%, 5.6&#xa0;%, and 1.7&#xa0;%, respectively. With a median follow-up of 12&#xa0;months, the pooled 1- and 2-year LC rates were 81&#xa0;% (95&#xa0;% CI: 77-86&#xa0;%) and 70&#xa0;% (95&#xa0;% CI: 61-79&#xa0;%), respectively. Despite the low level of evidence, a consensus was reached after the first round of voting for 11 practice recommendations, suggesting a substantial level of agreement among the experts.<br><br>CONCLUSIONS: Re-irradiation with SBRT for spine metastases following prior conventional radiation or SBRT was efficacious, safe, and is a recommended treatment option in appropriately selected patients. Joint practice recommendations are provided on behalf of ESTRO and ISRS to guide clinical practice.}, }
@article {pmid41344792, year = {2026}, author = {, }, title = {Quantifying the fatal and non-fatal burden of disease associated with child growth failure, 2000-2023: a systematic analysis from the Global Burden of Disease Study 2023.}, journal = {The Lancet. Child &amp; adolescent health}, volume = {10}, number = {1}, pages = {22-38}, pmid = {41344792}, issn = {2352-4650}, mesh = {Humans ; Child, Preschool ; *Global Burden of Disease/trends ; *Growth Disorders/epidemiology/mortality ; Infant ; Male ; Disability-Adjusted Life Years ; Female ; Thinness/epidemiology ; Prevalence ; Cost of Illness ; Child Mortality ; }, abstract = {BACKGROUND: Child growth failure (CGF), which includes underweight, wasting, and stunting, is among the factors most strongly associated with mortality and morbidity in children younger than 5 years worldwide. Poor height and bodyweight gain arise from a variety of biological and sociodemographic factors and are associated with increased vulnerability to infectious diseases. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 to estimate CGF prevalence, the risk of infectious diseases associated with CGF, and the disease mortality, morbidity, and overall burden associated with CGF.<br><br>METHODS: In this analysis we estimated the all-cause and cause-specific (diarrhoea, lower respiratory tract infections, malaria, and measles) disability-adjusted life-years (DALYs) lost and mortality associated with stunting, wasting, underweight, and CGF in aggregate. We combined the burden associated with mild, moderate, and severe forms of CGF: stunting was defined as height-for-age Z scores (HAZ) less than -1, underweight was defined as weight-for-age Z scores (WAZ) less than -1, and wasting was defined as weight-for-height Z scores (WHZ) less than -1, according to WHO Child Growth Standards. Population-level continuous distributions of HAZ, WAZ, and WHZ were estimated for 2000 to 2023 using data from surveys, literature, and individual-level study data. The risk of incidence of, and mortality due to, diarrhoea, lower respiratory infections, malaria, and measles was separately estimated in a meta-regression framework from longitudinal cohort data for Z scores less than -1. Finally, fatal outcomes associated with these diseases were estimated with vital registration, verbal autopsy, and case-fatality data, while non-fatal outcomes were estimated with surveys as well as health-care utilisation and case reporting data. The exposure prevalence and relative risk estimates were from continuous distributions, allowing for direct assessment of the attributable fractions for mild, moderate, and severe stunting, underweight, wasting, and the combined impact of child growth failure within populations. All estimates were age-specific, sex-specific, geography-specific, and year-specific.<br><br>FINDINGS: We estimated that, in children younger than 5 years in 2023, CGF was associated with 79&#xb7;4 million (95% uncertainty interval [UI] 47&#xb7;0-106) DALYs lost and 880&#x2008;000 (517&#x2008;000-1&#x2008;170&#x2008;000) deaths. This represented 17&#xb7;9% (10&#xb7;6-23&#xb7;8) of 444 million (434-457) total under-5 DALYs and 18&#xb7;8% (11&#xb7;1-25&#xb7;0) of all 4&#xb7;67 million (4&#xb7;59-4&#xb7;75) under-5 deaths. Compared to stunting (33&#xb7;0 million [24&#xb7;1-42&#xb7;2] DALYs, 373&#x2008;000 [272&#x2008;000-477&#x2008;000] deaths) and wasting (39&#xb7;2 million [23&#xb7;8-53&#xb7;0] DALYs, 428&#x2008;000 [256&#x2008;000-583&#x2008;000] deaths), childhood underweight was associated with the largest share of CGF-related disease burden: 52&#xb7;2 million (21&#xb7;9-75&#xb7;1) DALYs and 573&#x2008;000 (236&#x2008;000-824&#x2008;000) deaths in children younger than 5 years in 2023.<br><br>INTERPRETATION: CGF remains a leading factor associated with death and disability in children younger than 5 years, despite global attention and focused interventions to reduce the prevalence of associated CGF indicators. Our findings underscore the need for policies, strategies, and interventions that focus on all indicators of CGF to reduce its associated health burden.<br><br>FUNDING: Gates Foundation.}, }
@article {pmid41344861, year = {2026}, author = {Specht, JM and van Geel, JJL and Song, S and Liu, C and Hippe, DS and DiGregorio, NA and Brand, CJ and Linden, HM}, title = {The Role of Estrogen Receptor-Targeted PET with 16α-[18]F-Fluoro-17β-Estradiol in Predicting Response to Endocrine Therapies in Metastatic Breast Cancer: A Metaanalysis.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {67}, number = {1}, pages = {36-42}, pmid = {41344861}, issn = {1535-5667}, mesh = {Humans ; *Breast Neoplasms/diagnostic imaging/drug therapy/pathology/metabolism ; *Receptors, Estrogen/metabolism ; *Estradiol/analogs &amp; derivatives ; *Positron Emission Tomography Computed Tomography ; Female ; Neoplasm Metastasis ; Treatment Outcome ; }, abstract = {[[18]F]16α-fluoro-17β-fluoroestradiol ([[18]F]FES) PET/CT imaging enables whole-body assessment of functional estrogen receptor (ER) expression in metastatic breast cancer (mBC). Identifying imaging biomarkers that predict endocrine therapy (ET) response remains a critical need in optimizing treatment selection. Our objective was to assess the predictive utility of [[18]F]FES PET/CT imaging in determining response to ET, with a focus on interlesional heterogeneity and individual patient outcomes. Methods: A systematic literature review and metaanalysis were conducted using 6 major databases through April 2024. Ten studies met inclusion criteria based on quantitative SUV reporting, use of FES PET/CT in mBC, and correlation with clinical outcomes. All patients had ER-positive mBC and received ET. Primary endpoints included progression-free survival (PFS) and response to ET. Patients were stratified by baseline [[18]F]FES PET/CT SUVmean or SUVmax thresholds (including 1.8) and by interlesional [[18]F]FES heterogeneity (presence of both [[18]F]FES-positive and [[18]F]FES-negative lesions). Results: Responders had a significantly higher baseline SUVmean than nonresponders (standardized mean difference, 0.91; 95% CI, 0.49-1.34; P < 0.001). Patients with a baseline SUVmax below 1.5 were significantly less likely to respond (odds ratio, 0.11; 95% CI, 0.02-0.72; P = 0.02). Across 5 studies, patients with heterogeneous [[18]F]FES uptake had a shorter median PFS (2.4-12.4 mo) than did those with all [[18]F]FES-positive lesions (14.6-23.6 mo), a statistically significant difference (ratio of median PFS, 0.25; 95% CI, 0.17-0.36; P < 0.001). In an individual-level analysis (n = 101), lesion-level [[18]F]FES-heterogeneous uptake was associated with a PFS of 5.5 versus 21.6 mo and a hazard ratio of 5.4 (95% CI, 3.2-9.4; P < 0.001). An [[18]F]FES SUVmax threshold of at least 1.8 was more prognostic of PFS than were higher SUVmax thresholds. Conclusion: [[18]F]FES PET/CT imaging provides prognostic insight beyond static ER testing by identifying functional heterogeneity in mBC. Lesion-level FES heterogeneity based on an SUVmax threshold of 1.8 may help stratify patients unlikely to benefit from ET, guiding more personalized treatment strategies.}, }
@article {pmid41345384, year = {2025}, author = {Shadman, M and Harper, JS and Bokun, A and Xu, C and Lin, P and Graf, G and Lu, X}, title = {Real-world treatment patterns and clinical outcomes among patients with diffuse large B-cell lymphoma in a US healthcare claims database.}, journal = {Blood cancer journal}, volume = {16}, number = {1}, pages = {14}, pmid = {41345384}, issn = {2044-5385}, mesh = {Humans ; *Lymphoma, Large B-Cell, Diffuse/therapy/mortality/epidemiology ; Female ; Male ; Middle Aged ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Adult ; United States/epidemiology ; Treatment Outcome ; Cyclophosphamide/therapeutic use ; Doxorubicin/therapeutic use ; Vincristine/therapeutic use ; Prednisone/therapeutic use ; Databases, Factual ; Rituximab/therapeutic use ; Young Adult ; Aged, 80 and over ; Adolescent ; Immunotherapy, Adoptive ; }, abstract = {Treatment options for diffuse large B-cell lymphoma (DLBCL) have expanded, but real-world data on treatment patterns and outcomes remain limited. This study examined real-world outcomes in DLBCL patients treated between 10/1/2015 and 6/30/2024. Patients were stratified by lines of therapy (LOT) and treatments (1L rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]; 2L stem cell transplant [SCT]; and chimeric antigen receptor T-cell [CAR T] therapy (any LOT). Variables were reported descriptively. Time-to-event outcomes were assessed using the Kaplan-Meier method. LOT data from 9875 patients were included. R-CHOP-based regimens were the most common 1L treatment (61.7%-67.3% in 2016-2023; 49.4% in 2024). Conventional chemoimmunotherapy use decreased in 2L (81.6% in 2016 to 41.9% in 2024) and 3L (47.6% in 2016 to 22.1% in 2024), while novel therapies increased (43.0% in 2L and 55.9% in 3L in 2024). Median overall survival declined across LOT (1L: 58.1 months; 2L: 30.0 months), as did median time to next treatment (1L: 36.1 months; 2L: 10.6 months). Twelve-month treatment failure rates were 36.0% after 1L, 51.8% after 2L, and 42.2% after CAR T. Among CAR T recipients, 93 received one of 36 distinct subsequent regimens, indicating no standard of care. These findings highlight the unmet needs in DLBCL.}, }
@article {pmid41346251, year = {2025}, author = {Hershman, DL and Till, C and Leblanc, M and Ramsey, S and Unger, JM}, title = {Development and validation of a risk prediction model for acute care use among older advanced cancer patients on clinical trials.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djaf342}, pmid = {41346251}, issn = {1460-2105}, abstract = {BACKGROUND: patients with advanced cancer are at risk for unplanned Emergency Department (ED) visits and hospital stays (HS). The purpose was to develop and validate a risk prediction model to identify patients at the highest risk for acute care use.<br><br>METHODS: We identified advanced cancer patients &#x2265;65&#x2009;years treated on SWOG trials from 1999-2014 using data linked to Medicare claims. The primary outcome was acute care use (ED visits or HS). A 60% random sample training set was used to identify candidate variables. An adverse risk model was built by summing adverse factors and creating high vs low-risk groups by splitting at the median. This risk model was tested in the 40% validation set.<br><br>RESULTS: Among N&#x2009;=&#x2009;1397 patients from 6 trials, 839 comprised the training set. The proportion of patients with &#x2265;1 HS/ED visit was 67.5%. Adverse risk factors were performance status (0 vs.&#x2265;1), coronary artery disease, hypertension, and liver disease. Patients with &#x2265;2 factors (high-risk; 57.3%) vs. 0/1 risk factor (low-risk; 42.7%) were more likely to experience acute care (79.6% vs. 51.1%), corresponding to a&#x2009;>&#x2009;3-fold increase in odds (OR&#x2009;=&#x2009;3.38, 95%CI , 2.48-4.62). Results were similar in the test set, indicating successful validation. Among all patients, quartile-level proportions were 48.9% for zero risk factors vs. 84.0% for 3/4 risk factors. The C-statistic was 0.703.<br><br>CONCLUSIONS: A limited set of 4 variables predicted a threefold increased risk of acute care use in older patients with advanced cancer. Personalized interventions aimed at preventing acute care use could improve the quality of cancer care.}, }
@article {pmid41346295, year = {2026}, author = {Alexander, JL and Dávila Saldaña, BJ and Brazauskas, R and Dammalapati, SG and Griffith, LM and Shah, AJ and Shimano, KA and Ochs, HD and Bleesing, JJ and Ebens, CL and Kapadia, M and Bauchat, A and Kapoor, N and Oved, JH and Eissa, H and Lust, H and Keller, MD and Haines, H and Chandrakasan, S and Talano, JA and Rayes, A and Madden, L and Shereck, E and Miller, HK and Satter, LF and Martinez, C and Rozmus, J and Bednarski, JJ and Yu, LC and Chellapandian, D and Aquino, VM and Knutsen, A and Chong, H and Chopek, A and Gillio, AP and Joshi, A and Rangarajan, H and Moore, TB and Andolina, JR and DeSantes, KB and Vander Lugt, M and Prockop, SE and Shyr, DC and Sullivan, KE and Parikh, S and Weinacht, KG and Torgerson, TR and Marsh, R and Dvorak, CC and Chan, AY and Haddad, E and Heimall, JR and Pulsipher, MA and Leiding, JW and Kohn, DB and Puck, JM and Notarangelo, LD and Rawlings, DJ and Cowan, MJ and Petrovic, A and Pai, SY and Burroughs, LM}, title = {Hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.}, journal = {Blood advances}, volume = {10}, number = {5}, pages = {1783-1798}, pmid = {41346295}, issn = {2473-9537}, support = {R24 AI184316/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Wiskott-Aldrich Syndrome/therapy/mortality/diagnosis ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Male ; Female ; Child, Preschool ; Child ; Adolescent ; Infant ; Transplantation Conditioning/methods ; Young Adult ; Treatment Outcome ; Adult ; Transplantation, Homologous ; }, abstract = {Wiskott-Aldrich syndrome (WAS), an X-linked disorder characterized by immunodeficiency, thrombocytopenia, autoimmunity, and malignancy, can be effectively treated with allogeneic hematopoietic cell transplantation (HCT). Older age at HCT and mismatched donors are known to affect overall survival (OS). However, the influence of specific clinical manifestations or WAS variant class on OS and factors associated with event-free survival (EFS) remain incompletely defined. We analyzed outcomes of 308 patients with WAS who underwent HCT at 37 institutions of the Primary Immune Deficiency Treatment Consortium from 1990 to 2018. With a median follow-up of 5.3 years, the 5-year OS and EFS were 87.2% and 79.7%, respectively. Age ≥5 years, donor type, and a pre-HCT history of severe infection had a negative impact on OS and EFS, whereas pre-HCT autoimmunity had no impact. Reduced-intensity regimens were associated with lower T-cell and myeloid donor chimerism, particularly when non-busulfan-based regimens were used. Low myeloid donor chimerism was associated with lower platelet counts. Mixed chimerism was not consistently associated with post-HCT autoimmunity. Patients with class I (exon 1-2 missense and intron 5 hot spot variants) and class II variants (all others) had similar pre-HCT clinical symptom severity and no difference in OS, EFS, or platelet recovery post-HCT. In conclusion, our study showed excellent long-term OS and EFS after HCT for WAS, highlighting the importance of early HCT, before the development of severe infections. We confirmed that HCT using busulfan-based conditioning was associated with improved donor chimerism and platelet recovery. This trial was registered at www.clinicaltrials.gov as NCT02064933.}, }
@article {pmid41347212, year = {2022}, author = {Ak, &#xc7; and Chitsazan, AD and Gönen, M and Etzioni, R and Grossberg, AJ}, title = {Spatial prediction of COVID-19 pandemic dynamics in the United States.}, journal = {ISPRS international journal of geo-information}, volume = {11}, number = {9}, pages = {}, pmid = {41347212}, issn = {2220-9964}, support = {K08 CA245188/CA/NCI NIH HHS/United States ; }, abstract = {The impact of COVID-19 across the United States has been heterogeneous, with rapid spread and greater mortality in some areas compared with others. We used geographically-linked data to test the hypothesis that the risk for COVID-19 is defined by location and sought to define which demographic features are most closely associated with elevated COVID-19 spread and mortality. We leveraged geographically-restricted social, economic, political, and demographic information from US counties, to develop a computational framework using structured Gaussian processing to predict county-level case and death counts during the pandemic's initial and nationwide phases. After identifying the most predictive information sources by location, we applied an unsupervised clustering algorithm and topic modelling to identify groups of features most closely associated with COVID-19 spread. Our model successfully predicted COVID-19 case counts of unseen locations, after examining case counts and demographic information of neighboring locations, with overall Pearson's correlation coefficient and the proportion of variance explained of 0.96 and 0.84 during the initial phase and 0.95 and 0.87, respectively, during the nationwide phase. Aside from population metrics, presidential vote margin was the most consistently selected spatial feature in our COVID-19 prediction models. Urbanicity and 2020 presidential vote margins were more predictive than other demographic features. Models trained using death counts showed similar performance metrics. Topic modeling showed that counties with similar socioeconomic and demographic features tended to group together, and some of these grouped feature sets were associated with COVID-19 dynamics. Clustering of counties based on these feature groups found by topic modeling revealed groups of counties that experienced markedly different COVID-19 spread. We conclude that topic modeling can be used to group similar features and identify counties with similar features in epidemiologic research.}, }
@article {pmid41347976, year = {2025}, author = {Cassaday, RD}, title = {Sanctuary sites and extramedullary relapses in the chemo-free world: insights from immunotherapies in B-ALL.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {245-251}, pmid = {41347976}, issn = {1520-4383}, mesh = {Humans ; *Immunotherapy/methods ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/pathology/immunology ; Recurrence ; Tumor Microenvironment ; }, abstract = {When acute lymphoblastic leukemia (ALL) involves extramedullary sites, the appropriate pathologic term for this is lymphoblastic lymphoma. The biological mechanisms underpinning this process are not clear, but they are presumed to involve a multifactorial interplay between tumor cells and the microenvironment of the tissue in which they develop (eg, lymph nodes, thymus, leptomeninges). Importantly for clinicians, these factors may impair the efficacy of systemic therapy given to treat ALL. This gives rise to "sanctuary sites," so named because of the relative protection they provide to malignant blasts that may possess these characteristics. This has become increasingly relevant in the era of "chemotherapy-free" approaches for B-cell ALL, where the potency of antigen-targeted immunotherapies (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor-modified T cells) has been leveraged to reduce or eliminate the reliance on cytotoxic chemotherapy. Such approaches are appealing for their high response rates and favorable toxicity profiles compared to chemotherapy. However, extramedullary relapses have been observed with increased frequency: an outcome historically seen in around 10% of such cases, this can represent over 50% of relapses in some series. This review provides an overview of this emerging issue and what clinicians and investigators can do to address it.}, }
@article {pmid41347988, year = {2025}, author = {Gupta, S and McNeer, J and O'Brien, M and Rau, R and Teachey, D}, title = {The challenge of deintensifying chemotherapy for children and adolescents with B-ALL in the immunotherapy era.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {229-235}, pmid = {41347988}, issn = {1520-4383}, mesh = {Humans ; Adolescent ; Child ; *Immunotherapy/methods ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/drug therapy/immunology ; Female ; Male ; }, abstract = {Recent clinical trials have shown that the addition of immunotherapy has substantially improved cure rates for children and adolescents newly diagnosed with B-acute lymphoblastic leukemia. Most of these patients now have outcomes similar to those previously seen in only the most favorable subgroups. As such, efforts are underway to study whether the incorporation of immunotherapy can allow for elements of traditional toxic chemotherapy to be removed while maintaining excellent outcomes. In this article, we discuss important considerations for such studies, including those related to which patients are appropriate targets of deintensification efforts and which elements of therapy are or are not appropriate candidates for omission.}, }
@article {pmid41347997, year = {2025}, author = {Panch, SR and Raman, G and Bussel, JB}, title = {Refractory ITP: revisiting definitions, diagnostics, and management paradigms.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {312-323}, pmid = {41347997}, issn = {1520-4383}, mesh = {Humans ; *Purpura, Thrombocytopenic, Idiopathic/diagnosis/therapy/physiopathology/blood ; Hemorrhage/therapy ; Platelet Count ; Disease Management ; }, abstract = {Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by decreased platelet counts and a variable propensity for bleeding. Significant strides have delineated the pathophysiologic mechanisms of ITP and led to new therapeutics. Despite these advances, 5% to 30% of patients persist with low platelet counts and/or ongoing bleeding. This review summarizes the current definitions and pathophysiology of refractory ITP, revisiting diagnostic realms and management strategies for these difficult-to-treat patients.}, }
@article {pmid41348020, year = {2025}, author = {Pigazzi, M and Meshinchi, S and Locatelli, F}, title = {Using genomics to refine pediatric AML risk stratification.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {270-278}, pmid = {41348020}, issn = {1520-4383}, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/diagnosis/metabolism/therapy ; Nucleophosmin ; *Genomics/methods ; Child ; Mutation ; Risk Assessment ; Male ; Female ; }, abstract = {In the past 20 years, advances in genomic technologies have greatly improved our understanding of pediatric acute myeloid leukemia (AML). Today, cytogenetic tests can detect structural changes in approximately 75% of cases and remain a main tool for assessing risk. Recent technologies, such as next-generation sequencing, are revealing additional structural alterations (cryptic fusions) and mutations that often cooperate to influence disease biology and treatment response. This evolving genetic landscape has identified unique childhood subtypes of AML defined by specific fusions, such as NUP98::NSD1, CBFA2T3::GLIS2, and varied KMT2A rearrangements, which are linked to distinct clinical outcomes. Emerging data also point to the poor prognosis associated with certain subtypes of NPM1, like the NPM1-D isoform. Additionally, mutations in genes like WT1, DNMT3A, and TP53, the latter of which are rare in childhood AML, may influence patients' outcomes, particularly when occurring in combination. Targeted therapies, including FLT3, BCL2, and menin inhibitors, are beginning to reshape treatment, offering more personalized approaches. However, integrating these drugs effectively into the patient's treatment strategy remains challenging due to the genetic complexity and rarity of pediatric AML. Key issues ahead include identifying which genetic features truly affect outcomes, using this information to personalize therapy, predicting who will benefit from targeted drugs, and choosing the best markers to track disease response over time. Looking forward, collaborative efforts are urgently needed to validate pediatric-specific biomarkers, test novel drug combinations, and link genetic data to clinical outcomes to design trials and future treatment strategies.}, }
@article {pmid41348023, year = {2025}, author = {Ali, N and Sandmaier, BM}, title = {New age HCT conditioning regimens: what works and why?.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {465-475}, pmid = {41348023}, issn = {1520-4383}, mesh = {Humans ; *Transplantation Conditioning/methods ; *Hematopoietic Stem Cell Transplantation/methods ; Busulfan/analogs &amp; derivatives/therapeutic use ; Radioimmunotherapy/methods ; }, abstract = {Conditioning regimens play an essential role in allogeneic transplantation by facilitating engraftment and eradicating malignancies. The landscape of conditioning regimens has undergone an evolution in the concept of intensity. Novel conditioning strategies aim to provide highly efficacious regimens with improved toxicity profiles. Integrating disease- specific chemotherapy and targeted agents into conditioning regimens provides enhanced disease elimination and relapse prevention. Agents like treosulfan provide safer conditioning with a favorable toxicity profile for patients with older age or medical comorbidities and can lower the incidence of long-term complications for younger patients. Additionally, methodologies for precise and targeted radiation delivery with minimal off-target effects are emerging. A promising development is radioimmunotherapy-based regimens that preferentially deplete hematopoietic cells and spare nonhematopoietic tissues. These advancements necessitate reexamination and harmonization of conditioning intensity stratification schemes for a more personalized and selective approach.}, }
@article {pmid41348027, year = {2025}, author = {Wang'ondu, RW and Loh, ML}, title = {Revisiting novel genomic classifiers in the era of immunotherapy for pediatric B-ALL.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {252-261}, pmid = {41348027}, issn = {1520-4383}, mesh = {Humans ; Child ; *Immunotherapy/methods ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/genetics ; *Genomics ; Antibodies, Bispecific/therapeutic use ; Neoplasm, Residual ; Inotuzumab Ozogamicin/therapeutic use ; Algorithms ; Male ; }, abstract = {While recent improvements in survival for pediatric patients with newly diagnosed B-cell precursor acute lymphoblastic leukemia (B-ALL) have been attributed to risk stratification algorithms incorporating somatic genetics and early response dictating therapeutic intensity, recent antibody-based immunotherapeutic agents are changing the therapeutic landscape. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen T-cell receptor therapies are approved by the US Food and Drug Administration for the treatment of relapsed and refractory B-ALL in children, and some have been incorporated into frontline therapies. Studies in both pediatric and adult patients have recently demonstrated superiority of adding blinatumomab to the consolidation phase of treatment in the frontline setting. Revisiting genomic classifiers of B-ALL in the era of antibody-based immunotherapeutic agents may be necessary to maximize the benefits of current risk stratification algorithms in combination with immunotherapy. Available data suggest the efficacy of these agents across genomic subtypes. Here we consider the impact of immunotherapeutic agents within the context of minimal residual disease and molecular classification-based risk stratification.}, }
@article {pmid41348047, year = {2025}, author = {Raychaudhuri, S and Cassaday, RD and Percival, MM}, title = {Peri-transplant conundrums: optimizing maintenance therapy using MRD-directed approaches.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {523-530}, pmid = {41348047}, issn = {1520-4383}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Neoplasm, Residual ; *Hematopoietic Stem Cell Transplantation ; *Leukemia, Myeloid, Acute/therapy/genetics ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/genetics ; Antibodies, Bispecific/therapeutic use ; Sorafenib/therapeutic use ; Azacitidine/therapeutic use ; Aniline Compounds/therapeutic use ; *Maintenance Chemotherapy/methods ; Pyrazines ; }, abstract = {Improved understanding of the molecular underpinnings of acute leukemia has led to advances in the detection of very low levels of leukemia-specific abnormalities, known as measurable residual disease (MRD). The limit of detection for modern next-generation sequencing and polymerase chain reaction-based assays is as low as 10-6, allowing for quantitative and longitudinal monitoring in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In the period surrounding allogeneic hematopoietic cell transplantation (HCT), detectable MRD is clearly associated with poor outcomes, primarily due to an increased risk of morphologic relapse. In this review, we address the use of maintenance therapy for patients with acute leukemia, including those who are MRD-positive prior to and following HCT. Post-HCT azacitidine may have a role for MRD-positive AML. In AML with FLT3-internal tandem duplication mutation, post-HCT gilteritinib and sorafenib can be evidence-based strategies to target MRD. In ALL, blinatumomab is a powerful tool to eradicate MRD in patients with Philadelphia (Ph)-positive or Ph-negative ALL; tyrosine kinase inhibitors are indicated for post-HCT management of Ph+ ALL. Despite these advances, the optimal duration and type of intervention still remain unknown for many patients with acute leukemia who have peri-HCT MRD.}, }
@article {pmid41348052, year = {2025}, author = {Dima, D and Banerjee, R and Hansen, DK}, title = {CAR T-cell therapy and bispecific antibodies in the management of multiple myeloma.}, journal = {Hematology. American Society of Hematology. Education Program}, volume = {2025}, number = {1}, pages = {324-333}, pmid = {41348052}, issn = {1520-4383}, mesh = {Humans ; *Multiple Myeloma/therapy/immunology ; *Antibodies, Bispecific/therapeutic use ; *Immunotherapy, Adoptive/methods ; *Receptors, Chimeric Antigen/therapeutic use/immunology ; B-Cell Maturation Antigen/immunology ; }, abstract = {The introduction of CAR (chimeric antigen receptor) T-cell therapy and bispecific antibodies into clinical practice has revolutionized the treatment landscape of relapsed/refractory multiple myeloma (RRMM). Both modalities have shown impressive clinical efficacy with slightly different but overall manageable toxicity profiles. At present, two B-cell maturation antigen (BCMA)-targeted CAR T-cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, are approved for standard use in the United States. There are currently 4 commercially approved bispecific antibodies: teclistamab, elranatamab, and linvoseltamab, which target BCMA, as well as talquetamab, which targets the GPRC5D antigen on the surface of plasma cells. In this review, we explore (a) the advantages and challenges of integrating CAR T-cell therapy earlier in the RRMM treatment course; (b) the safety and efficacy of bispecific antibodies and their evolving role in the current RRMM treatment paradigm; (c) practical considerations for both modalities, focusing on patient selection and supportive care strategies; and (d) recommendations for sequencing of T-cell redirecting therapies to maximize long-term outcomes.}, }
@article {pmid41348987, year = {2025}, author = {Kilari, D and Henderson, NC and Yamamoto, K and Yao, Y and Hwang, C and Barata, PC and Bilen, MA and Graham, L and Garje, R and Rothstein, S and Haider, S and Park, JJ and Raychaudhuri, R and Pilling, A and Chin, E and Koshkin, VS and Tripathi, A and Cackowski, FC and Nauseef, JT and Sokolova, A and Ayanambakkam, A and Zakharia, Y and Schweizer, MT and Armstrong, AJ and Dorff, TB and Reichert, ZR and McKay, RR}, title = {Impact of SPOP Mutations on Clinical Outcomes in Metastatic Prostate Cancer.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500590}, doi = {10.1200/PO-25-00590}, pmid = {41348987}, issn = {2473-4284}, mesh = {Humans ; Male ; *Repressor Proteins/genetics ; *Prostatic Neoplasms/genetics/pathology/mortality/drug therapy ; Aged ; Middle Aged ; *Mutation ; *Nuclear Proteins/genetics ; Neoplasm Metastasis ; }, abstract = {PURPOSE: Previous studies suggest that SPOP mutations result in increased sensitivity to androgen receptor pathway inhibitors (ARPIs) but are limited by lack of granular data. We hypothesize that SPOP mutations are associated with improved outcomes across the spectrum of advanced prostate cancer (PC).<br><br>METHODS: Using the real-world clinicogenomic Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort database, we analyzed outcomes based on SPOP mutation status. The primary end point was overall survival (OS) from the diagnosis of metastatic disease. Secondary end points included real-world progression-free survival (PFS) and PSA90 response.<br><br>RESULTS: Among 2,097 patients with metastatic PC, 5.5% (N = 115) had SPOP-mutated tumors. Compared with SPOP wild-type, patients with SPOP mutations were older at diagnosis (median 65 v 63 years; P = .001) and had higher (&#x2265;8) Gleason sum (68% v 54%; P = .02), higher incidence of lung metastasis (17% v 6%; P = .001), and increased frequency of intraductal features (13% v 5%; P < .001). SPOP mutations were associated with improved PSA90 response with first ARPI exposure in the castrate-resistant setting (60% v 40.6%; OR, 2.20 [95% CI, 1.15 to 4.19]; P = .02) but not in the castrate-sensitive setting (78.9% v 71.5%; OR, 1.49 [95% CI, 0.66 to 3.37]; P = .43). Median PFS with first ARPI did not differ in SPOP-mutated versus wild-type group in both the castrate-sensitive (24.2 v 19.2 months; hazard ratio [HR], 0.80 [95% CI, 0.49 to 1.32]; P = .39) and castrate-resistant settings (15.0 v 12.4 months; HR, 0.81 [95% CI, 0.58 to 1.12]; P = .20). In multivariable analysis, SPOP mutations were associated with improved OS (HR, 0.65, P = .02).<br><br>CONCLUSION: SPOP mutations were associated with longer OS despite the presence of aggressive clinical features. The distinct clinical and molecular features of SPOP-mutated PC support its consideration as a unique molecular subtype with prognostic implications.}, }
@article {pmid41350402, year = {2026}, author = {Robertson, AJ and Kerr, B and Feder, AF}, title = {Intracellular interactions shape antiviral resistance outcomes in poliovirus via eco-evolutionary feedback.}, journal = {Nature ecology &amp; evolution}, volume = {10}, number = {3}, pages = {429-438}, pmid = {41350402}, issn = {2397-334X}, support = {T32-GM136534-02//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 2142718//National Science Foundation (NSF)/ ; }, mesh = {*Poliovirus/drug effects/physiology/genetics ; *Antiviral Agents/pharmacology ; *Drug Resistance, Viral/genetics ; *Biological Evolution ; Humans ; }, abstract = {Resistance evolution can undermine antiviral treatment. However, targeting antivirals to shared viral proteins could inhibit resistance evolution if susceptible viruses sensitize resistant ones during cellular coinfection. Pocapavir, a poliovirus capsid inhibitor, uses this sociovirological interference strategy. While susceptible viruses substantially suppress pocapavir resistance in cell culture, a pocapavir clinical trial found widespread resistance and limited clearance time improvements in treated participants. Here, to reconcile these findings, we present an intrahost eco-evolutionary model of pocapavir-treated poliovirus, which reproduces both in vitro interference and clinical resistance evolution. In the short term, high densities of susceptible viruses sensitize resistant ones, mirroring cell culture results. However, over multiple replication cycles, pocapavir's high potency collapses viral density, reducing coinfection and enabling resistance evolution, as observed clinically. Because resistance suppression relies on coinfection, enhancing susceptible virus survival could offer therapeutic advantages. Counterintuitively, we demonstrate that lessening antiviral potency can increase coinfection, limiting resistance while also maintaining low viral load. These findings suggest that antivirals relying on viral intracellular interactions must balance immediate neutralization with preserving future coinfection for sustained inhibition. Explicitly considering the eco-evolutionary feedback encompassing viral density, shared phenotypes and absolute fitness provides new insights for effective therapy design and illuminates viral evolutionary dynamics more broadly.}, }
@article {pmid41351263, year = {2026}, author = {Ferrier, K and Graff, M and Konigsberg, IR and Stanislawski, M and Highland, HM and Raffield, LM and Carson, AP and Boerwinkle, E and Norris, JM and Gignoux, CR and Hendricks, AE and Raghavan, S and North, KE and Young, KL and Justice, AE and Allison, MA and Budoff, MJ and Kasela, S and Aguet, F and Joseph, JJ and Kooperberg, C and Rich, SS and Rotter, JI and Lange, EM and Lange, LA}, title = {Epigenome-wide association study meta-analysis of BMI in African Americans.}, journal = {HGG advances}, volume = {7}, number = {1}, pages = {100552}, pmid = {41351263}, issn = {2666-2477}, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Black or African American/genetics ; *Body Mass Index ; CpG Islands ; DNA Methylation ; Epigenesis, Genetic ; Epigenome ; Genome-Wide Association Study ; *Obesity/ethnology/genetics ; }, abstract = {Despite considerable advances in identifying risk factors for obesity, gaps remain in our understanding about its etiology. Genetic variants explain only a small portion of variation in obesity-related traits such as body mass index (BMI). Epigenetic regulation, which controls gene expression and is influenced by environmental and genetic factors, may account for additional variability in BMI. Epigenetic studies of BMI have largely been conducted in European ancestry populations, despite the disproportionate burden of obesity in African Americans (AAs). We conducted a sex-stratified BMI epigenome-wide association study meta-analysis in AA participants from the Jackson Heart Study (n = 1,604) and the Multi-Ethnic Study of Atherosclerosis (n = 179) with Illumina EPIC (850,000) array data. Linear regression models with methylation as the outcome and continuous BMI as the predictor were stratified by study and sex and meta-analyzed. We identified 208 methylation sites (CpGs, p < 8.72 × 10[-8]) significantly associated with BMI; 151 had not been previously reported in the literature. Replication was performed in a separate sample of AA participants with 450,000 array data, which lacks many CpGs present in the 850,000 array. Replication testing was possible for only 29 of the 151 CpGs; 19 were statistically significant (p < 1.72 × 10[-3]). Sex-specific results showed 4 female-only and 3 male-only BMI-CpGs not identified in the sex-combined results. Differentially methylated region (DMR) analysis resulted in 66 DMRs, including several regions near genes previously implicated for obesity (e.g., SOCS3, TGFB1). Further analyses showed enrichment of genes and traits related to the immune system and inflammation-related pathways (e.g., the IL-6/JAK/STAT pathway).}, }
@article {pmid41351880, year = {2026}, author = {Wang, K and Saniei, S and Poddar, N and Martinez, IG and Chao, C and Autar, S and Fiore, P and Carcamo, S and Sreenath, M and Peplinski, JH and Ries, RE and Mei, AH and Rahman, NA and Mekerishvili, L and Quijada-Álamo, M and Freed, G and Zhang, M and Lachman, K and Diaz, Z and Gonzalez, MM and Zhang, J and Pham, G and Filipescu, D and Berisa, M and Balestra, T and Wheeler, N and Reisz, JA and D'Alessandro, A and Puleston, DJ and Bernstein, E and Chipuk, JE and Wunderlich, M and Tasian, SK and Marcellino, BK and Glass, IA and ,  and Sturgeon, CM and Landau, DA and Chen, Z and Papapetrou, EP and Izzo, F and Meshinchi, S and Hasson, D and Wagenblast, E and , }, title = {Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia.}, journal = {Cancer discovery}, volume = {16}, number = {3}, pages = {541-570}, pmid = {41351880}, issn = {2159-8290}, support = {S10OD030463//National Institutes of Health (NIH)/ ; //CureSearch for Children's Cancer (CSCC)/ ; 7039-25//Leukemia and Lymphoma Society (LLS)/ ; //Leukemia and Lymphoma Society (LLS)/ ; S10 OD026880/OD/NIH HHS/United States ; V2024-015//V Foundation for Cancer Research (VFCR)/ ; R01 CA292503/CA/NCI NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; R24 HD000836/HD/NICHD NIH HHS/United States ; 77-23//Damon Runyon Cancer Research Foundation (DRCRF)/ ; P30 CA196521/CA/NCI NIH HHS/United States ; S10OD026880//National Institutes of Health (NIH)/ ; UL1TR004419//National Center for Advancing Translational Sciences (NCATS)/ ; //Andrew McDonough B+ Foundation (AMBF)/ ; //Rally Foundation (Rally)/ ; R24HD000836//National Institutes of Health (NIH)/ ; R01 CA260711/CA/NCI NIH HHS/United States ; R01CA290681//National Institutes of Health (NIH)/ ; R01 CA290681/CA/NCI NIH HHS/United States ; 22-25847//Alex's Lemonade Stand Foundation for Childhood Cancer (ALSF)/ ; S10 OD030463/OD/NIH HHS/United States ; P30CA196521//National Institutes of Health (NIH)/ ; //Edward P. Evans Foundation/ ; R01CA292503//National Institutes of Health (NIH)/ ; //Pew Charitable Trusts (Pew)/ ; }, mesh = {Humans ; Mice ; Animals ; Child ; Cell Lineage ; *Leukemia, Myeloid, Acute/genetics/pathology/drug therapy ; Hematopoietic Stem Cells/metabolism/pathology ; Mutation ; Cell Transformation, Neoplastic/genetics ; Neoplastic Stem Cells/pathology/metabolism ; }, abstract = {UNLABELLED: Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of the developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell developmental stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model of NUP98::NSD1-driven pediatric acute myeloid leukemia that is particularly aggressive with WT1 comutations. Fetal-derived hematopoietic stem cells readily transform into leukemia, and WT1 mutations further enhance stemness and alter lineage hierarchy. In contrast, stem cells from later developmental stages become progressively resistant to transformation. Single-cell analyses revealed that fetal-origin leukemia stem cells exhibit greater quiescence and reliance on oxidative phosphorylation than their postnatal counterparts. These differences drive distinct therapeutic responses despite identical oncogenic mutations. In patients, onco-fetal transcriptional programs correlate with worse outcomes. By targeting key vulnerabilities of fetal-origin leukemia cells, we identified combination therapies that significantly reduce aggressiveness, highlighting the critical role of ontogeny in pediatric cancer treatment.<br><br>SIGNIFICANCE: This study signifies the critical consequences of developmental timing in cancer initiation, revealing that identical driver mutations in fetal- versus postnatal-origin leukemias exhibit fundamentally distinct biology and treatment responses. Recognizing these developmental differences opens avenues for personalized therapeutic strategies, improving outcomes for pediatric patients with aggressive disease subtypes in leukemia.}, }
@article {pmid41352870, year = {2025}, author = {Nagana Gowda, GA and Zhu, W and Raftery, D}, title = {NMR-based metabolomics: Where are we now and where are we going?.}, journal = {Progress in nuclear magnetic resonance spectroscopy}, volume = {150-151}, number = {}, pages = {101564}, pmid = {41352870}, issn = {1873-3301}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 AR074990/AR/NIAMS NIH HHS/United States ; R01 GM138465/GM/NIGMS NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; R01 GM131491/GM/NIGMS NIH HHS/United States ; }, mesh = {*Metabolomics/methods ; Humans ; Magnetic Resonance Spectroscopy/methods ; Mass Spectrometry/methods ; Biomarkers/analysis/metabolism ; Animals ; }, abstract = {The fast-growing field of metabolomics focuses on the analyses of complicated mixtures of small molecules present in biological samples. To date, metabolomics has provided a wealth of information on biological systems and impacted numerous areas of basic and life sciences. A major focus of metabolomics has been on biomedicine with the goal of biomarker discovery, drug discovery and improved mechanistic understanding of the pathogenesis of many human diseases. Analytical methods play a pivotal role in metabolomics, with the two most widely used platforms being nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Among their many complementary capabilities, NMR is generally more reproducible and quantitative, whereas MS is more sensitive. Recent technological advances in NMR have resulted in multifaceted developments, including improvements in sensitivity, resolution and speed, along with expanded metabolite identification and quantitation, which together provide exciting potential for future studies. In addition to NMR developments, the combination of NMR with MS provides numerous benefits that are becoming more evident over time. Hence, the metabolomics field has witnessed an increased number of studies and applications that combine NMR with MS in numerous areas, including new methods development for unknown identification, metabolite quantitation, disease biomarker discovery, mechanistic understanding of disease pathogenesis, and dietary risk factors of diseases among others. This report describes the current status of state-of-the-art methods in NMR-based metabolomics, along with recent advances and future prospects, with an emphasis on the benefits of combining NMR with MS.}, }
@article {pmid41354273, year = {2026}, author = {Merkel, EC and Gooley, T and Thakar, MS and Furlan, SN and Summers, C and Kirkey, DC and Hadland, B and Burroughs, LM and Carpenter, PA and Petrovic, A and Goshorn, R and Irwin, R and Bleakley, M and Cooper, T and Tarlock, K and Dahlberg, A}, title = {Post Hematopoietic Cell Transplantation Maintenance Therapy With Low-Dose Azacitidine in a Pediatric Population With High-Risk Myeloid Malignancies.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {4}, pages = {474.e1-474.e13}, doi = {10.1016/j.jtct.2025.12.003}, pmid = {41354273}, issn = {2666-6367}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA289886/CA/NCI NIH HHS/United States ; RC2 DK127989/DK/NIDDK NIH HHS/United States ; T32 HL125195/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Child ; *Azacitidine/therapeutic use/administration &amp; dosage ; Male ; Female ; Adolescent ; Retrospective Studies ; *Leukemia, Myeloid, Acute/therapy ; Child, Preschool ; *Myelodysplastic Syndromes/therapy ; *Antimetabolites, Antineoplastic/therapeutic use ; }, abstract = {BACKGROUND: Patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with high-risk features undergoing hematopoietic cell transplantation (HCT) experience high rates of relapse. Hypomethylating agent azacitidine (AZA) has been explored as post-HCT maintenance therapy at low doses to prevent relapse based on its potential for clinical efficacy and enhancing the graft-versus-leukemia effect.<br><br>OBJECTIVE: To better understand the feasibility, tolerability, and efficacy of post-HCT maintenance AZA in a pediatric population with high-risk myeloid malignancies who underwent allogeneic HCT.<br><br>STUDY DESIGN: A retrospective analysis was conducted of 24 pediatric patients (median age 12.4 years) with high-risk myeloid malignancies who received post-HCT AZA at a single institution. Descriptive measures were used to summarize participant characteristics. Point estimates of overall survival (OS) and relapse-free survival (RFS) were obtained using the method of Kaplan and Meier. Point estimates of relapse and non-relapse mortality were summarized using cumulative incidence estimates.<br><br>RESULTS: AZA began at a median of 81 days post-HCT. The AZA dose ranged between 32-50 mg/m[2] x 5 days and AZA continued for a median of 9 cycles. No significant myelosuppression or hospitalizations attributed to AZA were observed. Eighteen patients (75%) were diagnosed with grade II acute graft-versus-host disease (GVHD) before AZA initiation; 3 (16.7%) experienced &#x2264; grade II acute GVHD flares while tapering immunosuppressive treatment (IST) and receiving AZA. Of the 20 patients in remission at 1-year post-HCT, 18 (90%) had completed or were tapering IST. Six patients relapsed and the 3-year point estimate of relapse was 27%. There were 3 deaths due to relapsed disease. The 3-year point estimate of OS was 91% (one of the 3 deaths occurred beyond 3 years, at 3.2 years) and the 3-year estimate of RFS was 73%. The median follow-up among the 21 surviving patients was 29 months (range 12 to 80).<br><br>CONCLUSIONS: This is the largest reported pediatric cohort receiving post-HCT prophylaxis with AZA. Our findings suggest AZA is tolerable with limited toxicity post-HCT and can be administered to pediatric patients with myeloid malignancies as maintenance therapy. Outcomes were favorable warranting further study.}, }
@article {pmid41354605, year = {2026}, author = {Cheng, HH and Callis, S and Yu, EY and Delacroix, SE and Sokolova, AO and Tangen, CM and Lerner, SP and Dorff, TB and Lin, DW}, title = {Clinical Trial in Progress: SWOG S2210, a Phase 2 Study of Neoadjuvant Carboplatin for Localized High-risk Prostate Cancer with Germline BRCA1/2 Mutations.}, journal = {European urology focus}, volume = {12}, number = {1}, pages = {16-18}, doi = {10.1016/j.euf.2025.11.011}, pmid = {41354605}, issn = {2405-4569}, mesh = {Humans ; Male ; *Carboplatin/therapeutic use ; *Prostatic Neoplasms/genetics/drug therapy/pathology ; *Neoadjuvant Therapy/methods ; Germ-Line Mutation ; Clinical Trials, Phase II as Topic ; BRCA2 Protein/genetics ; *Antineoplastic Agents/therapeutic use ; BRCA1 Protein/genetics ; Genes, BRCA2 ; }, abstract = {SWOG S2210 is a phase 2 trial testing the use of biomarker-guided neoadjuvant carboplatin, a safe and accessible chemotherapy agent, for patients with localized high-risk prostate cancer and inherited BRCA1/2 mutations. The endpoints are pathologic complete response rates and survival outcomes.}, }
@article {pmid41356727, year = {2025}, author = {Mohty, M and Ye, Y and Banerjee, R}, title = {Skills, attitude and knowledge for early-career hematologists: a pragmatic, scientific framework.}, journal = {Clinical hematology international}, volume = {7}, number = {4}, pages = {37-40}, pmid = {41356727}, issn = {2590-0048}, }
@article {pmid41358143, year = {2025}, author = {Othus, M and Patel, SP and Chae, YK and Dietrich, E and Ahluwalia, MS and Kurzrock, R}, title = {Outcomes of Patients with Rare Cancers Treated with Combination Immune Checkpoint Inhibitors With and Without Prior anti-PD-1/L1 Exposure (NCI/SWOG S1609).}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {}, pmid = {41358143}, issn = {2994-9750}, support = {R01 CA264017/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; R01 CA277728/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: There are limited data on response and survival outcomes for patients who receive the combination of anti-PD-1 and anti-CLTA-4 after prior failure of an anti-PD-1/L1, in particular among patients with less common cancers. We analyzed a unique trial resource, an NCI-sponsored basket trial for participants with rare solid tumors conducted by SWOG that was open at over 1,000 sites across the USA (S1609/DART). Participants received Ipilimumab (1mg/kg every six weeks) plus nivolumab (240 mg every two weeks) (both intravenously). The trial eligibility allowed prior exposure to anti-PD-1/L1, and our objective was to compare response and survival outcomes for patients with and without prior anti-PD-1/PDL-1.<br><br>METHODS: Logistic and Cox regression models were used to evaluate associations between prior anti-PD-1/PDL-1 exposure and the endpoints of clinical benefit rate (CBR) (includes stable disease of at least six months and objective response by RECISTv1.1), progression-free survival (PFS), and overall survival (OS).<br><br>RESULTS: CBR was not significantly different between those with and without prior anti-PD-1/L1 exposure, 26% in both groups. There were no significant differences in PFS and OS between patients with and without prior anti-PD-1/L1 exposure on either univariate and multivariable analysis (multivariable hazard ratio, 95% confidence interval and p-value: PFS: 1.18, 0.83-1.68, p=0.36; OS: 1.11, 0.76-1.63, p=0.58).<br><br>CONCLUSIONS: There were no statistically or clinically significant differences in outcomes with and without prior anti-PD-1/L1 exposure for patients with a variety of rare cancers treated with nivolumab and ipilimumab. Patients with prior anti-PD-1/L1 exposure should be eligible for clinical trials evaluating combination immunotherapy.}, }
@article {pmid41358287, year = {2025}, author = {Sevilla-González, M and Wang, N and Hanson, PA and Bebo, A and Hitchcock, D and Hsu, S and Westerman, KE and Cromer, SJ and Barry, VG and Borns-Weil, Y and Zhang, Y and Ben-Yossef, O and Patel, CJ and Franceschini, N and Taylor, KD and Ávila-Pacheco, J and Clish, CB and Gertzen, RE and Raffield, LM and Kooperberg, C and Rich, SS and Dupuis, J and Rotter, JI and Liu, CT and Meigs, JB and Manning, AK}, title = {Dissecting Genetic and Environmental Determinants of Plasma Molecular Signatures and Their Link to Type 2 Diabetes Risk.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41358287}, support = {75N92021D00005/WH/WHI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; 75N98025D00025/OD/NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N98025D00027/OD/NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N98025D00026/OD/NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N98025D00028/OD/NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; 75N98025D00024/OD/NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; K99 DK139461/DK/NIDDK NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; 75N98025D00022/OD/NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; UM1 DK078616/DK/NIDDK NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Type 2 diabetes (T2D) is a heterogeneous disease shaped by both genetic, environmental, cultural, and socioeconomic factors, with well-documented disparities in incidence across populations. The molecular pathways underlying these disparities, however, remain poorly understood. Plasma metabolites and proteins integrate both genetic and environmental influences on type 2 diabetes (T2D) risk, providing insight into disease mechanisms. We aimed to quantify the variance in these molecular profiles explained by environmental and genetic ancestry domains and to apply causal inference approaches to identify environmentally and genetic ancestry influenced pathways contributing to T2D risk.<br><br>METHODS: We analyzed plasma proteomic and metabolomic profiles from 3,360 MESA participants (51.6% female), and in 1,333 participants from the Women's Health Initiative. To characterize the sources of variance in plasma proteomic and metabolomic profiles, we performed variance decomposition partitioning into four domains: biological (age, sex, BMI), genetic ancestry (principal components), lifestyle (smoking, alcohol intake, diet), and social determinants (self-reported race and ethnicity, income, education). To assess causal pathways towards T2D risk, we applied two-sample Mendelian Randomization to disentangle environmental and genetic contributors to T2D risk.<br><br>RESULTS: The largest share of variance in proteomic and metabolomic profiles was explained by biological and lifestyle factors, while race and ethnicity and genetic ancestry accounted for smaller but non-redundant contributions. Genetic ancestry was primarily associated with lipid and apolipoprotein variation, whereas race and ethnicity and socioeconomic factors were associated with immune and inflammatory signatures. Environmentally influenced metabolites (e.g., diacylglycerols, phosphatidylethanolamines, lysophosphatidylcholines) and vascular-inflammatory proteins were consistently linked to higher T2D risk, while genetic ancestry influenced triglycerides and IGFBP3 reflected inherited risk pathways. Mediation analyses showed that selected lipids and proteins (e.g., IGFBP2, HGF, SSC4D) explained 10-25% of racial/ethnic disparities in T2D. Mendelian randomization identified causal roles for seven lipid species and IGFBP3 in T2D risk.<br><br>CONCLUSIONS: Our results reveal both genetic and non-genetic sources of variation in proteomic and metabolomic profiles, uncovering environmental and genetic pathways contributing to T2D risk. These findings advance precision medicine by identifying modifiable molecular mediators of disparities and potential causal targets for prevention.}, }
@article {pmid41359796, year = {2026}, author = {Leaf, RK and Mones, JV and Shenoy, T and Warsame, M and Beltrami-Moreira, M and Panch, S and Leavitt, AD and Zon, RL and Kendall, EK and Shahamatdar, S and Lim, TL and Cui, C and Jiang, D and Kaunfer, SA and Durai, L and Hoge, ST and Dias, JA and Sha, C and Holmes, AN and Easton, N and Corley, EM and Zhao, E and Li, X and Spelman, A and Amos, CB and Soebbing, D and Shabih, M and Jamison, T and Liu, B and Hussein, G and Yadav, S and Elsaid, MI and Owen, DH and Meara, A and Juras, PK and Suresh, A and Heskel, M and Huang, JJ and Glezerman, IG and Go, RS and Reynolds, KL and Al-Samkari, H and Kroll, MH and Leaf, DE}, title = {Immune thrombocytopenia in patients treated with immune checkpoint inhibitors.}, journal = {Blood}, volume = {147}, number = {12}, pages = {1351-1364}, doi = {10.1182/blood.2025031449}, pmid = {41359796}, issn = {1528-0020}, mesh = {Humans ; Male ; *Immune Checkpoint Inhibitors/adverse effects/therapeutic use ; Female ; *Purpura, Thrombocytopenic, Idiopathic/chemically induced/drug therapy/mortality/epidemiology ; Middle Aged ; Aged ; Retrospective Studies ; Risk Factors ; *Neoplasms/drug therapy ; Adult ; Aged, 80 and over ; Platelet Count ; }, abstract = {Immune checkpoint inhibitor-associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.}, }
@article {pmid41360064, year = {2026}, author = {Sehn, LH and Hübel, K and Luminari, S and Scholz, CW and Salar, A and Paneesha, S and Wahlin, BE and Panayiotidis, P and Lee, HP and Jiménez-Ubieto, A and Sancho, JM and Kim, TM and Domingo Domenech, E and Kumode, T and Poh, C and Thieblemont, C and Deeren, D and de Wit, E and Arbushites, M and Vassallo, I and Trneny, M and , }, title = {Tafasitamab, lenalidomide, and rituximab in relapsed or refractory follicular lymphoma (inMIND): a global, phase 3, randomised controlled trial.}, journal = {Lancet (London, England)}, volume = {407}, number = {10524}, pages = {133-146}, doi = {10.1016/S0140-6736(25)01778-7}, pmid = {41360064}, issn = {1474-547X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects/therapeutic use ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; Double-Blind Method ; *Lenalidomide/administration &amp; dosage/adverse effects/therapeutic use ; *Lymphoma, Follicular/drug therapy/mortality ; Neoplasm Recurrence, Local/drug therapy ; Progression-Free Survival ; *Rituximab/administration &amp; dosage/adverse effects/therapeutic use ; }, abstract = {BACKGROUND: Follicular lymphoma is characterised by episodes of remission and relapse, with patients requiring multiple lines of therapy. Lenalidomide plus rituximab is a commonly used immunotherapy combination in patients with relapsed or refractory follicular lymphoma. We aimed to assess the efficacy and safety of adding tafasitamab, a CD19-targeted Fc-enhanced monoclonal antibody, to lenalidomide and rituximab in this setting.<br><br>METHODS: This phase 3, double-blind, randomised, placebo-controlled trial (inMIND) was done in 210 centres (including community-based haematology clinics, major hospitals, and academic institutions) in North America, Europe, and the Asia-Pacific region. Adults with relapsed or refractory follicular lymphoma, who had received at least one previous line of systemic therapy, were eligible for enrolment and randomly assigned (1:1) to receive treatment with up to 12 cycles (28-day cycle length) of tafasitamab (12 mg/kg by intravenous infusion on days 1, 8, 15, and 22 of cycles 1-3 and days 1 and 15 of cycles 4-12) or placebo, both with lenalidomide (20 mg/day orally on days 1-21 of cycles 1-12) and rituximab (375 mg/m[2] by intravenous infusion on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-5). Treatment assignment was achieved via an interactive voice or web response system; patients, investigators, and the funder were masked until the primary analysis. Study endpoints were investigator assessed unless otherwise specified. The primary endpoint was progression-free survival in the intention-to-treat population of all randomised patients; safety was assessed in all randomised patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04680052) and EUDRA-CT (2020-004407-13) and is active but no longer enrolling.<br><br>FINDINGS: Between April 16, 2021, and Aug 10, 2023, a total of 817 patients were assessed for eligibility; 548 patients with relapsed or refractory follicular lymphoma were enrolled and randomly assigned to treatment with either tafasitamab (n=273) or placebo (n=275). 299 (55%) of all randomised patients were male and 249 (45%) were female. The addition of tafasitamab to lenalidomide and rituximab resulted in significantly lower risk of progression, relapse, or death versus placebo (median progression-free survival by investigator 22&#xb7;4 months [95% CI 19&#xb7;2 to not evaluable] in the tafasitamab group vs 13&#xb7;9 months [11&#xb7;5-16&#xb7;4] in the placebo group; hazard ratio 0&#xb7;43 [95% CI 0&#xb7;32-0&#xb7;58]; p<0&#xb7;0001) in the planned primary analysis. Improvement in progression-free survival was confirmed by independent review committee. Adverse events were reported in 272 (99%) of 274 patients in the tafasitamab group and 270 (99%) of 272 patients in the placebo group. Most common adverse events occurring in either the tafasitamab group or placebo group were neutropenia (133 [49%] vs 123 [45%]) and diarrhoea (103 [38%] vs 77 [28%]). There were no deaths due to treatment-related adverse events in the tafasitamab group; two (1%) patients had fatal adverse events related to treatment in the placebo group.<br><br>INTERPRETATION: The addition of tafasitamab to lenalidomide and rituximab resulted in a statistically significant and clinically meaningful improvement in progression-free survival, with an acceptable safety profile in patients with relapsed or refractory follicular lymphoma. This combination represents a potential new standard-of-care treatment.<br><br>FUNDING: Incyte.}, }
@article {pmid41360798, year = {2025}, author = {Birukov, A and Lin, N and Mongiovi, J and Razquin, C and Wang, F and Semnani-Azad, Z and Tessier, AJ and Guasch-Ferré, M and Ley, SH and Manson, JE and Sinkey, RG and Haring, B and Shadyab, AH and Balasubramanian, R and Martínez-González, MA and Rexrode, KM and Hu, FB and Zhang, C and Zeleznik, OA and Sasamoto, N}, title = {Plasma metabolomic signature of breastfeeding and risk of cardiometabolic diseases.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {11124}, pmid = {41360798}, issn = {2041-1723}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; R01HL034594//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R03 CA259659/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01CA67262//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92021D00005/WH/WHI NIH HHS/United States ; K23 HL159331/HL/NHLBI NIH HHS/United States ; R03CA259659//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01CA49449//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92021D00003/WH/WHI NIH HHS/United States ; R01 HL034594/HL/NHLBI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; U01CA176726//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; Female ; *Breast Feeding/statistics &amp; numerical data ; *Metabolomics/methods ; *Cardiovascular Diseases/epidemiology/blood/metabolism ; Adult ; Middle Aged ; Prospective Studies ; *Diabetes Mellitus, Type 2/epidemiology/blood ; *Metabolome ; Incidence ; Risk Factors ; Triglycerides/blood ; Biomarkers/blood ; Proportional Hazards Models ; }, abstract = {Breastfeeding is inversely associated with cardiometabolic disease incidence in prospective studies; however, the metabolic pathways underlying these associations remain largely unknown. Here, we derive a plasma metabolomic score of lifetime total duration of breastfeeding using elastic net regularized regression in Nurses' Health Studies (n = 4349) and replicate in the Women's Health Initiative (n = 2088). Data include 181 untargeted plasma metabolites profiled by liquid chromatography mass spectrometry using blood samples collected in mid-life, and self-reported lifetime total duration of breastfeeding. We then examine the associations between the metabolite-based breastfeeding score and risk of T2D and CVD using multivariable Cox regression models and replicated in two external cohorts. The metabolite-based breastfeeding score comprised of 5 metabolites (i.e., C54:2 triglyceride, C56:2 triglyceride, C56:3 triglyceride, cotinine, indole-3-propionate), which show a modest but statistically significant correlation with lifetime total duration of breastfeeding. The metabolite-based breastfeeding score significantly inversely associate with T2D incidence (HR = 0.76, 95%CI = 0.71-0.82) and with CVD incidence (HR = 0.88, 95%CI = 0.84-0.93) independent of T2D and CVD risk factors. We identify plasma metabolite profiles in mid-life associated with breastfeeding duration, which is also linked to CVD and T2D risk.}, }
@article {pmid41361127, year = {2026}, author = {Zvolensky, MJ and Shepherd, JM and Bevers, LM and Redmond, BY and Garey, L and Jo, D and Asfar, T and Castillo-Avilés, R and Santiago-Torres, M and Bricker, JB}, title = {Quit behavior among Hispanic persons who smoke: evaluating differences in nicotine replacement therapy.}, journal = {Journal of behavioral medicine}, volume = {49}, number = {1}, pages = {57-65}, pmid = {41361127}, issn = {1573-3521}, support = {U54MD015946/MD/NIMHD NIH HHS/United States ; U54MD015946/MD/NIMHD NIH HHS/United States ; }, abstract = {Hispanic individuals experience significant health disparities related to smoking. Research focused on the methods employed to quit smoking among the Hispanic population is needed to better understand how to increase engagement with evidence-based smoking cessation guidelines and mitigate smoking-related health disparities. The present investigation sought to: (1) document smoking cessation methods used in previous quit attempts, including Nicotine Replacement Therapy (NRT), and (2) test group differences (NRT use vs not) in smoking-related vulnerability processes (i.e., cigarette dependence, perceived barriers for smoking cessation, severity of problems when trying to quit, and number of prior failed quit attempts). Participants were recruited nationally throughout the United States via Qualtrics Panels and were 302 Hispanic adults (38.1% female, Mage = 35.70, SD = 8.63) who endorsed daily cigarette smoking and a prior quit attempt. Results indicated that the most common method of quitting was 'cold turkey' (65.6%), but other methods were also employed (e.g., gradual reduction of cigarettes, enlisting social support). Moreover, there was a substantial number (57.9%) who used NRT in the form of nicotine gum or patch. Additionally, across each of the criterion variables studied, those who had used NRT demonstrated greater cigarette dependence, perceived barriers for smoking cessation, severity of problems when trying to quit, and number of prior failed quit attempts when compared to persons with no such history of NRT use. Overall, these data suggest that history of NRT use may identify a subgroup of Hispanic persons in need of more intensive smoking cessation treatment.}, }
@article {pmid41363134, year = {2025}, author = {Murphy, NR and Snidarich, M and Budak, JZ and Brown, MC and Weiner, BJ and Giustini, N and Caverly, TJ and Ross, K and DeCell, K and Crothers, K and Triplette, M}, title = {Tensions in Implementation: A Mixed-Methods Evaluation of a Lung Cancer Screening Shared Decision-Making Aid for People With HIV.}, journal = {Health promotion practice}, volume = {}, number = {}, pages = {15248399251388644}, doi = {10.1177/15248399251388644}, pmid = {41363134}, issn = {1552-6372}, abstract = {People with HIV (PWH) are at increased risk for lung cancer, but lung cancer screening (LCS) is understudied in this population. We previously adapted a shared decision-making (SDM) aid for PWH and demonstrated its efficacy in improving LCS knowledge. In this study, we conducted a mixed-methods evaluation of the implementation of this aid. Participants were LCS-eligible PWH. Forty participants reviewed HIV-adapted and individually tailored decision aids at SDM visits and completed pre-/post-visit surveys. Fifteen completed semi-structured interviews. Interviews were analyzed using thematic analysis guided by the Health Equity Implementation Framework and triangulated with surveys through joint displays. Participants generally approved of the SDM aid as it explained the risks and benefits of screening, but six key implementation tensions emerged: (1) Participants generally trusted clinician recommendations but highlighted how their lived experience with HIV informed some medical skepticism and desire for autonomy. (2) There was appreciation for HIV-focused material, but emphasis on individuality and the variable experiences of PWH. (3) Participants were interested and motivated regarding LCS but highlighted systemic barriers. (4) The aid improved comfort for many, but increased anxiety or confusion for others. (5) Some preferred SDM with their primary care clinician, while others prioritized the opinion of an LCS-focused clinician. (6) Several were motivated to quit smoking after SDM, while others were reassured to continue smoking by lower-than-expected risk estimates. This adapted decision aid was well-received, but interviews highlighted tensions in implementation. Iterative adaptation of the decision aid and communication strategies is needed to optimize SDM for PWH.}, }
@article {pmid41363715, year = {2025}, author = {Wassertheil-Smoller, S and Larson, JC and Xue, X and Greywoode, R and Bohm, M and Liu, L and Wallace, R and Wactawski-Wende, J and Haring, B and LaMonte, M}, title = {Low Diastolic Blood Pressure and Risk of Ischemic Colitis in the Women's Health Initiative Cohort.}, journal = {The American journal of gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.14309/ajg.0000000000003878}, pmid = {41363715}, issn = {1572-0241}, support = {75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005/NH/NIH HHS/United States ; }, abstract = {INTRODUCTION: To identify risk and protective factors in older women for incidence of ischemic colitis (IC) and 30-day mortality.<br><br>METHODS: We conducted a prospective study of 100,825 women in the Women's Health Initiative, with an average of 13.1-year follow-up and extensive phenotypic and outcomes data in diverse race and ethnic groups. Lasso Cox regression selected variables related to incidence of IC from multiple domains (demographic, comorbidities, risk factors, biomarkers, psychosocial factors, and dietary factors). Cox regressions modelled the selected variables to obtain adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).<br><br>RESULTS: The incidence rate of IC was twice as high among those with a history of cardiovascular disease (55.7 per 10,000 person-years) compared with those with no such history (27.3 per 10,000 person-years). After adjustment for multiple covariates, higher risk was associated with diastolic blood pressure below 90 mm Hg, using 2 or more types of antihypertensive medications compared with none (aHR 1.62, 95% CI 1.47-1.78), having gastrointestinal symptoms (aHR 1.31, 95% CI 1.20-1.42 highest vs lowest quartile). Higher fiber intake was associated with lower risk (aHR per increase of 10 g/d 0.93, 95% CI 0.89-0.97), and Black women had lower adjusted risk of IC than White women (aHR 0.73, 95% CI 0.63-0.83). Post-IC 30-day all-cause mortality was 10.6%, and sepsis was an important cause of death.<br><br>DISCUSSION: The incidence rate of IC in older women was twice as high in those with a history of cardiovascular disease and was associated with low diastolic blood pressure and multiclass antihypertensive treatment. Dietary fiber intake was associated with lower risk. Black women had lower risk of IC compared with White women.}, }
@article {pmid41364082, year = {2025}, author = {Beck, ML and Supiano, KP and Clayton, MF and Shannon Dorcy, K and Cloyes, KG}, title = {Oncology Nurses' Perceptions of Barriers and Facilitators to Conducting Spiritual Histories.}, journal = {Journal of hospice and palliative nursing : JHPN : the official journal of the Hospice and Palliative Nurses Association}, volume = {}, number = {}, pages = {}, doi = {10.1097/NJH.0000000000001194}, pmid = {41364082}, issn = {1539-0705}, abstract = {Nurses can relieve spiritual suffering experienced by advanced cancer patients through meaningful spiritual conversations (eg, spiritual histories), but may be reticent to do so, citing lack of knowledge, skills, and time as primary barriers. The Lift the Spirit (LtS), a novel online educational communication intervention targeting these barriers, was tested using a pilot quasi-experimental concurrent mixed-methods design. The LtS pilot integrated online education, simulated spiritual history assessment using the Faith, Importance, Community, Action tool, and post-test debriefing with nurse participants (n = 17) to elicit their perceptions of the facilitators and barriers of the LtS and conducting spiritual histories in clinical practice. Debrief interview data were deductively then inductively coded, and content analyzed to describe patterns of response. Participants described barriers and facilitators at the levels of institution/profession (lack of education and training), self (vulnerability and perceived riskiness), and patient (cultural difference) that were similar to barriers noted in the literature. Facilitators included feeling equipped and supported, and having external cues as reminders. No new barriers were uncovered, but the degree of negative affect (eg, angst, fear, and vulnerability) in the responses was discovered. The LtS, primarily the Faith, Importance, Community, Action tool and role-play components, demonstrated clinical utility in equipping nurses to overcome barriers to spiritual care in clinical practice.}, }
@article {pmid41364449, year = {2025}, author = {Lynch, RC and Gopal, AK}, title = {Pharma steps back from Hodgkin lymphoma: now what?.}, journal = {Blood advances}, volume = {9}, number = {23}, pages = {6218-6219}, pmid = {41364449}, issn = {2473-9537}, }
@article {pmid41364481, year = {2025}, author = {Cheng, KK and Copeland, V and Liu, A and Vijapurapu, S and Jao, M}, title = {Safety evaluation of outpatient ifosfamide regimens in adult sarcoma patients.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251399903}, doi = {10.1177/10781552251399903}, pmid = {41364481}, issn = {1477-092X}, abstract = {INTRODUCTION: Transitioning historically inpatient chemotherapy regimens to outpatient administration can reduce hospital stays, resource use, and healthcare expenditures while improving patient quality of life. However, agents like ifosfamide, commonly used in sarcoma, often necessitate inpatient administration for close monitoring of adverse effects. The Fred Hutchinson Cancer Center (FHCC) sarcoma group has developed criteria for outpatient ifosfamide administration after one successful inpatient administration. Nevertheless, there remains a paucity of literature characterizing the safety profile of outpatient ifosfamide administration.<br><br>METHODS: This was a single-center, retrospective, observational study that included adults 18 years and older with a diagnosis of sarcoma receiving an ifosfamide-based regimen in the outpatient setting at FHCC between March 2021 and September 2024. The primary outcome was a composite proportion of grade 3 or higher ifosfamide-related neurotoxicity, hemorrhagic cystitis, febrile neutropenia, and uncontrolled nausea or vomiting. Secondary outcomes included days of hospitalization saved with outpatient administration.<br><br>RESULTS: A total of 12 patients met the inclusion criteria. The most common outpatient treatment regimen was AIM (42%) followed by IE (25%) and VDC-IE (25%). Out of a total of 53 outpatient cycles, 15 cycles (28.3%) across 4 patients (33.3%) had at least 1 grade 3 or higher adverse effect of interest included in the primary outcome. A total of 257 hospitalization days were saved with outpatient administration, resulting in an estimated cost savings of $987,651.<br><br>CONCLUSION: Overall, among sarcoma patients meeting the FHCC outpatient ifosfamide criteria, administration of ifosfamide in the outpatient setting is safe with considerable cost savings to the institution.}, }
@article {pmid41364763, year = {2025}, author = {Lanzar, ZR and Aldridge, DL and Cruz-Morales, E and Howard, CA and Conway, IO and Zhong, Z and Eberhard, JN and Pereira, JA and Phan, AT and Ring, AM and Parker, M and Kanellopoulou, C and Min, B and Kedl, RM and Christian, DA and Hunter, CA}, title = {IL-27 promotes Treg cell expression of CD122 and fitness at homeostasis.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {50}, pages = {e2519141122}, pmid = {41364763}, issn = {1091-6490}, support = {R01 AI148249/AI/NIAID NIH HHS/United States ; F31 AI179240/AI/NIAID NIH HHS/United States ; U01 AI160664/AI/NIAID NIH HHS/United States ; R01 AI157247/AI/NIAID NIH HHS/United States ; R01 AI125247/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *T-Lymphocytes, Regulatory/immunology/metabolism ; *Homeostasis/immunology ; Mice ; *Interleukin-2 Receptor beta Subunit/metabolism/genetics/immunology ; *Interleukin-27/metabolism ; *Interleukins/metabolism ; Mice, Inbred C57BL ; Interleukin-2 ; Mice, Knockout ; }, abstract = {Regulatory T (Treg) cells express high levels of the IL-27R, and in the setting of infection and autoimmunity, the cytokine IL-27 promotes Treg cell activities that mitigate tissue pathology. However, IL-27 appears dispensable for Treg cell development and maintenance as lineage-specific depletion of the IL-27R on Treg cells does not impact these populations at steady state. In contrast, when mice were generated in which the Treg compartment comprised a mix of IL-27R-sufficient and -deficient Treg cells, those that lacked IL-27R were at a competitive disadvantage. Aging experiments illustrate that IL-27R-deficient Treg cells are preferentially eroded, and this defect was associated with reduced expression of CD122, the β chain of the IL-2/15R. Moreover, blockade of CD122 led to a similar loss of Treg cells, and in vitro and in vivo studies highlight that IL-27 promotes Treg cell expression of CD122 and improves responsiveness to IL-2/15. These datasets reveal that homeostatic IL-27 signals provide a competitive advantage that shapes the composition of the Treg cell pool by modulating responsiveness to growth factors.}, }
@article {pmid41365774, year = {2026}, author = {Su, CT and Banerjee, R and Li, L and Fedorenko, C and Cowan, A and Ramsey, SD and Shankaran, V}, title = {Association of Personal Credit Data With Financial Hardship and Treatment Outcomes in Patients With Multiple Myeloma.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {26}, number = {4}, pages = {e483-e491.e2}, pmid = {41365774}, issn = {2152-2669}, support = {K12 CA076930/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/economics/therapy ; Male ; Female ; Middle Aged ; Retrospective Studies ; Aged ; Treatment Outcome ; *Financial Stress/economics ; Adult ; }, abstract = {INTRODUCTION: Financial difficulty among patients with multiple myeloma (MM) is linked to reduced treatment adherence and worse outcomes. However, it is usually measured through patient questionnaires, which may be inconsistently offered or poorly completed. We hypothesized that credit data could detect financial difficulty and assessed its relationship with treatment outcomes.<br><br>METHODS: We conducted retrospective analyses using an integrated database with cancer registry data, insurance claims, and credit data for Western Washington State patients with MM diagnosed between 2012 to 2020. Financial difficulty was categorized into 4 tiers using credit attributes at diagnosis ("financial fragility") and during 2-year follow-up ("financial hardship"). We examined associations between financial fragility and suboptimal treatment, and identified predictors of financial hardship.<br><br>RESULTS: Among 396 MM patients, 35%, 38%, 5%, and 20% had no, mild, moderate, and severe financial fragility at diagnosis. Those with moderate/severe fragility were more likely to have delayed treatment initiation or interruptions (OR 1.67, 95% CI, 0.99-2.81, P = .06). Among 290 patients with 2-year follow-up, 69% showed no change in financial hardship from baseline. Financial fragility at diagnosis strongly predicted higher levels of future hardship (OR: 25.0, 95% CI, 11.17-56.13, P < .001). Patients receiving autologous transplant within the first year had lower odds of future hardship (OR 0.33, 95% CI, 0.12-0.90, P = .03).<br><br>DISCUSSION: Financial fragility at diagnosis is associated with suboptimal MM treatment and predict future hardship. Credit data could offer an alternative method to identify patients at risk.}, }
@article {pmid41368258, year = {2025}, author = {Tachiki, LM and Tykodi, SS}, title = {From surgery to systemic therapy in von Hippel-Lindau disease: insights from extended follow-up of LITESPARK-004.}, journal = {Translational andrology and urology}, volume = {14}, number = {11}, pages = {3446-3452}, pmid = {41368258}, issn = {2223-4691}, }
@article {pmid41368947, year = {2025}, author = {Gong, IY and Soto, MJ and Rafinejad-Farahani, B and Unger, JM and Conti, RM and Guerra, CE and Oza, A and Rosenthal, M and Rodin, D}, title = {Disparities in clinical trial participation among older adult Medicare beneficiaries with hematologic malignancies from 2006 to 2019: A SEER-Medicare analysis.}, journal = {Cancer}, volume = {131}, number = {24}, pages = {e70204}, pmid = {41368947}, issn = {1097-0142}, support = {HSR9020-23//Leukemia and Lymphoma Society/ ; }, mesh = {Humans ; Aged ; Female ; United States/epidemiology ; Male ; *Medicare/statistics &amp; numerical data ; SEER Program/statistics &amp; numerical data ; *Hematologic Neoplasms/therapy/epidemiology ; Aged, 80 and over ; Retrospective Studies ; *Clinical Trials as Topic/statistics &amp; numerical data ; *Healthcare Disparities/statistics &amp; numerical data ; *Patient Participation/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Clinical trials (CTs) are essential for expanding treatment options across hematologic malignancies (HM) and providing access to novel treatments. However, older adults with HM are often underrepresented in CTs, and a national-level evaluation of factors influencing their participation is lacking.<br><br>METHODS: The authors conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, identifying patients &#x2265;66 years old diagnosed with HM between 2006 and 2018 (follow-up to December 2019). CT participation was defined by Medicare claims for CT services. Cumulative incidence and Fine-Gray models were used to estimate participation rates and adjusted hazard ratios (aHRs) assessed the association between participation and sociodemographic factors.<br><br>RESULTS: The cohort (n&#xa0;=&#xa0;53,919) was 50% female, median age 78 years old, and 86% White. Cumulative incidence of CT participation was low at 2.7% at 1 year after diagnosis, increasing to 4.3% at 5 years. After adjustment for the competing risk of death, significantly lower CT participation was observed for older age (vs. 66-69 years: aHR for 70-74 years, 0.79 [95% CI, 0.71-0.88]; aHR for 75-79 years, 0.63 [95% CI, 0.56-0.70]; aHR for 80-84 years, 0.41 [95% CI, 0.36-0.46]; aHR for &#x2265;85 years, 0.21 [95% CI, 0.18-0.24]), female sex (aHR, 0.79 [95% CI, 0.73-0.86]), Black race (aHR, 0.73 [95% CI, 0.59-0.90]), certain comorbidities (aHR for pulmonary disease, 0.76 [95% CI, 0.68-0.85]; aHR for renal disease, 0.67 [95% CI, 0.59-0.76]), dual Medicare-Medicaid eligibility (aHR, 0.66 [95% CI, 0.56-0.77]), and distance to National Cancer Institute centers from the patient's ZIP code (aHR for &#x2265;250 miles, 0.64 [95% CI, 0.48-0.86]).<br><br>CONCLUSIONS: These results highlight the need for targeted interventions, such as CT navigator programs and decentralized trials, to increase older adult participation in HM CTs.}, }
@article {pmid41369204, year = {2025}, author = {Kenny, A and van der Laan, L and Gilbert, P and Carone, M}, title = {Inference on Controlled Effects for Assessing Immune Correlates of Protection Based on a Cox Model.}, journal = {Statistics in medicine}, volume = {44}, number = {28-30}, pages = {e70347}, doi = {10.1002/sim.70347}, pmid = {41369204}, issn = {1097-0258}, support = {R37AI054165//National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under Award Number/ ; }, mesh = {Humans ; Biomarkers ; Clinical Trials, Phase III as Topic ; Computer Simulation ; COVID-19/prevention &amp; control/immunology ; Proportional Hazards Models ; *Vaccine Efficacy ; *2019-nCoV Vaccine mRNA-1273/immunology ; }, abstract = {In vaccine research, it is important to identify biomarkers that can reliably predict vaccine efficacy against a clinical endpoint. Such biomarkers are known as immune correlates of protection (CoP) and can serve as surrogate endpoints in vaccine efficacy trials to accelerate the approval process. CoPs must be rigorously validated, and one method of doing so is through the controlled risk (CR) curve, a function that represents the causal effect of the biomarker on population-level risk of experiencing the endpoint of interest by a certain time post-vaccination. The CR curve can be estimated by leveraging a Cox proportional hazards model, but researchers currently rely on the bootstrap for inference, which can be computationally demanding. In this article, we analytically derive the asymptotic variance of this estimator, providing an analytic approach for constructing both pointwise and uniform confidence bands. We evaluate the finite sample performance of these methods in a simulation study and illustrate their use on data from the Coronavirus Efficacy (COVE) placebo-controlled phase 3 trial (NCT04470427) of the mRNA-1273 COVID-19 vaccine.}, }
@article {pmid41369537, year = {2026}, author = {Atuluru, P and Kwendakwema, CN and Bell-Brown, AM and Hopkins, T and Simianu, VV and Shankaran, V and Issaka, RB}, title = {Patient Perspectives on Barriers and Facilitators to 1-year Surveillance Colonoscopy Completion in Survivors of Colorectal Cancer: A Multimethod Analysis.}, journal = {Diseases of the colon and rectum}, volume = {69}, number = {3}, pages = {442-452}, pmid = {41369537}, issn = {1530-0358}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Colorectal Neoplasms/psychology/diagnosis/surgery/pathology ; Female ; *Colonoscopy/psychology/statistics &amp; numerical data/methods ; Aged ; *Cancer Survivors/psychology/statistics &amp; numerical data ; *Early Detection of Cancer/psychology/methods ; Middle Aged ; Surveys and Questionnaires ; Neoplasm Staging ; Neoplasm Recurrence, Local/diagnosis ; Washington/epidemiology ; Aged, 80 and over ; *Patient Compliance/psychology ; }, abstract = {BACKGROUND: Patients treated for stage I to III colorectal cancer are at high risk for developing new and recurrent colon cancers. Therefore, professional organizations recommend a surveillance colonoscopy approximately 1-year postsurgical resection to ensure early detection. Despite these guidelines, surveillance colonoscopy completion rates remain suboptimal.<br><br>OBJECTIVE: This multimethods study aimed to explore patient-identified barriers and facilitators affecting the completion of 1-year surveillance colonoscopies among stage I to III colorectal cancer survivors.<br><br>DESIGN: Multimethods study.<br><br>SETTINGS: The study was conducted within the Hutchinson Institute for Cancer Outcomes Research Value in Cancer Care Network, which comprises 46 clinics across 13 counties in Washington State.<br><br>PATIENTS: We enrolled stage I to III colorectal cancer survivors who had not completed surveillance colonoscopy within 18 months of surgery. Participants completed questionnaires and semistructured interviews between December 2023 and June 2024.<br><br>MAIN OUTCOME MEASURES: Questionnaire data and interview transcripts were independently coded and analyzed by 2 coders to identify key themes and subthemes related to barriers and facilitators of surveillance colonoscopy completion.<br><br>RESULTS: The study included 19 patients. The median (interquartile range) participant age was 73 (17.8) years, 9 (47.4%) were men, and 8 (42.1%) had stage I cancer. All participants reported cognitive and environmental factors as both barriers and facilitators to surveillance colonoscopy completion. The most reported barriers were fear of the colonoscopy results and cancer recurrence (cognitive) and challenges with the bowel preparation (environmental). The most frequently reported facilitators were patient's motivation to receive reassurance (cognitive) and clinic assistance in scheduling appointments (environmental).<br><br>LIMITATIONS: Results may not be generalizable due to population and selection bias of participants.<br><br>CONCLUSIONS: This study identified barriers and facilitators to completing a 1-year surveillance colonoscopy, which will guide future interventions. Addressing both psychological concerns and improving communication between patients and clinics could be key strategies to enhance adherence rates and improve long-term outcomes for colorectal cancer survivors. See Video Abstract .<br><br>ANTECEDENTES:Los pacientes tratados por c&#xe1;ncer colorrectal en estadio I-III corren un alto riesgo de desarrollar nuevos c&#xe1;nceres de colon y de que estos reaparezcan. Por lo tanto, las organizaciones profesionales recomiendan una colonoscopia de vigilancia aproximadamente un a&#xf1;o despu&#xe9;s de la resecci&#xf3;n quir&#xfa;rgica para garantizar la detecci&#xf3;n precoz. A pesar de estas directrices, las tasas de realizaci&#xf3;n de colonoscopias de vigilancia siguen siendo insuficientes.OBJETIVO:Este estudio multim&#xe9;todo ten&#xed;a como objetivo explorar las barreras y los facilitadores identificados por los pacientes que afectan a la realizaci&#xf3;n de colonoscopias de vigilancia al a&#xf1;o entre los supervivientes de c&#xe1;ncer colorrectal en estadio I-III.DISE&#xd1;O:Estudio multim&#xe9;todo.ENTORNO:El estudio se llev&#xf3; a cabo en el Hutchinson Institute for Cancer Outcomes Research Value in Cancer Care Network, que comprende 46 cl&#xed;nicas en 13 condados del estado de Washington.PACIENTES:Se inscribieron supervivientes de c&#xe1;ncer colorrectal en estadio I-III que no hab&#xed;an completado la colonoscopia de vigilancia en los 18 meses posteriores a la cirug&#xed;a. Los participantes completaron cuestionarios y entrevistas semiestructuradas entre diciembre de 2023 y junio de 2024.PRINCIPALES MEDIDAS DE RESULTADOS:Los datos de los cuestionarios y las transcripciones de las entrevistas fueron codificados y analizados de forma independiente por dos codificadores para identificar los temas y subtemas clave relacionados con las barreras y los facilitadores de la realizaci&#xf3;n de la colonoscopia de vigilancia.RESULTADOS:El estudio incluy&#xf3; a diecinueve pacientes. La mediana (rango intercuart&#xed;lico) de la edad de los participantes fue de 73 (17,8) a&#xf1;os, 9 (47,4 %) eran hombres y 8 (42,1 %) ten&#xed;an c&#xe1;ncer en estadio I. Todos los participantes informaron de factores cognitivos y ambientales como barreras o facilitadores para completar la colonoscopia de vigilancia. Las barreras m&#xe1;s mencionadas fueron el miedo a los resultados de la colonoscopia y a la recurrencia del c&#xe1;ncer (cognitivo) y las dificultades con la preparaci&#xf3;n intestinal (ambiental). Los facilitadores m&#xe1;s frecuentes fueron la motivaci&#xf3;n del paciente para recibir tranquilidad (cognitivo) y la ayuda de la cl&#xed;nica para programar las citas (ambiental).LIMITACIONES:Los resultados pueden no ser generalizables debido al sesgo de selecci&#xf3;n de la poblaci&#xf3;n y de los participantes.CONCLUSIONES:Este estudio identific&#xf3; barreras y facilitadores para completar una colonoscopia de vigilancia anual con el fin de orientar futuras intervenciones. Abordar las preocupaciones psicol&#xf3;gicas y mejorar la comunicaci&#xf3;n entre los pacientes y las cl&#xed;nicas podr&#xed;an ser estrategias clave para mejorar las tasas de adherencia y los resultados a largo plazo de los supervivientes de c&#xe1;ncer colorrectal. (AI-generated translation).}, }
@article {pmid41369553, year = {2026}, author = {Tsuji, T and Hirose, H and Sugiyama, D and Shindo, M and Hartantyo, RY and Saito, Y and Tatematsu, T and Sugio, S and Sanbo, M and Hirabayashi, M and Kojima, Y and Koseki, J and Hosoya, K and Yoshida, H and Ogimoto, T and Yasuda, Y and Hashimoto, K and Ajimizu, H and Sakamori, Y and Yoshida, H and Sano, N and Tanji, M and Ito, H and Terada, K and Hamaji, M and Menju, T and Konishi, H and Kumagai, S and Ghajar, CM and Kato, D and Date, H and Yoshizawa, A and Arakawa, Y and Ozasa, H and Moorhouse, AJ and Shimamura, T and Nishikawa, H and Hirai, T and Wake, H}, title = {Microglia Display Heterogeneous Initial Responses to Disseminated Tumor Cells.}, journal = {Cancer research}, volume = {86}, number = {6}, pages = {1414-1434}, pmid = {41369553}, issn = {1538-7445}, support = {20H05899//Japan Society for the Promotion of Science (JSPS)/ ; 20KK0170//Japan Society for the Promotion of Science (JSPS)/ ; 18H02598//Japan Society for the Promotion of Science (JSPS)/ ; 21H02662//Japan Society for the Promotion of Science (JSPS)/ ; JP25H01217//Japan Society for the Promotion of Science (JSPS)/ ; JPMJCR1755//Core Research for Evolutional Science and Technology (CREST)/ ; JPMJCR22P6//Core Research for Evolutional Science and Technology (CREST)/ ; JP23gm1410011//Japan Agency for Medical Research and Development (AMED)/ ; JP24zf0127012//Moonshot Research and Development Program (Moonshot)/ ; JP24zf0127010//Moonshot Research and Development Program (Moonshot)/ ; JPMJMS2012-3-4-1//Moonshot Research and Development Program (Moonshot)/ ; 21cm0106587h0001//Japan Agency for Medical Research and Development (AMED)/ ; 21K16140//Japan Society for the Promotion of Science (JSPS)/ ; 21J01531//Japan Society for the Promotion of Science (JSPS)/ ; JPMJAX2229//ACT-X/ ; }, mesh = {Animals ; *Microglia/pathology/immunology/metabolism ; Mice ; *Brain Neoplasms/secondary/immunology/pathology/genetics/metabolism ; Tumor Microenvironment/immunology ; Single-Cell Analysis ; Mice, Inbred C57BL ; Humans ; Cell Line, Tumor ; CD47 Antigen/genetics/metabolism ; Female ; }, abstract = {UNLABELLED: Brain metastases are frequent and often lethal complications of advanced cancers. Microglia, resident immune cells of the brain, are known to exert both anti- and protumor functions in late-stage metastases; however, their response during the initial outgrowth of metastatic lesions is not well characterized. Understanding how heterogeneous microglial subgroups are regulated in the developing tumor microenvironment could pave the way for therapeutic strategies to eliminate metastatic tumors at an early stage. In this study, we used a combination of in vivo fate map imaging, single-cell RNA sequencing, and a holographic photoconversion-based technique (opto-omics) to track tumor fate and early microglial responses over time in the same animals during the colonization of disseminated tumor cells. The microglial population was transcriptionally and morphologically heterogeneous, comprising both pro- and antitumor subsets. Genetic and pharmacologic perturbations revealed that microglial phenotypes could be shifted by inhibiting TGFβ signaling or by deleting the tumor cell surface antigens CD24 and CD47. These findings reveal targetable plasticity in early-stage microglial responses to brain metastasis and suggest that harnessing prophagocytic microglial states may offer a therapeutic window before systemic immunosuppression becomes dominant.<br><br>SIGNIFICANCE: In vivo imaging with optical labeling and transcriptomics reveals heterogeneous microglia and identifies that CD24/CD47 loss or TGF&#x3b2; modulation alters subpopulation fate, exposing a therapeutic window and actionable targets for brain metastases. See related commentary by Vallebuona and Smalley, p. 1345.}, }
@article {pmid41369932, year = {2026}, author = {Childers, CP and Selzer, DJ and Mabry, CD}, title = {Refining CPT Codes to Reflect the Complexity of Pediatric Appendicitis-Reply.}, journal = {JAMA surgery}, volume = {161}, number = {2}, pages = {208}, doi = {10.1001/jamasurg.2025.5369}, pmid = {41369932}, issn = {2168-6262}, }
@article {pmid41369938, year = {2026}, author = {Konstantopoulos, A and de Virgilio, C and Childers, CP}, title = {The Cost of Prolonged Surgical Training-Time Is Money.}, journal = {JAMA surgery}, volume = {161}, number = {2}, pages = {111-112}, doi = {10.1001/jamasurg.2025.5363}, pmid = {41369938}, issn = {2168-6262}, }
@article {pmid41370081, year = {2025}, author = {Shin, MB and Axeen, S and Cole, AM and Guo, XM and Islam, JY and Ko, LK and Volpi, CR and Winer, RL and Tsui, J}, title = {Nonadherence to Cervical Cancer Screening Guidelines in Commercially Insured US Adults, 2013-2021.}, journal = {JAMA network open}, volume = {8}, number = {12}, pages = {e2548512}, pmid = {41370081}, issn = {2574-3805}, }
@article {pmid41371208, year = {2025}, author = {Huckestein, BR and Thomas, PG}, title = {Memories are I(F)N-credibly protective.}, journal = {Immunity}, volume = {58}, number = {12}, pages = {2923-2925}, doi = {10.1016/j.immuni.2025.11.016}, pmid = {41371208}, issn = {1097-4180}, mesh = {Humans ; *Immunologic Memory/immunology ; *CD8-Positive T-Lymphocytes/immunology ; *Interferon-gamma/immunology/metabolism ; Animals ; *Lung/immunology/virology ; *Memory T Cells/immunology ; Virus Replication ; }, abstract = {Lung-resident memory CD8[+] T cells coordinate rapid antiviral defense mechanisms across lung compartments to quicky limit viral replication and spread. In this issue of Immunity, Mattingly et al. demonstrate the importance of CD8[+] Trm cell-derived interferon-γ in epithelial reprogramming for barrier defense in humans.}, }
@article {pmid41372127, year = {2025}, author = {Bents, SJ and Martin, ET and Stevens-Ayers, T and Andrews, C and Adler, A and Perofsky, AC and Krantz, EM and Blazevic, R and Kimball, L and Prentice, R and Hansen, C and Starita, L and Han, P and Englund, JA and Wolter, N and von Gottberg, A and Maake, L and Moyes, J and Cohen, C and Boeckh, M and Hay, JA and Waghmare, A and Viboud, C}, title = {Multiplex serology reveals age-specific immunodynamics of respiratory pathogens in the wake of the COVID-19 pandemic.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {11015}, pmid = {41372127}, issn = {2041-1723}, support = {/WT_/Wellcome Trust/United Kingdom ; 75N93021C00015/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/immunology/epidemiology/virology/transmission ; Child, Preschool ; SARS-CoV-2/immunology ; Child ; *Antibodies, Viral/blood/immunology ; Adult ; Influenza, Human/immunology/epidemiology/virology ; Middle Aged ; Adolescent ; Age Factors ; Infant ; Young Adult ; Male ; Female ; Aged ; Pandemics ; Washington/epidemiology ; South Africa/epidemiology ; }, abstract = {The rebound of endemic respiratory viruses following the COVID-19 pandemic was marked by atypical transmission dynamics, with children experiencing increased disease burden and out-of-season epidemics as restrictions relaxed. Here we used serology from a newly developed quantitative multiplex assay to assess the post-pandemic immunity debt. We assessed age-specific antibody dynamics across a broad range of respiratory viruses, including influenza, respiratory syncytial virus, seasonal coronaviruses, and SARS-CoV-2 using serology collected in King County, Washington, US, from 2020-2022 (n = 1508). We found that respiratory virus immunodynamics differed between individuals <5 years of age and older individuals, with young children experiencing larger boosts and quicker waning of antibodies across pathogens. We confirmed that these patterns are upheld in a non-pandemic setting by analyzing influenza serology collected in South Africa between 2016-2018 (n = 1028). We incorporated our serological insights into an influenza transmission model calibrated to epidemiological data from King County and show that consideration of age-specific immunodynamics may be important to anticipate the effects of pandemic perturbations.}, }
@article {pmid41372159, year = {2025}, author = {Pan, R and Ren, J and Chen, X and Flores, LF and Gonzalez, RVL and Adonnino, AA and Lofts, B and Waldo, J and Halmai, J and Devinsky, O and Fink, K and Liu, XS}, title = {Editing DNA methylation in vivo.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {527}, pmid = {41372159}, issn = {2041-1723}, support = {R01 NS126185/NS/NINDS NIH HHS/United States ; R01 MH134519/MH/NIMH NIH HHS/United States ; R01NS126185//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R01MH134519//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; F30 HD115371/HD/NICHD NIH HHS/United States ; }, mesh = {Animals ; *DNA Methylation/genetics ; *Gene Editing/methods ; Mice ; DNA Methyltransferase 3A ; Mice, Transgenic ; Promoter Regions, Genetic ; Methyl-CpG-Binding Protein 2/genetics/metabolism ; Proprotein Convertase 9/genetics/metabolism ; Liver/metabolism ; DNA (Cytosine-5-)-Methyltransferases/genetics/metabolism ; CRISPR-Cas Systems ; Proto-Oncogene Proteins/genetics/metabolism ; Male ; DNA-Binding Proteins/genetics/metabolism ; Epigenesis, Genetic ; Neurons/metabolism ; }, abstract = {DNA methylation is a crucial epigenetic mechanism that regulates gene expression. Precise editing of DNA methylation has emerged as a promising tool for dissecting its biological function. However, challenges in delivery have limited most applications of DNA methylation editing to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo. We demonstrate that targeted methylation of the Psck9 promoter in the liver of dCas9-DNMT3A mice results in decreased Pcsk9 expression and a subsequent reduction in serum low-density lipoprotein cholesterol level. Targeted demethylation of the Mecp2 promoter in dCas9-TET1 mice reactivates Mecp2 expression from the inactive X chromosome and rescues neuronal nuclear size in Mecp2[+/-] mice. Genome-wide sequencing analyses reveal minimal transcriptional off-targets, demonstrating the specificity of the system. These results demonstrate the feasibility and versatility of methylation editing, to functionally interrogate DNA methylation in vivo.}, }
@article {pmid41372729, year = {2025}, author = {Sarfraz, Z and Ranjan, T and Mustafayev, FNA and Jaramillo, M and Odia, Y and Venur, VA and Ahluwalia, MS}, title = {Emerging therapies for glioblastoma.}, journal = {Journal of neuro-oncology}, volume = {176}, number = {1}, pages = {116}, pmid = {41372729}, issn = {1573-7373}, mesh = {Humans ; *Glioblastoma/therapy ; *Brain Neoplasms/therapy ; *Immunotherapy/methods ; *Molecular Targeted Therapy/methods ; *Antineoplastic Agents/therapeutic use ; }, abstract = {Glioblastoma (GBM) remains associated with poor outcomes, with a median survival of 15-18 months despite maximal safe resection, radiotherapy, and temozolomide. Therapeutic development has increasingly centered on overcoming drug resistance, intratumoral diversity, and restricted delivery across the blood-brain barrier. Progress in targeted therapy includes evaluation of EGFR inhibitors, multitarget tyrosine kinase inhibitors, and FGFR-directed agents, while rare molecularly defined subsets such as BRAF V600E and NTRK fusions offer tumor-agnostic precision approaches. JAK/STAT inhibition, PARP blockade, and PI3K/AKT/mTOR pathway modulation remain under investigation, although clinical benefit has been inconsistent. In parallel, precision oncology platforms incorporating multi-omic profiling, patient-derived organoids, and functional drug testing are refining therapy selection and supporting rational drug combinations. Adaptive clinical trial frameworks such as GBM AGILE and INSIGhT are accelerating the evaluation of novel agents within stratified cohorts,while emerging approaches including ChemoID-guided therapy, radiogenomic profiling, and digital modeling are beginning to influence translational endpoints. Immunotherapy continues to be an active area of research, though efficacy has thus far been limited. Immune checkpoint inhibitors have not yet demonstrated significant survival benefits as monotherapy, but combination strategies with vaccines, oncolytic viruses, and engineered cellular therapies are under evaluation. CAR T-cell therapies are advancing toward bispecific and armored constructs with locoregional delivery, while oncolytic viruses such as DNX-2401 and PVSRIPO demonstrate potential for durable responses in select patients. Looking ahead, progress is likely to arise from biomarker-informed, multimodal regimens that integrate targeted agents, next-generation immunotherapies, and precision-guided strategies, while embedding translational endpoints into trial design to address the complex biology and therapeutic resistance of GBM.}, }
@article {pmid41374973, year = {2025}, author = {Surento, W and Fischer, R and Biswas, D and Hippe, DS and Kazerouni, AS and Kim, JY and Li, I and Gennari, JH and Rahbar, H and Partridge, SC}, title = {Multiparametric MRI Markers Associated with Breast Cancer Risk in Women with Dense Breasts.}, journal = {Cancers}, volume = {17}, number = {23}, pages = {}, pmid = {41374973}, issn = {2072-6694}, support = {U01CA152637//NIH/NCI/ ; R01CA207290//NIH/NCI/ ; R01CA190299//NIH/NCI/ ; }, abstract = {Background/Objectives: This study explored the associations of normal breast tissue characteristics on multiparametric MRI with clinical assessments of breast cancer risk in women with dense breasts. Methods: Women with dense breasts who underwent multiparametric MRI were included. Breast cancer risk was determined based on Tyrer-Cuzick (TC) lifetime risk scores, categorized as high (TC ≥ 20%) or low risk. Qualitative background parenchymal enhancement (BPE) assessment was obtained from imaging reports. Quantitative imaging markers were calculated, including median BPE, median apparent diffusion coefficient, and volume measures of the whole breast, fibroglandular tissue (FGT), blood vessels, and BPE regions. The associations between imaging markers and TC risk groups were evaluated using age-adjusted logistic regression and summarized by area under the receiver operating characteristic curve (AUC). Results: Seventy-seven women were evaluated; a total of 20 (26%) were low risk, and 57 (74%) were high risk. After adjusting for age and multiple testing, BPE:breast ratio (adj. p = 0.037), FGT:breast ratio (adj. p = 0.046), and BPE:vessel ratio (adj. p = 0.037) were positively associated with risk, while qualitative BPE was not (adj. p = 0.11). Overall, risk categorizations based on imaging markers were concordant with TC score in up to 70% of women. Conclusions: In women with dense breasts, quantitative measures from multiparametric MRI (BPE:breast, FGT:breast, and BPE:vessel ratios) moderately discriminated high- and low-risk groups, warranting further investigation of their value to supplement conventional breast cancer risk assessment tools.}, }
@article {pmid41374977, year = {2025}, author = {Chen, X and Fang, H and Wu, Y and Meshinchi, S and Naresh, KN and Reister, E and Langford, K and Eacker, SM and Liu, YJ}, title = {Comprehensive Detection of Chromosomal and Genomic Abnormalities via Next-Generation Sequencing-Based Genomic Proximity Mapping Improves Diagnostic Classification of Hematologic Neoplasms.}, journal = {Cancers}, volume = {17}, number = {23}, pages = {}, pmid = {41374977}, issn = {2072-6694}, support = {R44CA281528 and R44CA278140/CA/NCI NIH HHS/United States ; }, abstract = {Background/Objectives: Accurate detection of all classes of genomic structural variants (SVs), including chromosomal rearrangements and copy number alterations (CNAs), is essential for the diagnosis and classification of hematologic neoplasms. Conventional cytogenetic methods currently serve as routine clinical tools for detecting SVs. However, each commonly used cytogenetic test has specific limitations, and sequential application of these different tests may delay timely diagnosis and treatment. Methods: In this study, we evaluated the feasibility and utility of genomic proximity mapping (GPM), a novel high-throughput chromosome conformation capture (Hi-C)-based next-generation sequencing (NGS) method, to identify chromosomal and genetic aberrations in hematologic neoplasms in the clinical setting. GPM was performed on 18 cases of hematologic neoplasms (fresh/frozen cells or formalin-fixed paraffin-embedded tissue), and concordance with other methodologies was assessed, including karyotyping, FISH, RT-PCR, chromosomal microarray analysis (CMA), and/or RNA sequencing. Results: GPM reliably detected balanced and unbalanced chromosomal rearrangements, including chimeric gene fusions and gene juxtapositions, with 95.2% concordance with previously applied methods in cases with >10% tumor burden. Additionally, GPM can detect CNAs and copy-neutral loss of heterozygosity (cnLOH) simultaneously in a single assay. Furthermore, detection of genomic rearrangements not identified by other methods improved the accuracy of disease classification. Conclusions: These findings demonstrate that GPM is a powerful method for identifying clinically actionable variants in hematologic neoplasms, overcoming some limitations of current cytogenetic technologies and improving the diagnostic accuracy and classification in challenging cases.}, }
@article {pmid41378873, year = {2026}, author = {Hussein, A and Fischer, M and Valinetz, E and Pergam, SA and Selke, S and Pepper, G and Jerome, KR and Greninger, AL and Wald, A and Johnston, C}, title = {Herpes Simplex Virus Type 1 and Type 2 Western Blot Serology Test Results From 1999 to 2020 in a US Reference Laboratory.}, journal = {Sexually transmitted diseases}, volume = {53}, number = {5}, pages = {285-287}, doi = {10.1097/OLQ.0000000000002258}, pmid = {41378873}, issn = {1537-4521}, support = {P01 AI030731/AI/NIAID NIH HHS/United States ; T32 AI007044/AI/NIAID NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; }, mesh = {*Herpesvirus 1, Human/immunology/isolation &amp; purification ; Humans ; *Herpesvirus 2, Human/immunology/isolation &amp; purification ; Seroepidemiologic Studies ; *Blotting, Western ; *Herpes Simplex/epidemiology/diagnosis/virology ; *Antibodies, Viral/blood ; United States/epidemiology ; Female ; Male ; *Herpes Genitalis/epidemiology/diagnosis ; Adult ; Serologic Tests ; Laboratories ; Middle Aged ; Adolescent ; Young Adult ; }, abstract = {We analyzed 162,397 deidentified HSV Western blot results performed at the University of Washington Virology Laboratory from 1999 to 2020. The seroprevalence of HSV-1 declined by 0.53% per year, whereas indeterminate HSV-1 results increased by 0.08% annually. Similarly, HSV-2 seroprevalence decreased by 0.72%, and indeterminate results increased by 0.16% each year.}, }
@article {pmid41378902, year = {2025}, author = {Mandrycky, CJ and Ishida, T and Merkel, T and Rayner, SG and Heck, AM and Hadland, B and Zheng, Y}, title = {Under pressure: integrated endothelial cell response to hydrostatic and shear stresses.}, journal = {Vascular biology (Bristol, England)}, volume = {7}, number = {1}, pages = {}, pmid = {41378902}, issn = {2516-5658}, support = {K08 HL166696/HL/NHLBI NIH HHS/United States ; R01 HL168110/HL/NHLBI NIH HHS/United States ; UG3 TR003288/TR/NCATS NIH HHS/United States ; R01 AI148802/AI/NIAID NIH HHS/United States ; R33 HL154250/HL/NHLBI NIH HHS/United States ; R01 HL179317/HL/NHLBI NIH HHS/United States ; }, abstract = {Blood flow within the vasculature is a critical determinant of endothelial cell (EC) identity and functionality, yet the intricate interplay of various hemodynamic forces and their collective impact on endothelial and vascular responses is not fully understood. Specifically, the role of hydrostatic pressure in the EC flow response is understudied, despite its known significance in vascular development and disease. To address this gap, we developed in vitro models to investigate how pressure influences EC responses to flow. Our study demonstrates that elevated pressure conditions significantly modify shear-induced flow alignment and increase EC density. Bulk and single-cell RNA sequencing analyses revealed that, while shear stress remains the primary driver of flow-induced transcriptional changes, pressure modulates shear-induced signaling in a dose-dependent manner. These pressure-responsive transcriptional signatures identified in human ECs were conserved during the onset of circulation in early mouse embryonic vascular development, where pressure was notably associated with transcriptional programs essential to arterial and hemogenic EC fates. Our findings suggest that pressure plays a synergistic role with shear stress on ECs and emphasize the need for an integrative approach to EC mechanotransduction, one that encompasses the effects induced by pressure alongside other hemodynamic forces.}, }
@article {pmid41378983, year = {2025}, author = {Ahluwalia, MS and Solomon, S and Patel, SP and Sarfraz, Z and Othus, M and Chae, YK and Kurzrock, R}, title = {Efficacy and CNS Toxicity of Nivolumab and Ipilimumab in Rare Cancer Brain Metastases: A Multi-Center Basket Trial Analysis (NCI/SWOG S1609).}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-2900}, pmid = {41378983}, issn = {1557-3265}, abstract = {PURPOSE: To evaluate the efficacy and safety of dual immune checkpoint inhibitors (ICI) in patients with brain metastases (BM) from rare cancers.<br><br>PATIENTS AND METHODS: Patients with and without BM received nivolumab (240 mg every two weeks) and ipilimumab (1 mg/kg every six weeks) (NCI/SWOG S1609 DART trial, NCT02834013) across >1,000 sites. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method; hazard ratios (HR) with 95% confidence intervals (CI) were derived from Cox models. Systemic ORR was assessed by RECIST v1.1, and adverse events were graded using CTCAE v5.0. Intracranial outcomes were assessed in a subset of patients with BM to evaluate best intracranial response.<br><br>RESULTS: Among 727 patients, the systemic ORR was 11.5% in those without BM (n=707) and 10% in those with BM (n=20) (p=0.76). PFS and OS were similar between groups (PFS: HR=1.29, 95% CI 0.81-2.07, p=0.28; OS: HR=1.36, 95% CI 0.81-2.27, p=0.24). Intracranial response was evaluable in 12 patients with BM (60%). No intracranial complete or partial responses were observed, and six patients (50%) achieved intracranial stable disease as their best intracranial response. Grade &#x2265;3 CNS toxicities occurred in 3% of patients without BM and 5% of those with BM (p=0.43).<br><br>CONCLUSIONS: Dual-ICI therapy showed comparable efficacy and safety in patients with and without BM.}, }
@article {pmid41379444, year = {2025}, author = {Bowers, DC and Cooney, T and Chen, Y and Yuan, Y and Galvin, R and Im, C and Leisenring, W and Brady, SW and Smith, SA and Howell, RM and Arnold, MA and Conces, M and Yasui, Y and Diller, LR and Armstrong, GT and Neglia, JP and Turcotte, LM}, title = {Subsequent Meningiomas Among Survivors of Childhood Cancer.}, journal = {JAMA network open}, volume = {8}, number = {12}, pages = {e2548715}, pmid = {41379444}, issn = {2574-3805}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Meningioma/epidemiology/mortality/etiology ; Female ; Male ; *Cancer Survivors/statistics &amp; numerical data ; Adult ; Child ; Retrospective Studies ; Canada/epidemiology ; Incidence ; Adolescent ; *Meningeal Neoplasms/epidemiology/mortality ; Young Adult ; Middle Aged ; Risk Factors ; Child, Preschool ; United States/epidemiology ; *Neoplasms, Second Primary/epidemiology ; Infant ; Aged ; Longitudinal Studies ; }, abstract = {IMPORTANCE: Associations with chemotherapy, occurrence of multiple meningiomas, and mortality after subsequent meningioma diagnosis among survivors of childhood cancer remain unclear.<br><br>OBJECTIVES: To report the incidence of meningioma among childhood cancer survivors, identify novel risk factors for meningiomas, characterize survivors with multiple meningiomas, and describe cause-specific mortality following meningioma occurrence.<br><br>The Childhood Cancer Survivor Study is a retrospective cohort study with longitudinal prospective follow-up of childhood cancer survivors diagnosed between 1970 to 1999 in the US and Canada. Eligibility included diagnosis of cancer before age 21 years and surviving more than 5 years after diagnosis. Meningiomas were self-reported and confirmed by review of pathology reports. Childhood cancer diagnosis, chemotherapy details, and radiation therapy exposures from up to 5 years from diagnosis were abstracted from medical records.<br><br>MAIN OUTCOMES AND MEASURES: Cumulative incidence of meningioma was calculated starting from 5 years from the diagnosis. Overall survival (OS) from diagnosis of the first subsequent meningioma was estimated using Kaplan-Meier methods.<br><br>RESULTS: The CCSS cohort included 24&#x202f;886 survivors initially diagnosed from 1970 to 1999, including 471 survivors (263 female [56%]; median [range] age at last follow-up, 42.5 [19.7-66.3] years; median [range] age at primary cancer diagnosis, 5.6 [0-20.9] years) who were diagnosed with 710 meningiomas. Thirty-five years after primary cancer diagnosis, the cumulative incidence of a subsequent meningioma was 2.3% (95% CI, 2.1%-2.6%). Of the 471 survivors who developed meningioma, 137 (29.0%) had at least 2 meningiomas, and 80 (16%) met criteria for meningiomatosis. An increased risk of meningioma was associated with higher doses of cranial radiation therapy (eg, HR, 125.3 [95% CI, 58.1-270.5]), younger age at primary cancer diagnosis (eg, 0 to 4 years: HR, 4.0 [95% CI, 2.4-6.1]), female sex (HR, 1.6 [95% CI, 1.3-1.9]), and exposure to platinum, 6-mercaptopurine, and intrathecal chemotherapy, and a lower risk was associated with non-Hispanic Black race (HR, 0.5 [95% CI, 0.3-1.0]) and exposure to alkylating agents (HR,&#x2009;0.6 [95% CI, 0.5-0.8]). The all-cause cumulative mortality was 4.9%, 10.5% and 18.4% at 5, 10, and 15 years from the first subsequent meningioma diagnosis.<br><br>CONCLUSIONS AND RELEVANCE: Meningiomas have a relatively high incidence and mortality for childhood cancer survivors. Results from this study could justify screening for meningiomas in high-risk populations.}, }
@article {pmid41379459, year = {2026}, author = {Kang, IM and Forschmiedt, JK and Loch, MM and Lew, DL and Barlow, WE and Gralow, JR and Meric-Bernstam, F and Albain, KS and Hayes, DF and Lin, NU and Perez, EA and Goldstein, LJ and Rastogi, P and Schott, AF and Baehner, R and Sharma, P and Tripathy, D and Pusztai, L and Hortobagyi, GN and Kalinsky, K and Henry, NL}, title = {Cognitive Impairment and Chemoendocrine vs Endocrine Therapy in Pre- and Postmenopausal Women: A Secondary Analysis of the RxPONDER Randomized Clinical Trial.}, journal = {JAMA oncology}, volume = {12}, number = {2}, pages = {159-166}, pmid = {41379459}, issn = {2374-2445}, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Antineoplastic Agents, Hormonal/adverse effects/therapeutic use ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; *Breast Neoplasms/drug therapy ; *Cognitive Dysfunction/chemically induced ; Patient Reported Outcome Measures ; Postmenopause ; Premenopause ; }, abstract = {IMPORTANCE: Breast cancer treatment is associated with cancer-related cognitive impairment (CRCI). However, the association of endocrine therapy (ET) vs chemotherapy plus endocrine therapy (CET) with CRCI is poorly understood.<br><br>OBJECTIVE: To compare patient-reported CRCI between women with breast cancer treated with ET vs CET and to consider whether menopausal status may be associated.<br><br>This was a prespecified secondary analysis of RxPONDER (SWOG S1007), a multinational phase 3 randomized clinical trial of more than 5000 women with hormone receptor-positive ERBB2-negative (formerly HER2-negative) breast cancer with 1 to 3 involved lymph nodes and Oncotype DX (21-gene recurrence score) of 25 or less. Participants were enrolled from February 2011 to September 2017, with results first reported in December 2020. Participants were randomly assigned to CET or ET, with ongoing follow-up. This secondary analysis assessed cognitive function using the Patient-Reported Outcomes Measurement Information System Perceived Cognitive Function Concerns (PCF) questionnaire at baseline, 6, 12, and 36 months. Data were analyzed from July 2022 to August 2025.<br><br>INTERVENTION: Random assignment to CET or ET.<br><br>MAIN OUTCOMES AND MEASURES: Mean PCF standardized (T) scores by menopausal status over time using generalized estimating equations analysis for continuous outcomes.<br><br>RESULTS: Of the 568 patients who completed the baseline questionnaire and were included in the analysis, 139 (24%) were premenopausal (median [range] age, 47.8 [28.0-56.3] years) and 429 (76%) were postmenopausal (median [range] age, 62.3 [37.3-87.6] years). Among the 274 (48%) who received CET and the 294 (52%) who received ET alone, CET was determined to have a greater negative association with patient-reported CRCI in both the pre- and postmenopausal participants during the 36-month follow-up. In the ET alone group, PCF scores for premenopausal participants decreased from baseline to 6 and 12 months (53.53, 51.51, and 51.72, respectively) but recovered to baseline (54.36) at 36 months. For postmenopausal participants, mean PCF scores were essentially stable (51.72, 51.13, 51.11, and 51.70, respectively); however, in the CET group, PCF scores for both pre- and postmenopausal participants decreased from baseline to 6 and 12 months (premenopausal, 52.84, 49.27, 48.04; postmenopausal, 50.65, 48.39, 47.13, respectively) and did not return to baseline at 36 months (premenopausal, 49.25; postmenopausal, 48.44). The difference in longitudinal mean PCF scores over time between CET and ET groups was -3.02 (95% CI, -5.33 to -0.72; P&#x2009;=&#x2009;.01) for premenopausal and -2.37 (95% CI, -3.92 to -0.82; P&#x2009;=&#x2009;.003) for postmenopausal participants.<br><br>CONCLUSIONS AND RELEVANCE: This secondary analysis of the RxPONDER found that CET had a greater negative association with patient-reported CRCI compared to ET alone in both pre- and postmenopausal participants over a 36-month follow-up period. Interventions to prevent or treat CRCI are needed to improve the long-term quality of life of these patients treated with chemotherapy.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01272037.}, }
@article {pmid41380171, year = {2026}, author = {Doshi, S and Richardson, BA and Nazzinda, R and Mugerwa, H and Bittencourt, MS and Erem, G and Narendrula, A and Farquhar, C and Kityo, C and Longenecker, CT}, title = {The Association of Mild Kidney Disease With Coronary Artery Disease Is Stronger for People Living With HIV.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {101}, number = {1}, pages = {95-102}, pmid = {41380171}, issn = {1944-7884}, support = {D43 TW011596/TW/FIC NIH HHS/United States ; K23 HL123341/HL/NHLBI NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Male ; *HIV Infections/complications ; Middle Aged ; *Coronary Artery Disease/complications/epidemiology ; Cross-Sectional Studies ; Uganda/epidemiology ; Glomerular Filtration Rate ; *Kidney Diseases/complications ; Risk Factors ; }, abstract = {OBJECTIVE: To examine the association between mild kidney disease and coronary plaque parameters using coronary computed tomography angiography in people living with HIV (PWH) compared with people without HIV in Uganda.<br><br>DESIGN: Cross-sectional secondary analysis.<br><br>METHODS: We studied 165 participants aged >45 years with &#x2265;1 cardiovascular risk factor (78 PWH on stable antiretroviral therapy, 87 HIV-negative). Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR). Coronary artery disease (CAD) was characterized by segment involvement score (SIS), segment stenosis score (SSS), and coronary artery calcium score. Multivariable Tobit regression assessed associations of kidney function measures with CAD parameters, testing for differences by HIV status.<br><br>RESULTS: The median (interquartile range) age was 57.0 (53-62) years, 62.4% of subjects were female, and 87.3% had hypertension. Among PWH, mildly impaired eGFR (<90 mL/min/1.73 m2) was associated with higher SIS [&#x3b2; 3.31, 95% confidence interval (CI): 0.41 to 6.21, P = 0.03] and SSS (&#x3b2; 5.95, 95% CI: 0.54 to 11.36, P = 0.03). The association with SIS remained significant after adjusting for age, gender, and 10-year ASCVD score (&#x3b2; 2.58, 95% CI: 0.10 to 5.06, P = 0.04). Associations of ACR with coronary plaque were not statistically significant for participants with or without HIV (all P > 0.07).<br><br>CONCLUSION: In PWH, mildly reduced eGFR was associated with greater coronary plaque burden (SIS, SSS) but not coronary artery calcium; ACR showed no associations with any CAD measures. Incorporating kidney function measures into cardiovascular risk assessment may be valuable in HIV care.}, }
@article {pmid41380698, year = {2026}, author = {Kater, AP and Janssens, A and Eradat, H and Offner, F and Sandoval-Sus, JD and Shadman, M and Poulsen, CB and Christensen, JH and Thompson, MC and Guan, M and Steele, AJ and Rios, M and Holst Mørch, M and Oki, T and Valentin, R and Bellido, M and Eichhorst, B}, title = {Epcoritamab monotherapy for Richter transformation (EPCORE CLL-1): findings from a single-arm, multicentre, open-label, phase 1b/2 trial.}, journal = {The Lancet. Haematology}, volume = {13}, number = {1}, pages = {e8-e21}, doi = {10.1016/S2352-3026(25)00327-8}, pmid = {41380698}, issn = {2352-3026}, mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/pathology ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/pathology ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Lenalidomide/therapeutic use/administration &amp; dosage ; Treatment Outcome ; }, abstract = {BACKGROUND: Richter transformation is one of the most challenging B-cell lymphomas to treat, particularly in patients with high-risk chronic lymphocytic leukaemia features or who have had previous therapy for chronic lymphocytic leukaemia. Median survival remains 6-12 months across various therapeutic approaches. We evaluated the safety and preliminary activity of epcoritamab monotherapy, a subcutaneous CD3×CD20 bispecific antibody, in patients with Richter transformation.<br><br>METHODS: This multicentre, open-label, phase 1b/2 trial was conducted at 24 centres in nine countries (Australia, Belgium, Denmark, Germany, Israel, Italy, Spain, The Netherlands, and USA). Eligible patients were aged 18 years or older and had histologically confirmed Richter transformation (diffuse large B-cell lymphoma [DLBCL]), an Eastern Cooperative Oncology Group performance status of 0-2, and up to two previous lines of Richter transformation-directed therapy. The trial includes dose-escalation and dose-expansion phases. The expansion groups evaluate epcoritamab monotherapy (group 2A), epcoritamab plus lenalidomide (group 2B), and epcoritamab plus the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; group 2C). The current report describes results from group 2A. Epcoritamab was administered subcutaneously in step-up doses followed by 48 mg every week for cycles 1-3, every 2 weeks for cycles 4-9, and every 4 weeks thereafter until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate per Lugano 2014 criteria in the full analysis set (all patients who received &#x2265;1 dose of epcoritamab). It was evaluated against a null hypothesis of 30% versus an alternative of 50%. Prespecified subgroup analyses by line of therapy for Richter transformation and TP53 aberration and/or del(17p) status were performed. Safety was assessed in all treated patients. This trial is ongoing and registered with ClinicalTrials.gov, NCT04623541.<br><br>FINDINGS: Between Oct 18, 2021, and March 21, 2025, we enrolled 42 patients with Richter transformation. The median age was 69 years (range 50-80); and 32 (76%) of 42 patients were male and ten (24%) were female. Race or ethnicity data were available for 40 patients (37 [88%] identified as White, two [5%] as Asian, and one [2%] as Black or African American; ethnicity was not reported for two patients). The median time from diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma to Richter transformation was 7&#xb7;6 years (range 0-23&#xb7;9). 21 (50%) of 42 patients received epcoritamab as first-line Richter transformation-directed therapy. At a median follow-up of 22&#xb7;9 months (range 0&#xb7;5-39&#xb7;9), 20 of 42 patients had a response with an investigator-assessed overall response rate of 47&#xb7;6% (95% CI 32&#xb7;0-63&#xb7;6), which did not meet the prespecified alternative hypothesis (50%). Overall response occurred in 12 of 21 patients in the first-line population (overall response rate 57&#xb7;1%, 34&#xb7;0-78&#xb7;2), in eight of 21 patients in the second-line or later-line population (38&#xb7;1%, 18&#xb7;1-61&#xb7;6), and in eight of 20 patients with TP53 aberration and/or del(17p) alteration at baseline (40%, 19&#xb7;1-63&#xb7;9). The most common grade 3-4 adverse events were neutropenia in 19 (45%) of 42 patients, anaemia in 16 (38%) patients, thrombocytopenia in 16 (38%) patients, infection in nine (21%) patients, pneumonia in four (10%) patients, and COVID-19 in two (5%) patients. Cytokine release syndrome occurred in 36 (86%) patients with three (7%) being grade 3, immune effector cell-associated neurotoxicity syndrome in five (12%; all grade 1-2) patients and clinical tumour lysis syndrome in two (5%; all grade 1-2) patients. Three fatal adverse events were reported, one each due to general physical health deterioration in the context of progressive disease, sepsis, and cerebrovascular accident; none were considered by the investigator to be related to study treatment.<br><br>INTERPRETATION: In patients with Richter transformation, epcoritamab monotherapy showed clinically meaningful antitumour activity, although the investigator-assessed overall response rate was below the alternative hypothesis of 50%, with a safety profile consistent with previous studies. These findings support further investigation of epcoritamab as a potential treatment option for patients with Richter transformation.<br><br>FUNDING: Genmab A/S and AbbVie.}, }
@article {pmid41383769, year = {2025}, author = {Shen, BA and Asfahl, KL and Lim, B and Bertolli, SK and Minot, SS and Radey, MC and Penewit, K and Ngo, B and Salipante, SJ and Johnston, CD and Peterson, SB and Goodman, AL and Mougous, JD}, title = {The type VI secretion system governs strain maintenance in a wild mammalian gut microbiome.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41383769}, issn = {2692-8205}, support = {F32 AI164853/AI/NIAID NIH HHS/United States ; R01 DE027850/DE/NIDCR NIH HHS/United States ; R35 GM118159/GM/NIGMS NIH HHS/United States ; }, abstract = {Bacteria inhabiting the mammalian gut coexist in dense communities where contact-dependent antagonism mechanisms are widespread. The type VI secretion system (T6SS) is an interbacterial toxin delivery pathway prevalent among gut Bacteroidales, yet its function in naturally evolved microbiomes remains poorly defined. Here, we examine the physiological role of the T6SS in Bacteroides within a gut community derived from wild mice (the WildR microbiome). Using newly developed genetic tools and a strategy for functional replacement of strains within the WildR community, we demonstrate that the WildR isolate B. acidifaciens employs a T6SS to antagonize co-resident Bacteroidales. We also show that loss of T6SS function compromises the long-term maintenance of B. acidifaciens in the community but not its initial colonization, establishing the system as a determinant of strain persistence. The T6SS we identified resides on an integrative and conjugative element (ICE). ICE-seq, a targeted sequencing approach, reveals that the T6SS-ICE is distributed among select Bacteroidales and Muribaculaceae species in the WildR microbiome, between which it appears to be recently exchanged. We also show that transfer of the T6SS-ICE to WildR isolate Phocaeicola vulgatus confers transient colonization benefits in mice, but an eventual fitness cost. Our findings demonstrate that the T6SS can stabilize the presence of specific strains within a complex, co-evolved gut microbiome, yet its value is context dependent and constrained by the ecological and physiological landscape of the host community.}, }
@article {pmid41384541, year = {2025}, author = {Meissner, HC and Gilbert, PB and Eisnor, D and Wolfe, DN}, title = {Viral correlates of protection and the multifarious interactions of B and T cells.}, journal = {Human vaccines &amp; immunotherapeutics}, volume = {21}, number = {1}, pages = {2598695}, pmid = {41384541}, issn = {2164-554X}, mesh = {Humans ; *T-Lymphocytes/immunology ; Antibodies, Neutralizing/blood/immunology ; *B-Lymphocytes/immunology ; *Virus Diseases/immunology/prevention &amp; control ; Antibodies, Viral/blood/immunology ; Adaptive Immunity ; Animals ; Immunity, Innate ; Immunity, Cellular ; Immunity, Humoral ; }, abstract = {Validated, reproducible methods to assess immunity to a specific virus following either infection or vaccination are important for understanding susceptibility to existing and emerging infectious diseases. Correlates of protection for a specific viral illness involve humoral and cellular responses that differ by pathogen and by the portal of entry into the host. Contemporary understanding of a correlate of protection primarily is based on serum neutralizing antibody concentrations because of difficulty in assaying the complex interactions of T cells. A more comprehensive understanding of susceptibility and protection is needed. The goal of this paper is to enumerate the multiple variables that complicate understanding of cellular contributions to the innate and adaptive immune responses.}, }
@article {pmid41384688, year = {2026}, author = {Dsouza, JM and Sayar, E and Schweizer, MT and Harmon, S and Morrissey, C and Beltran, H and Nelson, PS and Cheng, L and Ding, CC and Haffner, MC}, title = {Molecular subtypes of metastatic prostate cancer: from pathophysiology to diagnosis.}, journal = {Histopathology}, volume = {88}, number = {1}, pages = {24-39}, doi = {10.1111/his.70033}, pmid = {41384688}, issn = {1365-2559}, support = {R37CA286450//NIH/NCI/ ; P30CA15704//NIH/NCI/ ; P50CA097186//NIH/NCI/ ; P01CA163227-06A1//NIH/NCI/ ; R01CA234715-03//NIH/NCI/ ; R01CA266452//NIH/NCI/ ; R01CA280056//NIH/NCI/ ; R50CA221836//NIH/NCI/ ; PO1CA163227//NIH/NCI/ ; CA282978//NIH/NCI/ ; R37CA241486-01A1//NIH/NCI/ ; P50 CA272390-01//NIH/NCI/ ; W81XWH-20-1-0111//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-21-1-0229//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-22-1-0278//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-18-1-0347//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-18-1-0689//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-17-1-0653//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-21-1-0264//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-14-2-0183//U.S. Department of Defence Prostate Cancer Research Program/ ; W81XWH-17-2-0043//U.S. Department of Defence Prostate Cancer Research Program/ ; PC230420//U.S. Department of Defence Prostate Cancer Research Program/ ; PC230582//U.S. Department of Defence Prostate Cancer Research Program/ ; 2021184/DDCF/Doris Duke Charitable Foundation/United States ; //V Foundation/ ; //Prostate Cancer Foundation Felix Feng PC-SYNERGY award/ ; //UCSF Benioff Initiative for Prostate Cancer Research/ ; //Safeway Foundation/ ; //Fred Hutch/UW Cancer Consortium/ ; //Brotman Baty Institute for Precision Medicine/ ; //UW/FHCC Institute for Prostate Cancer Research/ ; /RC/CCR NIH HHS/United States ; /CA/NCI NIH HHS/United States ; //National Institutes of Health Intramural Research Program project number ZIABC012163/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/diagnosis/genetics ; Neoplasm Metastasis/pathology/diagnosis ; Biomarkers, Tumor ; }, abstract = {Metastatic prostate cancer (mPC) is characterized by molecular and phenotypic heterogeneity. With increasing guideline-driven use of metastatic biopsies, more mPC specimens are being evaluated in surgical pathology. However, unlike localized prostate cancer, no standardized framework currently exists to guide the diagnostic workup of metastatic biopsies or reliably determine phenotypic subtypes. While many mPCs retain conventional acinar features, a growing subset exhibits phenotypic plasticity - including loss of prostate epithelial identity and emergence of neuroendocrine or other divergent lineages. This phenotypic diversity often occurs in castration-resistant prostate cancer as a mechanism of resistance to chronic androgen receptor pathway inhibition and is characterized by genomic alterations and epigenetic reprogramming. This review outlines the histologic and molecular spectrum of mPC and proposes a practical, pathology-informed diagnostic approach integrating morphologic assessment and immunohistochemistry. Adoption of a standardized diagnostic framework and multidisciplinary integration will be useful for employing precision oncology in advanced mPC.}, }
@article {pmid41385339, year = {2026}, author = {Nishitani, M and Graham, RA and Wang, T and Devos, J and Lee, SJ and Spellman, SR and Kitko, CL and MacMillan, ML and DeFilipp, Z and Gray, AN and Williams, KM and Takahashi, T and Schoettler, ML and Hashem, H and Rangarajan, HG and Prestidge, T and Ringden, O and Hamilton, BK and Sharma, A and Nusrat, R and El Jurdi, N and Bhatt, NS and Duncan, CN and Qayed, M}, title = {Impact of age on graft-versus-host disease and overall survival in pediatric hematopoietic cell transplant recipients.}, journal = {Blood advances}, volume = {10}, number = {6}, pages = {2108-2121}, pmid = {41385339}, issn = {2473-9537}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology/mortality/epidemiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Child ; Adolescent ; Child, Preschool ; Female ; Male ; Infant ; Age Factors ; Young Adult ; Incidence ; Infant, Newborn ; Transplantation, Homologous ; }, abstract = {Advances in graft-versus-host disease (GVHD) prevention and treatment have resulted in expanded donor options and improvement in treatment-related mortality (TRM). This analysis aimed to compare the incidence of acute and chronic GVHD (aGVHD and cGVHD, respectively) in pediatric patients by recipient age and to evaluate the impact of GVHD on overall survival (OS) and TRM. We included 14 099 patients aged ≤21 years who received their first allogeneic hematopoietic cell transplantation from 2002 to 2020, categorizing recipient age as 0 to 2 years (infants/toddlers), 3 to 12 years (school-aged), and 13 to 21 years (adolescent/young adult). There was no difference in grade 2 to 4 and 3 to 4 aGVHD by day 100 among age groups, except among patients with nonmalignant disease (NMD), among whom there was a small increase in incidence of severe aGVHD in older patients. Incidence of moderate/severe cGVHD by 1 year was higher with age. A similar impact of age was observed after adjusting for patient, donor, and transplant characteristics. Risk of severe aGVHD was higher in older children with NMD. Severe aGVHD and moderate/severe cGVHD were independently associated with inferior OS. In patients with malignant disease, both severe aGVHD and moderate/severe cGVHD were associated with increased risk of TRM. In conclusion, risk of moderate/severe cGVHD increases with recipient age, and risk of severe aGVHD is increased among older patients with nonmalignant conditions. Despite the low overall incidence of aGVHD and cGVHD in children, both are associated with significantly worse survival. These data highlight the need to consider GVHD outcomes at time of consultation and for improved prevention and treatment approaches.}, }
@article {pmid41385388, year = {2026}, author = {Amundsen, SK and Zhu, Y and Smith, GR}, title = {Chi hotspot control of RecBCD enzyme requires a RecB tether-RecC groove crosspoint interaction.}, journal = {Genetics}, volume = {232}, number = {2}, pages = {}, doi = {10.1093/genetics/iyaf240}, pmid = {41385388}, issn = {1943-2631}, support = {//G.R.S. from the National Institute of General Medical Sciences of the United States of America/ ; P30 CA015704/NH/NIH HHS/United States ; //Fred Hutch/University of Washington/Seattle Children's Cancer Consortium/ ; RRID:SCR_022606//Genomics &amp; Bioinformatics Shared Resource/ ; P30 CA015704/NH/NIH HHS/United States ; }, mesh = {*Exodeoxyribonuclease V/metabolism/genetics/chemistry ; *Escherichia coli Proteins/metabolism/genetics/chemistry ; Escherichia coli/genetics/enzymology ; Recombination, Genetic ; Protein Binding ; Homologous Recombination ; }, abstract = {Homologous genetic recombination is required for the faithful repair of broken DNA to continue life and for genetic diversification to propel evolution. The bacterial RecBCD enzyme promotes these processes through coordinated DNA helicase and nuclease activities, which are regulated by a Chi recombination hotspot sequence (5'-GCTGGTGG-3' in enteric bacteria) and the loading of the RecA DNA strand-exchange protein onto the newly generated 3' single-stranded DNA end. Chi's control of RecBCD requires a complex interaction of all three subunits at widely dispersed points in the 330 kDa three-subunit protein. Here, we describe an additional point that is critical for Chi's site-specific stimulation of recombination in Escherichia coli. This point, on the surface of RecBCD, is where the middle of the 19-amino-acid tether connecting the RecB helicase and nuclease domains fits into a groove on the surface of RecC. Deleting or changing even a single amino acid in this crosspoint dramatically reduces Chi hotspot activity. Surprisingly, severing the tether at the RecB helicase junction leaves Chi and RecBCD fully active, but severing the tether at the RecB nuclease junction abolishes Chi activity and strongly reduces recombination proficiency. This difference is accounted for by the critical role of the tether-groove interaction described here. We discuss how Chi controls RecBCD via the coordinated interaction of the tether-groove crosspoint and 13 other widely spaced points throughout RecBCD.}, }
@article {pmid41385397, year = {2025}, author = {Yazzie, D and Pete, D and Briscoe, C and Jim, MA and Meisner, A and Wiggins, C and Doyle, D and Yee, G and Goldtooth, C and Sanderson, PR and Keene, CN and Smith, M and Sehn, H and Damon, S and Kettering, CL and Emerson, M and Curley, C and Bea, J and Yazzie, S and Joe, N and Doherty, J and Dirk de Heer, H and , }, title = {Cancer incidence, stage at diagnosis, and trends across the Navajo Nation, 2014-2018.}, journal = {Cancer}, volume = {131}, number = {24}, pages = {e70202}, pmid = {41385397}, issn = {1097-0142}, support = {U54CA143925/CA/NCI NIH HHS/United States ; K00CA253685/CA/NCI NIH HHS/United States ; U1B1IHS0011-12-00//Indian Health Service/ ; U54CA143924/CA/NCI NIH HHS/United States ; K00 CA253685/CA/NCI NIH HHS/United States ; Cancer Health Research Centers//American Cancer Society/ ; HHSN2612018000014I/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *American Indian or Alaska Native/statistics &amp; numerical data ; Incidence ; Neoplasm Staging ; *Neoplasms/epidemiology/pathology/diagnosis/ethnology ; Registries ; SEER Program ; United States/epidemiology ; }, abstract = {BACKGROUND: American Indian/Alaska Native (AI/AN) people in the United States experience cancer disparities, but little is known about cancer patterns specific to each Tribal Nation. This study describes cancer incidence (2014-2018), trends (1998-2018), and stage of diagnosis across the Navajo Nation, one of the largest sovereign tribal nations worldwide.<br><br>METHODS: Cases from six Arizona, New Mexico, and Utah counties covering most of the Navajo Nation were identified by population-based cancer registries and linked with Indian Health Services patient registrations. Cancer incidence and stage at diagnosis were compared between Navajo and non-Hispanic White persons in the same counties. Trends from 1998 through 2018 were analyzed using Joinpoint regression.<br><br>RESULTS: Navajo people had significantly higher incidence than non-Hispanic White people of gallbladder (incidence rate ratio [RR]&#xa0;=&#xa0;6.25), stomach (RR&#xa0;=&#xa0;3.19), kidney (RR&#xa0;=&#xa0;1.89), myeloma (RR&#xa0;=&#xa0;1.80), and liver cancers (RR&#xa0;=&#xa0;1.79) and a lower incidence of cancers of the lung (RR&#xa0;=&#xa0;0.16), female breast (RR&#xa0;=&#xa0;0.49), leukemia (RR&#xa0;=&#xa0;0.49), prostate (RR&#xa0;=&#xa0;0.62), pancreas (RR&#xa0;=&#xa0;0.79), and non-Hodgkin lymphoma (RR&#xa0;=&#xa0;0.79). Diagnostic stage was not different for breast, cervical, and colorectal cancers, but two thirds of patients with cervical and colorectal cancer were diagnosed in later/unknown stages. Although all-site cancer rates did not change significantly from 1998 through 2018 among Navajo people, a significant decrease was found from 2010 through 2018 (-2.1% annual percentage change, p&#xa0;<&#xa0;.01).<br><br>CONCLUSIONS: Navajo people experience a higher incidence of kidney, stomach, liver, myeloma, and gallbladder cancers and a lower incidence of cancers of the breast, prostate, lung, non-Hodgkin lymphoma, and leukemia. Tailored and targeted prevention efforts may help reduce cancer disparities in the Navajo Nation.}, }
@article {pmid41387075, year = {2026}, author = {Beydoun, MA and Beydoun, HA and Tsai, J and Tinker, LF and Gradidge, PJ and Maldonado, AI and Le Kennedy, J and Allison, M and Jung, SY and Zonderman, AB and Evans, MK and Manson, JE}, title = {Anthropometric indices of obesity and their relationships with diabetes risk by race and ethnicity among postmenopausal women.}, journal = {Nutrition, metabolism, and cardiovascular diseases : NMCD}, volume = {36}, number = {3}, pages = {104430}, pmid = {41387075}, issn = {1590-3729}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Postmenopause/ethnology ; Middle Aged ; Waist Circumference/ethnology ; Risk Factors ; Aged ; Body Mass Index ; *Obesity/ethnology/diagnosis/physiopathology ; Risk Assessment ; Adiposity/ethnology ; Predictive Value of Tests ; *Anthropometry ; Proportional Hazards Models ; ROC Curve ; United States/epidemiology ; *Diabetes Mellitus/ethnology/diagnosis ; *Diabetes Mellitus, Type 2/ethnology/diagnosis ; *Ethnicity ; }, abstract = {BACKGROUND AND AIMS: Traditional measures of obesity such as body mass index (BMI) and waist circumference (WC) have shown inconsistent predictive utility for diabetes across diverse populations. Novel anthropometric measures that focus on abdominal adiposity and body shape may offer better risk assessment for diabetes. Yet, the utility of traditional and novel anthropometric measures in postmenopausal women and in different racial and ethnic groups remains unclear. The predictive utilities of traditional and novel anthropometric measures for diabetes risk were comprehensively assessed, among postmenopausal women, overall, and across racial and ethnic groups.<br><br>METHODS AND RESULTS: Using data from 91,392 diabetes-free Women's Health Initiative participants, predictive values of anthropometric measures were examined using Receiver Operating Characteristic (ROC) and Cox regression with Harrell's c-statistics. ROC analyses suggested that novel anthropometric measures with best predictive abilities were 'a Body Shape Index' (ABSI), 'Abdominal Volume Index', and 'Body Roundness Index', although WC and novel anthropometric measures had similarly modest predictive abilities to BMI (Areas Under the Curve <0.6). Cut-off points for anthropometric measures varied by race/ethnicity. Multivariable Cox regression modeling suggested that 'Clinica Universidad de Navarra-Body Adiposity Estimator', WC, ABSI, and BMI had the strongest associations with diabetes risk (adjusted hazard ratios [HRs]: 1.27, 1.26, 1.23, and 1.22 per 1-SD increase, respectively), although predictive accuracies involving any measure were modest (Harrell's c-statistics&#x223c;0.58-0.59).<br><br>CONCLUSIONS: In this comprehensive evaluation, anthropometric measures were marginally predictive of diabetes risk, and novel measures did not outperform traditional measures among postmenopausal women, irrespective of race/ethnicity.}, }
@article {pmid41388019, year = {2025}, author = {Chac, D and Heller, FJ and Banna, HA and Kaisar, MH and Markiewicz, SM and Pruitt, EL and Chowdhury, F and Bhuiyan, TR and Akter, A and Khan, AI and Dumayas, MG and Rice, A and Karmakar, PC and Dash, P and LaRocque, RC and Ryan, ET and Xu, L and Minot, SS and Harris, JB and Qadri, F and Weil, AA}, title = {Gut bacteria-derived sphingolipids alter innate immune responses to oral cholera vaccine antigens.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {638}, pmid = {41388019}, issn = {2041-1723}, support = {R35 GM133420/GM/NIGMS NIH HHS/United States ; T32HD007233//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI099243/AI/NIAID NIH HHS/United States ; T32 HD007233/HD/NICHD NIH HHS/United States ; R01 AI136979/AI/NIAID NIH HHS/United States ; K08 AI123494/AI/NIAID NIH HHS/United States ; R01 AI106878/AI/NIAID NIH HHS/United States ; D43 TW005572/TW/FIC NIH HHS/United States ; R01 106878//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI AI136979//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; R01 AI103055/AI/NIAID NIH HHS/United States ; K43 TW010362/TW/FIC NIH HHS/United States ; }, mesh = {Humans ; *Cholera Vaccines/immunology/administration &amp; dosage ; *Immunity, Innate/immunology ; *Gastrointestinal Microbiome/immunology/genetics ; *Sphingolipids/metabolism/immunology ; Vibrio cholerae/immunology ; *Cholera/prevention &amp; control/immunology/microbiology ; Administration, Oral ; Feces/microbiology ; Macrophages/immunology ; Bacteroides/metabolism/immunology ; Female ; Male ; Adult ; }, abstract = {The degree of protection conferred after receiving an oral cholera vaccine (OCV) varies based on age, prior exposure to Vibrio cholerae, and unknown factors. Recent evidence suggests that the microbiota may mediate some of the unexplained differences in oral vaccine responses. Here, we use metagenomic sequencing of the fecal microbiota at the time of vaccination and relate microbial features to immune responses after OCV using a reference-independent gene-level method. We find that the presence of sphingolipid-producing bacteria is associated with the development of protective immune responses after OCV. We test these associations by stimulating human macrophages with Bacteroides xylanisolvens metabolites and find that sphingolipid-containing extracts increase innate immune responses to OCV antigens. Our findings demonstrate a new analytic method for translating metagenomic sequencing data into strain-specific results associated with a biological outcome, and in validating this tool, we identify that microbe-derived sphingolipids impact immune responses to OCV antigens.}, }
@article {pmid41388301, year = {2025}, author = {Caceres-Palomo, L and Sanchez-Mejias, E and Trujillo-Estrada, L and Perez-Moreno, JJ and Lopez-Oliva, E and Lim, TE and DeFlitch, L and Chang, SH and Kampman, L and Corces, MR and Blurton-Jones, M and Moreno-Gonzalez, I and Pascual, A and Vitorica, J and Garcia-Leon, JA and Gutierrez, A}, title = {Human iPSC-derived APOE4/4 Alzheimer´s disease astrocytes exhibit a senescent and pro-inflammatory state that compromises neuronal support.}, journal = {Journal of neuroinflammation}, volume = {23}, number = {1}, pages = {9}, pmid = {41388301}, issn = {1742-2094}, support = {UM1 HG012076/HG/NHGRI NIH HHS/United States ; PI21/00915 and PI24/00274 (to AG) and PI21/00914 and PI24/00308 (to JV)//Instituto de Salud Carlos III/ ; U01 AG072573/AG/NIA NIH HHS/United States ; P01 AG073082/AG/NIA NIH HHS/United States ; B1-2020_04 (to JAGL)//Universidad de M&#xe1;laga/ ; UMA20-FEDERJA-048 (to JAGL), PY18-RT-2233 (to AG), SNGJ4-11 (to LCP)//Consejer&#xed;a de Econom&#xed;a, Innovaci&#xf3;n, Ciencia y Empleo, Junta de Andaluc&#xed;a/ ; P01AG073082, U01AG072573, and UM1HG012076 to MRC./NH/NIH HHS/United States ; PI-0276-2018 (to JAGL)//Consejer&#xed;a de Salud y Familias, Junta de Andaluc&#xed;a/ ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG066519/NH/NIH HHS/United States ; }, abstract = {UNLABELLED: Alzheimer´s disease (AD) is dominated by a complex cellular pathology which involves most brain cell types with glial cells increasingly recognized as playing fundamental roles in neurodegeneration. Astrocytes, which perform essential functions in preserving brain homeostasis, present a reactive phenotype in the AD brains with still unknown consequences. In this study, we generated and characterized human induced pluripotent stem cell (hiPSC)-derived astrocytes from AD patients harboring the APOE4/4 genotype, the greatest genetic risk factor for late-onset AD. Disease astrocytes showed a reactive phenotype. In addition, they showed altered mitochondrial network including perinuclear clustering of mitochondria, enhanced mitochondrial fusion and higher production of reactive oxygen species which, unexpectedly, were coincident with increased oxidative phosphorylation and glycolysis. As these mitochondrial features are related to the acquisition of cell senescence, we evaluated this at the transcriptome level and found that these AD-derived astrocytes significantly upregulated gene signatures of cellular senescence and displayed a senescence-associated secretory phenotype (SASP). To verify this finding, we observed senescence-related DNA damage response in a significant proportion of cells in the cerebral cortex of AD patients, with most of these cells being astrocytes. Finally, we confirmed that this astrocytic senescent and proinflammatory phenotype is associated with a reduced neuronal support, evidencing that APOE4/4 AD astrocytes present intrinsic features that may compromise brain homeostasis and promote neurodegeneration. Addressing the causes and consequences of this astrocytic dysfunctionality should help to elucidate novel therapeutic targets able to modify the neurodegeneration present in AD.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03607-z.}, }
@article {pmid41389316, year = {2026}, author = {McKay, RR and Pal, S and Xie, W and Aggen, D and Albiges, L and Apolo, A and Atkins, MB and Bangs, R and Beckermann, KE and Bellmunt, J and Berg, SA and Bilen, MA and Braun, D and Carlo, MI and Efstathiou, J and Galsky, M and Grivas, P and Gupta, S and Haas, N and Hakimi, AA and Hammers, H and Heng, DYC and Hirsch, M and Iyer, G and Jonasch, E and Koshkin, VS and Kryvenko, O and Lewis, B and Li, R and Matin, S and Maughan, B and McDermott, DF and McGregor, B and Meeks, J and Milowsky, M and Motzer, R and Necchi, A and Petrylak, D and Porten, S and Powles, T and Rini, B and Shuch, B and Siefker-Radtke, A and Sonpavde, G and Sridhar, SS and Suarez, C and Tang, C and Tripathi, A and Van Der Heijden, MS and Voss, M and Xu, W and Zhang, T and Rosenberg, J and Choueiri, TK}, title = {Advanced Urologic Cancer Consensus Conference (AUC3) 2025: Expert consensus on the management of renal cell and urinary tract cancers.}, journal = {CA: a cancer journal for clinicians}, volume = {76}, number = {1}, pages = {e70052}, pmid = {41389316}, issn = {1542-4863}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Antibodies, Monoclonal, Humanized/therapeutic use ; *Carcinoma, Renal Cell/therapy/pathology ; *Kidney Neoplasms/therapy/pathology ; Neoadjuvant Therapy/methods ; *Urologic Neoplasms/therapy/pathology ; }, abstract = {The therapeutic landscape for renal cell carcinoma (RCC) and urinary tract cancer (UTC) has transformed dramatically, creating complexity in treatment selection and sequencing. The 2025 Advanced Urologic Cancer Consensus Conference was convened to establish evidence-based expert consensus recommendations for optimal management. A multidisciplinary panel of 51 experts participated in a modified Delphi process addressing questions developed through iterative consensus-building covering RCC and UTC management. Voting occurred before and after the conference, and analyses focused on postmeeting responses. Consensus was defined as ≥75% agreement, with strong consensus as >90%. Strong consensus was found on the use of adjuvant pembrolizumab for higher risk RCC (pathologic T2 [pT2], grade 4; pT3-pT4, any grade; pTXN1; or fully resected metastatic disease) and on neoadjuvant therapy before cystectomy for localized UTC. There was strong consensus on the use of enfortumab vedotin plus pembrolizumab as frontline therapy for metastatic UTC and the use of platinum-based chemotherapy postprogression in biomarker-negative UTC. For RCC, there was consensus on the role of single-agent vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy after progression on frontline immune checkpoint inhibitor/vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy or dual immune checkpoint inhibitor therapy. However, there was a lack of consensus on other critical areas in the management of RCC and UTC. The 2025 Advanced Urologic Cancer Consensus Conference provides evidence-informed guidance for complex clinical scenarios while identifying critical research priorities. The group recognizes that the lack of consensus across multiple areas highlights the need for improved patient selection and prospective studies enabling optimal combination and sequencing approaches. This iterative annual process will address evolving treatment paradigms to optimize outcomes.}, }
@article {pmid41390126, year = {2026}, author = {Yeung, AK and Bonkovsky, HL and Balwani, M and Anderson, KE and Levy, C and Thapar, M and Wang, B and Chin, M and Savage, W and Desnick, R and Keel, S}, title = {Bitopertin shows efficacy in patients with erythropoietic protoporphyria: Results from the randomized, double-blind, placebo-controlled AURORA trial.}, journal = {Journal of the American Academy of Dermatology}, volume = {94}, number = {4}, pages = {1167-1176}, doi = {10.1016/j.jaad.2025.12.024}, pmid = {41390126}, issn = {1097-6787}, mesh = {Humans ; *Protoporphyria, Erythropoietic/drug therapy/blood ; Double-Blind Method ; Male ; Female ; Middle Aged ; Adult ; Protoporphyrins/blood ; Treatment Outcome ; Aged ; Young Adult ; Dose-Response Relationship, Drug ; }, abstract = {BACKGROUND: Erythropoietic protoporphyria is a rare genetic disorder of heme biosynthesis characterized by protoporphyrin-IX accumulation, painful phototoxic reactions, and hepatobiliary disease, for which no disease-modifying therapies are approved.<br><br>OBJECTIVE: To evaluate the efficacy and safety of bitopertin, an inhibitor of glycine transporter 1, in adults with erythropoietic protoporphyria.<br><br>METHODS: In this randomized, double-blind, phase 2 study, patients received once-daily oral bitopertin 20 mg, bitopertin 60 mg, or placebo for 17 weeks. The primary endpoint was percentage change from baseline in whole-blood metal-free protoporphyrin-IX levels at day 121.<br><br>RESULTS: Patients received bitopertin 20 mg (n = 26), 60 mg (n = 25), or placebo (n = 24). At day 121, the percentage change from baseline in whole-blood metal-free protoporphyrin-IX versus placebo was -29.6% (P = .004) with bitopertin 20 mg and -49.8% (P < .001) with bitopertin 60 mg. Bitopertin was associated with a reduced incidence of phototoxic reactions. Bitopertin was well tolerated with no notable safety concerns identified.<br><br>LIMITATIONS: Small sample size, short follow-up period, and no formal adjustments for between-group multiple-pairwise comparisons.<br><br>CONCLUSIONS: Bitopertin significantly reduced protoporphyrin-IX levels, showed improved measures of sunlight tolerance, and had a favorable safety profile in patients with erythropoietic protoporphyria.}, }
@article {pmid41390763, year = {2025}, author = {Singh, S and Islam, SMS and Liu, R and Adeniji, OS and Simons, LM and Saini, P and Tateno, H and Danesh, A and Denton, PW and Giron, LB and Jones, RB and Hultquist, JF and Xiao, H and Abdel-Mohsen, M}, title = {HIV-induced sialoglycans on infected CD4+ T cells promote immune evasion from myeloid cell-mediated killing.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {18}, pmid = {41390763}, issn = {2041-1723}, support = {R01 AA029859/AA/NIAAA NIH HHS/United States ; R15 AI178516/AI/NIAID NIH HHS/United States ; P20 GM103427/GM/NIGMS NIH HHS/United States ; R01 DK123733/DK/NIDDK NIH HHS/United States ; R01AI165079//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AG092241/AG/NIA NIH HHS/United States ; R01 NS117458/NS/NINDS NIH HHS/United States ; R01 AI165079/AI/NIAID NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Humans ; *HIV Infections/immunology/virology ; Female ; *Immune Evasion/immunology ; Mice ; *CD4-Positive T-Lymphocytes/immunology/virology/metabolism ; Sialic Acid Binding Immunoglobulin-like Lectins/metabolism/immunology ; *Myeloid Cells/immunology/metabolism ; *HIV-1/immunology ; *Polysaccharides/metabolism/immunology ; Neuraminidase ; Viral Load/drug effects ; Neutrophils/immunology ; Sialic Acid Binding Ig-like Lectin 3/metabolism/immunology ; *Sialic Acids/metabolism/immunology ; Glycosylation ; Antigens, Differentiation, Myelomonocytic ; Antigens, CD ; Lectins ; }, abstract = {Sialic acid-containing glycans (sialoglycans) on pathological cells interact with Siglecs, glyco-immune checkpoint receptors expressed on myeloid cells, suppressing the cytotoxic functions of these immune cells. Using targeted glycomic analyses and gene editing, we show that HIV infection reprograms the glycosylation machinery of infected cells to increase the expression of the sialoglycan ligands for Siglec-3, -7, and -9. These ligands engage Siglecs on myeloid cells, impairing their ability to target HIV-infected cells. Selective disruption of these interactions using 10-1074-SiaD, an HIV-specific antibody conjugated to sialidase, an enzyme that removes sialic acids, significantly enhances monocyte- and neutrophil-mediated killing of HIV-infected cells in autologous assays. Treatment with 10-1074-SiaD in female humanized mice infected with HIV reduces viral load and decreases inflammation. These findings reveal an immune evasion mechanism exploited by HIV to evade myeloid cell immune surveillance and highlight the potential of targeting sialoglycan-Siglec interactions to improve immune clearance of HIV-infected cells.}, }
@article {pmid41391604, year = {2025}, author = {Greenlee, H and Santiago-Torres, M and Contento, I and Koch, PA and Rillamas-Sun, E and Gray, HL and Brickman, AM and Gaffney, AO and Thomson, CA and Crane, TE and Dominguez, N and Sepulveda, J and Marín-Chollom, AM and Paul, R and Shi, Z and Ulanday, KT and Accordino, M and Camacho, FJ and Crew, KD and Kalinsky, K and Taback, B and Trivedi, MS and Hale, C and Reaves, B and Beauchemin, MP and Castellano, M and Fuentes, Y and Eddy, M and Bella, AL and Meisner, A and Hershman, DL}, title = {¡Mi Vida Saludable!: Results of a Randomized, Controlled, 2 × 2 Factorial Trial of an In-Person and eHealth Diet and Physical Activity Intervention in Latina Breast Cancer Survivors.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {126}, number = {5}, pages = {156260}, doi = {10.1016/j.jand.2025.156260}, pmid = {41391604}, issn = {2212-2672}, support = {R01 CA186080/CA/NCI NIH HHS/United States ; R21 CA152903/CA/NCI NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, abstract = {BACKGROUND: Latina breast cancer survivors experience health disparities. Effective lifestyle interventions are sparse.<br><br>OBJECTIVE: This trial tested the effectiveness of a culturally tailored diet and physical activity (PA) intervention in Latina breast cancer survivors.<br><br>DESIGN: Using a 2 &#xd7; 2 factorial design, women were randomized to receive 4 weekly in-person group sessions; 11 months of eHealth communications, in-person sessions, and eHealth; or control. Follow-up data were collected at months 6 and 12.<br><br>PARTICIPANTS: Eligibility criteria were self-identification as Latina, post-treatment for early-stage breast cancer, and consuming <5 daily servings of fruits and vegetables (F/V) and/or engaging in <150 min/wk of moderate-to-vigorous PA (MVPA). A total of 167 women from New York City were enrolled from July 2016 to October 2018, with 93.4% retention at 12-month follow-up (n = 156).<br><br>INTERVENTION: All participants received a Fitbit for self-monitoring and a 1-on-1 health coaching session. In-person group sessions included nutrition and PA education, cooking classes, fitness classes or a grocery store visit, and social activities. The eHealth communications included motivational text messaging, e-mailed newsletters, and study website access. Activities were conducted in Spanish and English.<br><br>MAIN OUTCOME MEASURES: Primary outcomes were 12-month change in F/V servings/d and energy density of food. Secondary outcomes were 12-month change in MVPA and anthropometry.<br><br>STATISTICAL ANALYSIS: Outcomes comparing intervention arms with the control were examined using generalized estimating equations.<br><br>RESULTS: At baseline (n = 167), mean age was 56.7 years; 82.3% had overweight or obesity. At month 12, daily F/V intake for women in the in-person sessions increased by 10% and decreased by 44% for women in the control group, a +96% group difference (P = .01); no other between-group differences were observed. At month 12, women in the control group had a 53% increase in minutes per week of MVPA, and women in the in-person plus eHealth group had a 34% decrease, a -57% group difference (P = .01); no other between-group differences were noted. No changes in energy density or weight between groups were observed.<br><br>CONCLUSIONS: Women randomized to the in-person &#xa1;Mi Vida Saludable! classes modestly increased F/V intake at 12 months relative to control. Those receiving eHealth communication did not have diet, MVPA, or weight change relative to control. More research is needed to understand how to support Latina breast cancer survivors in making sustained diet and PA changes.}, }
@article {pmid41394685, year = {2025}, author = {Korber, B and Seaman, MS and Mkhize, NN and Greene, K and Gao, H and Shen, X and Domin, E and Tang, H and Theiler, J and Wagh, K and Moore, PL and Williamson, C and Mullins, JI and Doria-Rose, NA and Montefiori, D and Giorgi, EE}, title = {Contemporary HIV-1 envelope pseudovirus panels for detecting and assessing B cell lineages with broadly neutralizing antibody potential.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41394685}, issn = {2692-8205}, support = {INV-036842/GATES/Gates Foundation/United States ; INV-007368/GATES/Gates Foundation/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, abstract = {Although a protective HIV-1 vaccine has not yet been realized, significant progress has been made in vaccine designs that trigger B cell lineages with potential to produce broadly neutralizing antibodies (bnAbs). Advancing these strategies by optimizing vaccine boosting regimens requires early detection of maturing antibodies with neutralizing activity against native envelope glycoprotein (Env) trimers and streamlined strategies to identify antibodies as they begin to manifest desired levels of breadth and potency. Thus, we designed three types of pseudovirus screening panels based on Envs of contemporary HIV-1 isolates to facilitate detection of bnAb lineages that are on favorable trajectories during a vaccination course. The panels were selected from Tier 2 Transmitted Founder Lineage (TFL) HIV-1 Envs from placebo participants in the Antibody Mediated Prevention (AMP) efficacy trials. Using 15 bnAbs to evaluate the neutralization sensitivity of the viruses, we selected 8-member bnAb class-specific panels most sensitive to bAbs representing their class: V2-apex, V3-glycan, CD4-receptor binding site (CD4bs), Membrane-Proximal External Region (MPER), or fusion peptide (FP). Next, we combined the most sensitive viruses among the class-specific panels to create a 12-virus panel to enable optimal detection of low-titer bnAb activity across epitope specificities. Finally, as HIV-1 continues to evolve greater levels of antigenic diversity and as current global pseudoviruses bnAb panels rely on viruses collected more than twenty years ago, we showed the importance of using contemporary viral panels to assess bnAb breadth and potency and designed a 12-virus panel representative of the spectrum neutralization profiles among AMP placebo viruses. We characterized pseudoviruses bearing each selected Env using standardized human sera to confirm their Tier 2 status and biological relevance. These updated panels enable sensitive screening of neutralization activity in vaccine studies and can also provide a realistic assessment of the expected breadth and potency of maturing responses against contemporary HIV-1 Envs.}, }
@article {pmid41396068, year = {2026}, author = {Lee, P and Nelson, PS}, title = {The Multifaceted Role of Androgen Receptor Signaling in Immunity: Implications for Oncology.}, journal = {Molecular cancer research : MCR}, volume = {24}, number = {3}, pages = {155-168}, pmid = {41396068}, issn = {1557-3125}, support = {P01 CA163227/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; CA097186//National Cancer Institute (NCI)/ ; P01CA163227//National Cancer Institute (NCI)/ ; //DOD Prostate Cancer Research Program (PCRP)/ ; //Prostate Cancer Foundation (PCF)/ ; }, mesh = {Humans ; *Receptors, Androgen/metabolism/immunology/genetics ; Animals ; *Signal Transduction/immunology ; *Neoplasms/immunology/metabolism ; Mice ; Immunity, Innate ; Male ; Adaptive Immunity ; }, abstract = {Whereas the androgen receptor (AR) is canonically known for its role in the prostate and testis, AR signaling exerts broad immunomodulatory effects through direct and indirect signaling in multiple immune cell compartments and contributes significantly to sex differences in autoimmunity, infection, and cancer. Mouse model perturbations of androgen signaling through castration, testicular feminization, and cell type-specific Ar knockout have provided important insights into cell-intrinsic and -extrinsic mechanisms by which AR signaling affects innate and adaptive immunity. However, the precise molecular underpinnings of these effects remain largely unknown. Moreover, despite convincing epidemiologic and correlative observations that highlight the importance of AR signaling in human immune function, it remains unclear how reliably findings in mice will translate to humans. A better understanding of how to augment immune function through androgen signaling modulation could have significant clinical relevance for the treatment of cancer, as well as other disease states involving immune dysregulation. In this review, we discuss the current evidence for the functional effects of AR signaling within the major immune cell compartments of the innate and adaptive immune systems. We also review ongoing clinical efforts that modify AR signaling for the purpose of enhancing antitumor immunity.}, }
@article {pmid41397186, year = {2025}, author = {Huang, AH and Lee, GY and Lu, CA and Sahin, IH and King, GT and Safyan, RA and Cohen, SA and Zhen, DB and Shankaran, V and Harris, WP and Coveler, AL and Malhotra, J and Forbes, VE and Gold, PJ and Chiorean, EG and Hsieh, RW}, title = {Rechallenge With an Epidermal Growth Factor Receptor Inhibitor in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500646}, doi = {10.1200/OP-25-00646}, pmid = {41397186}, issn = {2688-1535}, abstract = {PURPOSE: Clonal evolution is a mechanism of treatment resistance against epidermal growth factor receptor inhibitors (EGFRi) in metastatic colorectal cancer (mCRC). When EGFRi is discontinued, EGFRi-resistant tumor subclones decay with time, allowing for EGFRi rechallenge at later time. We conducted a meta-analysis to investigate the efficacy of EGFRi rechallenge in mCRC.<br><br>METHODS: Clinical trials and observational studies investigating the efficacy of EGFRi rechallenge in mCRC were included from PubMed and Embase from inception to December 8, 2024. Hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were aggregated using Bayesian random-effects models. Objective response rates (ORRs) were aggregated using meta-random-effects models.<br><br>RESULTS: Twenty-nine studies were included. The pooled median PFS, median OS, and ORR were 3.83 months (95% CI, 3.25 to 4.50), 10.43 months (95% CI, 8.14 to 13.36), and 14.61% (95% CI, 8.70 to 23.51), respectively. EGFRi rechallenge was associated with significantly longer pooled PFS (HR, 0.54 [95% CI, 0.31 to 0.93]) and numerically longer pooled OS (HR, 0.71 [95% CI, 0.46 to 1.09]) than non-EGFRi systemic therapy. Patients without detectable RAS/RAF mutations by circulating tumor DNA (ctDNA) at the time of EGFRi rechallenge had significantly longer OS (HR, 0.43 [95% CI, 0.24 to 0.75]) and PFS (HR, 0.40 [95% CI, 0.26 to 0.62]) than those with ctDNA RAS/RAF mutations. Studies with EGFRi-free intervals &#x2265;4 months before rechallenge (18.77%) had a numerically greater pooled ORR than those with EGFRi-free intervals <4 months (6.60%). No unexpected adverse events were reported, and treatment discontinuation because of adverse events was 2.7%.<br><br>CONCLUSION: EGFRi rechallenge is associated with significantly longer PFS, numerically longer OS, and clinically meaningful ORR as compared with non-EGFRi systemic therapy in mCRC, particularly for ctDNA RAS/RAF wild-type mCRC.}, }
@article {pmid41397203, year = {2025}, author = {Kouadio, C and Selukar, S and Othus, M and Chevret, S}, title = {Detecting the Cure Model Appropriateness in Randomized Clinical Trials With Long-Term Survivors.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500084}, doi = {10.1200/CCI-25-00084}, pmid = {41397203}, issn = {2473-4276}, mesh = {Humans ; *Randomized Controlled Trials as Topic/methods ; *COVID-19/virology/mortality/epidemiology/therapy ; SARS-CoV-2/isolation &amp; purification ; *Cancer Survivors/statistics &amp; numerical data ; Computer Simulation ; *Models, Statistical ; }, abstract = {PURPOSE: To evaluate the appropriateness of a cure model when analyzing right-censored end points of a randomized clinical trial (RCT) in malignancy in the presence of long-term survivors. We aim to derive how the ratio estimation of censored cured subjects (RECeUS), previously proposed for a homogeneous population, could be extended for use in RCTs.<br><br>METHODS: Based on the RECeUS method, four decision rules were considered to assess the appropriateness of a cure model. They considered the eligibility conditions to be met: in both arms, in at least one randomized arm, in the entire sample, or when only considering an average of the conditions, respectively. A simulation study was performed to evaluate their performance and the impact of the link function when considering the appropriateness of cure models. We also illustrate the method using two real data examples from two RCTs conducted in patients with acute leukemia and COVID-19 disease.<br><br>RESULTS: Simulation results show that the best decision rule that can be applied in all considered treatment effect scenarios might be to check the criteria in at least one randomized arm. Regardless of the rules, the cure model appeared to be appropriate in both RCT data.<br><br>CONCLUSION: When analyzing survival data from RCTs, the appropriateness of a cure model could be considered in the face of a plateau shape of the survival curves. To ensure that the presence of such a plateau in the survival curves is a reliable indicator of the presence of cured patients in the population, the RECeUS method should be used in each randomized arm separately, with criteria met in at least one randomized arm.}, }
@article {pmid41397238, year = {2026}, author = {Cloos, J and Valk, PJM and Thiede, C and Döhner, K and Roboz, GJ and Wood, BL and Walter, RB and Wang, S and Wierzbowska, A and Wei, AH and Wu, D and Vergez, F and Venditti, A and van der Reijden, BA and van de Loosdrecht, AA and Tiong, IS and Thol, FR and Subklewe, M and Roumier, C and Reuvekamp, T and Ravandi, F and Preudhomme, C and Plesa, A and Othman, J and Ossenkoppele, GJ and Ofran, Y and Mimoun, A and Maurillo, L and Majchrzak, A and de Leeuw, D and Kern, W and Kim, DDH and Ikoma-Colturato, MRV and Haaksma, LH and Guzman, ML and Feuring, M and Depreter, B and Czyz, A and Bücklein, V and Baer, C and Bachas, C and Freeman, SD and Buccisano, F and Hourigan, CS and Dillon, R and Heuser, M}, title = {2025 update on MRD in acute myeloid leukemia: a consensus document from the ELN-DAVID MRD Working Party.}, journal = {Blood}, volume = {147}, number = {11}, pages = {1147-1167}, doi = {10.1182/blood.2025031480}, pmid = {41397238}, issn = {1528-0020}, mesh = {Humans ; *Neoplasm, Residual/diagnosis ; *Leukemia, Myeloid, Acute/therapy/genetics/diagnosis/pathology ; Consensus ; Prognosis ; Hematopoietic Stem Cell Transplantation ; Practice Guidelines as Topic ; }, abstract = {Measurable residual disease (MRD) monitoring has become a critical component in the management of acute myeloid leukemia (AML), to inform prognosis, guide therapy, and serve as a key end point in clinical trials. The 2025 update of the MRD guideline provides a comprehensive and refined framework for MRD assessment, aligned with the European LeukemiaNet (ELN) 2022 genetic risk classification. Developed by members of the ELN AML MRD Working Party, the guidelines incorporate expert consensus determined through a 2-stage Delphi round. They address the clinical implementation of MRD methodologies, technical considerations, integration into clinical trials, and future directions. Importantly, MRD recommendations are tailored to individual prognostic and genetic subgroups. A new qualitative MRD response category, designated as optimal, warning, or high risk of treatment failure, has been introduced to facilitate contextual interpretation of the MRD burden and its clinical relevance. Notably, ultrahigh-sensitivity next-generation sequencing-based MRD assessment is now recommended for FLT3 internal tandem duplication-mutated AML after intensive chemotherapy and before allogeneic hematopoietic cell transplantation. A total of 56 recommendations were formulated, with 53 achieving a high level of consensus (≥90%). These updated guidelines represent a major step forward toward harmonizing MRD assessments in AML and enhancing its clinical utility across diverse treatment settings.}, }
@article {pmid41397550, year = {2026}, author = {Saultz, JN and Bolon, YT and Wang, T and Spellman, SR and Lee, SJ and He, M and Camacho-Bydume, C and Krishna, C and Chowell, D and Shaffer, BC and Hsu, KC and Paczesny, S and Gadalla, SM and Marsh, SGE and Betts, BC and Arrieta-Bolaños, E}, title = {Higher HLA-DRB1 Evolutionary Divergence Is Associated with Reduced Relapse and Improved Survival after Matched Unrelated Hematopoietic Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {4}, pages = {434.e1-434.e11}, pmid = {41397550}, issn = {2666-6367}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/mortality ; Male ; Female ; *HLA-DRB1 Chains/genetics/immunology ; Adult ; Child ; Adolescent ; Graft vs Host Disease ; Middle Aged ; Child, Preschool ; Recurrence ; Unrelated Donors ; Young Adult ; }, abstract = {HLA evolutionary divergence (HED) can serve as a surrogate for the degree of immunopeptidome diversity of HLA phenotypes. Different degrees of HED in the patient-donor pair may influence the presentation of peptides relevant for alloreactive responses involved in graft-versus-host and graft-versus-leukemia (GvL) effects, potentially impacting outcomes after hematopoietic cell transplantation (HCT). This study was conducted to test whether higher HED scores (both class I and class II) correlate with improved GvL and survival after HLA-matched HCT. The study cohort comprised pediatric and adult patients (n = 9231) reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) database who underwent a first HCT from 8/8 matched unrelated donors between 2008 and 2018 for the treatment of acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, or lymphoma were included. HED was calculated on the amino acid sequences of HLA-A, -B, -C, and -DRB1, and class I (HLA-A, -B, and -C), and HLA-DRB1 HED scores were assigned to each patient-donor pair. The association between increasing HED (top quartile versus lower 3 quartiles) and HCT outcome was evaluated with malignant disease relapse, disease-free survival (DFS), and overall survival (OS) as primary endpoints. Secondary endpoints were transplantation-related mortality (TRM), acute and chronic graft-versus-host disease (GvHD), and engraftment. Greater HLA-DRB1 HED was associated with significantly decreased malignant disease relapse (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.79 to 0.94; P = .0014), better disease-free survival (HR, 0.92; 95% CI, 0.86 to 0.98; P = .0067), and improved OS (HR, 0.91; 95% CI, 0.85 to 0.96; P = .0019) in the total population after adjustment for other significant clinical variables. There was no significant association between HLA-DRB1 HED and TRM or the risk of acute or chronic GVHD. Conversely, higher (upper quartile) HLA class I HED did not significantly impact OS, DFS, TRM, relapse, or acute and chronic GVHD compared with the lower 3 quartiles. In addition, neither HLA-class I nor HLA-DRB1 HED significantly impacted neutrophil or platelet engraftment post-transplantation. Our findings demonstrate that higher HLA-DRB1 HED scores are associated with reduced relapse and improved DFS and OS in patients undergoing matched unrelated donor transplantation for hematologic malignancies. These findings contribute to the growing evidence supporting the importance of HED in post-transplantation outcomes; however, further refinement and validation are needed before incorporating HED into clinical transplantation risk assessment.}, }
@article {pmid41398395, year = {2026}, author = {Zhou, X and Sevilla-Gonzalez, M and Phipps, AI and Udler, M and Castellví-Bel, S and Chan, AT and Pellatt, AJ and Schoen, RE and Giovannucci, E and Gunter, MJ and Florez, JC and Peters, U and Song, M and Merino, J}, title = {Diabetogenic processes for insulin resistance-linked hyperinsulinaemia are associated with colorectal cancer.}, journal = {Diabetologia}, volume = {69}, number = {4}, pages = {942-952}, pmid = {41398395}, issn = {1432-0428}, support = {R01 CA285851/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Colorectal Neoplasms/epidemiology/genetics/metabolism/etiology ; *Insulin Resistance/physiology/genetics ; *Hyperinsulinism/genetics/metabolism/complications ; Female ; Male ; Middle Aged ; *Diabetes Mellitus, Type 2/genetics/metabolism/complications ; Aged ; Adult ; Risk Factors ; }, abstract = {AIMS/HYPOTHESIS: Type 2 diabetes has been associated with increased risk of colorectal cancer (CRC), but the specific diabetogenic pathways contributing to this risk remain unclear.<br><br>METHODS: We analysed individual-level data from 129,420 participants of European ancestry in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR), comprising 58,531 patients with CRC and 70,889 control participants. We applied eight validated partitioned polygenic scores (PPSs) representing distinct diabetogenic processes: two related to relative insulin secretion insufficiency and six to insulin resistance with varying degrees of preserved insulin secretion. Adjusted ORs and 95% CIs for CRC and early-onset CRC were estimated using conditional logistic regression.<br><br>RESULTS: PPSs reflecting insulin resistance-linked hyperinsulinaemia, particularly those related to lipodystrophy, body fat and obesity, were associated with higher odds of CRC (p<0.001 for each). Compared with individuals in the lowest decile, those in the highest decile had ORs of 1.09 (95% CI 1.05, 1.14), 1.13 (1.09, 1.18) and 1.15 (1.10, 1.20) for lipodystrophy, body fat and obesity, respectively. In contrast, PPSs for insulin secretion insufficiency or insulin resistance without hyperinsulinaemia were not associated with CRC. The obesity-related hyperinsulinaemic insulin resistance PPS was also associated with higher odds of early-onset CRC (OR for top vs bottom decile=1.26; 95% CI 1.13, 1.41), with the strongest association among those with obesity (OR 1.75; 95% CI 1.46, 2.11; p value for interaction with BMI <0.001).<br><br>CONCLUSIONS/INTERPRETATION: Diabetogenic processes characterised by insulin resistance-linked hyperinsulinaemia were associated with increased odds of CRC, including early-onset disease. These findings offer new insights into diabetes-CRC pathogenesis, and may inform targeted prevention strategies.}, }
@article {pmid41400994, year = {2025}, author = {Holland, M and Ahmed, M and Young, JM and Drurey, JR and McFadyen, S and Ostrowski, EA and Levin, TC}, title = {Hypermutable hotspot enables the rapid evolution of self/non-self recognition genes in Dictyostelium.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {51}, pages = {e2520843122}, pmid = {41400994}, issn = {1091-6490}, support = {R35 GM150681/GM/NIGMS NIH HHS/United States ; R01-GM74108//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 1176659//Burroughs Wellcome Fund (BWF)/ ; R35-GM150681//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {*Dictyostelium/genetics ; *Evolution, Molecular ; *Protozoan Proteins/genetics ; Phylogeny ; Genome, Protozoan ; Mutation ; Haplotypes ; }, abstract = {Cells require highly polymorphic receptors to perform accurate self/non-self recognition. In the amoeba Dictyostelium discoideum, polymorphic TgrB1 and TgrC1 proteins are used to bind sister cells and exclude cheaters, but it remains unknown how cells continually generate their extreme genetic diversity. Here, we created a collection of chromosome-length, whole genome sequences from 10 D. discoideum isolates and sister species to understand the evolution of the large tgr gene family. Our dataset includes AX2-214, a widely used D. discoideum lab strain, as well as complete genomes for two Chlamydia-like endosymbionts harbored within amoebae. We find that tgrB1 and C1 lie in a hypermutational hotspot, with haplotypes that undergo repeated intralocus recombination, duplications, transpositions, and inversions. These structural dynamics are highly localized adjacent to tgrB and C, resulting in the gain and loss of dozens of genes. The tgrBC genes themselves frequently duplicate and recombine, leading to the rapid generation of unique tgrBC repertoires. In the broader tgr gene family, some genes (e.g., tgrN) are single copy and syntenic across all the genomes, whereas others (e.g., tgrA) prolifically duplicate at similar rates to Dictyostelium transposons. Thus, the tgr genes are among the most rapidly evolving families genome-wide. We propose that the intense diversification within the tgrBC locus can help explain how these genes acquire such extreme levels of polymorphism, with parallels to the MHC immune genes in mammals and other allorecognition systems. This collection of amoeba genomes is also a useful resource for future comparative genomics and molecular evolution studies in Amoebozoa.}, }
@article {pmid41401851, year = {2026}, author = {Barachini, S and Montali, M and Burzi, IS and Pardini, E and Infirri, GS and Cassano, RC and Petrini, I}, title = {The role of the bone marrow microenvironment in leukemic stem cell resistance: Pathways of persistence and selection.}, journal = {Critical reviews in oncology/hematology}, volume = {218}, number = {}, pages = {105090}, doi = {10.1016/j.critrevonc.2025.105090}, pmid = {41401851}, issn = {1879-0461}, mesh = {Humans ; *Neoplastic Stem Cells/pathology/metabolism/drug effects ; *Drug Resistance, Neoplasm ; *Tumor Microenvironment/drug effects ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology/drug therapy/metabolism/genetics ; *Bone Marrow/pathology/metabolism ; Protein Kinase Inhibitors/therapeutic use/pharmacology ; Signal Transduction ; Stem Cell Niche ; Animals ; }, abstract = {Chronic Myeloid Leukemia is driven by the BCR::ABL1 fusion gene, which transforms bone marrow stem cells. Tyrosine kinase inhibitors have markedly improved patients' outcomes. However, only about 20 % of patients are cured, remaining free of relapses after the achievement of a profound and durable molecular remission of the disease and the suspension of tyrosine kinase inhibitors. In most cases, leukemic stem cells persist and contribute to disease relapse after treatment suspension or the development of acquired resistance to tyrosine kinase inhibitors. Emerging evidence underscores the pivotal role of the bone marrow microenvironment in sustaining leukemic stem cells and contributing to drug resistance. Stromal progenitor cells within the bone marrow niche play a key role in supporting the persistence and survival of resistant leukemic stem cells. This review examines how the bone marrow microenvironment and its components promote drug resistance through mechanisms such as metabolic reprogramming, aberrant signaling, and protective cellular interactions. These insights reveal potential therapeutic strategies aimed at disrupting the leukemic stem cell supportive niche to achieve more effective eradication of resistant clones. Understanding the complex interplay between leukemic stem cells and their microenvironment is crucial for developing targeted treatments that can overcome resistance and achieve long-term remission in patients with chronic myeloid leukemia.}, }
@article {pmid41405835, year = {2026}, author = {Diaz, AE and Kwan, ML and Laurent, CA and Rillamas-Sun, E and Roh, JM and Iribarren, C and Rana, JS and Kushi, LH and Reding, KW and Quesenberry, CP and Greenlee, H and Cheng, RK}, title = {Disparities in cardiometabolic and cardiovascular risk after breast cancer: the Pathways Heart Study.}, journal = {JNCI cancer spectrum}, volume = {10}, number = {1}, pages = {}, pmid = {41405835}, issn = {2515-5091}, support = {R01 CA105274/CA/NCI NIH HHS/United States ; R01 CA214057/CA/NCI NIH HHS/United States ; U01 CA195565/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/ethnology/epidemiology ; Middle Aged ; *Cardiovascular Diseases/epidemiology/ethnology ; Prospective Studies ; Aged ; Incidence ; California/epidemiology ; *Health Status Disparities ; White People/statistics &amp; numerical data ; Hypertension/epidemiology/ethnology ; Hispanic or Latino/statistics &amp; numerical data ; Cardiometabolic Risk Factors ; Dyslipidemias/ethnology/epidemiology ; Proportional Hazards Models ; Ethnicity/statistics &amp; numerical data ; Black or African American/statistics &amp; numerical data ; Diabetes Mellitus/ethnology/epidemiology ; Asian/statistics &amp; numerical data ; Native Hawaiian or Pacific Islander/statistics &amp; numerical data ; Adult ; Risk Factors ; White ; }, abstract = {BACKGROUND: Cardiometabolic risk factors and cardiovascular disease (CVD) incidence in racially and ethnically underrepresented women with breast cancer are not well characterized.<br><br>METHODS: The Pathways Heart Study is a prospective cohort of 14&#x2009;942 women diagnosed with invasive breast cancer between 2005 and 2013 at Kaiser Permanente Northern California. Incidence of cardiometabolic risk factors and CVD outcomes was determined from electronic health records and calculated with a competing risk framework for non-CVD death. Fine-Gray proportional hazards regression estimated subdistribution hazard ratios by race and ethnicity compared with non-Hispanic White women, with additional Asian subgroup analysis.<br><br>RESULTS: Participants were, on average, 61&#x2009;years old at diagnosis; 65% were non-Hispanic White, 7.5% were Black, 14.4% were Asian, 11.9% were Hispanic, 0.4% were Pacific Islander, and 0.8% were American Indian or Alaska Native. Black and Asian women had 1.2 to 1.3 times higher incident hypertension risk; Black, Asian, Hispanic, and Pacific Islander women had 1.5 to 3.0 times higher incident diabetes risk; and Asian women had 1.2 times higher incident dyslipidemia risk. Black women had 1.3 to 1.4 times higher risk of incident ischemic heart disease, heart failure, and overall CVD. Filipino women had 1.6 times higher risk of stroke. South Asian women had 2.5 to 2.6 times higher ischemic heart disease and heart failure risk.<br><br>CONCLUSIONS: Compared with non-Hispanic White women, racially and ethnically diverse women with breast cancer experienced a higher risk of incident diabetes, hypertension, and dyslipidemia. Black and Asian women, particularly Filipino and South Asian women, had a higher risk of incident CVD. Better characterization of health disparities in cardio-oncology is critical to inform future CVD prevention and treatment.}, }
@article {pmid41406404, year = {2026}, author = {Yeh, JM and Seguin, CL and Stratton, KL and Leisenring, WM and Armstrong, GT and Henderson, TO and Hudson, MM and Nathan, PC and Neglia, JP and Oeffinger, KC and Diller, LR and Knudsen, AB}, title = {Benefits, Harms, and Burden of Colorectal Cancer Screening Among Childhood Cancer Survivors Previously Treated With Abdominopelvic Radiation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {4}, pages = {286-299}, pmid = {41406404}, issn = {1527-7755}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U01 CA253913/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/etiology/economics/epidemiology ; *Early Detection of Cancer/economics/methods/adverse effects ; Adult ; Middle Aged ; Cost-Benefit Analysis ; Female ; Male ; Quality-Adjusted Life Years ; Colonoscopy/economics ; *Cancer Survivors ; Child ; Pelvis/radiation effects ; }, abstract = {PURPOSE: Childhood cancer survivors treated with abdominopelvic radiation (RT) are at increased risk of colorectal cancer (CRC), yet adherence to Children's Oncology Group screening guidelines remains low. Estimating the benefits, burdens, and costs of all guideline-recommended screening modalities, including those not previously evaluated, may help identify strategies that align with survivors' preferences and access, potentially improving adherence.<br><br>METHODS: Using data from the Childhood Cancer Survivor Study and published studies, we adapted a CRC simulation model to evaluate CRC screening among 5-year survivors. Strategies included colonoscopy, multitarget stool DNA (mtsDNA), and fecal immunochemical testing (FIT) at various intervals, starting at age 25-45 years. Outcomes included CRC cases and deaths, additional colonoscopies per additional life-year gained (burden-to-benefit ratio [BBR]), and cost per quality-adjusted life-year gained (QALYG; incremental cost-effectiveness ratios [ICERs]).<br><br>RESULTS: At age 45 years, survivors had a 0.6% cumulative CRC risk (relative risk, 3.3 v average-risk individuals). Without screening, an estimated 75 per 1,000 survivors would be diagnosed with CRC in their lifetime and 30 would die from CRC. Screening averted 47-73 cases and 23-29 CRC deaths per 1,000. Based on average-risk BBR benchmarks, the optimal strategies by modality were colonoscopy every 10 years starting at age 30 years, mtsDNA every 3 years starting at age 30 years, and FIT every 3 years starting at age 25 years (then annually as of age 45 years, as recommended for average-risk individuals). ICERs were $146,000 in US dollars (USD)/QALYG, $166,000 (USD)/QALYG, and $123,000 (USD)/QALYG, respectively.<br><br>CONCLUSION: Early initiation of screening with colonoscopy or stool-based tests may substantially reduce CRC incidence and early mortality among survivors treated with abdominopelvic RT, with reasonable burden-to-benefit trade-offs, and be considered cost-effective. These findings can facilitate clinician-survivor discussions on CRC screening and inform guideline refinements.}, }
@article {pmid41407856, year = {2026}, author = {Dekker, J and Oksuz, BA and Zhang, Y and Wang, Y and Minsk, MK and Kuang, S and Yang, L and Gibcus, JH and Krietenstein, N and Rando, OJ and Xu, J and Janssens, DH and Henikoff, S and Kukalev, A and Andréa, W and Winick-Ng, W and Kempfer, R and Pombo, A and Yu, M and Kumar, P and Zhang, L and Belmont, AS and Sasaki, T and van Schaik, T and Brueckner, L and Peric-Hupkes, D and van Steensel, B and Wang, P and Chai, H and Kim, M and Ruan, Y and Zhang, R and Quinodoz, SA and Bhat, P and Guttman, M and Zhao, W and Chien, S and Liu, Y and Venev, SV and Plewczynski, D and Azcarate, II and Szabó, D and Thieme, CJ and Szczepińska, T and Chiliński, M and Sengupta, K and Conte, M and Esposito, A and Abraham, A and Zhang, R and Wang, Y and Wen, X and Wu, Q and Yang, Y and Liu, J and Boninsegna, L and Yildirim, A and Zhan, Y and Chiariello, AM and Bianco, S and Lee, L and Hu, M and Li, Y and Barnett, RJ and Cook, AL and Emerson, DJ and Marchal, C and Zhao, P and Park, PJ and Alver, BH and Schroeder, AJ and Navelkar, R and Bakker, C and Ronchetti, W and Ehmsen, S and Veit, AD and Gehlenborg, N and Wang, T and Li, D and Wang, X and Nicodemi, M and Ren, B and Zhong, S and Phillips-Cremins, JE and Gilbert, DM and Pollard, KS and Alber, F and Ma, J and Noble, WS and Yue, F}, title = {An integrated view of the structure and function of the human 4D nucleome.}, journal = {Nature}, volume = {649}, number = {8097}, pages = {759-776}, pmid = {41407856}, issn = {1476-4687}, support = {U54 DK107981/DK/NIDDK NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; U54 DK107967/DK/NIDDK NIH HHS/United States ; U01 DA052715/DA/NIDA NIH HHS/United States ; U01 CA200060/CA/NCI NIH HHS/United States ; U54 DK107979/DK/NIDDK NIH HHS/United States ; U01 DK127405/DK/NIDDK NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; U01 CA200147/CA/NCI NIH HHS/United States ; UM1 HG011593/HG/NHGRI NIH HHS/United States ; U01 HL130007/HL/NHLBI NIH HHS/United States ; UM1 HG011536/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; U01 DA052769/DA/NIDA NIH HHS/United States ; U01 DA040612/DA/NIDA NIH HHS/United States ; U01 DK127420/DK/NIDDK NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; UM1 HG011585/HG/NHGRI NIH HHS/United States ; U01 CA200059/CA/NCI NIH HHS/United States ; U01 HL157989/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Genome, Human/genetics ; *Cell Nucleus/genetics/metabolism/chemistry ; Chromatin/genetics/chemistry/metabolism ; Fibroblasts/cytology/metabolism ; DNA Replication ; Transcription, Genetic ; Single-Cell Analysis ; Genomics ; Cell Line ; Human Embryonic Stem Cells/cytology/metabolism ; }, abstract = {The dynamic three-dimensional (3D) organization of the human genome (the 4D nucleome) is linked to genome function. Here we describe efforts by the 4D Nucleome Project[1] to map and analyse the 4D nucleome in widely used H1 human embryonic stem cells and immortalized fibroblasts (HFFc6). We produced and integrated diverse genomic datasets of the 4D nucleome, each contributing unique observations, which enabled us to assemble extensive catalogues of more than 140,000 looping interactions per cell type, to generate detailed classifications and annotations of chromosomal domain types and their subnuclear positions, and to obtain single-cell 3D models of the nuclear environment of all genes including their long-range interactions with distal elements. Through extensive benchmarking, we describe the unique strengths of different genomic assays for studying the 4D nucleome, providing guidelines for future studies. Three-dimensional models of population-based and individual cell-to-cell variation in genome structure showed connections between chromosome folding, nuclear organization, chromatin looping, gene transcription and DNA replication. Finally, we demonstrate the use of computational methods to predict genome folding from DNA sequence, which will facilitate the discovery of potential effects of genetic variants, including variants associated with disease, on genome structure and function.}, }
@article {pmid41408582, year = {2025}, author = {Reding, KW and L Vasbinder, A and Cheng, RK and Barac, A and Wang, Y and Szewczyk, WJ and Haque, R and Ballinger, TJ and Breathett, K and Shadyab, AH and Shih, R and Nuno, T and Wild, RA and Zhang, X and Nassir, R and Mouton, C and Lane, DS and Martin, LW and Manson, JE and Stefanick, ML and Simon, MS and Jones, V}, title = {Racial differences in breast cancer-specific mortality and CVD-specific mortality after breast cancer in post-menopausal women.}, journal = {Cardio-oncology (London, England)}, volume = {11}, number = {1}, pages = {112}, pmid = {41408582}, issn = {2057-3804}, abstract = {BACKGROUND: Racial disparities in all-cause mortality after breast cancer (BC) have been documented. While elevated risk of BC mortality experienced by Black women is clear, it is unclear the relative contribution of cardiovascular disease (CVD) mortality to the survival disparity in Black women.<br><br>METHODS: This analysis from the Women's Health Initiative (WHI) included 8,410 women diagnosed with invasive BC during follow-up. Cardiovascular (CV) events were defined as adjudicated myocardial infarction, heart failure, or stroke. Cause of death was determined through adjudication by medical chart review, ICD codes, death certificate, and/or autopsy report. 10-year cumulative incidence rates were calculated for CV events, CVD mortality, and BC mortality, stratified by race. Sub-distribution hazards ratios (sHR) were calculated using Fine and Gray models to account for competing risks.<br><br>RESULTS: In BC survivors (mean age&#x2009;=&#x2009;70.9 years, median follow-up =&#x2009;15.1 years), 8.5% self-reported as Black. Compared to White women, Black women had higher 10-year cumulative incidence of non-fatal CV events (10.9% vs. 8.2%, P&#x2009;=&#x2009;0.001) and BC mortality (15.3% vs. 11.5%, P&#x2009;=&#x2009;0.039). In contrast, White women had higher 10-year incidence of CVD mortality (7.2% vs. 10.1%, P&#x2009;=&#x2009;0.001). BC mortality in Black women represented a higher proportion of death (35% vs. 20%), which was not true for White women.<br><br>CONCLUSION: Our study reinforces prior findings that racial disparities are experienced by Black women with BC. This may be in large part driven by BC mortality. However, if improvements in BC mortality are made to reduce this gap, disparities in CVD mortality may become more prominent due to racial disparities in CV events.}, }
@article {pmid41411147, year = {2026}, author = {Curtis, DJ and Hill, GR}, title = {Posttransplant cyclophosphamide in HLA-matched peripheral blood transplantation: what's next?.}, journal = {Blood}, volume = {147}, number = {6}, pages = {633-638}, pmid = {41411147}, issn = {1528-0020}, mesh = {Humans ; *Cyclophosphamide/therapeutic use ; *Graft vs Host Disease/prevention &amp; control/immunology/etiology ; *Peripheral Blood Stem Cell Transplantation/methods/adverse effects ; *HLA Antigens/immunology ; Transplantation Conditioning/methods ; *Immunosuppressive Agents/therapeutic use ; Histocompatibility Testing ; }, abstract = {The use of posttransplant cyclophosphamide was initially pioneered as a means of permitting haploidentical transplantation across HLA barriers. This approach has now become a standard of care for the prevention of significant acute and chronic graft-versus-host disease (GVHD) after related and unrelated HLA-matched allogeneic peripheral blood stem cell transplant across a full spectrum of conditioning intensities. This article discusses recent advances, the mechanisms of action, and important unresolved questions in the prevention of GVHD that will help inform new prospective clinical studies.}, }
@article {pmid41413856, year = {2025}, author = {Harrison, TA and Zaidi, SH and Yin, H and Steinfelder, RS and Qu, C and Aglago, EK and Berndt, SI and Boardman, LA and Brenner, H and Buchanan, DD and Campbell, PT and Cao, Y and Chan, AT and Chanock, SJ and Doheny, KF and Drew, DA and Figueiredo, JC and French, AJ and Gallinger, S and Georgeson, P and Giannakis, M and Goode, EL and Gruber, SB and Gsur, A and Gunter, MJ and Harlid, S and Hoffmeister, M and Huang, WY and Hullar, MA and Huyghe, JR and Jenkins, MA and Lin, Y and Moreno, V and Murphy, N and Newcomb, PA and Newton, CC and Nowak, JA and Obón-Santacana, M and Ogino, S and Shelford, T and Song, M and Thomas, CE and Toland, AE and Ugai, T and Um, CY and Van Guelpen, B and Trinh, QM and Sun, W and Hudson, TJ and Hsu, L and Peters, U and Phipps, AI}, title = {Genomic characterization of colorectal tumors: insights into significantly mutated genes, pathways, and survival outcomes.}, journal = {BMC cancer}, volume = {26}, number = {1}, pages = {109}, pmid = {41413856}, issn = {1471-2407}, support = {U01 HG004438/HG/NHGRI NIH HHS/United States ; BM1206//COST Action/ ; U01 CA261961/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; 2017SGR723//Ag&#xe8;ncia de Gesti&#xf3; d'Ajuts Universitaris i de Recerca/ ; Genrisk//Centro de Investigaci&#xf3;n Biom&#xe9;dica en Red de Epidemiolog&#xed;a y Salud P&#xfa;blica/ ; U01/U24 CA074783//U.S. Department of Health and Human Services/ ; 01KH0404, 01ER0814, 01ER0815, 01ER1505A, 01ER1505B, 01KD2104A//German Federal Ministry of Education and Research/ ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; GCTRA18022MORE//Fundaci&#xf3;n Cient&#xed;fica Asociaci&#xf3;n Espa&#xf1;ola Contra el C&#xe1;ncer/ ; R01 CA059045/CA/NCI NIH HHS/United States ; Z01 CP 010200, U01 HG004446, U01 HG 004438//U.S. Department of Health and Human Services/ ; U01 HG004446/HG/NHGRI NIH HHS/United States ; U01 CA137088, R01 CA059045, U01 CA164930, R01 CA248857//U.S. Department of Health and Human Services/ ; R01 CA285851/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U24 CA074783/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; 509348, 209057, 251553, 504711//National Health and Medical Research Council/ ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735//U.S. Department of Health and Human Services/ ; U01 CA137088/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; LE22A10-2//Junta de Castilla y Le&#xf3;n/ ; PT13/0010/0013 and ICOBIOBANC//Institut Catala d'Oncologia/ ; R01 CA068535//U.S. Department of Health and Human Services/ ; UM1 CA167552/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, BR 1704/17-1//Deutsche Forschungsgemeinschaft/ ; BRIDGE 829675//Austrian Research Funding Agency (FFG)/ ; 001/WHO_/World Health Organization/International ; HHSN268201700006I//Center for Inherited Disease Research/ ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA215151/CA/NCI NIH HHS/United States ; PI14-613//Federaci&#xf3;n Espa&#xf1;ola de Enfermedades Raras/ ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/mortality/pathology ; Male ; Female ; *Mutation ; Middle Aged ; Aged ; Genomics/methods ; Exome Sequencing ; Proto-Oncogene Proteins B-raf/genetics ; Prognosis ; Aged, 80 and over ; Adult ; *Biomarkers, Tumor/genetics ; Signal Transduction/genetics ; }, abstract = {BACKGROUND: Identifying significantly mutated genes in tumors aids in understanding disease etiology and survival and may aid in the discovery of new drug targets. We aimed to detect and characterize mutated genes from a large, well-characterized group of colorectal cancers.<br><br>METHODS: In tumor and paired normal samples from 6,111 colorectal patients, we sequenced 199 genes identified from whole exome sequencing of over 1,100 tumors. Analyses focused on non-silent mutations. We classified significantly mutated genes after stratification by hypermutation status, and estimated associations of mutated genes/pathways with disease-specific (DS)-survival using Cox regression, adjusting for age, sex, mutation burden, hypermutation status, and study while accounting for multiple comparisons (n&#x2009;=&#x2009;4,874).<br><br>RESULTS: We identified 57 genes that were significantly mutated in colorectal cancer, including 9 that were not previously reported. Among individual genes, only BRAF p.V600E mutations were significantly associated with poorer survival after correction for multiple testing (HR 1.96, P&#x2009;=&#x2009;2.07&#x2009;&#xd7;&#x2009;10[-&#x2009;10]), with a more pronounced association among those with non-hypermutated tumors (HR 2.24, P&#x2009;=&#x2009;1.79&#x2009;&#xd7;&#x2009;10[-&#x2009;12]). We also observed statistically significant associations with survival for four mutated pathways: TP53/ATM (HR 1.24, P&#x2009;=&#x2009;7.96&#x2009;&#xd7;&#x2009;10[-&#x2009;4]), RTK/RAS (HR 1.33, P&#x2009;=&#x2009;3.81&#x2009;&#xd7;&#x2009;10[-&#x2009;6]), TGF-beta (HR 1.25, P&#x2009;=&#x2009;1.85&#x2009;&#xd7;&#x2009;10[-&#x2009;3]), and WNT (HR 0.81, P&#x2009;=&#x2009;2.52&#x2009;&#xd7;&#x2009;10[-&#x2009;03]).<br><br>CONCLUSIONS: We identified 9 significantly mutated genes, some of which are known drug targets. Among individual genes, only the BRAF p.V600E mutation was significantly associated with DS-survival, suggesting a limited survival impact from mutations driving colorectal cancer development.}, }
@article {pmid41414919, year = {2025}, author = {Ignacio, RB}, title = {Reply To Gianella: Redefining Science Together.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf644}, pmid = {41414919}, issn = {1537-6613}, }
@article {pmid41415362, year = {2025}, author = {Bhatia, V and Tsao, A and Chong, T and Challita, PP and Liang, K and Sayar, E and Huang, J and Lawlor, ER and Haffner, MC and Nabet, B and Lee, JK}, title = {Armoring STEAP1 CAR T cells with IL-18 potentiates antitumor activity in Ewing sarcoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41415362}, issn = {2692-8205}, support = {P30 CA016042/CA/NCI NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Ewing sarcoma (EwS) is a highly aggressive cancer driven by the EWS::FLI1 fusion oncoprotein affecting children, adolescents, and young adults. Six transmembrane epithelial antigen 1 (STEAP1) is a cell surface antigen transcriptionally controlled by EWS::FLI1 that is broadly expressed in EwS, positioning it as a rational immunotherapy target. However, translating CAR T therapy to solid tumors requires overcoming barriers to potency while maintaining safety.<br><br>METHODS: Analyses of transcriptome and proteome data were performed to evaluate the effects of EWS::FLI1 perturbation on STEAP1 expression at the transcript and protein levels in EwS models. STEAP1 expression was validated in EwS patient tissues by immunohistochemistry. Second-generation STEAP1-BB&#x3b6; CAR T cells were tested in orthotopic and disseminated EwS xenograft models. To enhance antitumor activity, an IL-18-armored STEAP1 CAR was engineered. Dose-dependent therapeutic efficacy and safety were evaluated through measurement of tumor burden, survival, and observation for gross toxicities.<br><br>RESULTS: STEAP1 was expressed in ~97% of primary EwS tumors and directly associated with EWS::FLI1 fusion protein expression in EwS cell lines. In orthotopic EwS models, STEAP1 CAR T cells induced complete tumor regression at 5 x 10[6] cells. In disseminated disease models, responses were dose-dependent with no evidence of antigen loss. Notably, IL-18 armored STEAP1 CAR T cells achieved complete responses in ~80% of mice at a reduced dose of 10[6] cells without overt toxicity.<br><br>CONCLUSIONS: These data establish STEAP1 as a clinically relevant and highly expressed target in EwS and demonstrate that IL-18 armoring significantly improves CAR T cell efficacy by enhancing potency evident through antitumor activity at reduced cell dose. STEAP1 CAR T cells are currently under evaluation in a first-in-human phase 1/2 dose-escalation clinical trial for metastatic castration-resistant prostate cancer (NCT06236139) and these studies support future clinical translation of STEAP1 CAR T cell therapy for relapsed/refractory EwS.}, }
@article {pmid41415367, year = {2025}, author = {Garza, R and Marchioni, JM and Honeycutt, JD and Hurlburt, NK and Torres, C and Garcia, A and Loranc, E and Yemington, E and Towers, D and Ssewanyana, I and Pancera, M and Lavinder, JJ and Jagannathan, P and Greenhouse, B and Bol, S and Bunnik, EM}, title = {The N-terminal region of malaria vaccine candidate Plasmodium falciparum asparagine-rich merozoite antigen is immunodominant and targeted by polyreactive antibodies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41415367}, issn = {2692-8205}, support = {U19 AI089674/AI/NIAID NIH HHS/United States ; U01 AI150741/AI/NIAID NIH HHS/United States ; S10 OD030432/OD/NIH HHS/United States ; R01 AI153425/AI/NIAID NIH HHS/United States ; T32 GM145432/GM/NIGMS NIH HHS/United States ; F30 AI176697/AI/NIAID NIH HHS/United States ; P30 CA054174/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, abstract = {The development of malaria blood-stage vaccines has been hampered by sequence variation in many Plasmodium falciparum proteins involved in erythrocyte invasion. In the past few years, asparagine-rich merozoite antigen (PfARMA) has emerged as a potential vaccine candidate due to its low amino acid sequence diversity and the association between anti-PfARMA antibody levels and protection to malaria. Here, we used samples from P. falciparum-exposed individuals to study naturally acquired B cell and antibody responses to PfARMA. B cell responses to PfARMA were dominated by IgM[+] B cells that recognized the N-terminal intrinsically disordered region 1 (IDR1) of PfARMA. A human monoclonal antibody (hmAb) to IDR1 was non-neutralizing, while a second hmAb binding to the folded domain showed weak neutralizing activity. Both PfARMA-specific plasma IgM and IgG responses predominately targeted IDR1 and their levels increased with P. falciparum exposure. However, in contrast to previous reports, these antibody responses did not correlate with protection in age and exposure-matched children. Interestingly, approximately 30% of unexposed individuals had IgG that also targeted IDR1 and was polyreactive, binding to regions with high asparagine content. Finally, we determined that PfARMA is located in or near PfEBA-175[+] micronemes. These data suggest that while IgG to the folded domain of PfARMA may inhibit parasite growth, antibody responses to PfARMA are primarily directed to IDR1 and may not directly contribute to protection against malaria.}, }
@article {pmid41419161, year = {2026}, author = {Chandrakasan, S and Westbrook, A and Griffith, LM and Hagin, D and Iyengar, S and Mangurian, C and Scalchunes, C and Sullivan, KE and Zablocki, A and Bakshi, N and Sinha, C and Burroughs, LM and Chan, AY and Dvorak, CC and Haddad, E and Heimall, J and Kohn, DB and Leiding, JW and Notarangelo, LD and Pai, SY and Puck, JM and Pulsipher, MA and Marsh, RA and Torgerson, T and Cowan, MJ and Ochs, HD and Parikh, S}, title = {Clinical spectrum of Wiskott-Aldrich syndrome carriers: Self-reported survey of 193 carriers.}, journal = {Clinical immunology (Orlando, Fla.)}, volume = {283}, number = {}, pages = {110658}, pmid = {41419161}, issn = {1521-7035}, support = {R13 AI094943/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U54 AI082973/AI/NIAID NIH HHS/United States ; R24 AI184316/AI/NIAID NIH HHS/United States ; U01 HL069294/HL/NHLBI NIH HHS/United States ; U54 NS064808/NS/NINDS NIH HHS/United States ; }, mesh = {Humans ; *Wiskott-Aldrich Syndrome/genetics/epidemiology ; Female ; Adult ; Male ; Middle Aged ; Heterozygote ; Eczema/epidemiology/genetics ; Self Report ; Thrombocytopenia/epidemiology/genetics ; Young Adult ; Prevalence ; Adolescent ; Aged ; Autoimmune Diseases/epidemiology/genetics ; Surveys and Questionnaires ; }, abstract = {Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with microthrombocytopenia, eczema, immunodeficiency, autoimmunity and malignancies resulting from WAS pathogenic variants. Prevalence of disease in heterozygous female carriers has not been described previously. An online Qualtrics survey was designed in collaboration with the Wiskott-Aldrich Foundation, the Immune Deficiency Foundation, the Primary Immune Deficiency Treatment Consortium and Emory University to describe the incidence of thrombocytopenia, eczema, infections, autoimmune disorders, malignancies, and psychosocial factors. 193 carriers with a median age of 39 years participated in this survey. Respondents were predominantly White and were mothers of WAS patients. We observed a high prevalence of thrombocytopenia (13 %), eczema (22 %), infections (33 %) and autoimmunity (24 %) in this self-reported survey. No hematological malignancies were reported. Guilt (91 %), anxiety (41 %) and depression (44 %) were very prevalent. Comprehensive clinical and immunologic studies of WAS carriers should be prioritized to define appropriate health screening, preventive approaches, and counselling for carriers. SUMMARY: This self-reported survey describes the disease burden in 193 carriers of X-linked Wiskott-Aldrich syndrome. It highlights the increased incidence of thrombocytopenia, eczema, infections and autoimmunity in WAS carriers and the need for more comprehensive studies of WAS carriers.}, }
@article {pmid41419380, year = {2026}, author = {Jadvar, H and Iravani, A}, title = {Therapy strategies to defeat prostate cancer heterogeneity.}, journal = {Seminars in nuclear medicine}, volume = {56}, number = {1}, pages = {18-21}, doi = {10.1053/j.semnuclmed.2025.11.025}, pmid = {41419380}, issn = {1558-4623}, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/radiotherapy/therapy/genetics ; }, abstract = {Metastatic prostate cancer heterogeneity is a multifactorial spatiotemporally dynamic process that leads to disease progression, emergence of treatment resistance and eventual treatment failure. Understanding of the root causes of tumor heterogeneity is the key to develop strategies for more effective therapies. The intra-patient (inter-tumor), and inter-patient heterogeneity demands combinatorial treatment strategies anchored to patient-specific disease biology that can successfully tackle the complexity of the disease in the hopes of overcoming the biological barriers to cancer control. The aim of this article is to briefly review the elements of metastatic prostate cancer heterogeneity and propose approaches to tackle the ensuing therapeutic challenges to achieve durable clinical efficacy in the context of radiopharmaceutical therapy.}, }
@article {pmid41419476, year = {2025}, author = {Gustin, AT and Broedlow, CA and Hager, K and Coronado, E and Wangari, S and Iwayama, N and Ahrens, CY and Garrison, WD and Guerriero, KA and De Paris, K and Londono-Renteria, B and Gale, M and Klatt, NR and Kublin, JG and Manuzak, JA}, title = {Distinct gastrointestinal microbial signatures predict parasite levels in controlled Plasmodium infections in both rhesus macaques and humans.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {550}, pmid = {41419476}, issn = {2041-1723}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; P51 OD010425/OD/NIH HHS/United States ; K01 OD024876/OD/NIH HHS/United States ; P51 OD011104/OD/NIH HHS/United States ; K01OD024876//U.S. Department of Health &amp; Human Services | NIH | NIH Office of the Director (OD)/ ; }, mesh = {Macaca mulatta ; Animals ; Humans ; *Gastrointestinal Microbiome/genetics ; Adult ; RNA, Ribosomal, 16S/genetics ; *Plasmodium falciparum ; *Parasitemia/parasitology/microbiology ; *Malaria/parasitology/drug therapy/microbiology ; Male ; Female ; *Malaria, Falciparum/parasitology/drug therapy/microbiology ; Antimalarials/therapeutic use ; }, abstract = {Functions of the gastrointestinal (GI) microbiome include maintenance of immune homeostasis and protection against infectious disease. Current assessments of the role of the GI microbiome in Plasmodium infection have been primarily conducted using mouse models and observational human cohorts. Here, we experimentally assessed associations between pre-infection GI microbiome composition and acute Plasmodium parasitemia using 16S rRNA sequencing and samples from rhesus macaques (RMs) and adult humans enrolled in a previously conducted controlled human malaria infection (CHMI) trial (NCT04072302) originally designed to test the efficacy of KAF156, a novel imidazolopiperazine class of antimalarial drugs. We identified distinct pre-infection 16S microbial signatures that were associated with increased risk for above median parasitemia in RMs infected with P. fragile and CHMI participants infected with P. falciparum. Further, we identified a Bifidobacterium feature set that accurately stratified parasitemia risk and could therefore serve as a foundation for a potential biomarker panel to aid prevention efforts in malaria endemic regions. Together, our findings demonstrate that pre-infection GI microbiome composition is indicative of risk for Plasmodium parasitemia, and our observation that the pre-infection microbiome-P. fragile dynamic in RMs mirrors the pre-infection microbiome-P. falciparum interaction in CHMI participants supports the future use of this model in pre-clinical investigations of novel microbiome-targeting approaches to reduce malaria burden.}, }
@article {pmid41419585, year = {2025}, author = {Christie, JR and Eddy, K and Malthaner, RA and Qiabi, M and Verma, S and Breadner, D and Lang, P and Nair, VS and Mattonen, SA}, title = {Assessing clinician performance using a multi-modality clinical decision-support system for lung cancer prognostication.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {1688}, pmid = {41419585}, issn = {2045-2322}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; T32CA009515/CA/NCI NIH HHS/United States ; RGPIN-2020-06498//Natural Sciences and Engineering Research Council of Canada/ ; 152218//Cancer Research Society/ ; }, mesh = {Humans ; *Lung Neoplasms/diagnosis/surgery/pathology ; *Decision Support Systems, Clinical ; Prognosis ; Male ; Female ; Deep Learning ; Middle Aged ; Neoplasm Recurrence, Local ; }, abstract = {Surgery is the primary treatment for early-stage lung cancer. Adjuvant therapy is offered to patients who are at a high risk of recurrence, however, determining the patients that would benefit from additional therapy is often difficult. In this study, we aimed to develop a clinical decision support system (CDSS) for post-surgery lung cancer prognostication integrating a multi-modality deep learning model (DLM). Pre-operative medical images and clinical, surgical, and pathological information were fed into an externally validated DLM. A CDSS was then developed to display the patient information and DLM results for potential clinical use. Four oncologists evaluated each patient's recurrence probability, their confidence level, and their post-surgery recommendations both with and without the DLM information. The CDSS DLM information demonstrated the potential to improve user prediction performance and confidence. This exploratory study is the first to integrate a multi-modality DLM for prognostication with a CDSS, as well as the first study of clinician attitudes towards CDSSs for lung cancer.}, }
@article {pmid41420651, year = {2025}, author = {Ignacio, RB and Pagkas-Bather, J and Gonsalves, G and Gianella, S}, title = {Why Americans are Dying Younger? NIH Is Not the Problem. Our Broken Healthcare Delivery Is.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciaf671}, pmid = {41420651}, issn = {1537-6591}, abstract = {The United States leads the world in biomedical innovation, with NIH-funded research driving transformative advances in cancer, HIV, and gene therapy. Yet, these breakthroughs cannot achieve their full impact in a fragmented and inequitable health system. Millions remain uninsured, preventive care is undervalued, and social determinants perpetuate life expectancy gaps. Political efforts to restrict or defund the NIH threaten progress and disproportionately harm underserved populations. Biomedical research alone cannot fix systemic failures but strengthening science while repairing care delivery systems is essential to improving population health and ensuring that innovations benefit all.}, }
@article {pmid41420662, year = {2025}, author = {Ignacio, RB and Pagkas-Bather, J and Gonsalves, G and Gianella, S}, title = {Why Americans are Dying Younger? NIH Is Not the Problem. Our Broken Healthcare Delivery Is.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf592}, pmid = {41420662}, issn = {1537-6613}, abstract = {The United States leads the world in biomedical innovation, with NIH-funded research driving transformative advances in cancer, HIV, and gene therapy. Yet, these breakthroughs cannot achieve their full impact in a fragmented and inequitable health system. Millions remain uninsured, preventive care is undervalued, and social determinants perpetuate life expectancy gaps. Political efforts to restrict or defund the NIH threaten progress and disproportionately harm underserved populations. Biomedical research alone cannot fix systemic failures but strengthening science while repairing care delivery systems is essential to improving population health and ensuring that innovations benefit all.}, }
@article {pmid41420827, year = {2025}, author = {Godbey, EA and Draper, NL and Connelly-Smith, L and Alquist, C and Schwartz, J and Fernando, L and Jones, A and Schmidt, AE and Harmon, C and Lee, E and Linnik, Y and Cooling, L}, title = {Poor Mobilization and Plerixafor Use in Matched Related Peripheral Hematopoietic Progenitor Cell Donors.}, journal = {Journal of clinical apheresis}, volume = {40}, number = {6}, pages = {e70074}, pmid = {41420827}, issn = {1098-1101}, mesh = {Humans ; Cyclams ; Benzylamines ; *Hematopoietic Stem Cell Mobilization/methods ; *Heterocyclic Compounds/pharmacology ; Middle Aged ; Female ; Male ; Adult ; *Peripheral Blood Stem Cells/cytology ; Tissue Donors ; Aged ; }, abstract = {Plerixafor (PLX) is FDA approved for use in autologous peripheral blood stem cell donors but not in allogeneic donors. This study was completed by members of the ASFA HPC Donor Subcommittee to examine the incidence and characteristics of poor mobilizers (PM) among matched related donors (MRD), as well as factors associated with PLX use in MRD. Risks of poor mobilization in MRD were older age, especially donors older than 60 years, lower baseline platelet counts, and heavier recipients. PLX use in PM was low but safe, tripling the success rate for collection. This study adds evidence to the body of literature to support use of PLX in allogeneic donors who are PM.}, }
@article {pmid41421757, year = {2026}, author = {Onyeaka, HK and Mate-Kole, MN and Acheampong, IA and Arthur, A and Song, MT and Akhiwu, TO and Mensah, D and Ozoalor, C and Chido-Amajuoyi, OG and Amonoo, HL}, title = {Geographic location and clinical trial knowledge, invitation, and participation among adults in the United States.}, journal = {Contemporary clinical trials}, volume = {161}, number = {}, pages = {108193}, doi = {10.1016/j.cct.2025.108193}, pmid = {41421757}, issn = {1559-2030}, mesh = {Humans ; United States ; Female ; Male ; Cross-Sectional Studies ; Adult ; Middle Aged ; *Clinical Trials as Topic ; *Health Knowledge, Attitudes, Practice ; *Rural Population/statistics &amp; numerical data ; *Patient Selection ; *Urban Population/statistics &amp; numerical data ; Aged ; Young Adult ; *Patient Participation/statistics &amp; numerical data ; Adolescent ; }, abstract = {BACKGROUND/AIMS: Clinical trials are essential to evaluating novel treatments and improving disease-related outcomes through innovative therapies. Despite underrepresentation of rural communities in clinical trial outreach and participation, geographic disparities in clinical trials have been minimally explored. We examined clinical trial knowledge, invitation, and participation among participants in urban and rural geographic locations in the United States.<br><br>METHODS: We conducted cross-sectional data analysis on self-reported data from Health Information National Trends Survey (HINTS) 5&#xa0;Cycle 4. Population-level estimates were obtained using jack-knife replicate weights.<br><br>RESULTS: Geographic location was not associated with clinical trial knowledge, invitation, and participation. However, the relatively low absolute invitation rates across urban and rural populations may suggest that substantial gaps in recruitment persist universally, regardless of geographic location in the United States.<br><br>CONCLUSIONS: In this nationally representative study, we found no statistically significant differences in clinical trial knowledge, invitation or participation by geographical location in the United States. Our findings suggest that geographic residence may not be a primary barrier to clinical trial engagement once sociodemographic differences are accounted for. Targeted efforts to improve awareness and reduce structural barriers, along with continued investment in equitable recruitment strategies, will be important to ensuring that clinical trials reflect the diversity of the populations they aim to serve.}, }
@article {pmid41423517, year = {2025}, author = {Chambwe, N and Kennedy, SR and Kohrn, BF and Lazarchuk, P and Leutert, M and Qin, G and Tercan, B and Sanchez-Contreras, M and Tang, W and Graber, JJ and Paddison, PJ and Villén, J and Shmulevich, I and Monnat, RJ}, title = {Cellular heterogeneity and therapeutic response profiling of human IDH + glioma stem cell cultures.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {3177}, pmid = {41423517}, issn = {2045-2322}, mesh = {Humans ; *Isocitrate Dehydrogenase/metabolism/genetics ; *Neoplastic Stem Cells/drug effects/metabolism/pathology/radiation effects ; Temozolomide/pharmacology ; *Glioblastoma/pathology/genetics ; *Brain Neoplasms/pathology/genetics/therapy ; *Glioma/pathology/genetics ; Gene Expression Profiling ; Tumor Cells, Cultured ; }, abstract = {Glioblastoma stem cell (GSC) cultures are initiated from glioblastoma (GBM) surgical resection tissue. When grown appropriately they can capture and propagate key GBM molecular and cellular features. We have characterized cellular, genomic and proteomic features of four isocitrate dehydrogenase (IDH)-expressing (IDH +) GSC cultures as cellular models for ~ 90% of adult GBMs. We demonstrate that GSC cultures can be continuously propagated in defined, serum-free media and 5% oxygen without specialized growth substrates; have culture-specific genomic and mtDNA variants together with gene/protein expression profiles; and display reproducible dose-survival curves for the GBM standard-of-care therapies ionizing radiation (IR) and temozolomide (TMZ). In order to better define GSC culture cellular heterogeneity and dynamics, we used lentiviral DNA barcoding, mtDNA variants and single cell gene expression profiling over 40 days after IR treatment. GSC cultures are versatile in their ability to support many in vitro protocols including high throughput screens as well as xenograft, organoid and other disease modeling protocols. They provide a simple cellular disease model for better understanding GBM biology, and for identifying new, potentially more effective GBM therapies and treatment regimens.}, }
@article {pmid41423715, year = {2026}, author = {Nakao, M and Schwengfelder, J and Richter, C and Peters, N and Ozawa, S}, title = {Comparison of two established approaches for generating Hounsfield look-up tables for CT-based SPR prediction.}, journal = {Medical physics}, volume = {53}, number = {1}, pages = {e70236}, doi = {10.1002/mp.70236}, pmid = {41423715}, issn = {2473-4209}, support = {23K14869//Japan Society for the Promotion of Science/ ; }, mesh = {*Tomography, X-Ray Computed/instrumentation ; Humans ; Phantoms, Imaging ; *Radiotherapy Planning, Computer-Assisted/methods ; *Image Processing, Computer-Assisted/methods ; Calibration ; }, abstract = {BACKGROUND: To ensure consistency in treatment planning across institutions, inter-center variations in Hounsfield look-up tables (HLUTs) have been evaluated using different methods in Japan and Europe. In Japan, the Hiroshima High-Precision Radiotherapy Cancer Center (HIPRAC) developed the computed tomography number calibration audit (HIPRAC-CTCA) based on a stoichiometric method, while in Europe, the European Particle Therapy Network (EPTN) implemented a method using validated tissue-equivalent inserts. Comparing these approaches is essential to improving consistency and reliability.<br><br>PURPOSE: This study aims to enhance the reliability of the HIPRAC method by comparing it with the EPTN consensus guide-based HLUT generation methods used in multi-institutional evaluations.<br><br>METHODS: HLUTs were generated using the HIPRAC and EPTN methods for both head and body phantom configurations. The HIPRAC-based HLUT was created by measuring CT numbers of tough lung and tough bone inserts, applying the stoichiometric method, and calculating the theoretical HLUTs for representative tissues based on the International Commission on Radiological Protection Publication 110. The EPTN-based HLUT was generated by measuring the CT numbers of validated tissue-equivalent inserts, calculating the CT numbers of human tissues using the stoichiometric method, and determining the HLUT through piecewise linear regression between CT numbers and stopping-power ratios (SPRs) for both tissue-equivalent inserts and human tissues. &#x394;SPR values were calculated by subtracting the EPTN-based HLUT from the HIPRAC-based HLUT and were categorized into lung, soft tissue, and bone groups. Representative brain tumor and prostate cancer cases were analyzed to evaluate spot-wise range shifts (&#x394;R80) when applying the two HLUTs.<br><br>RESULTS: Both methods showed good agreement in lung, soft tissue, and bone, with all &#x394;SPR values within&#xa0;&#xb1;&#xa0;2% and mean differences &#x2264; 1%. In cortical bone, &#x394;SPR reached approximately 2%-3%, leading to minor range shifts. In the clinical case analysis, mean &#x394;R80 were -0.28&#xa0;mm for the brain tumor case and -0.45&#xa0;mm for the prostate cancer case, indicating that proton range differences between the two HLUTs were negligibly small.<br><br>CONCLUSIONS: The established HLUT generation methods for CT-based SPR prediction developed in Japan and Europe were compared and showed good agreement across all tissue types. Range differences in clinical cases were minor, and &#x394;SPR variations in cortical bone corresponded to negligible proton range deviations. These findings indicate that the European and Japanese approaches are practically equivalent and support the validity and reliability of the HIPRAC-CTCA method.}, }
@article {pmid41427272, year = {2025}, author = {Vaz, J and Zhu, S and Useche, M and Shih, L and Marchiano, E and Beronja, S and Clurman, BE and Rodriguez, C and Barber, B and Chan, M and Gujral, TS}, title = {Subtype-Specific Dependencies and Drug Vulnerabilities Enable Precision Therapeutics in Head and Neck Cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41427272}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA273081/CA/NCI NIH HHS/United States ; }, abstract = {Molecular heterogeneity in head and neck squamous cell carcinoma (HNSCC) is well recognized, yet existing subtype frameworks remain largely descriptive and have not translated into therapeutic decision-making. Here, we establish a mechanistic platform that converts transcriptomic diversity into drug-actionable tumor states. Integrating multi-cohort RNA-seq from 727 tumors across five independent datasets, genome-scale CRISPR dependency maps, and pharmacologic screening, we define distinct tumor survival circuits across HPV-negative HNSCC and nominate subtype-matched therapeutic strategies. These circuits encompass a proliferative axis (MYC, MET/FAK, inflammatory and translational programs), an epithelial-differentiated/adhesion program, an EMT-like state with stromal activation, and mitochondrial/oxidative metabolic states, each mapping to selective liabilities (e.g., mitotic/autophagy control, ERBB/PI3K and cadherin signaling, OXPHOS/mitochondrial translation, and G2/M-integrin-Notch pathways, respectively). We then develop a transcriptomic predictor of EGFR-inhibitor response using machine learning and validate it in prospectively collected, fresh patient-derived 3D microtumors. The resulting 13-gene signature identifies erlotinib-responsive tumors (R = 0.93) and maps biologically to an epithelial-differentiated state, outperforming EGFR expression alone. Our study establishes a subtype-to-dependency-to-therapy framework, enabling precision stratification and providing a clinically feasible path for prospective biomarker deployment.}, }
@article {pmid41427323, year = {2025}, author = {Raman, P and Khan, H and Young, JM and Tsukiyama, T and Malik, HS}, title = {Dynamic evolution of EZHIP, an inhibitor of the Polycomb Repressive Complex 2 in mammals.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41427323}, issn = {2692-8205}, support = {K99 GM149928/GM/NIGMS NIH HHS/United States ; R01 GM074108/GM/NIGMS NIH HHS/United States ; R35 GM139429/GM/NIGMS NIH HHS/United States ; }, abstract = {The Polycomb Repressive Complex 2 (PRC2) is an ancient, conserved chromatin-interacting complex that controls gene expression, facilitating differentiation and cellular identity during development. Its regulation is critical in most eukaryotes. EZHIP was recently characterized as a PRC2 inhibitor and 'oncohistone mimic' in mammals. Although Ezhip expression is typically restricted to the germline, its aberrant expression in pediatric brain tumors inhibits PRC2-mediated H3K27 methylation and drives disease progression. To gain a deeper understanding of its normal functions, we systematically examined Ezhip evolution across 70 mammals using comparative genomics, synteny analysis, and motif discovery. Bolstering previous work, we find that Ezhip originated and has been strictly retained on the X chromosome in placental mammals. In addition to the highly conserved H3K27M-like histone mimic motif, our motif analysis reveals seven previously unidentified EZHIP motifs, including a putative nuclear localization signal, and tandem repeats that are largely well-conserved in placental mammals, except in some lineages. We hypothesize that these motifs are also critical to EZHIP's functions, including in PRC2 interaction and inhibition. We show that Ezhip has evolved under strong diversifying selection in primates and underwent dynamic expansions and losses across species. Some paralogs, such as Ezhip2 in primates, also evolved under positive selection. Based on its evolutionary attributes and germ-cell expression, we propose that Ezhip arose and evolved rapidly due to inter-parental conflict over fetal development in utero in placental mammals. Our work provides a foundation for further investigations into EZHIP's essential, potentially multifaceted roles in mammalian reproduction and disease.}, }
@article {pmid41428135, year = {2025}, author = {Pinker, K and Comstock, C and Leung, JWT and LoGullo, R and Rahbar, H and Seely, JM and Trop, I and Sung, J}, title = {Image-guided biopsy of breast lesions-when to use what biopsy technique: the United States and Canadian perspective.}, journal = {Insights into imaging}, volume = {16}, number = {1}, pages = {289}, pmid = {41428135}, issn = {1869-4101}, }
@article {pmid41428730, year = {2025}, author = {Hyppa, RW and Smith, GR}, title = {Mutual, spatially limited control of meiotic DNA break formation by Mre11-Rad50-Nbs1 DNA repair complex and Tel1 (ATM) protein kinase.}, journal = {Nucleic acids research}, volume = {53}, number = {22}, pages = {}, pmid = {41428730}, issn = {1362-4962}, support = {NIH R35 GM118120//National Institutes of Health of the United States of America/ ; NIH P30 CA015704//National Institutes of Health of the United States of America/ ; }, mesh = {*Meiosis/genetics ; *Schizosaccharomyces pombe Proteins/metabolism/genetics/physiology ; *DNA Breaks, Double-Stranded ; *Schizosaccharomyces/genetics/metabolism ; Endodeoxyribonucleases/metabolism/genetics ; *DNA-Binding Proteins/metabolism/genetics ; *Protein Serine-Threonine Kinases/metabolism/genetics/physiology ; Exodeoxyribonucleases/metabolism/genetics ; *Intracellular Signaling Peptides and Proteins/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *DNA Repair ; MRE11 Homologue Protein ; *Nuclear Proteins/metabolism ; Chromosomal Proteins, Non-Histone ; }, abstract = {Meiotic recombination is initiated by DNA double-strand breaks (DSBs); factors that control DSB frequencies are important to produce viable progeny. In many organisms, the ATM (Tel1) protein kinase prevents excessive meiotic DSBs, especially nearby DSBs on the same chromatid. Normally, two close DSBs are less frequent than expected from independence, a feature called DSB interference, which is lost in tel1Δ mutants. In the fission yeast Schizosaccharomyces pombe, high-level DSB formation depends on linear elements, Hop1, and meiotic cohesin complexes; we show here that these complexes impart competition between nearby DSB sites. When these complexes are impaired, Tel1 substantially represses DSB formation, and in its absence, two close DSBs on the same chromatid occur frequently and manifest high negative interference. After mitotic DNA damage, the conserved Mre11-Rad50-Nbs1 (MRN) complex is required for DNA resection, and the Tel1 kinase activity is needed to complete DSB repair. We found that during meiosis mre11Δ and rad50Δ mutants, like tel1Δ mutants, lack DSB interference and display highly negative DSB interference in meiotic complex mutants. Thus, MRN at a DSB site appears critical for Tel1 function in meiosis and reveals a complex interplay of positive and negative factors controlling meiotic DSB formation.}, }
@article {pmid41432537, year = {2026}, author = {Zhang, Z and Ray, RM and An, R and Klonoff-Cohen, HS and Thomas, DB}, title = {Mammographic Density as a Mediator for Breast Cancer Risk: Pooled Analysis of Four Population-Based Case-Control Studies on Women with Screening Mammograms before Age 50.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {35}, number = {3}, pages = {465-474}, doi = {10.1158/1055-9965.EPI-25-0884}, pmid = {41432537}, issn = {1538-7755}, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging/epidemiology/pathology ; *Mammography/methods ; Middle Aged ; Risk Factors ; Case-Control Studies ; Breast Density ; Adult ; Early Detection of Cancer/methods ; Breast/pathology ; }, abstract = {BACKGROUND: Multiple risk factors influence breast cancer risk, but the role of percent mammographic density (PMD) in mediating these associations remains unclear.<br><br>METHODS: In this pooled analysis of women who had screening mammograms before age 50 years, we assessed whether PMD mediates associations between reproductive, structural, and lifestyle factors and breast cancer risk. Causal mediation analysis was used to estimate direct and indirect effects and the proportion mediated by PMD.<br><br>RESULTS: PMD partially mediated 29% of the association between breast calcifications and breast cancer risk, with a natural indirect effect odds ratio (ORNIE) of 1.16 [95% confidence interval (CI), 1.04-1.30; P = 0.009]. A history of breast biopsies was marginally associated with increased risk (P = 0.083), with 83.1% of this effect mediated by PMD (ORNIE = 1.28; 95% CI, 1.11-1.49; P = 0.001). PMD mediated 48.6% of the reduced risk among parous versus nulliparous women (ORNIE = 0.76; 95% CI, 0.65-0.90; P = 0.001). No significant mediation by PMD was observed for first-degree family history of breast cancer, age at first live birth, or smoking. Adult body mass index showed inconsistent mediation with opposing direct and indirect effects, reducing breast cancer risk via lower PMD but increasing risk through density-independent pathways, yielding a null total effect.<br><br>CONCLUSIONS: Our findings highlight PMD's important role as a mediator in linking certain reproductive and structural factors to breast cancer risk in younger women, offering insights into early-onset breast cancer.<br><br>IMPACT: This underscores PMD's potential as both a biomarker and a target for risk prediction and prevention.}, }
@article {pmid41432664, year = {2025}, author = {Duong, A and Bui, H and Fritzsche, D and Ruplin, A}, title = {Antiandrogen therapies: Management of drug interactions with anticoagulation.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251406879}, doi = {10.1177/10781552251406879}, pmid = {41432664}, issn = {1477-092X}, abstract = {BackgroundSecond-generation antiandrogens have significantly improved outcomes in patients with prostate cancer; however, their complex pharmacokinetic profiles can result in significant drug-drug interactions (DDIs) in patients with comorbid conditions which require chronic anticoagulation.ObjectiveThis review aims to describe the DDIs between antiandrogens and commonly used anticoagulants, with a focus on understanding the clinical implications of pharmacokinetics and drug metabolism.MethodsA comprehensive literature review of pharmacokinetic data, clinical trials, and prescribing information was performed. Drug metabolism of antiandrogens and anticoagulants was examined, including the effects of CYP450 enzyme and/or P-glycoprotein (P-gp) inhibition and induction on anticoagulant efficacy and safety.ResultsEnzalutamide and apalutamide are strong inducers of CYP3A4, which may reduce exposure to warfarin, apixaban, and rivaroxaban. Apalutamide induces P-gp, and therefore has DDIs with all direct oral anticoagulants (DOACs). Darolutamide and abiraterone exhibit minimal CYP450 induction and inhibition, and do not interact with warfarin or DOACs.ConclusionDrug-drug interactions between antiandrogens and anticoagulants are common and can affect therapeutic efficacy and safety. Clinical decision-making surrounding drug selection requires an interprofessional approach grounded in pharmacokinetic knowledge to ensure safe and effective care in patients with prostate cancer.}, }
@article {pmid41433208, year = {2026}, author = {Piliper, EA and Reed, J and Greninger, AL}, title = {Corrected and republished from: "Clinical validation of an RSV neutralization assay and analysis of cross-sectional sera associated with 2021-2023 RSV outbreaks to investigate the immunity debt hypothesis".}, journal = {Microbiology spectrum}, volume = {14}, number = {2}, pages = {e0173925}, pmid = {41433208}, issn = {2165-0497}, mesh = {Humans ; *Respiratory Syncytial Virus Infections/immunology/epidemiology/virology/diagnosis ; *Neutralization Tests/methods/standards ; *Antibodies, Neutralizing/blood/immunology ; *Antibodies, Viral/blood/immunology ; *Respiratory Syncytial Virus, Human/immunology/genetics ; Disease Outbreaks ; Cross-Sectional Studies ; Female ; Adult ; Male ; Infant ; Middle Aged ; Aged ; }, abstract = {UNLABELLED: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory infections and hospitalization in infants and the elderly. Newly approved vaccines and the prophylactic antibody nirsevimab have heightened interest in RSV immunologic surveillance, necessitating the development of high-throughput assays assessing anti-RSV neutralizing activity. Quantitative viral neutralization remains the best correlate of protection for RSV infection and the gold standard for RSV immunological testing. Here, we developed a high-throughput RSV strain A2 focus-reduction neutralization test validated to CLIA/GCLP standards using both clinical specimens and commercially available reference sera. The assay is highly accurate, generating reference serum neutralizing titers within twofold of established assays, with an analytical measurement range between 8 and 1,798 international units (IU) per mL. Neutralizing activity measured by the assay strongly correlated with antibody titer determined via indirect ELISA (ρ = 1.0, P = 0.0014). Individuals recently having tested RT-qPCR positive for RSV had a 7.5-fold higher geometric mean neutralizing titer relative to RSV PCR negatives (P < 0.0001). The validated assay was then used to investigate the immunity debt hypothesis for resurgent RSV outbreaks in the 2022-2023 season, using adult clinical remnant sera sent for HSV-1/2 antibody testing. There was no difference in geometric mean anti-RSV neutralizing titers between sera sampled before and after the 2022-2023 RSV outbreak (P = 0.68). These data are consistent with limited changes in RSV neutralizing antibody levels in adults across the 2022-2023 RSV outbreak.<br><br>IMPORTANCE: Population surveillance studies of serum neutralizing activity against RSV are crucial for evaluating RSV vaccine efficacy and vulnerabilities to new strains. Here, we designed and validated a high-throughput assay for assessing anti-RSV neutralizing activity, standardized its measurements for comparison with other methodologies, and demonstrated its applicability to real-world samples. Our assay is precise, linear, and yields measurements consistent with other standardized assays, offering a methodology useful for large-scale studies of RSV immunity. We also find no significant difference in neutralizing titers among adults between taken before and after large RSV outbreaks associated with the latter stages of the COVID-19 public health emergency, underlining the need for a greater understanding of the dynamics of serological responses to RSV infection.}, }
@article {pmid41435136, year = {2026}, author = {Karasaki, S and Berberian, AG and Zewdie, HY and Cushing, LJ and VoPham, T}, title = {Geospatial Approaches for Environmental Justice: A Critical Review.}, journal = {Annual review of public health}, volume = {47}, number = {1}, pages = {19-39}, doi = {10.1146/annurev-publhealth-090924-033158}, pmid = {41435136}, issn = {1545-2093}, mesh = {Humans ; *Environmental Justice ; *Environmental Exposure ; *Spatial Analysis ; Geographic Information Systems ; }, abstract = {Environmental justice (EJ) research is an interdisciplinary field of study concerned with the unequal distribution of environmental burdens and benefits across different sociodemographic identities (e.g., race, class). While considerations of space and time with respect to environmental exposures and health outcomes have always been central to EJ, the state of the science on geospatial methods, measures, and technologies is rapidly advancing, as are their applications in research. We find that geospatial technologies have extended researchers' abilities to more precisely link the spatial extents of environmental exposures to when and where people live, work, and play. Geospatial data are also useful in analyzing systemic oppression and structural racism as root causes of environmental injustice via metrics of segregation and redlining. This review provides an overview of how geospatial methods and technologies are being applied to EJ research for (a) population identification, (b) exposure assessment, (c) outcome ascertainment, and (d) research translation.}, }
@article {pmid41436303, year = {2026}, author = {Abe, T and Berger, AH}, title = {New insights in regulation of RAS isoforms revealed by protein structures.}, journal = {Trends in biochemical sciences}, volume = {51}, number = {1}, pages = {6-7}, pmid = {41436303}, issn = {0968-0004}, support = {R37 CA252050/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *ras Proteins/metabolism/chemistry ; Protein Isoforms/metabolism/chemistry ; *Transcription Factors/metabolism/chemistry ; Protein Conformation ; }, abstract = {Leucine zipper-like post translational regulator 1 (LZTR1) functions as a RAS degrader, but the molecular basis of LZTR1-RAS regulation has remained unclear. A recent report by Dharmaiah et al. presents crystal structures of the LZTR1 Kelch domain bound to RIT1, MRAS, or KRAS, providing the first atomic-level insights into LZTR1 substrate recognition.}, }
@article {pmid41439754, year = {2026}, author = {Tantalo, LC and Chamakuri, KD and Greninger, AL and Lieberman, NAP and Giacani, L}, title = {Susceptibility to Penicillin G and Ceftriaxone in 3 Clinical Treponema pallidum Isolates Is Not Altered by Amino Acid Polymorphisms in the Tp0705 Penicillin Binding Protein.}, journal = {Sexually transmitted diseases}, volume = {53}, number = {5}, pages = {319-322}, pmid = {41439754}, issn = {1537-4521}, support = {R56 AI175016/AI/NIAID NIH HHS/United States ; }, mesh = {*Ceftriaxone/pharmacology ; Humans ; *Treponema pallidum/drug effects/genetics/isolation &amp; purification ; *Anti-Bacterial Agents/pharmacology ; *Syphilis/microbiology/drug therapy ; *Penicillin G/pharmacology ; *Penicillin-Binding Proteins/genetics ; Microbial Sensitivity Tests ; Polymorphism, Genetic ; Male ; }, abstract = {We demonstrated no differences in susceptibility to penicillin G and ceftriaxone in 3 modern Treponema pallidum isolates (UW244B, UW249B, and UW330B), each carrying a variant of the penicillin-binding protein Tp0705. This suggests that these polymorphisms should not be a reason for concern when β-lactams are prescribed for syphilis treatment.}, }
@article {pmid41439761, year = {2026}, author = {Hyams, B and Lowry, KP and Kerlikowske, K}, title = {Digital screening mammograms: current status and future prospects.}, journal = {Expert review of medical devices}, volume = {23}, number = {2}, pages = {173-184}, doi = {10.1080/17434440.2025.2609759}, pmid = {41439761}, issn = {1745-2422}, mesh = {Humans ; *Mammography/methods/trends ; Female ; *Breast Neoplasms/diagnostic imaging ; *Early Detection of Cancer/methods ; Artificial Intelligence ; }, abstract = {INTRODUCTION: Mammography has been a cornerstone of breast cancer screening for decades, demonstrating population-level reductions in breast cancer mortality. Limitations of mammography include reduced sensitivity in dense breast tissue, false-positive recalls and biopsies, and possible overdiagnosis. Emerging mammography technologies, including digital breast tomosynthesis (DBT), contrast-enhanced mammography (CEM), and artificial intelligence (AI) applications, seek to address these limitations and improve screening outcomes.<br><br>AREAS COVERED: In this review, we discuss endpoints for the assessment of emerging mammography technologies, including cancer detection, interval cancer, and advanced cancer rates. We review clinical trial data for DBT, highlighting studies reporting interval and advanced cancer rates, and contrast performance in average-risk and high-risk populations. We review CEM as a new modality for supplemental screening in women with dense breasts. Lastly, we cover the rapidly expanding space of AI-supported mammography tools, including those for lesion detection, exam triage, breast density assessment, and risk prediction.<br><br>EXPERT OPINION: Emerging technologies in digital screening mammography have demonstrated improvements in surrogate endpoints like cancer detection, however, their effect on clinically meaningful outcomes such as interval cancer and advanced cancer reduction remains unproven. To ensure that innovations translate into tangible patient benefit, future research should prioritize clinically relevant endpoints and real-world evaluation.}, }
@article {pmid41446058, year = {2025}, author = {Schaefer-Babajew, D and Binet, L and Santos, GSS and Ruprecht, C and Deimel, LP and ElTanbouly, MA and Gharrassi, D and Uhe, C and Yao, KH and Hernandez, B and Agrawal, P and Gazumyan, A and Stamatatos, L and Hartweger, H and Nussenzweig, MC}, title = {Antibody Mediated Diversification of Primary and Secondary Immune Responses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41446058}, issn = {2692-8205}, support = {P01 AI100148/AI/NIAID NIH HHS/United States ; UL1 TR001866/TR/NCATS NIH HHS/United States ; UM1 AI144462/AI/NIAID NIH HHS/United States ; UM1 AI191237/AI/NIAID NIH HHS/United States ; }, abstract = {Humoral immune responses are characterized by increasing antibody affinity and diversity over time. Increased affinity is mediated by a combination of immunoglobulin gene somatic mutation and iterative cycles of selection in germinal centers. Less is understood about how diversity increases in parallel with affinity. Here we examine the role of antibody feedback in diversifying immune responses in mice that produce B cells that are incapable of secreting antibodies. To this end, we produced two strains of mice, one that expresses only membrane and secreted forms of IgM, and a second that produces only the membrane bound form of IgM. Analysis of primary and secondary immune responses show that antibody feedback significantly diversifies both primary and secondary immune responses even when antibodies are present at levels that are 10-30 fold lower than physiologic. The data have significant implication for sequential vaccination approaches aimed at shepherding immunity to produce broadly neutralizing antibodies to highly diversified pathogens such as HIV-1 and Influenza.}, }
@article {pmid41446115, year = {2025}, author = {Soares, RF and Chang, CH and Koerich, LB and Malik, HS and Kuhn, GCS}, title = {Retention of a single Cenp-C gene in different syntenic locations in the montium group of Drosophila species.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41446115}, issn = {2692-8205}, support = {R01 GM074108/GM/NIGMS NIH HHS/United States ; }, abstract = {Chromosome segregation in eukaryotes requires the orchestrated interaction of chromosomes with microtubules, mediated by the kinetochore multiprotein complex that assembles on specific chromosomal regions known as centromeres. In most eukaryotes, two centromeric proteins, CenH3 and Cenp-C, are essential for centromere function. In Drosophila, the localization of CenH3 (referred to as Cid in Drosophila) depends on its chaperone CAL1 and Cenp-C. Previous studies have shown that both Cid and Cenp-C underwent a coincident gene duplication and likely functional specialization in the Drosophila subgenus. Independently, Cid duplications led to Cid1, Cid3, and Cid4 paralogs in the montium group (Sophophora subgenus), but it is unknown whether this group also underwent parallel duplications of Cenp-C. Here, we investigate this possibility by analyzing sequenced genomes of 23 montium group species. We identified Cenp-C genes in five distinct syntenic loci; we named these genes Cenp-C1b, Cenp-C1c, Cenp-C1d, Cenp-C1e and Cenp-C3. Despite their distinct synteny, most montium group species only encode a single Cenp-C; their phylogeny mirrors the species phylogeny, and they appear to have retained Cenp-C protein motifs indicative of function. A closer examination revealed that these Cenp-C genes resulted from gene translocations or alternate retention (duplication followed by loss of the ancestral copy); only one species, D. vulcana, retains two intact Cenp-C paralogs. Therefore, unlike the Drosophila genus, the co-retention of three Cid paralogs in the montium group has not resulted in a coincident Cenp-C paralog co-retention. Our work highlights differences in functional retention and likely specialization of the two most conserved centromeric proteins in eukaryotes.}, }
@article {pmid41446208, year = {2025}, author = {Gómez-Garzón, C and Chen, Q and O'Brien, VP and Salama, NR}, title = {Metaplasia Enables Stomach Colonization by Fusobacterium animalis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41446208}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R00 CA263036/CA/NCI NIH HHS/United States ; R01 AI054423/AI/NIAID NIH HHS/United States ; R21 CA270512/CA/NCI NIH HHS/United States ; }, abstract = {Infection with Helicobacter pylori is the major risk factor for gastric cancer worldwide; yet the exact mechanisms behind this link remain unclear. H. pylori-associated tissue changes often disrupt the gastric microbiome, enabling secondary gastric colonization by oral bacteria. Among these secondary colonizers, Fusobacterium species have documented associations with several gastrointestinal cancers. We found that both F. animalis and F. nucleatum invade cultured human gastric adenocarcinoma cells, but F. animalis exhibited higher adherence and invasion, and hypoxic conditions promoted higher bacterial survival. Both adherence and invasion were inhibited by exogenous GalNAc, a glycan commonly observed in membrane glycoproteins of adenocarcinoma cells, and a target of the fusobacterial adhesin Fap2. Using a mouse model of gastric metaplasia, we found that F. animalis colonized gastric tissue only after metaplasia onset, growing in multispecies biofilms in the mucus layer, while F. nucleatum colonized neither healthy nor metaplastic gastric tissue. Metaplasia led to upregulation of Gal-GalNAc in the stomach, and reduced gastric acidity allowed higher F. animalis loads in this model. By contrast, inflammation and the presence of H. pylori did not significantly influence stomach colonization by F. animalis. Overall, our data support a model in which H. pylori-induced metaplasia makes the stomach susceptible to secondary infection by another cancer-associated microbe, F. animalis.}, }
@article {pmid41446269, year = {2025}, author = {Lin, C and Gheorghe, V and Chou, J and Alibai, S and Kim, S and Nazanin, EA and Xu, Y and Ma, X and Wilson, LL and Moser, RD and Kemp, CJ and Chen, J and Kopetz, S and Hart, T}, title = {Functional modules predict cancer-relevant genetic interactions in mammalian cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41446269}, issn = {2692-8205}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R35 CA274234/CA/NCI NIH HHS/United States ; R35 GM130119/GM/NIGMS NIH HHS/United States ; U01 CA275886/CA/NCI NIH HHS/United States ; }, abstract = {Genetic interactions can reveal gene function and identify cancer-relevant synthetic lethals, but systematic mapping in human cells is constrained by inefficient reagents, vast combinatorial search space, and diversity of cell types. Here, we leverage principles from yeast genetic networks to identify human gene modules enriched for genetic interactions. Using our Cas12a-based In4mer combinatorial knockout platform, we screen all pairwise interactions within receptor tyrosine kinase and DNA damage response modules across eight diverse cancer cell lines. We identify hundreds of unreported synthetic lethals, including a dense network within the protein glycosylation machinery, and confirm that interactions in 2D cell culture are maintained in more physiologically relevant models. Our targeted modules show up to 16-fold enrichment of interaction density, providing a scalable strategy for systematic interaction mapping.}, }
@article {pmid41446897, year = {2025}, author = {Zhai, G and Bar, M and Cowan, AJ and Rubinstein, S and Shi, Q and Zhang, N and Xie, E and Ma, W}, title = {AI for evidence-based treatment recommendation in oncology: a blinded evaluation of large language models and agentic workflows.}, journal = {Frontiers in artificial intelligence}, volume = {8}, number = {}, pages = {1683322}, pmid = {41446897}, issn = {2624-8212}, abstract = {BACKGROUND: Evidence-based medicine is crucial for clinical decision-making, yet studies suggest that a significant proportion of treatment decisions do not fully incorporate the latest evidence. Large Language Models (LLMs) show promise in bridging this gap, but their reliability for medical recommendations remains uncertain.<br><br>METHODS: We conducted an evaluation study comparing five LLMs' recommendations across 50 clinical scenarios related to multiple myeloma diagnosis, staging, treatment, and management, using a unified evidence cutoff of June 2024. The evaluation included three general-purpose LLMs (OpenAI o1-preview, Claude 3.5 Sonnet, Gemini 1.5 Pro), one retrieval-augmented generation (RAG) system (Myelo), and one agentic workflow-based system (HopeAI). General-purpose LLMs generated responses based solely on their internal knowledge, while the RAG system enhanced these capabilities by incorporating external knowledge retrieval. The agentic workflow system extended the RAG approach by implementing multi-step reasoning and coordinating with multiple tools and external systems for complex task execution. Three independent hematologist-oncologists evaluated the LLM-generated responses using standardized scoring criteria developed specifically for this study. Performance assessment encompassed five dimensions: accuracy, relevance, comprehensiveness, hallucination rate, and clinical use readiness.<br><br>RESULTS: HopeAI demonstrated superior performance across accuracy (82.0%), relevance (85.3%), and comprehensiveness (74.0%), compared to OpenAI o1-preview (64.7, 57.3, 36.0%), Claude 3.5 Sonnet (50.0, 51.3, 29.3%), Gemini 1.5 Pro (48.0, 46.0, 30.0%), and Myelo (58.7, 56, 32.7%). Hallucination rates were consistently low across all systems: HopeAI (5.3%), OpenAI o1-preview (3.3%), Claude 3.5 Sonnet (10.0%), Gemini 1.5 Pro (8.0%), and Myelo (5.3%). Clinical use readiness scores were relatively low for all systems: HopeAI (25.3%), OpenAI o1-preview (6.0%), Claude 3.5 Sonnet (2.7%), Gemini 1.5 Pro (4.0%), and Myelo (4.0%).<br><br>CONCLUSION: This study demonstrates that while current LLMs show promise in medical decision support, their recommendations require careful clinical supervision to ensure patient safety and optimal care. Further research is needed to improve their clinical use readiness before integration into oncology workflows. These findings provide valuable insights into the capabilities and limitations of LLMs in oncology, guiding future research and development efforts toward integrating AI into clinical workflows.}, }
@article {pmid41447755, year = {2026}, author = {Nair, MS and Scarborough, J and Reddy, CA and Bommireddy, AR and Brooks, E and Almassi, N and Weight, CJ and Campbell, S and Ornstein, MC and Nizam, A and Gilligan, T and Wee, C and Gupta, S and Scott, JG and Mastroianni, A and Tendulkar, R and Mian, OY}, title = {Trimodality Therapy for Bladder Cancer: A Single Institution Retrospective Analysis of Factors Associated With Outcomes for High-Risk Patients Undergoing Organ-Sparing Therapy.}, journal = {Clinical genitourinary cancer}, volume = {24}, number = {1}, pages = {102477}, pmid = {41447755}, issn = {1938-0682}, support = {L30 CA220908/CA/NCI NIH HHS/United States ; U54 CA274513/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/therapy/mortality/pathology ; Male ; Female ; Retrospective Studies ; Aged ; Middle Aged ; *Organ Sparing Treatments/methods ; Cystectomy/methods ; Aged, 80 and over ; Treatment Outcome ; Combined Modality Therapy ; Neoplasm Recurrence, Local/epidemiology ; Neoadjuvant Therapy ; Disease-Free Survival ; Risk Factors ; }, abstract = {PURPOSE: We sought to define patient and disease characteristics associated with outcomes after trimodality therapy (TMT) for high-risk nonmuscle invasive and muscle invasive bladder cancer (MIBC). A retrospective analysis of a large single institution cohort treated with bladder preservation therapy was performed to identify factors associated with survival.<br><br>METHODS AND MATERIALS: Patients with high-risk non-MIBC or MIBC who underwent definitive bladder sparing treatment between 2006 and 2022 were included. Variables for analysis included age, sex, Charlson Comorbidity Index (CCI), surgical candidacy, neoadjuvant/induction chemotherapy (NAC), tumor size, presence of hydronephrosis, carcinoma in-situ, and histologic subtype. Kaplan-Meier analysis was done to calculate rates of overall survival (OS) and disease-free survival (DFS), while cumulative incidence analysis was done to calculate rates of cancer specific mortality (CSM) and local recurrence. Cox proportional hazards regression was done to identify factors associated with OS and DFS. Competing risk regression was done to identify factors associated with CSM and local recurrence.<br><br>RESULTS: 226 patients were included in the cohort with a median follow up of 18.9 months (range 0.9-172.3). The median age was 79 years (range 49-98) and 79.2% were male. On univariate Cox proportional hazards regression, younger age, NAC, and cystectomy candidacy were associated with improved OS (P < .0001, HR = 1.05, 95% CI, 1.03-1.08; P = .04, HR = 0.62, 95% CI, 0.39-0.99; P < .0001, HR = 0.42, 95% CI, 0.27-0.65; respectively). On multivariable analysis, only younger age and cystectomy eligibility were associated with improved OS (P = .002, HR = 1.04, 95% CI, 1.02-1.07; P = .006, HR = 0.52, 95% CI, 0.33-0.83; respectively).<br><br>CONCLUSION: This study finds cystectomy eligibility to be associated with improved survival and underscores the importance of multi-disciplinary assessment in determining candidacy for organ preserving therapy in MIBC patients.}, }
@article {pmid41448829, year = {2026}, author = {Balduzzi, A and Valsecchi, MG and Tran, TH and Zuna, J and Leoni, V and Cario, G and Fazio, G and Gandemer, V and Tasian, SK and van der Sluis, IM and Peccatori, N and Parasole, R and Monterisi, S and Loh, ML and Devidas, M and Hunger, SP and Kairalla, JA and De Lorenzo, P and Silverman, LB and Biondi, A}, title = {Philadelphia chromosome-positive acute lymphoblastic leukaemia in children and adolescents: A changing treatment landscape and a methodological challenge.}, journal = {British journal of haematology}, volume = {208}, number = {3}, pages = {1127-1132}, pmid = {41448829}, issn = {1365-2141}, support = {U10CA180899/CA/NCI NIH HHS/United States ; 1U01CA243072/CA/NCI NIH HHS/United States ; U10CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; 70112958//Deutsche Krebshilfe/ ; U01 CA232486/CA/NCI NIH HHS/United States ; NW25-03-00276//Agentura Pro Zdravotnick&#xfd; V&#xfd;zkum &#x10c;esk&#xe9; Republiky/ ; 1U01CA232486/CA/NCI NIH HHS/United States ; //Ministero della Salute/ ; U01 CA243072/CA/NCI NIH HHS/United States ; }, }
@article {pmid41448830, year = {2025}, author = {Yamada, MM and Chandrasekhar, S and Gooley, TA and Chen, RE and Doolittle-Amieva, C and Ansstas, G and Bhatia, S and Hall, ET and Nghiem, PT and Park, SY and Chen, DY}, title = {Real-world outcomes of talimogene laherparepvec as salvage therapy for advanced melanoma.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {12}, pages = {}, pmid = {41448830}, issn = {2051-1426}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/drug therapy/mortality/therapy/pathology ; Male ; Female ; Middle Aged ; Aged ; *Salvage Therapy/methods ; Adult ; *Oncolytic Virotherapy/methods ; Aged, 80 and over ; *Biological Products/therapeutic use/pharmacology ; Treatment Outcome ; Herpesvirus 1, Human ; *Skin Neoplasms/mortality ; Retrospective Studies ; }, abstract = {BACKGROUND: Talimogene laherparepvec (T-VEC) is an oncolytic herpes simplex virus therapy approved for treatment of unresectable and metastatic melanoma. However, real-world use often occurs in heavily pretreated patients, where evidence of effectiveness remains limited. This study evaluates treatment responses and clinical factors influencing T-VEC outcomes in patients with diverse treatment histories.<br><br>METHODS: We analyzed patients with metastatic melanoma treated with T-VEC between 2015 and 2024. Objective responses (OR), complete response (CR) and partial response were assessed using univariate and multivariate Cox regression models. Durability of responses, progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan-Meier estimates.<br><br>RESULTS: Among 121 patients, 105 (87%) patients received &#x2265;1 prior lines of systemic therapy; 48 (40%) had a current or prior history of distant metastatic disease, and 42 (35%) had both injectable and non-injectable disease at the T-VEC initiation. Median PFS was 12.2 months (95%&#x2009;CI 6.2 to 20.9), and median OS was 35.5 months (95%&#x2009;CI 25.8 to 63.9). Of 113 evaluable patients, 76 (67%, 95%&#x2009;CI 58% to 76%) achieved an OR, including 39 (35%, 95%&#x2009;CI 26% to 44%) CR. The probability OR by 6 months was 56% (95% CI 46% to 65%). Of the 39 patients achieving CR, 37 (95%) remained alive and progression-free at last follow-up (median 19.1 months). In multivariate analysis, the adjusted HR (aHR) for OR in patients with non-injectable distant metastases at T-VEC initiation relative to those without was 0.43 (95% CI 0.23 to 0.78; p=0.006). The aHR for OR among those immunosuppressed compared with those not immunosuppressed was 0.18 (95% CI 0.04 to 0.69; p=0.013), indicating a reduced likelihood of response for patients who were immunosuppressed. Unadjusted HRs for achieving an OR after 1, 2, and &#x2265;3 prior therapies (vs none) were 1.20 (95% CI 0.57 to 2.52; p=0.627), 1.21 (95% CI 0.52 to 2.80; p=0.653), and 0.77 (95% CI 0.35 to 1.68; p=0.507), respectively.<br><br>CONCLUSIONS: This study demonstrates T-VEC's potential efficacy in achieving meaningful disease control and response durability in patients with unresectable and/or metastatic melanoma, including those with diverse prior-treatment histories and comorbidities.}, }
@article {pmid41448908, year = {2025}, author = {Mukui, I and Peacock, S and Donnell, D and Gati-Mirembe, B and Krows, M and Bukusi, EA and Imaan, L and Kotze, P and Gill, KM and Macdonald, P and Louw, C and Jaggernath, M and Marais, A and Peters, RPH and Delany-Moretlwe, S and Ward, A and du Preez, P and Kasaro, M and Gandhi, M and Heffron, R and Celum, C and , }, title = {High prevalence and incidence of curable sexually transmitted infections among young women using oral HIV pre-exposure prophylaxis in sub-Saharan Africa: results from the INSIGHT Cohort study.}, journal = {Sexually transmitted infections}, volume = {}, number = {}, pages = {}, doi = {10.1136/sextrans-2025-056625}, pmid = {41448908}, issn = {1472-3263}, abstract = {BACKGROUND: HIV pre-exposure prophylaxis (PrEP) programmes in Africa reach young women at risk of sexually transmitted infections (STIs). We evaluated curable STI prevalence, incidence and risk factors among women initiating PrEP.<br><br>METHODS: From August to December 2022, sexually active women aged 16-30 years from 15 South African sites, and one site each in Eswatini, Kenya, Malawi, Uganda and Zambia were enrolled into the INSIGHT cohort and offered oral emtricitabine/tenofovir PrEP with follow-up at 1, 3 and 6 months. At each visit, STI symptoms were assessed and treatment provided based on syndromic management or diagnostic testing. Diagnostic tests included nucleic acid amplification for Chlamydia trachomatis and Neisseria gonorrhoeae, the rapid OSOM for Trichomonas vaginalis at enrolment and month 6, and serological testing for syphilis at enrolment using rapid plasma reagin with confirmatory Treponema pallidum particle agglutination. Prevalence and incidence of each STI were calculated, and predictors assessed using multivariable regression.<br><br>RESULTS: Of 3087 participants offered daily oral PrEP with a median age of 23 (IQR 21-27), 3011 had STI results and 30.9% had one or more&#x2009;STIs, with 15.7% reporting symptoms. The prevalence of C. trachomatis, N. gonorrhoeae, T. vaginalis and syphilis was 20.8%, 6.8%, 6.0% and 4.4%, respectively. The incidence of one or more&#x2009;STIs (C. trachomatis, N. gonorrhoeae or T. vaginalis) was 49.3/100 person-years (95%&#x2009;CI 45.3 to 53.4) with 12.7% reporting symptoms. The incidence of C. trachomatis was 30.6/100 person-years (95%&#x2009;CI 27.5 to 33.7), N. gonorrhoeae 10.8/100 person-years (95%&#x2009;CI 9.0 to 12.6) and T. vaginalis 11.5/100 person-years (95%&#x2009;CI 9.7 to 13.4). An incident STI diagnosis was associated with low alcohol use (adjusted incidence rate ratio (aIRR) 1.3; 95%&#x2009;CI 1.0 to 1.6) and moderate alcohol use (aIRR 1.4; 95%&#x2009;CI 1.1 to 1.8), and having an STI diagnosed at enrolment (aIRR 1.8; 95%&#x2009;CI 1.5 to 2.1).<br><br>CONCLUSION: The high prevalence and incidence of STIs among African women initiating PrEP, most of whom did not report symptoms, highlights the need for aetiologic testing to detect STIs, guide treatment and reduce reproductive health sequelae and risk of transmission.<br><br>TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT05746065.}, }
@article {pmid41451118, year = {2025}, author = {McNeil, AJ and Parks, K and Pogharian, M and Cowen, EW and Lehman, J and Lee, SJ and Zhao, A and Pavletic, SZ and Saknite, I and Coco, J and Fabbri, D and Tkaczyk, ER and Dawant, BM}, title = {Improving U-Net Segmentation of Cutaneous Chronic Graft-Versus-Host Disease in Clinical Photographs with Semi-Supervised Training.}, journal = {Proceedings of SPIE--the International Society for Optical Engineering}, volume = {13407}, number = {}, pages = {}, pmid = {41451118}, issn = {0277-786X}, support = {IK2 CX001785/CX/CSRD VA/United States ; R01 HL169944/HL/NHLBI NIH HHS/United States ; TL1 TR002244/TR/NCATS NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; }, abstract = {Measuring skin involvement in chronic graft-versus-host disease (cGVHD) currently requires expert manual assessment, which is costly, time-consuming, and shows high interrater disagreement (>20% surface area). In our previous work, automated image analysis showed promise for measuring affected skin area under controlled photography conditions. Our aim is to improve the performance of these methods in standard clinical photographs without the need for costly expert annotations using a semi-supervised approach. A baseline U-Net model was trained in a fully supervised manner using 360 3D photographs from 36 cGVHD patients, with expert-marked ground truth contours of affected skin. The model was then iteratively retrained by incorporating an additional 5648 unlabeled photographs from 83 new patients using a semi-supervised method. Testing on clinical photographs of 20 held-out patients, the median surface area error improved from 19.2% (interquartile range 6.3 - 33.8) at baseline to 10.2% (4.5 - 22.6) after retraining. Semi-supervised training therefore provides an effective method for translating a pre-trained U-Net segmentation model to standard clinical photographs, without the need for additional expert annotations. Such models could help standardize cGVHD assessment and tracking, alleviating the need for costly expert evaluations and providing a reliable tool that would significantly enhance the current standard of manual assessment.}, }
@article {pmid41452615, year = {2026}, author = {Unger, JM and Fisch, MJ and Jones, SMW and Henry, NL and Hershman, DL}, title = {Baseline Fatigue and Severe Toxic Effects in Patients With Cancer Receiving Systemic Therapy.}, journal = {JAMA oncology}, volume = {12}, number = {2}, pages = {185-193}, pmid = {41452615}, issn = {2374-2445}, mesh = {Humans ; *Fatigue/chemically induced/epidemiology/diagnosis/etiology ; *Neoplasms/drug therapy/complications ; Female ; Male ; Middle Aged ; Aged ; *Antineoplastic Agents/adverse effects ; Patient Reported Outcome Measures ; Severity of Illness Index ; Cohort Studies ; Adult ; *Drug-Related Side Effects and Adverse Reactions/epidemiology ; }, abstract = {IMPORTANCE: Fatigue is a common symptom reported by patients with cancer, yet its role as a predictor of treatment-related toxic effects has not been well characterized. Understanding whether fatigue measured at treatment initiation may be associated with subsequent toxic effects could help guide individualized treatment planning and symptom monitoring.<br><br>OBJECTIVE: To evaluate the association between baseline patient-reported fatigue and the risk of adverse events (AEs) in cancer treatment trials.<br><br>This cohort study and pooled analysis assessed baseline fatigue data from 17 SWOG phase 2 and 3 trials conducted from 1990 to 2022. Patients were enrolled across multiple cancer types and treatment settings. Data analysis was performed from March 1, 2023, to October 17, 2025.<br><br>EXPOSURES: Baseline fatigue, classified on a 5-point Likert scale, analyzed as binary thresholds (eg, <some vs&#x2009;&#x2265;some fatigue) and across fatigue severity levels.<br><br>MAIN OUTCOMES AND MEASURES: Adverse events were classified using the Common Terminology Criteria for Adverse Events (CTCAE), with multiple versions mapped to version 4. Symptomatic AEs followed the Patient-Reported Outcomes-CTCAE framework; laboratory-based or measurable toxic effects were considered objective (hematologic vs nonhematologic). Primary outcomes were grade 3 or higher (severe), grade 4 or higher (life-threatening), and grade 5 (fatal) AEs. Odds ratios (ORs) were estimated using generalized estimating equations. To account for confounding, the analysis was clustered by trial and adjusted for age, sex, race, and obesity.<br><br>RESULTS: Among 7086 patients (mean [SD] age, 62.1 [15.2] years; 2107 females [29.7%] and 4979 males [70.3%]) with prostate, lung, colorectal, lymphoma, breast, melanoma, ovarian, or pancreatic cancer, 103&#x202f;738 AEs were reported. At baseline, 2771 participants (39.1%) reported&#x2009;some or more fatigue. Proportions with maximum AEs rated grade 3 or higher, grade 4 or higher, and grade 5 were 3128 participants (44.1%), 1001 (14.1%), and 62 (0.9%), respectively. Compared with those reporting no or minimal fatigue, patients with some fatigue or more had higher risks of severe or worse toxic effects (odds ratio [OR], 2.09; 95% CI, 1.58-2.78; P&#x2009;<&#x2009;.001), life-threatening or fatal toxic effects (OR, 1.96; 95% CI, 1.36-2.82; P&#x2009;<&#x2009;.001), and fatal toxic effects (OR, 2.35; 95% CI, 1.07-5.19; P&#x2009;=&#x2009;.03). A dose-response pattern was evident: patients reporting quite a lot or very much fatigue had an approximately 5-fold higher risk of fatal toxic effects (OR, 4.99; 95% CI, 1.84-13.51; P&#x2009;=&#x2009;.002). Findings were consistent across symptomatic, hematologic, and nonhematologic AE categories.<br><br>CONCLUSIONS AND RELEVANCE: This cohort study found that baseline patient-reported fatigue was associated with an increased risk of cancer treatment-related toxic effects. Fatigue assessments at treatment initiation may serve as an early clinical marker of risk for toxic effects and may help inform personalized treatment strategies and symptom monitoring.}, }
@article {pmid41459525, year = {2025}, author = {Chapuis, AG and Orozco, JJ and Milano, F}, title = {Intrathecal rituximab for the treatment of Epstein-Barr virus-associated encephalitis.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1736017}, pmid = {41459525}, issn = {1664-3224}, mesh = {Humans ; Male ; *Encephalitis, Viral/drug therapy/diagnosis/virology/etiology ; *Epstein-Barr Virus Infections/drug therapy/virology/diagnosis/immunology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Herpesvirus 4, Human ; *Immunologic Factors/administration &amp; dosage ; Injections, Spinal ; *Rituximab/administration &amp; dosage/therapeutic use ; Treatment Outcome ; Young Adult ; }, abstract = {Epstein-Barr virus (EBV)-associated encephalitis is seen in patients who have undergone allogeneic hematopoietic stem cell transplant and can be associated with significant morbidity and mortality. The mainstay of treatment has been antiviral therapy with nucleoside analogues and reduction of immunosuppression. Here, we describe an adult patient diagnosed with refractory EBV-associated encephalitis within 30 days post-allogeneic transplant successfully treated with intrathecal rituximab, which, to our knowledge, is the first case treated in this manner.}, }
@article {pmid41459934, year = {2026}, author = {Reed, JC and Downs, C and McAllister, K and Mauer, C and McClurkan, CL and Wilson, D and Holzhauer, K and Dickerson, JA and Cannon, CA and Babu, TM and Golden, MR and Koelle, DM and Greninger, AL}, title = {Differentiating mpox infection and vaccination using a validated multiplex orthopoxvirus IgG serology assay.}, journal = {Journal of clinical microbiology}, volume = {64}, number = {2}, pages = {e0154825}, pmid = {41459934}, issn = {1098-660X}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; 2022//Center for AIDS Research, University of Washington/ ; AI027757/NH/NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Viral/blood ; *Immunoglobulin G/blood ; *Orthopoxvirus/immunology ; Sensitivity and Specificity ; Adult ; Male ; *Mpox, Monkeypox/diagnosis/immunology ; Middle Aged ; Female ; Young Adult ; Vaccination ; *Serologic Tests/methods ; Vaccinia virus/immunology ; Adolescent ; Monkeypox virus/immunology ; *Poxviridae Infections/diagnosis ; }, abstract = {UNLABELLED: The resurgence of monkeypox virus (MPXV) has increased demand for validated serological assays to assess exposure and immunity. Cross-reactivity among orthopoxviruses, stemming from high sequence conservation, complicates distinguishing antibody responses from natural MPXV infection versus vaccination or other orthopoxvirus exposures. We validated the Meso Scale Discovery (MSD) V-PLEX Orthopoxvirus Panel 1 (IgG) Kit, which quantifies antibody levels to five MPXV antigens and their vaccinia virus (VACV) orthologs, following Good Clinical Laboratory Practice guidelines. We assessed assay performance using serum from 26 individuals with prior mpox, 52 JYNNEOS vaccine recipients, and 179 unexposed controls. The assay reliably detected antibody responses in all exposed cohorts with peak levels observed 2 months post-vaccination. Antibody levels to specific antigens also correlated with Modified Vaccinia Ankara neutralization titer, particularly for MPXV B6R/VACV B5R, MPXV E8L/VACV D8L, and MPXV M1R/VACV L1. Receiver operating characteristic analysis showed that some individual antigens achieved high sensitivity and specificity for exposure detection (area under the curve [AUC] > 0.96 for VACV D8L, MPXV B6R, VACV B5R); however, individual antigens performed poorly in distinguishing infection from vaccination. In contrast, antibody level ratios between some MPXV and VACV orthologs effectively differentiated MPXV infection from vaccinia vaccination with high sensitivity and specificity (e.g., MPXV A35R/VACV A33R ortholog ratio, AUC = 0.97, sensitivity = 0.97, specificity = 0.96). Our findings validate the MSD assay for clinical research and serosurveillance to assess MPXV immunity and support the utility of ortholog pair ratio analysis as a strategy to discriminate vaccinated and infected individuals.<br><br>IMPORTANCE: Mpox continues to spread around the world, with recent data showing increasing incidence in the United States. While there are multiple Food and Drug Administration (FDA)-authorized real-time PCR tests for diagnostic use, there are no FDA-authorized serological tests and few laboratory-developed serological tests offered. We evaluated the Meso Scale Discovery V-PLEX Orthopoxvirus Panel 1 (IgG) Kit according to Good Clinical Laboratory Practice guidelines and found that the assay reliably detected antibody responses in monkeypox virus (MPXV)- and vaccinia virus (VACV)-exposed cohorts and could distinguish them from unexposed cohorts. Intriguingly, we found that antibody level ratios between certain MPXV and VACV orthologs could distinguish prior mpox infection from vaccinia vaccination. Overall, these data highlight the use of multi-antigen panels in challenging scenarios for serological testing, such as the cross-reactivity presented by orthopoxviruses.}, }
@article {pmid41460282, year = {2025}, author = {Woolf-King, SE and Dalton, MR and Firkey, M and Sheinfil, A and Bucci, V and Estrada, B and Ramos, J and Hahn, JA and Bricker, J and Gump, B and Bendinskas, KG and Maisto, SA}, title = {A Randomized Feasibility/Acceptability Trial of Acceptance and Commitment Therapy for People with HIV Who Drink at Unhealthy Levels.}, journal = {AIDS and behavior}, volume = {}, number = {}, pages = {}, pmid = {41460282}, issn = {1573-3254}, support = {K24 AA022586/AA/NIAAA NIH HHS/United States ; R34AA026246-03S1/AA/NIAAA NIH HHS/United States ; R34AA026246/AA/NIAAA NIH HHS/United States ; }, abstract = {Unhealthy alcohol use is prevalent among people with HIV (PWH) and associated with significant health-related consequences. We describe here a randomized feasibility/acceptability trial of a brief, telephone-delivered transdiagnostic acceptance and commitment therapy (ACT) intervention for PWH who drink at unhealthy levels. This pilot trail was designed to match the procedures of a planned definitive RCT that will compare the ACT intervention to a brief alcohol intervention (BI). We randomly assigned PWH and unhealthy alcohol use 1:1 to either the ACT or the BI intervention and collected self-report and biomarker data post-treatment and again at 3-, 6-, and 12-months. The primary objectives of this pilot trial were to assess feasibility of recruitment, retention, and intervention delivery, and acceptability of intervention content. We also collected preliminary primary (alcohol use) and secondary (symptoms of anxiety, depression, and experiential avoidance) outcome data to examine general patterns of results at a purely descriptive level. In total, 192 participants were screened, 117 of whom were eligible, and 49 of whom were randomized to either the ACT (n = 24) or BI (n = 25) condition. Results provided evidence of feasibility and acceptability indicating that a definitive trial should proceed. Preliminary outcome data also suggested that ACT is a promising treatment for unhealthy alcohol use and co-morbid symptoms of depression, anxiety, and experiential avoidance. A definitive trial is currently underway and will determine the comparative efficacy of ACT versus BI for unhealthy alcohol use for PWH.}, }
@article {pmid41460828, year = {2025}, author = {Osuga, H and Chan, MC and Brower, K and Ray, LJ and Chowning, JT}, title = {Ten simple rules for running a virtual program to introduce computational biology at the high school level.}, journal = {PLoS computational biology}, volume = {21}, number = {12}, pages = {e1013830}, pmid = {41460828}, issn = {1553-7358}, }
@article {pmid41460962, year = {2026}, author = {Nguyen, CL and Funes, J and Ghale, R and Duong, N and Victor, K and Gipson, B and Zhang, ZJ and Dai, A and Li, R and Armijo, G and Huang, A and Martinez, M and Chen, Y and Ghazarian, D and Docampo, M and Pathak, K and Pirrotte, P and Markey, KA and Peled, JU and Paredes, J and Burgos da Silva, M and van den Brink, MRM}, title = {Enterococcus faecalis induces MHC-II expression by the intestinal epithelium during murine graft-versus-host disease.}, journal = {Blood}, volume = {147}, number = {13}, pages = {1485-1497}, pmid = {41460962}, issn = {1528-0020}, support = {P01 CA023766/CA/NCI NIH HHS/United States ; R01 CA228308/CA/NCI NIH HHS/United States ; U01 AI124275/AI/NIAID NIH HHS/United States ; R01 HL125571/HL/NHLBI NIH HHS/United States ; R01 CA228358/CA/NCI NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; K08 HL143189/HL/NHLBI NIH HHS/United States ; R01 HL123340/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 AG052359/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; *Graft vs Host Disease/immunology/microbiology/pathology ; *Enterococcus faecalis/immunology/physiology ; Mice ; *Intestinal Mucosa/microbiology/immunology/metabolism/pathology ; *Histocompatibility Antigens Class II/immunology/genetics ; Mice, Inbred C57BL ; Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Killer Cells, Natural/immunology ; Germ-Free Life ; CD4-Positive T-Lymphocytes/immunology ; Disease Models, Animal ; }, abstract = {Intestinal Enterococcus domination has been associated with an increased risk of mortality from acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), a curative-intent treatment for patients with hematologic malignancies. In this study, we investigated interactions between Enterococcus and the intestinal epithelium as a mechanism to aggravate GVHD. We observed that endogenous intestinal Enterococcus outgrowth was associated with increased GVHD mortality and major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells in the colon in an MHC-disparate mouse model of GVHD. Monocolonization of nontransplanted gnotobiotic mice with Enterococcus faecalis was sufficient to induce colonic MHC-II expression. Conversely, select species within the genus Enterococcus, as well as a consortium of 4 anaerobic commensal bacteria including Blautia producta, did not affect colonic MHC-II expression in gnotobiotic mice. In addition, E faecalis colonization induced inflammatory responses in CD4+ T cells and natural killer cells from the colonic lamina propria, the 2 main sources of interferon gamma production that drives MHC-II expression in nonprofessional antigen-presenting cells. We further explored the potential therapeutic benefit of establishing colonization resistance against E faecalis through administration of a lantibiotic-producing B producta strain after allo-HCT. Colonization of transplanted mice with a consortium of commensal bacteria containing the lantibiotic-producing B producta strain prevented intestinal Enterococcus domination after transplantation and improved GVHD survival. Our results demonstrate a potential mechanism by which Enterococcus aggravates GVHD through increased MHC-II expression in the intestinal epithelium. Targeting the Enterococcus-epithelium-MHC-II axis thus presents a therapeutic opportunity to prevent lethal GVHD.}, }
@article {pmid41460964, year = {2026}, author = {Abramson, JS and Straus, DJ and Bartlett, NL and Burke, JM and Lynch, RC and Domingo Domenech, E and Hess, B and Schuster, SR and Linhares, Y and Gandhi, M and Shah, HR and Jurczak, W and Re, A and Hahn, U and Prince, HM and Guo, W and Davis, G and Ho, L and Fanale, M and Yasenchak, CA and Lee, HJ}, title = {Brentuximab vedotin and nivolumab in combination with chemotherapy for nonbulky, early-stage classical Hodgkin lymphoma.}, journal = {Blood}, volume = {147}, number = {15}, pages = {1713-1722}, pmid = {41460964}, issn = {1528-0020}, mesh = {Humans ; *Hodgkin Disease/drug therapy/pathology/mortality ; Nivolumab/administration &amp; dosage/adverse effects ; Female ; Male ; Middle Aged ; Adult ; Brentuximab Vedotin/administration &amp; dosage ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; Aged ; Young Adult ; Doxorubicin/administration &amp; dosage/adverse effects ; Adolescent ; Neoplasm Staging ; Dacarbazine/administration &amp; dosage/adverse effects ; }, abstract = {Most patients with early-stage classical Hodgkin lymphoma (cHL) are treated with doxorubicin, bleomycin, vinblastine, and dacarbazine with or without radiation therapy, although studies are now evaluating the incorporation of novel agents paired with abbreviated chemotherapy. We present the efficacy and safety of AN+AD (brentuximab vedotin [BV] and nivolumab in combination with doxorubicin and dacarbazine) in patients with early-stage cHL. In this phase 2 study, patients with nonbulky (<10 cm) Ann Arbor stage I or II cHL received 4 cycles of AN+AD. The primary end point was complete response (CR) rate at end of treatment (EOT) by investigator. At the time of this analysis, 154 patients received ≥1 dose of AN+AD. The objective response rate at EOT was 96% (95% confidence interval [CI], 91.7-98.6), and the CR rate was 92% (95% CI, 86.0-95.4). In the favorable (n = 56) and unfavorable (n = 97) subgroups, CR rates were 95% (95% CI, 85.1-98.9) and 91% (95% CI, 83.1-95.7), respectively. The proportion of patients with duration of CR of at least 2 years was 96% (95% CI, 90.9-98.4). At a median follow-up of 27.9 months, the estimated 2-year progression-free survival rate was 97% (95% CI, 92.0-98.8). Any-grade and grade ≥3 treatment-emergent adverse events occurred in 99% and 44% of patients, respectively; no events of febrile neutropenia were reported. Any-grade treatment-emergent immune-mediated adverse events occurred in 22% of patients. One disease-related death was reported after the safety reporting period. Results from this study support the use of BV and nivolumab in combination with limited chemotherapy for patients with nonbulky, early-stage cHL. This trial was registered at www.clinicaltrials.gov as NCT03646123.}, }
@article {pmid41461080, year = {2026}, author = {Lucia, MS and Callis, S and Tangen, C and Almutairi, F and Chatzitolios, A and Kravtsov, O and Lenon, S and Manuchua, V and Simko, JP and Szecsei, CM and Yeh, YA and Zhang, L and Iczkowski, KA}, title = {Whole-Slide Telepathology Grading of Prostate Cancer in Biopsies Using International Society of Urological Pathology Criteria: Interobserver and Intraobserver Concordance and Implications for Active Surveillance.}, journal = {The Journal of urology}, volume = {215}, number = {5}, pages = {544-552}, doi = {10.1097/JU.0000000000004919}, pmid = {41461080}, issn = {1527-3792}, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology ; Neoplasm Grading ; Observer Variation ; *Watchful Waiting ; *Telepathology ; *Prostate/pathology ; Urology ; Biopsy, Needle ; Societies, Medical ; Aged ; Middle Aged ; }, abstract = {PURPOSE: Subjectivity of prostate cancer (PCa) grading affects biomarker investigations, assessments of imaging, and treatment decisions, especially for active surveillance. We conducted the first telepathology concordance study of PCa needle biopsy grading using contemporary International Society of Urologic Pathology guidelines.<br><br>METHODS: Whole slide images (n = 120) of PCa biopsy cases across grade groups (GGs) were examined by 11 urologic pathologists. Forty cases were blindly regraded, oversampling cases with lower agreement on first review. Pathologists provided GG, percentage and type of pattern Gleason 4, and tumor length. Consensus for a case was defined as GG agreement by &#x2265; 7 pathologists. GG agreement among and within pathologists was measured using model-based weighted Kappa statistics (&#x3ba;w).<br><br>RESULTS: Consensus was achieved on 86/120 (72%) cases. Of 34 cases not achieving consensus, most were GG2 vs GG1 (41%) or GG2 vs GG3 (38%). The inter-rater &#x3ba;w was 0.34 (95% CI 0.28, 0.39) indicating fair agreement. Forty regraded cases had an intra-rater &#x3ba;w of 0.49 (95% CI 0.46, 0.53; moderate agreement). Sixty-four percent of the repeated grades agreed. Of the repeated ratings that did not agree, 38% involved GG1 vs GG2. Of the GG1 vs GG2 paired repeated ratings, 77% reported 1% to 10% pattern 4, and indicated common observation was "poorly formed glands."<br><br>DISCUSSION: Inter-rater and intra-rater variability in GG is significant, particularly discerning GG1 from GG2 with &#x2264; 10% grade 4. These observations have profound implications for treatment decisions (surveillance vs definitive therapy) and studies of new biomarkers and imaging of prostate cancer.}, }
@article {pmid41461276, year = {2026}, author = {Fan, YY and Salinas, ML and Mullens, DA and Davidson, LA and Goldsby, JS and Ivanov, IV and Jayaraman, A and Cai, JJ and Levy, L and Hullar, MA and Navarro, SL and Lampe, JW and Chapkin, RS}, title = {Pesco-Vegetarian Food Components Promote Colonocyte Ferroptosis in Preclinical Mouse Models and a Randomized Crossover Trial in Healthy Human Adults.}, journal = {The Journal of nutrition}, volume = {156}, number = {2}, pages = {101287}, pmid = {41461276}, issn = {1541-6100}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; R21 CA245456/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *Ferroptosis/drug effects ; Mice ; *Colon/cytology/drug effects ; Male ; Adult ; Female ; Fish Oils/administration &amp; dosage ; Cross-Over Studies ; *Diet, Vegetarian ; Dietary Fiber/administration &amp; dosage ; Mice, Inbred C57BL ; Pectins ; Pilot Projects ; Lipid Peroxidation ; }, abstract = {BACKGROUND: Diet plays a critical role in colorectal cancer (CRC) prevention. Pesco-vegetarians, who consume both high fiber and fish containing n-3 (ω-3) polyunsaturated fatty acid (PUFA), have the lowest CRC risk. Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid hydroperoxides that has emerged as a target for anticancer therapies.<br><br>OBJECTIVES: This study aimed to assess the broad utility of diet modulation as a promising avenue to modulate ferroptosis in the colon.<br><br>METHODS: 1) Immortalized young adult mouse colonic epithelial cells (YAMC) were treated with control linoleic acid or docosahexaenoic acid (DHA) &#xb1; butyrate (But), followed by cell viability and lipid peroxidation measurements, 2) mice were fed diets containing fish oil and highly fermentable pectin (FP) compared with control corn oil and poorly fermentable cellulose (CC). Colons were isolated and used for bulk and single-cell ribonucleic acid-sequencing (RNA)-seq analysis, 3) a crossover pilot study was conducted by supplementing 30 healthy adults with soluble corn fiber (33 g/d) + fish oil (7.7 g/d n-3 PUFA) (SCF+FO) or maltodextrin + corn oil (MD+CO) for 30 d followed by a 60 d wash period and then 30 d of MD+CO or SCF+FO. Exfoliated colonocyte mRNA was isolated from stool and RNA-seq was performed for transcriptomic analysis.<br><br>RESULTS: In vitro treatment of DHA and But reduced YAMC cell viability (P < 0.05), increased lipid peroxidation, a key biomarker of ferroptosis, compared with the counterpart group. In vivo FP-fed mice promoted lipid peroxidation in colonocytes relative to the control CC-fed mice (P < 0.05), and the induction of ferroptosis transcriptional networks exclusively in colonic epithelial cells. Furthermore, human subjects supplemented with SCF+FO exhibited an upregulation in intestinal ferroptosis-related gene expression, as compared with similar doses of MD+CO.<br><br>CONCLUSIONS: Our findings demonstrate that dietary fish oil and fermentable fiber combination induces ferroptosis exclusively in colonocytes. The human pilot study was registered at clinicaltrials.gov as NCT04211766.}, }
@article {pmid41461908, year = {2026}, author = {,  and Alberts, T and Albritton, CF and Alcazar, R and Aljabri, Z and Alvarez, M and Aradhey, A and Ayalew, M and Azizian, N and Balayah, Y and Ball, DD and Barragan, E and Beshoar, C and Best, L and Biggane, E and Biggane, J and Blick, J and Blosser, M and Brown, AK and Campbell, MC and Canizares, Z and Chanhuhwa, FN and Chen, Y and Chin, DR and Chowdhury, K and Collins, T and Compton, B and Da Silva, J and Davis, NR and DeCaro, N and Delgadillo, F and Deng, Y and Duncan, J and Egwu, AC and Ekalle, GD and Elnawam, N and Enke, R and Ewhe, N and Ferrel, MA and Fierst, J and Freymiller, G and Fuller, K and Fulton-Wright, L and Gaysinskaya, V and Gill, T and Gillespie, E and Gonzalez Moreno, P and Goodwin, S and Graham, N and Graham, ME and Graves, JL and Grob, E and Gutierrez, R and Hager, A and Hakim, ST and Harris, A and Hoffman, AM and Hoffmann, T and Horton, AM and Hughes, A and Humphries, EM and Ikechi-Konkwo, JS and Ishtiaq, A and Jackson, R and James, JR and James, K and Jamison, SA and Jimenez, A and Johnson, R and Kauffman, A and Kaur, H and Kc, K and Keeton, A and Kelly, OE and Kerr, J and Kucher, N and Kuehu, DL and Larson, WA and Lee, J and Lee, A and Leek, JT and Lemaic, D and Liburd, LE and Lopez, AF and Mahmanzar, M and Mamae, K and Manjikian, R and Marone, M and Marquez, K and Martinson, A and Mavruk Eskipehlivan, S and Medrano, A and Melendrez-Vallard, M and Meller, R and Méndez, LB and Mendez Gonzalez, MP and Mesquita, N and Miller, CM and Mohd-Ibrahim, I and Mortensen, P and Mosher, S and Muja, A and Nasrin, N and Nasu, M and Nguyen, MH and Nguyen, BT and Nishiguchi, M and O'Connor, LM and Okie, D and Olowookorun, T and Ostrovsky, A and Ozuna, K and Pandey, A and Patel, SB and Paul, G and Pawar, S and Pearson, A and Petrik, D and Platero, J and Pontino, C and Pratap, AP and Pratap, S and Qin, Y and Rai, SK and Ray, N and Repesh, E and Rhinehardt, K and Roche, B and Rodriguez, A and Roy, S and Roy, S and Sawa, A and Schatz, MC and Sen, SK and Serikawa, R and Smith, T and Smith, L and Sniezek, J and Stewart, RD and Suarez-Martinez, EB and Taganna, J and Tan, FJ and Tsotakos, N and Udolisa, N and Ulbricht, K and Veo, T and Vessio, J and Walker, L and Wang, O and Wang, Q and Wappel, R and Wesby, K and Whitford, M and Wild, N and Xie, X and Yang, H and York, S and Zirkle, L}, title = {Unearthing soil biodiversity through collaborative genomic research and education.}, journal = {Nature genetics}, volume = {58}, number = {1}, pages = {3-8}, pmid = {41461908}, issn = {1546-1718}, support = {U24 HG010263/HG/NHGRI NIH HHS/United States ; 2011934//National Science Foundation (NSF)/ ; U24 HG013013/HG/NHGRI NIH HHS/United States ; 75N92022P00232//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; T34 GM151403/GM/NIGMS NIH HHS/United States ; 5T34GM151403//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 2221924//National Science Foundation (NSF)/ ; U41 HG006620/HG/NHGRI NIH HHS/United States ; U54 HG013243/HG/NHGRI NIH HHS/United States ; 1839895//National Science Foundation (NSF)/ ; 2000157//National Science Foundation (NSF)/ ; U24HG013013//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 75N92023P00302//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, abstract = {The BioDIGS project is a nationwide initiative involving students, researchers and educators across more than 40 research and teaching institutions. Participants lead sample collection, computational analysis and results interpretation to understand the relationships between the soil microbiome, environment and health.}, }
@article {pmid41466427, year = {2025}, author = {Kareithi, T and Roche, SD and Meisner, A and Omollo, V and Ong'wen, PA and Harkey, K and Kiptinness, C and Otieno, P and Juma, L and Malen, RC and Anyona, MO and Curran, K and Banerjee, P and Gichuru, E and Asewe, M and Yu, K and Pintye, J and Mugambi, ML and Shah, PD and Sharma, M and Were, D and Ngure, K and Bukusi, EA and Ortblad, KF and , }, title = {Testing different models of pharmacy-based HIV pre- and post-exposure prophylaxis initiation and management in Kenya: protocol for a cluster-randomized controlled trial.}, journal = {Trials}, volume = {27}, number = {1}, pages = {95}, pmid = {41466427}, issn = {1745-6215}, support = {INV-033052/GATES/Gates Foundation/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; INV-033052/GATES/Gates Foundation/United States ; }, mesh = {Humans ; Kenya/epidemiology ; *HIV Infections/prevention &amp; control ; *Pre-Exposure Prophylaxis/methods ; *Post-Exposure Prophylaxis/methods ; *Anti-HIV Agents/administration &amp; dosage ; Randomized Controlled Trials as Topic ; *Community Pharmacy Services/organization &amp; administration ; *Pharmacies ; }, abstract = {BACKGROUND: In Kenya, as in many African countries, private pharmacies are ubiquitous, frequently accessed, and underutilized for the delivery of HIV prevention services. Whether enabling private pharmacies to initiate and manage clients on HIV pre- and post-exposure prophylaxis (PrEP and PEP) leads to greater uptake and continuation than the current standard-pharmacy referral to clinic-based PrEP/PEP-is unknown. To address this gap and inform how private pharmacies might partner with the public sector, we are testing several models of pharmacy-delivered PrEP/PEP in comparison to the current standard.<br><br>METHODS: The Pharm PrEP cRCT is a 60-pharmacy, four-arm cluster-randomized controlled trial ongoing in Central and Western Kenya (first enrollment: 26 June 2023). Eligible pharmacies were licensed by the government, had a private room, and were willing to complete research activities (including a 3-day provider training). Study pharmacies were randomized 1:1:1:1 to (1) client-sustained delivery, in which clients pay pharmacies 250 KES (~$2 USD) per PrEP/PEP visit; (2) implementor-sustained delivery, in which clients pay nothing and implementors pay pharmacies 250 KES per PrEP/PEP visit; (3) implementor-sustained&#x2009;+&#x2009;counselor-supported delivery, in which clients pay nothing, delivery is supported by an HIV testing services (HTS) counselor, and implementors pay pharmacies 100 KES (~$1 USD) per PrEP/PEP visit; or 4) referral (control), in which clients pay nothing and implementors pay pharmacies 100 KES per referral to clinic-based PrEP/PEP. Pharmacies delivering PrEP/PEP receive supporting commodities free from government stock. Primary outcomes are PrEP initiation and continuation (any refilling) reported by clients 60&#xa0;days post-enrollment; secondary outcomes include PEP initiation, PEP-to-PrEP transition, repeat PEP use, PrEP/PEP initiation, and PrEP/PEP continuation at 60 and 270&#xa0;days post-enrollment. Primary analyses will compare each intervention arm to the control; secondary analyses will compare intervention arms to one another. We will additionally assess implementation outcomes (e.g., acceptability, feasibility, cost) from client and provider perspectives.<br><br>DISCUSSION: This trial will generate evidence on the potential benefits of leveraging private pharmacies for delivery of PrEP and PEP and the relative effectiveness of pharmacy delivery when subsidized by clients, implementors, and/or supported by HTS counselors. The findings may inform enabling policy and approaches for scale-up.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05842122. Registered on&#xa0;April 5, 2023.}, }
@article {pmid41467111, year = {2026}, author = {Mukhtar, RA and Flanagan, MR}, title = {Locoregional Considerations for Invasive Lobular Carcinoma.}, journal = {Current breast cancer reports}, volume = {18}, number = {1}, pages = {2}, pmid = {41467111}, issn = {1943-4588}, abstract = {PURPOSE OF REVIEW: This article summarizes recent literature on locoregional management of patients with invasive lobular carcinoma (ILC), including approaches to breast surgery, axillary management, and neoadjuvant therapy.<br><br>RECENT FINDINGS: Breast conservation therapy is safe in ILC, but has comparatively high rates of positive margins, which can be reduced by routine use of shave margins and oncoplastic surgery. Studies demonstrating the safety of de-escalation of axillary surgery have not included enough patients with ILC to draw strong conclusions; current guidelines do not support omission of sentinel node surgery in most patients with ILC. Neoadjuvant chemotherapy may improve breast conservation and increase nodal pathologic complete response in molecularly selected patients using genomic assays.<br><br>SUMMARY: The locoregional management of patients with ILC requires special considerations based on its unique features. ILC specific studies are needed to address knowledge gaps for patients diagnosed with this common tumor type.}, }
@article {pmid41467901, year = {2026}, author = {Hanson, F and Hickner, B and Fisher, C and Hein, H and Kukreja, K and Goss, J and Galvan, TN and Leung, DH and Banc-Husu, AM and Masand, P and Patel, K and Lopez-Terrada, D and Heczey, A and Vasudevan, S and Voeller, J}, title = {Case of Advanced Hepatocellular Carcinoma Treated With Transarterial Radioembolization and Subsequent Liver Transplantation in a 22-Month-old.}, journal = {Journal of pediatric hematology/oncology}, volume = {48}, number = {1}, pages = {e35-e40}, doi = {10.1097/MPH.0000000000003152}, pmid = {41467901}, issn = {1536-3678}, mesh = {Humans ; *Carcinoma, Hepatocellular/therapy/pathology ; *Liver Neoplasms/therapy/pathology ; *Liver Transplantation ; *Embolization, Therapeutic/methods ; Infant ; Male ; Yttrium Radioisotopes/therapeutic use ; }, abstract = {Hepatocellular carcinoma (HCC) is a rare malignancy in children, typically requiring chemotherapy, surgical resection, and/or transplant for treatment. Whether HCC arises as a novel tumor (de novo) or in the setting of chronic liver disease determines treatment strategy. We describe a case of a pediatric patient with unresectable HCC due to macrovascular invasion and tumor thrombus of the portal vein who received transarterial radioembolization (TARE) and underwent successful orthotopic liver transplantation outside of Milan criteria.}, }
@article {pmid41468926, year = {2025}, author = {Rangarajan, HG and Chellapandian, D and Atshan, R and Ahn, KW and Kumar, S and Knight, TE and Leung, W and Ganguly, S and Williams, KM and Shah, NN and Bhatt, NS and Lust, H and Prestidge, T and Brown, VI and Hayashi, RJ and Choe, M and Saad, A and Bidgoli, A and Thakar, MS and Wirk, B and MacMillan, ML and Lalefar, NR and Hematti, P and Schultz, KR and Phillips, CL and Mehta, PA and Qayed, M and Sharma, A and Broglie, L and Satwani, P}, title = {Impact of Extramedullary Disease at Diagnosis on Outcomes Post Allogeneic Hematopoietic Cell Transplant in Children and Young Adults With Acute Myeloid Leukemia: A CIBMTR Report.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, pmid = {41468926}, issn = {2666-6367}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; U01 AI184132/AI/NIAID NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; }, abstract = {Conflicting reports exist regarding the impact of extramedullary disease (EMD) at diagnosis upon outcomes after allogeneic hematopoietic cell transplantation (HCT) in children and young adults with acute myeloid leukemia (AML). We retrospectively analyzed the effect of EMD at diagnosis on post-HCT outcomes in a large cohort of children and young adults (21 and younger) who had AML and received their first myeloablative allogeneic HCT for AML during 2008 to 2019 (N = 938; 52% males). Data were obtained from the Center for International Blood and Marrow Transplant Research database. Patients were grouped based on EMD at diagnosis as bone marrow (BM) involvement only (Group I; n = 630); BM + central nervous system (CNS) involvement (Group II; n = 212), and BM + other EMD ± CNS (Group III n = 96). All patients were in a morphologic complete remission (CR) with no evidence of EMD pre-HCT. Outcomes compared included 3-yr progression-free survival (PFS), overall survival (OS), non-relapse mortality (NRM), and relapse incidence (RI). Group III patients were younger at HCT (Group III median age 3, versus age 11 in Group I, and age 10 in Group II) and more often had high Pediatric Disease Risk Index scores (52% in Group III versus 22% in Group I and 25% in Group II). At a median follow-up of 70 mo (range 3-155 mo), the 1-yr and 3-yr PFS, NRM, RI, and OS were similar among all 3 groups on univariate analysis. On multivariable analysis, the presence of EMD was associated with decreased RI: Group II, with a hazard ratio (HR) of 0.70 (95% CI, 0.52-0.94; P = .020) and Group III with an HR of 0.70 (95% CI, 0.46-1.05; P = .086) compared to Group I. There was no difference in PFS (P = .21), NRM (P = .27), and OS (P = .82) among the groups. In our study, in patients with AML who proceeded to HCT in CR, the presence of EMD at diagnosis was not associated with adverse outcomes or increased relapse risk.}, }
@article {pmid41469386, year = {2025}, author = {Li, B and Lin, R and Ni, T and Yan, G and Burns, M and Li, JJ and Yao, Z}, title = {CellScope: high-performance cell atlas workflow with tree-structured representation.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {1130}, pmid = {41469386}, issn = {2041-1723}, support = {A-8001562-00-00//Ministry of Education - Singapore (MOE)/ ; A-0008520-00-00//Ministry of Education - Singapore (MOE)/ ; A-8002931-00-00//Ministry of Education - Singapore (MOE)/ ; }, mesh = {*Single-Cell Analysis/methods ; Humans ; Workflow ; Algorithms ; *Software ; Cluster Analysis ; *Computational Biology/methods ; Cell Lineage/genetics ; Gene Expression Profiling/methods ; Animals ; }, abstract = {Single-cell sequencing enables comprehensive profiling of individual cells, revealing cellular heterogeneity and function with unprecedented resolution. However, current analysis frameworks lack the ability to simultaneously explore and visualize cellular hierarchies at multiple biological levels. To address these limitations, we present CellScope, a promising framework for constructing high-resolution cell atlases at multiple clustering levels. CellScope employs a two-stage manifold fitting process for gene selection and noise reduction, followed by agglomerative clustering, and integrates UMAP visualization with hierarchical clustering to intuitively represent cellular relationships simultaneously at multiple levels-such as cell lineage, cell type, and cell subtype levels. Compared to established pipelines such as Seurat and Scanpy, CellScope comprehensively improves clustering performance, visualization clarity, computational efficiency, and algorithm interpretability, while reducing dependence on hyperparameters across a multitude of single-cell datasets. Most importantly, it can reveal biological insights that other contemporary methods are unable to detect, thereby deepening our understanding of cellular heterogeneity and function, and potentially informing disease research.}, }
@article {pmid41470899, year = {2025}, author = {Kadro, ZO and Rillamas-Sun, E and Langley, BO and Meisner, A and Contento, I and Koch, PA and Ogden Gaffney, A and Hershman, DL and Greenlee, H}, title = {Associations Between the Food Environment and Food Insecurity on Fruit, Vegetable, and Nutrient Intake, and Body Mass Index, Among Urban-Dwelling Latina Breast Cancer Survivors Participating in the &amp;iexcl;Mi Vida Saludable! Trial.}, journal = {Nutrients}, volume = {17}, number = {24}, pages = {}, pmid = {41470899}, issn = {2072-6643}, support = {R01 CA186080/CA/NCI NIH HHS/United States ; R01 CA186080-02S1/CA/NCI NIH HHS/United States ; UL1 TR001873/TR/NCATS NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Body Mass Index ; *Breast Neoplasms ; *Cancer Survivors/statistics &amp; numerical data ; *Diet ; *Food Insecurity ; Food Supply ; Fruit ; *Hispanic or Latino/statistics &amp; numerical data ; Urban Population ; Vegetables ; }, abstract = {Background: Socioeconomic disparities may drive cancer inequities in Hispanic/Latino populations. We examined associations of perceived access to healthy foods (AHF) and food insecurity (FI) with diet and body mass index (BMI) changes in Latina breast cancer (BC) survivors. Methods: Latina BC survivors in a 12-month intervention trial aiming to increase fruit/vegetable intake and physical activity were analyzed. AHF was from a modified, validated neighborhood environment scale and dichotomized (low-medium vs. high). FI was defined as eating less and/or going hungry due to a lack of money. AHF and FI surveys were self-reported. Outcomes included dietary intake, diet quality, and BMI. Fruit/vegetable intake was log-transformed. Relationships between AHF and FI and changes in diet and BMI were evaluated using generalized estimating equations. Results: Of women with AHF data (n = 86), 58% reported low-medium access and 42% reported high access. Fruit/vegetable (FV) intake declined overall from baseline to 12 months, with greater reductions among low-medium AHF women (-32%, 95% CI: -51%, -7%) compared with high AHF women (-17%, 95% CI: -40%, +13%). Statistically significant 12-month decreases in total calories, carbohydrates, sugars, and fat occurred in low-medium AHF women but not high AHF women, and changes in total energy density, carbohydrates, sugars, and BMI at 12 months were statistically significantly different between women with low-medium AHF and women with high AHF, p ≤ 0.05. Among 157 women, 23% reported FI. Reductions in fruit/vegetable intake were larger in women with FI (-39%, 95% CI: -57%, -14%) than in women without FI (-10% reductions, 95% CI: -25%, +8%) and between-group differences were significant at both 6 and 12 months, p ≤ 0.05. Most diet measures decreased for both FI and non-FI women, with greater decreases among those with FI. Conclusions: Latina BC survivors with FI or perceived limited AHF experienced greater declines in indicators of healthy diets including FV intake. Future interventions should integrate strategies to measure AHF and FI to address disparate access to healthy food options.}, }
@article {pmid41472424, year = {2026}, author = {Wallace, PK and Jellison, ER and Thornton, S and Kluepfel, K and Back, J and Beadnell, TC and Bebes, A and Behrends, J and Belkina, AC and Black, M and Bogdanoski, G and Bollati-Fogolín, M and Bonte, S and Van der Borght, K and Brinkman, RR and Brundage, K and Bushnell, T and Chiu, DT and Chow, N and Ciccolella, CO and Cochran, M and Czechowska, K and Dagla, K and Daniel, B and de la Cruz, G and Van Duyse, J and Font, LF and Fornas, &#xd2; and Garcia-Garcia, S and Gardner, R and Van Gassen, S and Gimenes, D and Grenfell, R and Grider-Hayes, MJ and Grose, R and Hall, C and Hally, KE and Hameetman, M and Hogg, K and Houston, J and Irish, JM and Isterdael, GV and Jaimes, M and Janetzki, S and Kim, C and Koladiya, A and Lamote, J and Lannigan, J and Leconte, J and Litwin, V and Longhini, A and Loof, N and Lozano-Andrés, E and Lundsten, K and Mage, P and Mair, F and Martins, CG and McCausland, M and McGuire, HM and Meskas, J and Murphy, W and Nolan, J and Oliveira, B and Ordoñez-Rueda, D and Orlowski-Oliver, E and Petersen, CC and Poulton, NJ and Putri, G and Quadrini, KJ and Ramasz, B and Ruhrmund, D and Singh, VV and Small, SJ and Smith, NJ and Spidlen, J and Stegen, C and Tak, T and Thompson, S and Thomson, M and Vocelle, D and Walker, RV and Walsh, RE and Wang, L and Wang, YF and Weglarz, M and Winker, M and Wood, JCS and Woolard, S and Yeh, NY and Yuecel, R and Rajwa, B}, title = {Cyt-Geist: Current and Future Challenges in Cytometry: Reports of the CYTO 2025 Conference Workshops.}, journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology}, volume = {109}, number = {1}, pages = {5-41}, doi = {10.1002/cytoa.70002}, pmid = {41472424}, issn = {1552-4930}, }
@article {pmid41473276, year = {2025}, author = {Nutt, WS and Kluesner, MG and Bingham, E and Gad, E and Miller, D and Zepeda, V and Snyder, AJ and Marsh, SA and Liudahl, SM and Hoffman, M and LeBlanc, L and Volfbeyn, ME and Garrison, SM and Sarvothama, M and Barry, KC and Headley, MB and Marcondes, M and Srivastava, S}, title = {NKTR-255, a polymer-conjugated IL-15, synergizes with CAR-T cell therapy to activate endogenous anti-tumor immunity and improve tumor control.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41473276}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; F31 CA294918/CA/NCI NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R37 CA276285/CA/NCI NIH HHS/United States ; F30 CA305905/CA/NCI NIH HHS/United States ; }, abstract = {CAR-T cells have yet to show widespread efficacy in solid tumors due in part to their poor persistence and loss of function in the tumor microenvironment. Further, heterogenous expression of most CAR target antigens in solid tumors can lead to escape of antigen-null tumors that resist CAR-T killing. Strategies to cooperatively boost both CAR-T and endogenous anti-tumor immunity could curb tumor escape and may be critical for achieving durable efficacy in cancer patients. NKTR-255 is a polymer-conjugated IL-15 with extended half-life that can boost endogenous T and NK cells, as well as CD19 CAR-T activity in B cell malignancies. However, whether NKTR-255 is sufficient to overcome CAR-T dysfunction in the suppressive solid tumor microenvironment, and how NKTR-255 and CAR-Ts together re-shape endogenous anti-tumor immunity, is not known. Using an autochthonous mouse model of ROR1[+] lung adenocarcinoma, we show that NKTR-255 significantly boosted accumulation, reduced exhaustion, and improved function of tumor-infiltrating CAR-T cells. Compared with NKTR-255 or CAR-T treatment alone, combination of NKTR-255 and CAR-T therapy synergistically increased tumor-infiltrating CD11b[+] cytotoxic NK cells, activated dendritic cells, and endogenous tumor-specific T cells that preserved a PD-1[+]Tcf1[+] stem-like phenotype. Consequently, NKTR-255 and CAR-T combination therapy induced complete elimination of ROR1[+] tumor and significantly improved survival, with enhanced tumor control dependent on activity of both CAR-Ts and endogenous T cells. Altogether, our data suggest that combining NKTR-255 with CAR-T therapy is a promising strategy to enhance both CAR-T and endogenous anti-tumor immunity to promote coordinated control of aggressive tumors.}, }
@article {pmid41474700, year = {2025}, author = {Kwendakwema, CN and Eastment, MC and Wanje, G and Richardson, BA and Mwaringa, E and Sherr, K and Mandaliya, KN and Barnabas, RV and Jaoko, W and McClelland, RS}, title = {Cross-sectional study evaluating organizational climate, change commitment, and change efficacy for predicting family planning clinics' success in increasing HIV counseling and testing in Mombasa, Kenya.}, journal = {PLOS global public health}, volume = {5}, number = {12}, pages = {e0005542}, pmid = {41474700}, issn = {2767-3375}, abstract = {Increasing HIV testing and counselling (HTC) is a first step to reducing HIV transmission. Implementing HTC in family planning (FP) clinics has been proposed to increase HIV testing coverage in at-risk populations. The Systems Analysis and Improvement Approach (SAIA) was used to improve HTC rates in FP clinics in Mombasa, Kenya. This hypothesis-generating exploratory analysis evaluated the associations between organizational climate characteristics, organizational readiness for implementing change, and successful implementation of HTC. Surveys were conducted with clinic managers and staff from FP clinics implementing SAIA to increase HTC. Likert-style questions were used to characterize organizational climate metrics and organizational readiness for implementing change (ORIC). Linear regression was performed to examine the association between organizational climate metrics, ORIC domains, and two FP client outcomes: 1) percentage of clients receiving pre-HIV test counseling, and 2) percentage of clients tested for HIV. Eleven clinic staff and 10 clinic managers completed the surveys. For clinic staff, higher innovation and flexibility scores were associated with higher change commitment (β = 0.20, CI 0.09-0.31, p = 0.001) and change efficacy (β = 0.17, CI 0.07-0.26, p = 0.002). Higher clinic manager scores for innovation and flexibility were associated with a higher change commitment (β = 0.44, CI 0.04-0.84, p = 0.03). Additionally, clinic managers' scores for management support (β = 0.25, CI 0.06-0.45, p = 0.01), commitment to facility (β = 0.78, CI 0.60-0.96, p = 0.001), and relative priority (β = 0.24, CI 0.08-0.39, p = 0.004) were positively associated with higher change commitment and change efficacy. In contrast, clinic managers' scores for tradition were negatively associated with change commitment (β = -0.38, CI -0.75-0.01, p = 0.05). Clinic staff perceptions of management support were positively associated with the proportion of clients counseled for HIV testing (β = 1.20, CI 0.08-2.32, p = 0.04). Support from leadership and innovation/flexibility are important predictors of change commitment and change efficacy. Strong management support may increase the likelihood of successful implementation of SAIA to improve HTC.}, }
@article {pmid41476111, year = {2026}, author = {Van Buren, E and Zhang, Y and Li, X and Selvaraj, MS and Li, Z and Zhou, H and Palmer, ND and Arnett, DK and Blangero, J and Boerwinkle, E and Cade, BE and Carlson, JC and Carson, AP and Chen, YI and Curran, J and Duggirala, R and Fornage, M and Franceschini, N and Graff, M and Gu, C and Guo, X and He, J and Heard-Cosa, N and Hou, L and Hung, YJ and Kalyani, RR and Kardia, SLR and Kenny, E and Kooperberg, C and Kral, BG and Lange, L and Levy, D and Li, C and Liu, S and Lloyd-Jones, D and Loos, RJF and Manichaikul, AW and Martin, LW and Mathias, R and Minster, RL and Mitchell, BD and Mychaleckyj, JC and Naseri, T and North, K and O'Connell, J and Perry, JA and Peyser, PA and Psaty, BM and Raffield, LM and Vasan, RS and Redline, S and Reiner, AP and Rich, SS and Smith, JA and Spitzer, B and Tang, H and Taylor, KD and Tracy, R and Viali, S and Yanek, L and Zhao, W and ,  and Rotter, JI and Peloso, GM and Natarajan, P and Lin, X}, title = {cellSTAAR: incorporating single-cell-sequencing-based functional data to boost power in rare variant association testing of noncoding regions.}, journal = {Nature methods}, volume = {23}, number = {2}, pages = {338-349}, pmid = {41476111}, issn = {1548-7105}, support = {N01-HC-95162//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; UL1-TR001881//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; R01-DK117445//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R03- HL154284//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL104135-04S1//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01-HC-95163//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; R35-CA197449//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; N01-HC-95169//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-MD012765//U.S. Department of Health &amp; Human Services | NIH | National Institute on Minority Health and Health Disparities (NIMHD)/ ; R01- HL071250//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HG012064//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; R35 CA197449/CA/NCI NIH HHS/United States ; N01-HC-95166//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; K01 AG059898/AG/NIA NIH HHS/United States ; U01 HG012064/HG/NHGRI NIH HHS/United States ; R01-HL071259//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; T32 ES007142/ES/NIEHS NIH HHS/United States ; N01-HC-95167//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; DK063491//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; R01 HL163560/HL/NHLBI NIH HHS/United States ; HHSN268201700005I/HL/NHLBI NIH HHS/United States ; R01-HL142711//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; UL1-TR-001420//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; N01-HC-95159//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; R01- HL113338//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL173044//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01-HC-95168//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01-HC-95164//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL071205//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HG009088//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; HL046389//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; UL1-RR033176//U.S. Department of Health &amp; Human Services | NIH | National Center for Research Resources (NCRR)/ ; U19-CA203654//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; N01-HC-95160//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; 1R35-HL135818//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; UL1-TR-000040//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; N01-HC-95161//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; HL105756//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054472//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; P42 ES016454/ES/NIEHS NIH HHS/United States ; U01- HL072524//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; N01-HC-95165//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; U01-HL054473//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL071251//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054509//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01-HL071258//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01-HL054495//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92021F00229//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL153805//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; UL1-TR-001079//U.S. Department of Health &amp; Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; R01-HL055673-18S1//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL127564//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL071051//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; Whole Genome Sequencing/methods ; *Genome-Wide Association Study/methods ; Genetic Variation ; Regulatory Sequences, Nucleic Acid/genetics ; Chromatin/genetics ; Polymorphism, Single Nucleotide ; Genome, Human ; }, abstract = {Understanding how rare genetic variants influence complex traits remains a major challenge, particularly when these variants lie in noncoding regions of the genome. The effects of variants within candidate cis-regulatory elements (cCREs) often depend on the cell type, making interpretation difficult. Here we introduce cellSTAAR, which integrates whole-genome sequencing data with single-cell assay for transposase-accessible chromatin using sequencing data to capture variability in chromatin accessibility across cell types via the construction of cell-type-specific functional annotations and regulatory elements. To reflect the uncertainty in cCRE-gene linking, cellSTAAR uses a comprehensive strategy to link cCREs to their target genes. We applied cellSTAAR to data from the Trans-Omics for Precision Medicine consortium (n ≈ 60,000) and replicated our findings using the UK Biobank (n ≈ 190,000). Across four lipid traits, cellSTAAR improved the detection of biologically meaningful associations and enhanced biological interpretability. These results demonstrate the potential of cell-type-aware approaches to boost discovery in rare variant whole-genome sequencing association studies.}, }
@article {pmid41477868, year = {2026}, author = {Lee, J and Jung, H and Kim, EG and Ahn, J and Haffner, MC and Nelson, PS and Kim, KP and Lee, JK and Yi, EC and Kim, KM}, title = {Phenotypic discovery and therapeutic evaluation of an ITGA3B1-targeting antibody-drug conjugate for bladder cancer.}, journal = {Science advances}, volume = {12}, number = {1}, pages = {eady0041}, pmid = {41477868}, issn = {2375-2548}, mesh = {*Urinary Bladder Neoplasms/drug therapy/metabolism/pathology ; Humans ; *Immunoconjugates/pharmacology/therapeutic use/chemistry ; Animals ; Cell Line, Tumor ; Mice ; Xenograft Model Antitumor Assays ; *Integrin alpha3beta1/antagonists &amp; inhibitors/metabolism/immunology ; Oligopeptides/pharmacology/chemistry ; Proteomics ; Drug Discovery ; Phenotype ; Integrin alpha3 ; }, abstract = {Antibody-drug conjugates (ADCs) require antibodies with both high specificity and efficient internalization, features often overlooked by conventional discovery pipelines that rely on preselected antigens and recombinant proteins. Here, we describe an integrated phenotypic platform that combines target-unbiased live-cell biopanning with in situ chemical cross-linking and mass spectrometry to concurrently identify internalizing antibodies and their membrane-bound cognate antigens in a native cellular context. Using this approach, we identified 2E7, an antibody with rapid internalization and specificity for the integrin α3β1 (ITGA3B1) heterodimer. Integrated transcriptomic and proteomic analyses revealed pronounced overexpression of ITGA3B1 across multiple solid tumors, with particularly elevated levels in aggressive bladder cancer subtypes. A 2E7-MMAE (monomethyl auristatin E) ADC exhibited potent, dose-dependent antitumor activity in bladder cancer xenograft models, leading to tumor regression and prolonging survival. This study establishes a generalizable framework for function-first ADC discovery and nominates ITGA3B1 as a promising therapeutic target in bladder cancer.}, }
@article {pmid41478324, year = {2026}, author = {Ahmed, S and Kumar, A and Carpenter, P and Herrera, A and Kelly, K and Pinnix, C and Rutherford, S and Grover, N and Evens, A and Lynch, R and Kenkre, V and Merryman, R and Sauter, C and Nishihori, T and Moskowitz, A and Awan, F and Svoboda, J and Winter, J and Allen, P and Ermoian, R and Ansell, S and Aljuhaishi, T and Nieto, Y and Hamadani, M and Perales, MA}, title = {American Society of Transplantation and Cellular Therapy Clinical Practice Recommendations for Transplantation in Classical Hodgkin Lymphoma.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {3}, pages = {250-260}, doi = {10.1016/j.jtct.2025.12.944}, pmid = {41478324}, issn = {2666-6367}, mesh = {Humans ; *Hodgkin Disease/therapy ; *Hematopoietic Stem Cell Transplantation/methods ; United States ; *Cell- and Tissue-Based Therapy/methods ; Societies, Medical ; Practice Guidelines as Topic ; }, abstract = {Autologous hematopoietic cell transplantation (auto-HCT) remains the standard therapeutic approach for patients with chemotherapy-sensitive relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). Over the past decade, the therapeutic landscape for cHL has evolved substantially with the introduction of novel agents, including antibody-drug conjugates and immune checkpoint inhibitors, which have demonstrated significant efficacy in the relapsed setting and are now incorporated into frontline treatment regimens. These advances have not only expanded the armamentarium available for disease management but have also led to improved long-term outcomes, raising important considerations regarding the optimal sequencing of therapies and the evolving role of transplantation in the modern treatment paradigm. HCT remains a cornerstone in the management of cHL; however, consensus is lacking regarding the optimal timing of auto-HCT, the sequencing and integration of novel therapeutic agents, the potential role of maintenance therapy following auto-HCT, and the appropriate indications and timing for allogeneic (allo) HCT. Therefore, the American Society of Transplantation and Cellular Therapy Committee on Practice Guidelines undertook a project to formulate consensus recommendations to address this unmet need. The RAND-modified Delphi method was used to generate 20 consensus statements with key recommendations as follows: (1) use of auto-HCT consolidation after salvage therapy in the first relapse setting, for patients with chemotherapy-sensitive R/R cHL in complete response; (2) preferred use of pre-HCT salvage therapy regimens with novel agents; (3) consultation for allo-HCT in eligible patients who have disease relapse after auto-HCT; (4) guidance regarding optimal stem cell donor source; (5) selection of conditioning regimen for both auto-HCT and allo-HCT; and (6) preferred graft versus host disease prophylaxis in the modern era. These clinical practice recommendations serve as a tool to guide clinical management of R/R cHL.}, }
@article {pmid41478442, year = {2026}, author = {Kotini-Shah, P and Duran-Luciano, P and Kansal, M and Nasrollahi, F and Lee, UJ and Yuan, Y and Rangel, MO and Kaplan, R and Ponce, SG and Shah, SJ and Cai, J and Bilsker, MS and Pu, M and Hurwitz, BE and Rodriguez, CJ}, title = {Global Longitudinal Strain Reference Values in the Hispanic/Latino Population: Echocardiographic Study of Latinos (ECHO-SOL).}, journal = {The American journal of cardiology}, volume = {261}, number = {}, pages = {41-49}, pmid = {41478442}, issn = {1879-1913}, support = {N01 HC065236/HL/NHLBI NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; R01 HL104199/HL/NHLBI NIH HHS/United States ; N01 HC065233/HL/NHLBI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Echocardiography/methods ; Global Longitudinal Strain ; *Heart Failure/ethnology/physiopathology ; *Hispanic or Latino ; Reference Values ; Risk Factors ; *Stroke Volume/physiology ; United States/epidemiology ; *Ventricular Dysfunction, Left/ethnology/physiopathology/diagnostic imaging ; *Ventricular Function, Left/physiology ; }, abstract = {Global longitudinal strain (GLS) is a sensitive measure for detecting early cardiac dysfunction, but prone to variability by age, race/ethnicity, and sex. To date, GLS has not been described in Hispanics/Latinos, nor has GLS been associated with heart failure risk factors. Data from the Echocardiographic-Study of Latinos, a population-based study of Hispanics/Latinos in the United States, was used. A reference healthy sample was used to define the 95th-percentile lower limit of normal GLS value of -14.2% which was applied to the target population to describe the distribution of GLS across age, gender, and Hispanic/Latino background groups. The proportion of normal/abnormal GLS and left ventricular ejection fraction are described, as well as the proportion of abnormal GLS across prevalent heart failure risk factors (hypertension, obesity, and diabetes). Survey statistics and weighted frequencies were used in all analyses. The study sample consisted of 1,818 adult participants (mean age 56.4 years; 42.6% female). The overall ECHO-SOL target population had a mean GLS of -17.6% with 12.1% having prevalent abnormal GLS. GLS was significantly worse in men than women, and abnormal GLS was more prevalent among individuals of Cuban background than any other Hispanic/Latino background group. More than half (56.4%) of individuals with abnormal GLS had values within the normal left ventricular ejection fraction range, and there were worsening GLS values with increasing heart failure risk factor burden (p < 0.01). In conclusion, our study establishes the first Hispanic/Latino-specific GLS reference values, emphasizing the importance of representative populations in the derivation of myocardial deformation thresholds. Abnormal GLS was prevalent among Hispanics/Latinos, and increasing heart failure risk factor burden correlated with worsening GLS, reinforcing the role of risk factors in early cardiovascular risk assessment.}, }
@article {pmid41479450, year = {2025}, author = {Collienne, L and Matsen, FA}, title = {Tree rearrangement graphs admit paths of decreasing Robinson-Foulds distance.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {41479450}, issn = {2331-8422}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; }, abstract = {Tree rearrangements such as Nearest Neighbor Interchange (NNI) and Subtree Prune and Regraft (SPR) are commonly used to explore phylogenetic treespace. Computing distances based on them, however, is often intractable, so the efficiently computable Robinson-Foulds (RF) distance is used in practice. We investigate how the RF distance behaves along paths in the NNI and SPR graphs, where trees are nodes, edges represent single rearrangements. We show that any two trees are connected by a path along which the RF distance to the target decreases monotonically in the NNI graph and strictly in the SPR graph; we also exhibit trees for which no strictly decreasing NNI path exists.}, }
@article {pmid41482012, year = {2026}, author = {Dussault, N and Ma, J and Ivey, N and Bernal, T and Clifton, D and Jones, CA and Santivasi, WL}, title = {Caring Through Complexity: Developing a Palliative Care Opioid and Stimulant Use Disorder Workflow.}, journal = {Journal of pain and symptom management}, volume = {71}, number = {4}, pages = {e480-e491}, doi = {10.1016/j.jpainsymman.2025.12.017}, pmid = {41482012}, issn = {1873-6513}, mesh = {Humans ; *Palliative Care/methods ; *Workflow ; *Opioid-Related Disorders/therapy ; *Analgesics, Opioid/therapeutic use ; Quality Improvement ; Male ; Female ; *Substance-Related Disorders/therapy ; Adult ; Middle Aged ; }, abstract = {CONTEXT: Caring for individuals with serious illness and opioid or stimulant use disorder (OUD/STuD) is complex. Palliative care (PC) providers often lack addiction medicine training and report discomfort managing this population.<br><br>OBJECTIVES: This quality improvement project aimed to assess PC team comfort, provide targeted education, and create an institutional PC workflow around caring for individuals with OUD/STuD.<br><br>METHODS: This project was conducted within an academic health system's PC program. A preintervention survey assessed baseline comfort caring for individuals with OUD/StUD. The intervention included the development and dissemination of 1) an evidence-based, locally adapted workflow guiding opioid prescribing and clinic management protocols stratified by substance use risk and 2) educational sessions on buprenorphine for pain, substance use risk assessment, and safe opioid management. During implementation, the workflow was iteratively updated based on challenges identified in patient cases (i.e., diagnostic uncertainty, unexpected urine toxicology screens). A postintervention survey assessed changes in provider comfort after implementation.<br><br>RESULTS: Of the 27 individuals who completed the presurvey (response rate 73%), 66% felt uncomfortable overall caring for individuals with OUD/StUD; among prescribers, only 19% felt comfortable managing opioids for this population. The workflow was applied to ten patients (ages 38-76; all with cancer). In the post survey (n = 23, response rate 62%), fewer respondents (35%) felt uncomfortable overall caring for individuals with OUD/StUD and a majority of prescribers (52%) felt comfortable managing opioids for this population.<br><br>CONCLUSION: Developing evidence-based, locally adapted workflows and educational sessions can improve PC provider comfort around caring for patients with OUD/StUD.}, }
@article {pmid41482160, year = {2025}, author = {Masurekar, AN and Burkett, KM and Rahgozar, A and Walter, RB and Othus, M and Abrol, K and Mortezaagha, P and Thyagu, S and Nampoothiri, RV and Kennah, M and Kekre, N and Giguere, P and Abduallah, Y and Atkins, H and Cieniak, C and Berardi, P and Ramsay, T and Mallick, R and Carrier, M and Bredeson, C and Allan, D}, title = {Defining the Limits of Pre-Transplant Risk Prediction in AML: Evidence From Machine Learning and Regression Models.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.12.996}, pmid = {41482160}, issn = {2666-6367}, abstract = {BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) is associated with considerable morbidity and mortality. Machine learning (ML) techniques are increasingly applied to predict outcomes in medicine.<br><br>OBJECTIVES: To evaluate the role of ML in predicting overall survival (OS) after allo-HCT for AML and compare ML with traditional Cox regression.<br><br>STUDY DESIGN: Using an internal cohort of 2253 patients and 14 pre-allo-HCT variables, we developed three models: Cox regression with time-varying coefficients (Cox-TVC), Elastic-net Cox Regression (Cox-EN), and Random Survival Forest (RSF). Performance was evaluated using multiple metrics including C-index, net reclassification improvement (NRI) and decision curve analysis (DCA). Patients were stratified into tertiles of model predicted 24-month mortality. External validation was performed in 252 single-center patients with uniform measurable residual disease (MRD) assessment.<br><br>RESULTS: Model-derived risk scores strongly correlated (r = 0.886 to 0.963). Across models, age &#x2265; 60 years, MRD positivity, and adapted European LeukemiaNet (aELN) adverse risk were the strongest predictors. Effects of age attenuated over time (HR for age &#x2265;60: 2.59 [95% CI: 1.54 to 4.35] at 1 year, 1.92 [95% CI: 1.04 to 3.56] at 5 years). Compared with Hematopoietic Cell Transplant Comorbidity-Index (HCT-CI) and aELN, models improved risk stratification (NRI: 31% to 44%, p < .001). Discrimination remained modest but was higher in external cohort compared with internal cohort (0.69 to 0.71 versus 0.60 to 0.61), likely reflecting uniform MRD assessment. At a 25%, risk threshold for clinical decision-making, models identified approximately 1 additional high-risk patient per 100 versus HCT-CI, or aELN. At 2-years, 25% to 27% of patients categorized as low-risk had died, while 45% to 48% categorized as high-risk were alive.<br><br>CONCLUSIONS: ML approaches improved risk stratification over HCT-CI and aELN but performed comparably with Cox model. Individual outcome prediction using static pre-transplant models remained modest. Progress will require MRD standardization, richer data, and dynamic peri- and post-transplant modeling.}, }
@article {pmid41484084, year = {2026}, author = {Zhang, S and Tang, TH and Kinsella, S and Mazziotta, F and Schweizer, MT and McAfee, MS and Munkhbat, A and Su, Y and Voillet, V and Martin, LE and Smith, CW and Asano, Y and Hailemariam, M and Bakhtiari, J and Lee, B and Yeung, C and Chen, H and Rizzi, AM and Chen, DG and Furiya, K and Horst, N and Zhang, T and Le, P and McKenna, K and Oda, SK and Rongvaux, A and Greenberg, PD and Schmitt, TM and Chapuis, AG}, title = {A CD8αβ co-receptor modified to contain an intracellular CD28 signaling tail enhances TCR-engineered T cell function independent of solid-tumor-associated co-stimulatory ligands.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {753}, pmid = {41484084}, issn = {2041-1723}, support = {P01CA225517//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P01 CA225517/CA/NCI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01CA18029-41//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Animals ; Humans ; Mice ; *CD28 Antigens/genetics/metabolism/immunology ; *CD8 Antigens/genetics/metabolism/immunology ; Signal Transduction ; *Receptors, Antigen, T-Cell/metabolism/genetics/immunology ; CD8-Positive T-Lymphocytes/immunology ; Antigens, Neoplasm/immunology ; *Neoplasms/immunology/therapy ; CD4-Positive T-Lymphocytes/immunology ; Ligands ; Immunotherapy, Adoptive/methods ; Female ; }, abstract = {Adoptive transfer of T cells engineered with tumor-specific T cell receptors (TCRs) has shown limited efficacy in solid tumors, hindered by insufficient persistence, tumor trafficking, and dependence on tumor-associated co-stimulatory ligands. In a phase I trial (NCT04639245) for patients with metastatic MAGE-A1-expressing tumors and adequate organ function; one participant received treatment, which was well-tolerated. In this case and NSG murine models, infusion of CD4/CD8 T cells co-expressing a class-I MAGE-A1-specific TCR and CD8αβ, failed to control tumor progression. To enhance function downstream of TCR signaling, here we investigate the adaptability of TCR components to synthetic modification. Leveraging the obligate co-expression of CD8αβ required for class-I TCR function in CD4 T cells, we identify CD8β as a tractable site for engineering without loss of function. In vitro screening demonstrates incorporation of the CD28 intracellular tail, yielding a CD8/CD28 chimeric co-receptor, most effectively enhances cytokine production, T cell persistence, and tumor control in immunodeficient murine models while preserving stem-like transcriptional features compared to native CD8β. Further rational modification of the CD28 binding motifs improves tumor control in vivo with increased intratumoral accumulation and reduced exhaustion. This benefit also extends to PRAME and WT1-specific TCRs in vitro supporting generalizability.}, }
@article {pmid41484087, year = {2026}, author = {Kinsella, S and Evandy, CA and Cooper, K and Kirsche, E and Warren, M and deRoos, P and Cardinale, A and Iovino, L and Granadier, D and Smith, CW and Hopwo, K and Sullivan, LB and Velardi, E and Dudakov, JA}, title = {Damage-induced pyroptosis drives endogenous thymic regeneration by activating the purinergic receptor P2Y2.}, journal = {Cell death &amp; disease}, volume = {17}, number = {1}, pages = {157}, pmid = {41484087}, issn = {2041-4889}, support = {R01 HL145276/HL/NHLBI NIH HHS/United States ; R01-HL145276//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 HL165673/HL/NHLBI NIH HHS/United States ; R01-HL165673//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P01 AG052359/AG/NIA NIH HHS/United States ; ASH Scholar//American Society of Hematology (ASH)/ ; R35 HL171556/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U01-AI70035//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; U01 AI170035/AI/NIAID NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Pyroptosis/radiation effects/drug effects ; *Thymus Gland/metabolism/radiation effects/physiology ; *Receptors, Purinergic P2Y2/metabolism ; *Regeneration/drug effects ; Mice ; Thymocytes/metabolism ; Mice, Inbred C57BL ; Epithelial Cells/metabolism ; Adenosine Triphosphate/metabolism ; }, abstract = {T cell recovery is critical following damage, such as hematopoietic cell transplantation (HCT), with increased reconstitution associated with improved clinical outcomes. Endogenous thymic regeneration, a crucial process for restoring immune competence following cytoreductive therapies such as HCT conditioning, is often delayed, limiting T cell reconstitution. Fully understanding the molecular mechanisms driving regeneration is therefore crucial for uncovering therapeutic targets that can be exploited to enhance thymic function. Here, we identified that CD4+ CD8+ thymocytes rapidly and acutely undergo lytic cell death, specifically pyroptosis, following acute damage caused by ionizing radiation, and release damage-associated molecular patterns (DAMPS) into the thymic microenvironment, including ATP. Extracellular ATP stimulates the P2Y2 purinergic receptor on thymic epithelial cells (TECs)-a stromal cell crucial for supporting T cell development-resulting in the upregulation FOXN1, the master TEC transcription factor. Targeting the P2Y2 receptor with a P2Y2 agonist, UTPγS, promotes rapid regeneration of the TEC compartment in vivo following acute damage. These findings reveal a novel damage-sensing mechanism employed by the thymus where thymocytes adopt an alternative cell death mechanism which promotes thymic repair via P2Y2 signaling in TECs. This work identifies P2Y2 as a promising therapeutic target for enhancing thymus regeneration and improving immune recovery after HCT.}, }
@article {pmid41486674, year = {2026}, author = {Kanetsky, PA and Almstrup, K and Cherlin, S and Cortessis, VK and Ferlin, A and Gietema, JA and González-Neira, A and Grotmol, T and Hamilton, RJ and Haugen, TB and Kiemeney, LA and Kim, J and Krausz, C and Lessel, D and Lothe, RA and Nead, KT and Nsengimana, J and Poynter, JN and Rajpert-DeMeyts, E and Richiardi, L and Schwartz, SM and Skotheim, RI and Stewart, DR and Turnbull, C and Wiklund, F and Zheng, T and Nathanson, KL and McGlynn, KA and , }, title = {The Testicular Cancer Consortium (TECAC): Filling Knowledge Gaps in the Genetic Etiology of Testicular Germ Cell Tumors.}, journal = {Andrology}, volume = {}, number = {}, pages = {e70168}, pmid = {41486674}, issn = {2047-2927}, support = {PC-35142/GF/NIH HHS/United States ; PK01-2007-0375//Norwegian Cancer Society/ ; PR-2006-0387//Norwegian Cancer Society/ ; 101136622//European&#xa0;Union/ ; P30 CA016520/CA/NCI NIH HHS/United States ; CAN2019/0343//Swedish Cancer Society/ ; R01CA114478/GF/NIH HHS/United States ; 71081//Norwegian Cancer Society/ ; R01CA104786/GF/NIH HHS/United States ; 2010/808//Swedish Cancer Society/ ; S-12/07//Nordic Cancer Union/ ; CAN2012/823//Swedish Cancer Society/ ; R01 CA114478/CA/NCI NIH HHS/United States ; N01 CN067009/CN/NCI NIH HHS/United States ; C588/A19167//Cancer Research UK Programme/ ; HHSN26120130003C/GF/NIH HHS/United States ; U01 CA164947/CA/NCI NIH HHS/United States ; 2019/011633//Swedish Research Council/ ; R01 CA104786/CA/NCI NIH HHS/United States ; III-FIS PI17/01822//Spanish Ministry of Health Instituto Carlos/ ; 270870//Norwegian Cancer Society/ ; R01 CA085914/CA/NCI NIH HHS/United States ; //Movember Foundation/ ; R01CA085914/GF/NIH HHS/United States ; U01CA164947/GF/NIH HHS/United States ; ZO1-CP-10144//National Cancer Institute, Intramural Research Program/ ; 2011/484//Swedish Cancer Society/ ; N01 PC035142/CA/NCI NIH HHS/United States ; CN-67009/GF/NIH HHS/United States ; P30CA016520/GF/NIH HHS/United States ; 2008/708//Swedish Cancer Society/ ; 418975//Norwegian Cancer Society/ ; Z01 CP010144/ImNIH/Intramural NIH HHS/United States ; Dell'ElceFamilyFund//Princess Margaret Cancer Foundation/ ; 70113348//Deutsche Krebshilfe/ ; 223319//Norwegian Cancer Society/ ; /WT_/Wellcome Trust/United Kingdom ; D15D18000410001//Italian Ministry for Education, University and Research/ ; }, abstract = {BACKGROUND: The Testicular Cancer Consortium (TECAC) was established in 2012 and is comprised of researchers from over 25 centers in Europe and North America. TECAC's overarching goal is to investigate the genetic susceptibility of testicular germ cell tumors (TGCT) to better understand their biology, impact prevention strategies, and inform treatment decisions.<br><br>OBJECTIVES: To provide an overview of TECAC genetic and phenotypic holdings.<br><br>MATERIALS AND METHODS: TECAC has composed by-laws describing the consortium structure and governance, codified the processes for manuscript development and data transfer, and developed guidance for the transfer of biological samples and access to data.<br><br>RESULTS: TECAC has assembled a vast amount of genetic information on males with TGCT-including SNP-array data on over 13,500 cases, whole-exome sequencing data on over 4500 cases, and low-pass whole-genome sequence data on over 2700 cases. Genetic information on males without TGCT (controls) is derived from studies designed to assess risk factors for TGCT and from publicly available resources. When available, corresponding phenotypic information is collected and harmonized. Fifteen publications have resulted from genetic and phenotypic information curated by TECAC.<br><br>DISCUSSION: The sharing of genetic and phenotypic data by TECAC centers to inform large studies of TGCT susceptibility has led to novel insights into the genetic architecture of this cancer, including the roles of genes involved in male germ cell development, sex determination, chromosomal segregation, and RNA transcription. These findings would not have been achievable by individual centers or smaller collaborative efforts.<br><br>CONCLUSION: We invite investigators from any discipline who have access to collections of germline DNA, somatic cell DNA, or genomic information on males with TGCT to consider joining TECAC to further strengthen our efforts to reduce the global burden of TGCT.}, }
@article {pmid41487700, year = {2026}, author = {Ruiz, E and Gay, HA and Ixquiac, M and Velarde, A and Sun, B and García-Ramirez, J and Laugeman, E and Li, B and Michalski, J and de Falla, V and Hugo, G and Van Rheenen, J}, title = {Lessons Learned From an Epic Transformation of a Radiation Oncology Department in Guatemala: Keys to Success.}, journal = {Advances in radiation oncology}, volume = {11}, number = {1}, pages = {101928}, pmid = {41487700}, issn = {2452-1094}, abstract = {PURPOSE: We describe the radical modernization of a radiation oncology department in a developing country, Guatemala, from 2015 to the beginning of 2024. The Instituto de Cancerología y Hospital Dr. Bernardo del Valle S (INCAN) is the only public radiotherapy clinic serving patient referrals from the Ministry of Public Health and Social Assistance program.<br><br>METHODS AND MATERIALS: We describe the state of the radiation oncology department in 2015 versus 2024 while chronicling its gradual transformation. This multifaceted collaboration involved academic centers, government agencies, International Atomic Energy Agency (IAEA), industry, and nonprofits and continues to this day. We analyze the infrastructure, staff, radiotherapy equipment, physics equipment, patient careCo-60 decommissioning, and educational initiatives.<br><br>RESULTS: We graphically illustrate the impact of these changes in treatment delivery time, consults, follow-up visits, CT simulations, new patients treated in each linear accelerator, new patients treated with 2D, 3D, IMRT/VMAT, and superficial techniques, new patients treated with 2D LDR, 2D HDR, or 3D techniques, causes of linear accelerator downtime, and weekly patients on treatment. We provide a figure of the various sequential and parallel steps to modernize a radiation oncology department. We describe the complexities of radioisotope repatriation and safe disposal. We provide a comprehensive table of wisdom pearls regarding project governance, team, education, finances, culture, and language. We also discuss the impact of artificial intelligence in contouring.<br><br>CONCLUSION: The transformation of the INCAN radiation oncology department in Guatemala is a testimony to many's hard work, vision, and perseverance for the betterment of Guatemalan patients while facing incredible financial hardship. We hope that what we have learned in the past nine years will help others achieve even greater success in a shorter time.}, }
@article {pmid41488033, year = {2026}, author = {Courville, EL and Seifert, R and Sadigh, S and Chen, X and Calli, JL and Hasserjian, R and Siddon, AJ}, title = {Joining the National Resident Matching Program Fellowship Match: the hematopathology experience.}, journal = {Academic pathology}, volume = {13}, number = {1}, pages = {100230}, pmid = {41488033}, issn = {2374-2895}, abstract = {Hematopathology fellowships are a critical subspecialty within the field of pathology, and with a progressively earlier and earlier fellowship interview timeline, hematopathology decided to join the Pathology Fellowship Match in 2025. The pros and cons of participating in the National Resident Matching Program Match were evaluated, and ultimately it was decided to be undertaken. The National Resident Matching Program requires that 75% of programs and fellowship positions should be entered in order to sponsor the Match. The Society for Hematopathology Education Committee lead the process to recruit hematopathology fellowships into the Match, initiating a survey to assess initial interest, creating a listserv for program director questions, and maintaining a website with programs that ultimately decided to participate. The initial survey results showed that 79% of hematopathology program directors responded "yes" or "maybe" to whether they would participate in a formal Match. The Society for Hematopathology Education Committee then proceeded with a memorandum of understanding to show commitment to the Match. Multiple efforts to disseminate information followed, including informational webinars, social media outreach, and emails to program directors. Ultimately 83% of hematopathology fellowships participated in the 2025 Match, with 85% of positions filling, and 94.7% of hematopathology applicants matching. A follow-up program director survey showed that 98% of respondents planned to participate in the 2026 Match. This feedback solidifies that the Pathology Fellowship Match has shown mutual benefit for programs and applicants.}, }
@article {pmid41488889, year = {2026}, author = {Jain, J and Pugh, K and Handa, S and Dvorak-Kornaus, KM and Zhao, Q and Walter, RB and Cook, R and Saultz, J and Swords, R and Li, J and Laszlo, GS and Grieselhuber, NR and Mims, AS and Larkin, KTM and Sahasrabudhe, K and Blachly, JS and Behbehani, GK and Eisfeld, AK and Long, M and Srisuwananukorn, A and Koenig, KL and Borate, U}, title = {Safety of gemtuzumab ozogamicin with cytarabine, daunorubicin, and midostaurin induction in FLT3-mutated AML.}, journal = {Blood neoplasia}, volume = {3}, number = {1}, pages = {100171}, pmid = {41488889}, issn = {2950-3280}, abstract = {This phase 1 study investigated the addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy with cytarabine, daunorubicin, and midostaurin in 21 patients with newly diagnosed (ND) FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML). Four dose levels of GO were evaluated. The use of GO was tolerable, with all dose-limiting toxicities similar to those seen in standard-of-care treatment. After induction, the median time to platelet recovery was 26 days, and the median time to absolute neutrophil count (ANC) recovery was 27 days. The maximum tolerated dose was cytarabine 100 mg/m[2] on days 1 to 7, midostaurin 50 mg twice daily on days 8 to 21, daunorubicin 60 mg/m[2] on days 1 to 3, and GO 3 mg/m[2] on days 1 and 4. For the 18 patients who were evaluable for response after induction therapy, 16 patients (76%) achieved a composite complete response (complete remission [CR] + CR with incomplete hematologic recovery), and 2 (10%) had stable disease. Of the 14 patients who proceeded to consolidation, 5 discontinued the study for transplant, 1 for disease progression, and 1 for physician discretion. Seven patients completed consolidation therapy, all of whom achieved a CR. In total, 13 of the 21 patients (62%) received a hematopoietic stem cell transplant. Our results show that GO can safely be combined with intensive chemotherapy with midostaurin in ND, FLT3-mutated AML. This trial was registered at www.clinicaltrials.gov as #NCT03900949.}, }
@article {pmid41489165, year = {2026}, author = {Yang, Z and Rizopoulos, D and Newcomb, LF and Erler, NS}, title = {Time-Dependent Predictive Accuracy Metrics in the Context of Interval Censoring and Competing Risks.}, journal = {Biometrical journal. Biometrische Zeitschrift}, volume = {68}, number = {1}, pages = {e70108}, pmid = {41489165}, issn = {1521-4036}, support = {CA253910/NH/NIH HHS/United States ; }, mesh = {Humans ; *Biometry/methods ; Time Factors ; Male ; Prostatic Neoplasms ; Models, Statistical ; ROC Curve ; }, abstract = {Evaluating the performance of a prediction model is a common task in medical statistics. Standard accuracy metrics require the observation of the true outcomes. This is typically not possible in the setting with time-to-event outcomes due to censoring. Interval censoring, the presence of time-varying covariates, and competing risks present additional challenges in obtaining those accuracy metrics. In this study, we propose two methods to deal with interval censoring in a time-varying competing risk setting: a model-based approach and the inverse probability of censoring weighting (IPCW) approach, focusing on three key time-dependent metrics: area under the receiver-operating characteristic curve, Brier score, and expected predictive cross-entropy. The evaluation is conducted over a medically relevant time interval of interest, [ t , Δ t) $[t, \Delta t)$ . The model-based approach includes all subjects in the risk set, using their predicted risks to contribute to the accuracy metrics. In contrast, the IPCW approach only considers the subset of subjects who are known to be event-free or experience the event within the interval of interest. We performed a simulation study to compare the performance of the two approaches with regard to the three metrics. Furthermore, we demonstrated the three metrics using the two approaches on an example prostate cancer surveillance cohort. Risk predictions were generated from a joint model handling the interval-censored cancer progression and the competing event, early treatment, and repeatedly measured biomarkers.}, }
@article {pmid41491041, year = {2026}, author = {Ahmad, K and Wooten, M and Takushi, BN and Vidaurre, V and Chen, X and Henikoff, S}, title = {Cell-cycle-dependent repression of histone gene transcription by histone H4.}, journal = {Nature structural &amp; molecular biology}, volume = {33}, number = {1}, pages = {145-156}, pmid = {41491041}, issn = {1545-9985}, support = {K99 GM152821/GM/NIGMS NIH HHS/United States ; R35 GM127075/GM/NIGMS NIH HHS/United States ; }, mesh = {*Histones/genetics/metabolism ; Animals ; *Drosophila melanogaster/genetics/cytology/metabolism ; Humans ; *Transcription, Genetic ; DNA Replication ; *Cell Cycle ; *Drosophila Proteins/genetics/metabolism ; Promoter Regions, Genetic ; Chromatin/metabolism ; }, abstract = {In all eukaryotes, DNA replication is coupled to histone synthesis to coordinate chromatin packaging of the genome. Canonical histone genes coalesce in the nucleus into the histone locus body (HLB), where gene transcription and 3' mRNA processing occurs. Both histone gene transcription and mRNA stability are reduced when DNA replication is inhibited, implying that the HLB senses the rate of DNA synthesis. In Drosophila melanogaster, the S-phase-induced histone genes are tandemly repeated in an ~100 copy array, whereas, in humans, these histone genes are scattered. In both organisms, these genes coalesce into HLBs. Here, we use a transgenic histone gene reporter and RNA interference in Drosophila to identify canonical H4 histone as a unique repressor of histone synthesis during the G2 phase in germline cells. Using cytology and CUT&amp;Tag chromatin profiling, we find that histone H4 uniquely occupies histone gene promoters in both Drosophila and human cells. Our results suggest that repression of histone genes by soluble histone H4 is a conserved mechanism that coordinates DNA replication with histone synthesis in proliferating cells.}, }
@article {pmid41493843, year = {2026}, author = {He, AR and Bouattour, M and Gupta, VG and Evesque, L and Zhen, DB and Park, JO and Sookprasert, A and Salvatierra, A and Vaccaro, G and Oh, SC and Ostoich, SA and Satoh, T and Kuzko, A and Żotkiewicz, M and Rokutanda, N and Oh, DY}, title = {Predictors of overall survival in advanced biliary tract cancer in the phase 3 TOPAZ-1 study.}, journal = {Hepatology communications}, volume = {10}, number = {1}, pages = {}, pmid = {41493843}, issn = {2471-254X}, }
@article {pmid41493894, year = {2026}, author = {Ramírez, P and Lankowski, AJ and Gallardo-Cartagena, JA and Gonzales, P and Valencia, J and Lama, JR and León, M and Salvatierra, J and Sanchez, H and Cabello, R and Konda, KA and Sanchez, JL and , }, title = {Implementation of Daily Oral PrEP at HIV/AIDS Service Organizations in Lima, Peru: Early Findings From the PrEP PERU Demonstration Study.}, journal = {Journal of the International Association of Providers of AIDS Care}, volume = {25}, number = {}, pages = {23259582251411793}, pmid = {41493894}, issn = {2325-9582}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Peru/epidemiology ; *Pre-Exposure Prophylaxis/methods ; Male ; Adult ; *HIV Infections/prevention &amp; control/epidemiology ; Prospective Studies ; Homosexuality, Male/statistics &amp; numerical data ; Administration, Oral ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; *Tenofovir/administration &amp; dosage/therapeutic use ; Medication Adherence ; COVID-19/epidemiology ; }, abstract = {BackgroundDespite global declines in HIV incidence, new infections continue to rise in Latin America. Oral tenofovir-based HIV pre-exposure prophylaxis (PrEP) is effective and can reduce incidence where implemented. PrEP PERU is a prospective cohort study evaluating daily oral PrEP delivery at HIV/AIDS service organizations (ASOs) in Peru.MethodsWe assessed 12-month PrEP retention and adherence among men who have sex with men (MSM) enrolled at 4 ASOs in Lima before the COVID-19 pandemic. The analysis included participants with ≥12 months of follow-up before the March 2020 lockdown. Follow-up visits occurred at weeks 4, 12, and quarterly thereafter. We used robust Poisson regression to evaluate associations between baseline characteristics and 2 outcomes: retention (attending ≥3 follow-up visits within 12 months) and optimal adherence (proportion of days covered ≥80%).ResultsAmong 264 MSM who initiated PrEP, median age was 31 years (IQR: 27-37). Retention at 12 months was 71%, and 55% achieved optimal adherence. Retention was associated with age ≥30 and bisexual identity in adjusted models. Optimal adherence was associated with being employed at baseline.ConclusionsPrEP delivery through ASOs in Lima is feasible and supports sustained engagement among MSM. Targeted strategies are needed to improve outcomes among younger individuals.}, }
@article {pmid41494138, year = {2026}, author = {Hicks, LK and Messersmith, HJ and Al Hadidi, S and Banerjee, R and Derman, BA and Kumar, S and Wildes, TM and Bal, S and Bhella, S and Chmielewski, C and Costello, C and Dabney, R and Hartley-Brown, M and Langerak, A and Lipe, B and Martin, T and McCurdy, A and Mian, H and Riva, E and Seth, R and Subramanian, L and Mikhael, J}, title = {Treatment of Multiple Myeloma: ASCO-Ontario Health (Cancer Care Ontario) Living Guideline.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {10}, pages = {914-941}, doi = {10.1200/JCO-25-02587}, pmid = {41494138}, issn = {1527-7755}, mesh = {Humans ; *Multiple Myeloma/therapy/drug therapy ; Ontario ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {PURPOSE: To provide updated guidance regarding the therapy for multiple myeloma.<br><br>METHODS: ASCO and Ontario Health (Cancer Care Ontario) convened a joint Expert Panel and conducted an updated systematic review of the literature.<br><br>RESULTS: The updated review identified a total of 161 relevant randomized trials.<br><br>UPDATED RECOMMENDATIONS: Daratumumab therapy may be offered to patients with high-risk smoldering myeloma. Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as initial therapy for transplant eligible patients. They should also be offered at least lenalidomide maintenance, with or without daratumumab, carfilzomib, and/or dexamethasone. Quadruplet therapy with daratumumab or isatuximab, combined with bortezomib, lenalidomide, and dexamethasone, should be offered as therapy for suitable transplant-ineligible patients. Patients with relapsed or refractory multiple myeloma should be offered triplet therapy or T-cell redirecting therapies according to a set of recommended principles.Additional information is available at www.asco.org/hematologic-malignancies-guidelines.}, }
@article {pmid41494888, year = {2026}, author = {Kwendakwema, CN and Lan, KF and Kim, HN and Gopal, AK and Menon, MP}, title = {HIV, HBV, and HCV Testing in Newly Diagnosed Diffuse Large B-Cell Lymphoma: Experience From a Comprehensive Cancer Center.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {26}, number = {4}, pages = {e536-e541}, doi = {10.1016/j.clml.2025.12.010}, pmid = {41494888}, issn = {2152-2669}, mesh = {Humans ; Female ; Male ; *Lymphoma, Large B-Cell, Diffuse/diagnosis/drug therapy/complications ; Middle Aged ; *Hepatitis C/diagnosis/epidemiology ; *Hepatitis B/diagnosis/epidemiology ; *HIV Infections/diagnosis/epidemiology/complications ; Aged ; Hepacivirus/isolation &amp; purification ; Adult ; Hepatitis B virus/isolation &amp; purification ; Retrospective Studies ; Risk Factors ; }, abstract = {PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype non-Hodgkin lymphoma. HIV, hepatitis B (HBV), and hepatitis C (HCV) infections are DLBCL risk factors. DLBCL remains a leading cause of cancer-related morbidity and mortality in those with HIV. DLBCL treatments can also increase the HBV reactivation risk and acute liver injury in HCV. We assessed HBV, HCV, and HIV screening rates in DLBCL patients receiving systemic therapy in a comprehensive cancer system.<br><br>MATERIALS AND METHODS: We analyzed newly diagnosed DLBCL patients receiving anti-CD20 therapies between January 2018 and December 2023. Patients were considered screened if they had viral testing or a prior diagnosis within 12 months before to 3 months after starting treatment. We used chi-squared and Fisher's exact tests to examine associations between patients who were and were not screened HBV, HCV, and HIV. We used univariate and multivariate logistic regression to identify the factors associated with screening.<br><br>RESULTS: A total of 535 patients with DLBCL were treated (median age 64, 42% female, 82% white). Among these patients, 410 (77%) had HBV testing or a known infection, 275 (51.4%) had HIV testing or a known infection, and 307 (53%) had HCV testing or a known infection. Younger people were more likely to be tested for HIV and HCV. There was no association between age and HBV testing.<br><br>CONCLUSION: Pre-treatment HIV, HBV, and HCV screening rates in newly diagnosed DLBCL patients remains suboptimal. Interventions to increase viral testing in this population could help reduce treatment-related morbidity and mortality.}, }
@article {pmid41495079, year = {2026}, author = {Yao, TH and Treekitkarnmongkol, W and Putluri, N and Sankaran, D and Nguyen, T and Balasenthil, S and Hurd, MW and Chen, M and Brand, RE and Lampe, PD and Kamal, AHM and Putluri, V and Hu, TY and Maitra, A and Koay, EJ and Killary, AM and Sen, S and Kundu, S}, title = {Machine learning-based multimodal biomarkers enable accurate diagnosis and early detection of pancreatic ductal adenocarcinoma.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {658}, pmid = {41495079}, issn = {2045-2322}, abstract = {While there has been some progress on discovering clinically validated biomarkers for early detection in pancreatic ductal adenocarcinoma (PDAC), several challenges remain. Most approaches rely on single-modality biomarkers with limited sensitivity and/or specificity. Using data from a multicenter study with an age-matched cohort (n = 203 with healthy controls n = 46, pancreatitis controls n = 36, and diagnosed cases n = 121), we developed a machine learning approach integrating 2,096 microRNAs, 125 metabolites, and CA19-9. Our method performs unsupervised selection of an optimal subset of biomarkers with maximal discriminatory power for diagnosis and early detection. In training data, the selected biomarker panel achieved [Formula: see text] area under the curve (AUC) and [Formula: see text] sensitivity when controlling specificity at [Formula: see text]. The classification results under the selected multimodal panel generalize well for validation samples. The panel outperforms recently proposed microRNA-based approaches and identifies key biomarkers (such as aminobutyric acid and homovanillic acid) with high classification importance. Decision tree–based cut-offs are derived to enhance clinical interpretability, revealing the association between the low aminobutyric acid level and non-cancer status. These results highlight the superior discriminative ability and interpretability of the proposed multimodal biomarker panel, offering a promising tool for PDAC diagnosis and early detection.}, }
@article {pmid41495267, year = {2026}, author = {Werwath, KE and Lawn, RB and Salem, MT and Li, T and Mitchell, BL and Shen, H and Gordon, SD and Kung, B and Stafford, C and Vemuri, M and Ratanatharathorn, A and Meijsen, J and Shadyab, AH and Kooperberg, C and Koenen, KC and Crandall, CJ and Martin, NG and Duncan, LE}, title = {Trans-ancestry GWAS of hot flashes reveals potent treatment target and overlap with psychiatric disorders.}, journal = {Communications medicine}, volume = {6}, number = {1}, pages = {51}, pmid = {41495267}, issn = {2730-664X}, support = {R01 MH123486/MH/NIMH NIH HHS/United States ; R01 CA067262/CA/NCI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; R21 MH125358/MH/NIMH NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; MH125358//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01 CA049449/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Most women experience hot flashes (hot flushes) during the menopause transition. Menopausal hot flashes typically persist for years, and for a sizeable minority of women, are substantially impairing. Genetic investigations can improve understanding of hot flash etiology.<br><br>METHODS: We conducted a trans-ancestry genome-wide association study (GWAS) of hot flashes (N&#x2009;=&#x2009;149,560) among post-menopausal women age 35-88. The outcome variable was self-reported hot flashes in four samples (total n&#x2009;=&#x2009;42,489) and menopausal hormone therapy as a proxy in one sample (n&#x2009;=&#x2009;107,071). We estimated the heritability of hot flashes and genetic correlations with psychiatric phenotypes using linkage disequilibrium score regression.<br><br>RESULTS: In our trans-ancestry meta-analysis, the top locus lies on chromosome 4 in the neurokinin 3 receptor gene (TACR3, p&#x2009;=&#x2009;7.2&#xd7;10[-41]). We also identify another locus on chromosome 4 with top SNP rs13107507 (p&#x2009;=&#x2009;3.5&#xd7;10[-8]). Gene results implicate TACR3, GRID1, NUDT4, and PHF21B. SNP heritability is estimated to be 8% (h[2]liab&#x2009;=&#x2009;.08, h[2]SNP&#x2009;=&#x2009;.04, se&#x2009;=&#x2009;.02). Genetic correlations are statistically significant between hot flashes and PTSD (rg&#x2009;=&#x2009;0.25, p&#x2009;=&#x2009;0.01), schizophrenia (rg&#x2009;=&#x2009;0.17, p&#x2009;=&#x2009;0.02), depression (rg&#x2009;=&#x2009;0.21, p&#x2009;=&#x2009;0.01), and ADHD (rg&#x2009;=&#x2009;.22, p&#x2009;=&#x2009;0.03).<br><br>CONCLUSIONS: These genomic findings are consistent with independent, robust basic science research which led to a recently developed treatment for hot flashes, namely, a neurokinin 3 receptor antagonist. This non-hormonal class of hot flash drugs blocks the receptor coded for by the top locus reported here (TACR3, the neurokinin 3 receptor gene). Hot flash GWAS results provide an example of how GWAS findings can point to potent treatment targets for complex brain phenotypes.}, }
@article {pmid41497576, year = {2025}, author = {Jones, JD and Valenzuela, Y and Pacheco, M and Nelson, L}, title = {Research Participation Among American Indian and Alaskan Native Individuals Living With Parkinson's Disease.}, journal = {Parkinson's disease}, volume = {2025}, number = {}, pages = {3207928}, pmid = {41497576}, issn = {2090-8083}, support = {P30 AG066509/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: There is a notable gap in racial and ethnic representation in Parkinson's disease (PD) research, particularly among American Indian and Alaska Native (AIAN) populations, despite a higher prevalence of PD in these groups. This study investigated research participation among AIAN individuals in terms of perceived access to research opportunities, willingness to participate, and potential concerns about participation.<br><br>METHODS: Data were obtained from the online Fox Insight (FI) study. A total sample of 4412 individuals who self-reported their race as White (n&#x2009;=&#x2009;4363) or AIAN (n&#x2009;=&#x2009;49) were selected. The Attitudes and Beliefs Regarding Research and Genetic Testing for PD survey was administered to assess participants' attitudes and knowledge about the research process, opportunities, and preferences.<br><br>RESULTS: A significantly smaller proportion of AIAN individuals (34.7%) reported concurrent or past participation in PD research compared with White non-AIAN participants (52.9%). Despite this lower participation rate and limited knowledge of research opportunities, a large majority of AIAN individuals (89.8%) expressed a willingness to participate in research. Additionally, both AIAN and White non-AIAN participants reported similar rates of concerns about research participation. Among AIAN individuals, the most common barriers were distance from research site, transportation, and time commitments.<br><br>CONCLUSION: These findings highlight that low research participation among AIAN individuals may be more associated with low engagement from the research community rather than unwillingness or relatively greater research concerns. Building stronger partnerships with tribal communities and involving community leaders to build trust may improve research representation among AIAN populations.}, }
@article {pmid41497599, year = {2025}, author = {Trofimov, A and Montague, Z and Russell, ML and Ignacio, RB and Stevens-Ayers, T and Zamora, D and Mielcarek, M and Boeckh, MJ and Matsen, F and Nourmohammad, A}, title = {Genetic and environmental imprints on T cell receptor repertoires as predictors of graft-versus-host disease.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41497599}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Hematopoietic cell transplantation (HCT) as potentially curative treatment for patients with hematologic malignancies relies on T cells to mediate the potentially curative graft-versus-tumor (GVT) effect, which may be associated with graft-versus-host disease (GVHD), a potentially life-threatening complication. T cells recognize peptides presented by Human Leukocyte Antigen (HLA) molecules. It is commonly believed that matching HLA alleles between donors and recipients ensures similarity in their T cell receptor (TCR) repertoires, thereby reducing the risk of GVHD and graft rejection. However, TCR repertoires are shaped by multiple factors beyond HLA genetics, including sex, age, and immune history. The extent to which genetic variation and past infections influence TCR repertoire composition and GVHD risk remains unclear. Here, we show that while HLA haplotypes contribute to broad TCR repertoire differences, recent viral infections significantly impact TCR composition and influence GVHD risk. Analyzing 401 patients who were uniformly transplanted from healthy HLA-identical sibling HCT donors, we introduced HLA-TCR coherence, a metric that quantifies the extent to which an individual's TCR repertoire reflects their HLA haplotype. We find that higher TCR-HLA coherence is associated with greater HLA heterozygosity and an increased incidence of severe acute GVHD (grade 3-4) in transplant recipients. Furthermore, in silico identification of virus-associated TCRs (vaTCRs) using TCR sequencing and viral serology reveal specific vaTCRs predictive of either increased or decreased GVHD risk. These findings suggest that beyond HLA allele matching, donor-specific immune history and repertoire characteristics are critical determinants of GVHD risk. Thus, a more systematic integration of donor immune history may offer a complementary avenue for refining donor selection and potentially improving transplant outcomes.}, }
@article {pmid41498421, year = {2026}, author = {Ulschmid, CM and Li, X and Wang, T and Logan, BR and Pidala, J and MacMillan, ML and Kitko, CL and Lee, SJ and Spellman, SR and Saber, W}, title = {Validated clinical risk score for acute graft-versus-host disease in adult allogeneic hematopoietic cell transplantation.}, journal = {Blood advances}, volume = {10}, number = {4}, pages = {1348-1360}, pmid = {41498421}, issn = {2473-9537}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology/diagnosis ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Female ; Male ; Adult ; Middle Aged ; Transplantation, Homologous/adverse effects ; Risk Factors ; Acute Disease ; Risk Assessment ; Transplantation Conditioning/adverse effects ; Aged ; }, abstract = {Acute graft-versus-host disease (aGVHD) contributes to significant morbidity after allogeneic hematopoietic cell transplantation (allo-HCT). We aimed to develop and validate a clinical score to identify patients with significantly different risk for developing aGVHD. Analysis included adults who underwent allo-HCT during 2008-2019. Eligibility criteria were widely inclusive of transplant indications, donor types, graft types, conditioning regimens, and GVHD prophylaxis regimens. The final cohort of 21 796 patients was randomly split into training and validation cohorts, with 15 258 (70%) and 6538 (30%) patients, respectively. The primary outcome was grade 2 to 4 aGVHD, and the secondary outcome was grade 3 to 4 aGVHD, by day 100 posttransplant. Risk scores were developed using the training cohort, tested using the validation cohort, and stratified into 4 percentile groups. The odds of grade 2 to 4 aGVHD by day 100 posttransplant were 1.50 (95% confidence interval [CI], 1.29-1.75; P< .0001) for the 25th to 50th percentile group, 2.0 (95% CI, 1.78-2.40; P< .0001) for the 50th to 75th percentile group, and 3.1 (95% CI, 2.72-3.65; P< .0001) for the >75th percentile group compared with the ≤25th percentile group in the validation cohort. The odds of grade 3 to 4 aGVHD by day 100 posttransplant were 1.4 (95% CI, 1.11-1.74; P = .0043) in the 25th to 50th percentile group, 2.0 (95% CI, 1.61-2.49; P< .0001) in the 50th to 75th percentile group, and 3.2 (95% CI, 2.64-3.98; P< .0001) in the >75th percentile group compared with the ≤25th percentile group in the validation cohort. Here, to our knowledge, we have developed the first validated, widely inclusive clinical risk score for the development of aGVHD after allo-HCT.}, }
@article {pmid41499715, year = {2026}, author = {Wan, YH and Pernikoff, S and Aldridge, NT and Lang, K and Dudley, HM and Scharffenberger, SC and Kher, G and Phipps, W and Pancera, M and Boonyaratanakornkit, J and McGuire, AT}, title = {Monoclonal neutralizing antibodies elicited by infection with Kaposi sarcoma-associated herpesvirus reveal critical sites of vulnerability on gH/gL.}, journal = {PLoS pathogens}, volume = {22}, number = {1}, pages = {e1013772}, pmid = {41499715}, issn = {1553-7374}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA239593/CA/NCI NIH HHS/United States ; U01 CA295050/CA/NCI NIH HHS/United States ; }, mesh = {*Herpesvirus 8, Human/immunology ; Humans ; *Antibodies, Neutralizing/immunology ; *Antibodies, Monoclonal/immunology ; *Antibodies, Viral/immunology ; *Viral Envelope Proteins/immunology ; *Sarcoma, Kaposi/immunology/virology ; Epitopes/immunology ; *Herpesviridae Infections/immunology ; }, abstract = {Kaposi sarcoma-associated herpesvirus (KSHV) is an oncogenic virus that causes Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. A vaccine that prevents KSHV infection or serves in the treatment of KSHV-related diseases represents a critical unmet need, however, the types of immune responses a vaccine should elicit have not been well defined. The gH/gL glycoprotein complex is an important target of KSHV-neutralizing antibodies, but the epitope specificities targeted by these antibodies remain unknown. Here, we isolated 12 gH/gL-specific monoclonal antibodies (mAbs) from KSHV-infected donors and performed structure/function analyses. These mAbs bind recombinant gH/gL with nanomolar affinities and epitope binning analyses revealed that the mAbs bind to 5 epitope clusters on gH/gL. Seven mAbs were able to neutralize KSHV infection of epithelial cell lines. Two potent neutralizing mAbs mapped to the EphA2 binding site as determined by inhibition of the receptor-ligand interaction and negative stain electron microscopy (nsEM) of the mAb/gH/gL complex. The epitopes of other neutralizing mAbs targeting novel sites of vulnerability were determined by a combination of cryogenic electron microscopy and nsEM. Together, these mAbs help to define the relevant epitope targets for KSHV vaccine design, have utility in understanding the role of antibodies in preventing KSHV infection, enable the development of immunotherapy approaches, and provide valuable tools to understand the molecular details of the KSHV entry process.}, }
@article {pmid41502557, year = {2026}, author = {Franzese, C and Tanadini-Lang, S and Verellen, D and Wiersema, L and Hörner-Rieber, J and Romero, AM and Pasquier, D and Bruynzeel, A and Boda-Heggemann, J and Depuydt, T and Sibolt, P and Douir, N and Kuncman, &#x141; and Beijst, C and Stephens, H and de la Pinta, C and Cuccia, F and Milder, M and Nicosia, L and Onishi, H and Louie, AV and Sahgal, A and Lo, SS and Slotman, BJ and Guckenberger, M and Scorsetti, M}, title = {Clinical practice, barriers to implementation, and priorities for equitable access of Stereotactic Body Radiation Therapy: An analysis of the global status by the ESTRO SBRT Focus Group.}, journal = {Clinical and translational radiation oncology}, volume = {57}, number = {}, pages = {101096}, pmid = {41502557}, issn = {2405-6308}, abstract = {BACKGROUND: Stereotactic Body Radiation Therapy (SBRT) has become an established treatment for several primary and metastatic malignancies; however, considerable heterogeneity remains in its definition, clinical indications, and technical delivery.<br><br>METHODS: In May 2025, the SBRT Focus Group of the European Society for Radiotherapy and Oncology (ESTRO), in collaboration with International Stereotactic Radiosurgery Society (ISRS), the Radiosurgery Society (RSS), and the Japanese Society for Radiation Oncology (JASTRO), conducted a global survey. A 44-item questionnaire explored SBRT indications, technical aspects, dose/fractionation, and barriers to implementation. Descriptive statistics summarized the responses.<br><br>RESULTS: Overall, 289 professionals from 59 countries participated. Routine use of SBRT was reported by 96.6&#xa0;% of respondents, with lung, bone, liver and prostate as the most frequent indications. Pancreatic tumor (48.4&#xa0;%), renal cell carcinoma (46.4&#xa0;%), and ventricular tachycardia (12.4&#xa0;%) represented emerging indications. C-arm linacs (89.2&#xa0;%) and in-room Cone beam CT (CBCT) (92.0&#xa0;%) were the dominant technologies. Motion management relied mainly on 4D-CT internal target volume (ITV) (88.9&#xa0;%) and deep inspiration breath-hold (DIBH) (57.8&#xa0;%). Fractionation was consistent for lung and prostate but heterogeneous for liver, and pancreas. Only 3.5&#xa0;% reported routine use of online adaptive SBRT, while 61.5&#xa0;% reported artificial intelligence (AI) use, mainly for organs-at-risk delineation. Key barriers included limited clinical trial funding (35.2&#xa0;%), high equipment costs (34.2&#xa0;%), insufficient reimbursement (27.7&#xa0;%), and workforce shortages (33.9&#xa0;%).<br><br>CONCLUSIONS: This ESTRO international survey provides the first global overview of SBRT practices. It demonstrates broad adoption but also substantial variability, highlighting the need for consensus guidelines, greater trial access, and expanded education to harmonize SBRT delivery and ensure equitable care worldwide.}, }
@article {pmid41503123, year = {2026}, author = {Özpolat, T and Byrne, DA and Bailey, SL and Chauhan, A and Reisz, JA and Johnson, HJ and Doan, J and Ronquillo, M and Adili, R and Fu, X and D'Alessandro, A and Stolla, M}, title = {Transfusion-induced functional and metabolic shifts in stored platelets: limitations of in vitro assessment.}, journal = {Blood vessels, thrombosis &amp; hemostasis}, volume = {3}, number = {1}, pages = {100120}, pmid = {41503123}, issn = {2950-3272}, abstract = {The impact of the stored platelet extracellular environment on function and the ability of platelets to change their function upon transfer into in vivo environments remain poorly understood. Human platelets were stored ex vivo at 20°C to 24°C (room temperature-stored platelets [RTPs]) or 1°C to 6°C (cold-stored platelets [CSPs]) and tested for function in the concomitant storage plasma or fresh plasma. In mice, we tested platelet function after ex vivo storage in concomitant plasma and after transfusion to mice ex vivo and in vivo. We also investigated stored platelet-rich plasma before and after transfusion to mice for metabolomics by liquid chromatography-tandem mass spectrometry. In in vitro, human RTPs showed a greater ability than CSPs to improve αIIbβ3 integrin activation upon dilution with fresh frozen plasma. Mouse RTPs' in vitro integrin activation improved more than that for CSPs after transfusion. Surprisingly, in mice, CSPs facilitated significantly greater platelet accumulation than RTPs in vivo. In contrast, fibrin generation was significantly more robust in RTPs than in CSPs during the early stages of hemostasis. In mouse RTPs, more metabolites changed significantly upon transfusion than in mouse CSPs. Transfusion decreased carnitine species, fatty acid metabolites, and amino acids only in RTPs, whereas polyamines decreased only in CSPs. The recovery from storage-induced oxidative stress was more complete in RTPs than in CSPs. Our findings highlight the severe limitations of in vitro testing of stored platelets. Platelet-rich plasma undergoes profound changes in metabolomic composition following transfusion. We further demonstrate the ability of platelets to undergo marked changes upon transfusion in RTPs more so than CSPs.}, }
@article {pmid41503158, year = {2026}, author = {Elz, AE and Gratz, D and Long, A and Sowerby, D and Hadadianpour, A and Newell, EW}, title = {Evaluating the practical aspects and performance of commercial single-cell RNA sequencing technologies.}, journal = {NAR genomics and bioinformatics}, volume = {8}, number = {1}, pages = {lqaf215}, pmid = {41503158}, issn = {2631-9268}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {*Single-Cell Analysis/methods/economics ; Humans ; *Sequence Analysis, RNA/methods/economics ; Transcriptome ; Gene Expression Profiling/methods ; Leukocytes, Mononuclear/metabolism ; Receptors, Antigen, T-Cell/genetics ; }, abstract = {The rapid development of updated and new commercially available single-cell transcriptomics platforms provides users with a range of experimental options. Cost, sensitivity, throughput, flexibility, and ease of use all influence the selection of an optimal workflow. We performed a comprehensive comparison of single-cell transcriptomic approaches using multiple standardized PBMCs from different donors. We report on standard single-cell metrics, including cell recovery, sequencing efficiency, sensitivity, cell annotation, and differential gene expression for seven recently available kits that interrogate whole transcriptome mRNA, and two that incorporate TCR profiling. We also discuss workflow throughput, sample requirements, timing, cost, and labor as critical factors to consider. Apart from the platform-specific experimental constraints, our findings highlight how differences in cell recovery and sensitivity influence the ability to resolve niche cell subtypes such as CD4 + and CD8 + T-cells. Platforms with higher intra-sample variation had reduced sequencing efficiency, which cumulatively impacts reproducibility and overall experiment cost. By including TCR chain recovery for multiple donors, we provide the first comparison of T-cell specific performance in the only assays available for single cell TCR recovery. This work provides a basis by which users can balance performance and practical considerations when selecting a single-cell RNA sequencing platform.}, }
@article {pmid41504443, year = {2026}, author = {Kara, D and Pancera, M and Hassanzadeh-Ghassabeh, G and Schoonooghe, S and Masic, V and Hartley-Tassell, L and Mishra, BP and Ve, T and Haselhorst, T and von Itzstein, M and Hansman, GS}, title = {Structural insights into a broadly reactive nanobody that binds pathogenic and non-pathogenic lagoviruses.}, journal = {Journal of virology}, volume = {100}, number = {2}, pages = {e0199025}, pmid = {41504443}, issn = {1098-5514}, support = {24070//Australian Synchrotron/ ; //Griffith University/ ; }, }
@article {pmid41506266, year = {2026}, author = {Lu, G and Zhang, S and Feng, M and Kim, E and Cho, D and Kim, JH and Caris, H and Silberstein, L and Choi, GB and Huh, JR}, title = {In vivo detection of immune responses via cytokine activity labeling.}, journal = {Cell}, volume = {189}, number = {3}, pages = {939-955.e26}, pmid = {41506266}, issn = {1097-4172}, support = {R01 DK110559/DK/NIDDK NIH HHS/United States ; R01 MH119459/MH/NIMH NIH HHS/United States ; RF1 AG080738/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Mice ; Interferon-gamma/metabolism/immunology ; Interleukin-17/metabolism/immunology/genetics ; CD8-Positive T-Lymphocytes/immunology/metabolism ; *Cytokines/metabolism/immunology ; Mice, Inbred C57BL ; Humans ; Intestinal Mucosa/immunology/metabolism ; }, abstract = {While much is known about the identity and regulation of cytokine-producing cells, the cell types that respond to cytokines remain largely uncharacterized. To address this knowledge gap, we developed "cytokine cellular locating platforms" (CyCLoPs), a reporter system that translates cytokine receptor engagement into a genetically traceable signal. In vitro, CyCLoPs demonstrated high specificity, robust signal-to-background ratios, and broad applicability for probing diverse cytokine receptor interactions. In vivo, interleukin (IL)-17A-CyCLoPs reporter mice enabled the identification of IL-17A-responsive intestinal epithelial cells predominantly localized in the ileal villi following commensal bacterial colonization. Interferon-gamma (IFN-γ)-CyCLoPs reporter mice allowed for the detection of IFN-γ-exposed CD8[+] T cells within tumors, which expressed CD36, CD38, and leptin receptor and displayed gene signatures associated with reduced effector function. Collectively, CyCLoPs offers a platform for the direct visualization and characterization of cytokine-induced cellular responses and provides a tool for investigating how cytokines orchestrate distinct immunological outcomes in health and disease.}, }
@article {pmid41506486, year = {2026}, author = {Gem, H and Ebadi, M and Sebastian, G and Abasaeed, R and Lloid, M and Dean, DR and Rashidi, A}, title = {Longitudinal Multicompartment Oral Mucositis Assessment in Adults Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation: A Contemporary Prospective Cohort Analysis.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.01.004}, pmid = {41506486}, issn = {2666-6367}, abstract = {Oral mucositis (OM) is a frequent, debilitating complication of myeloablative allogeneic hematopoietic cell transplantation (HCT). OM grading tools used in HCT practice rely on subjective or summary scoring, potentially missing clinically important details. To test the performance of the oral mucositis assessment scale (OMAS), a validated comprehensive OM assessment tool that collects granular objective findings from 7 intraoral sites, in a contemporary cohort. We longitudinally evaluated site-specific OM characteristics using OMAS in 47 myeloablative allogeneic HCT recipients. A total of 249 assessments were completed at baseline (preconditioning) and on d +7, +14, +21, +28, and +84 post-transplant. Total and site-specific scores strongly correlated with patient-controlled analgesia use. D +7 involvement of the floor of mouth (P = .013), soft palate (P = .008), and ventrolateral tongue (P = .003) was associated with a greater total mucositis score. OM was overall more severe in men, driven by higher scores on d +7 (P = .013) and in the soft palate (P = .013). Graft-versus-host disease prophylaxis regimens based on post-transplantation cyclophosphamide or methotrexate led to more severe d +14 OM than those based on mycophenolate mofetil (P = .028). In this prospective analysis of myeloablative allogeneic HCTs in a contemporary cohort, OMAS provided clinically relevant, granular, site-specific data not captured by popular summary-based scoring systems. We expect our findings to facilitate the development of effective strategies to prevent and treat OM.}, }
@article {pmid41509072, year = {2025}, author = {White, AN and Ingersoll, R and Eswaraka, J and Uthamanthil, R and Roble, G and Chitty, AI and Nikolaidis, N and Vinard, A and Kraft, M and Winter, MK}, title = {Voices from the Bench: Focus Group Insights on Shared Research Resource Sustainability Amid Federal Policy Shifts.}, journal = {Journal of biomolecular techniques : JBT}, volume = {36}, number = {4}, pages = {25-34}, pmid = {41509072}, issn = {1943-4731}, mesh = {Humans ; Focus Groups ; United States ; *Biomedical Research/economics ; }, abstract = {Shared Research Resources (SRRs) are essential for sustaining research excellence, particularly in financially constrained environments. This study examines how federal policy uncertainties exacerbate existing challenges in SRR operations and management. Findings from focus groups-including over 220 leaders in academic administration and SRRs-highlight that staffing, funding, and cross-campus collaboration disproportionately impact resource-limited institutions, widening disparities in research capabilities. Evaluating SRRs' role in supporting research during financial instability is critical. Active administrative engagement in supporting SRRs helps institutions to secure funding and align priorities with institutional goals. SRRs improve operational efficiency through shared infrastructure models and standardized procurement policies, reducing duplication and optimizing resource utilization. Workforce adaptability is key to sustainability, with cross-training and strategic recruitment fostering resilience amid financial uncertainty. This study underscores the interconnected nature of funding diversification, leadership alignment, operational efficiency, workforce adaptability, and policy reform in sustaining SRR systems. This study draws on collective insights from SRR staff across all organizational levels, from technical personnel and directors to administrators and institutional leaders, to capture a comprehensive, ground-level perspective on the conditions necessary for long-term viability. Institutions that recognize SRRs as strategic partners in addressing systemic research barriers will be better positioned to foster a more equitable, efficient, and sustainable research ecosystem.}, }
@article {pmid41509424, year = {2025}, author = {Richardson, RB and Kikawa, C and Garg, A and Bednarski, E and Salim, M and Bacsik, D and Veit, EC and Hermacinski, A and Hamilton, R and García-Sastre, A and Bloom, JD and Lim, JK and Evans, MJ}, title = {Coevolutionary constraints of Zika virus nonstructural protein 5 replication and interferon antagonism activities.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509424}, issn = {2692-8205}, support = {F31 AI191695/AI/NIAID NIH HHS/United States ; R01 AI166594/AI/NIAID NIH HHS/United States ; R01 AI175303/AI/NIAID NIH HHS/United States ; }, abstract = {The flavivirus nonstructural protein 5 performs multiple functions during infection, including RNA replication and type I interferon signaling antagonism. Although flavivirus NS5 proteins inhibit IFN signaling through distinct mechanisms, which suggests evolutionary flexibility, the evolutionary constraints for these activities to coexist within a single protein remain to be determined. Here, we mapped the Zika virus NS5 STAT2 antagonism determinants and compared them with replication constraints defined by deep mutational scanning. Antagonism and replication determinant extensively overlapped, and no single amino acid substitution eliminated antagonism without impairing replication. Resolving these fitness landscapes in parallel identified specific combinations of partially functional substitutions that retained replication capacity while markedly reducing antagonism. These viruses were profoundly attenuated in human STAT2 knock-in mice. Our results uncover a fundamental evolutionary constraint linking replication and immune evasion activities in NS5, highlight that STAT2 antagonism is essential for ZIKV pathogenesis and provide new avenues for attenuated ZIKV vaccines.}, }
@article {pmid41509443, year = {2025}, author = {Yanagi, KS and Chen, BJ and Kunjo, SO and Topalidou, I and Lehrbach, N}, title = {Lysine deficiency within a conserved lysine desert is critical for EEL-1/HUWE1 to support ubiquitin proteasome system function.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509443}, issn = {2692-8205}, support = {P40 OD010440/OD/NIH HHS/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; T32 AG066574/AG/NIA NIH HHS/United States ; }, abstract = {The ubiquitin proteasome system (UPS) is the primary mechanism for targeted protein degradation in eukaryotic cells. Dysfunction of this system is a driver of human disease and a hallmark of aging and late-onset neurodegenerative disorders. Understanding the mechanisms that ensure robust protein turnover may provide new avenues for treatment in these contexts. E3 ubiquitin ligases play critical roles in supplying ubiquitinated substrates to the proteasome, with HUWE1 being an enormous, versatile, and highly conserved member of this family. Here, we show that the C. elegans HUWE1 ortholog, EEL-1, contributes to robust protein turnover during challenges to the proteolytic capacity of the proteasome. We demonstrate that the ability of EEL-1/HUWE1 to safeguard protein turnover requires ubiquitin-binding domains within the substrate-binding arena and the HECT-type ubiquitin ligase activity, supporting a model in which EEL-1 ensures degradation by increasing ubiquitination of pre-ubiquitinated substrates. EEL-1 contains extensive lysine-deficient regions, found at conserved locations in its substrate-binding arena. Through unbiased mutagenesis screening and precise engineering of the EEL-1 protein, we uncover that introducing lysine residues into these regions is detrimental to UPS function. Together, our findings indicate a central and evolutionarily ancient role for EEL-1/HUWE1 in maintaining optimal UPS function and support targeting this E3 for therapeutic manipulation.}, }
@article {pmid41509475, year = {2026}, author = {Liu, Z and Niu, Y and Le, T and Chen, DG and Su, Y and Zheng, Y}, title = {Single-cell Tree-based Model for Genomic-Disease Association.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509475}, issn = {2692-8205}, support = {K99 CA293142/CA/NCI NIH HHS/United States ; K99 HG012797/HG/NHGRI NIH HHS/United States ; R00 HG012797/HG/NHGRI NIH HHS/United States ; }, abstract = {The rapid maturation of single-cell multi-omics technologies has enabled unprecedented resolution for mapping disease states and identifying disease-associated biomarkers. In practice, biomarkers are often discovered through differential detection that treat genomic features as independent contributors to phenotypes, while the combinatorial interactions that drive clinical outcomes remain a practical challenge. We present scanCT (single-cell analysis of Clinical Tree), a tree-based framework that identifies groups of genomic features associated with distinct disease phenotypes in a highly interpretable manner. scanCT uses an unbiased, model-based variable-selection procedure for data-driven split selection, which is important for handling the diverse distributional properties of single-cell data across modalities. The tree architecture captures feature interaction effects, and the association modeling enables adjustment for confounding factors. We apply scanCT to longitudinal single-cell multi-omics COVID-19 datasets spanning diverse clinical outcomes and multiple time points per patient. scanCT identifies phenotype-specific gene and protein markers while accounting for age and sex, and it reveals interpretable synergistic marker combinations that help explain differences in patient clinical phenotypes.}, }
@article {pmid41509490, year = {2025}, author = {Liu, D and Song, B and Li, Z and Zhang, S and Fabiha, T and Zhao, J and Inoki, A and Piccand, J and Soh, CL and Dixon, G and Zhong, A and Hu, N and Luo, R and Ozlusen, B and Menon, V and Zhou, T and Qiu, X and Gradwohl, G and Yang, D and Dey, K and Sun, W and Li, W and Huangfu, D}, title = {A stem cell knockout village reveals lineage rewiring and a non-canonical islet cell fate in monogenic diabetes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41509490}, issn = {2692-8205}, support = {UM1 HG012654/HG/NHGRI NIH HHS/United States ; T32 GM152349/GM/NIGMS NIH HHS/United States ; P30 CA134274/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 HL168174/HL/NHLBI NIH HHS/United States ; R01 HD111256/HD/NICHD NIH HHS/United States ; R01 DK096239/DK/NIDDK NIH HHS/United States ; }, abstract = {Genetics studies have identified a core set of regulators essential for pancreatic β cell development, many of which are mutated in monogenic diabetes. However, how these mutations alter developmental trajectories to produce pathological cell states remains elusive. Here we introduce a knockout village framework that enables longitudinal scRNA-seq profiling of 79 human pluripotent stem cell mutant lines targeting 30 developmental regulators, including 15 diabetes genes, across five islet differentiation stages. We show that loss of lineage regulators impairs β cell formation in a stage-specific manner and rewires developmental trajectories towards competing lineages. Notably, several monogenic diabetes gene mutations drive a shift from β cells to enterochromaffin (EC)-like cells, a recently recognized non-canonical islet cell fate. These EC-like cells exhibit incomplete activation of hormone regulation programs, along with elevated neuron signatures. Leveraging the diversity of cell fate outcomes across mutants, we predicted and experimentally validated ISL1 as a key downstream effector of PDX1 and PAX6 that safeguards β cell identity against an EC-like fate. Together, our findings reveal cell fate rewiring as a widespread, previously underappreciated pathological mechanism in monogenic diabetes and establish a scalable platform for uncovering developmental vulnerabilities in human genetic disorders.}, }
@article {pmid41509676, year = {2026}, author = {Sloan, A and Mortezavi, M and Gerhart, J and Banerjee, A and Alami, NN and Najera, I and Ahadieh, S and Dalam, AB and Schiffer, JT and Patel, R and Johnston, C}, title = {Orolabial and Genital Herpes Clinical Trials: A Meta-analysis of Endpoints.}, journal = {Open forum infectious diseases}, volume = {13}, number = {1}, pages = {ofaf776}, pmid = {41509676}, issn = {2328-8957}, abstract = {Although several antiviral agents are licensed for the treatment of orolabial and genital herpes simplex virus infections, new therapies are needed. Trial design is challenging for these indications due to the heterogeneity of endpoints in prior trials. We conducted a systematic review and meta-analysis of randomized placebo-controlled trials published between 1995 and 2024 consisting of adults with established herpes simplex virus infection who were immunocompetent and nonpregnant. A total of 22 articles met the inclusion criteria. For episodic treatment, endpoints included time to healing, proportion with an aborted lesion, and time to cessation of symptoms. For daily suppressive therapy, endpoints included time to first recurrence, proportion recurrence-free at 1 year, and total shedding rate. We observed that over the last 30 years, clinical trials have used various endpoints with nonstandardized definitions. A reassessment of appropriate endpoints along with regulatory guidance would assist with consistent study design for evaluation of new agents.}, }
@article {pmid41510809, year = {2026}, author = {Sutliff, NA and Chao, E and Bennett, SR and Nip, Y and Lakhdari, O and Canton, DA and Zhu, Y and Tapscott, SJ}, title = {Identification of KHDC1L, a DUX4-regulated protein, as a novel plasma biomarker in facioscapulohumeral muscular dystrophy.}, journal = {Human molecular genetics}, volume = {35}, number = {2}, pages = {}, doi = {10.1093/hmg/ddaf183}, pmid = {41510809}, issn = {1460-2083}, mesh = {Humans ; *Muscular Dystrophy, Facioscapulohumeral/blood/genetics/pathology ; *Homeodomain Proteins/genetics/metabolism/blood ; Biomarkers/blood ; Muscle, Skeletal/metabolism/pathology ; Male ; Myoblasts/metabolism ; Female ; Adult ; Middle Aged ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is caused by aberrant expression of the double homeobox transcription factor DUX4 in skeletal muscle. Because direct measurement of DUX4 in FSHD muscle is technically challenging, DUX4-regulated transcripts in muscle biopsies have been used as surrogates; however, this approach is invasive, limited to a single muscle, and less suitable for repeated monitoring. Thus, we sought to identify DUX4-regulated circulating biomarkers that could integrate DUX4 activity across all affected muscles and enable more frequent measurement. We performed mass spectrometry on conditioned media from DUX4-inducible immortalized human myoblasts (MB135iDUX4) and identified a top candidate-KHDC1L, the protein product of a DUX4-regulated mRNA previously shown to correlate with DUX4 expression in muscle. Western blotting confirmed KHDC1L release into the supernatant of DUX4-expressing cells. Plasma profiling demonstrated elevated KHDC1L levels in individuals with FSHD compared to healthy controls, supporting its role as a circulating readout of DUX4 activity. These findings suggest that plasma KHDC1L is a potential pharmacodynamic marker of DUX4 activity, providing a minimally invasive tool for disease monitoring and a potential response marker to evaluate emerging FSHD therapies.}, }
@article {pmid41512041, year = {2026}, author = {Gao, J and Brusselmans, M and Carvalho, LM and Suchard, MA and Baele, G and Matsen, FA}, title = {Biological causes and impacts of rugged tree landscapes in phylodynamic inference.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {2}, pages = {e2510938123}, pmid = {41512041}, issn = {1091-6490}, support = {G0E1420N//Fonds Wetenschappelijk Onderzoek (FWO)/ ; R01 AI153044/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; 101094685//EC | ERC | HORIZON EUROPE European Research Council (ERC)/ ; R01 AI162611/AI/NIAID NIH HHS/United States ; S10OD028685//Fred Hutchinson Cancer Center (FHCRC)/ ; G098321N//Fonds Wetenschappelijk Onderzoek (FWO)/ ; }, mesh = {*Phylogeny ; Bayes Theorem ; Genetic Variation ; Models, Genetic ; }, abstract = {Phylodynamic analysis has been instrumental in elucidating epidemiological and evolutionary dynamics of pathogens. Bayesian phylodynamics integrates out phylogenetic uncertainty, which is typically substantial in phylodynamic datasets due to limited genetic diversity. Phylodynamic inference does not, however, scale with modern datasets, partly due to difficulties in traversing tree space. Here, we characterize tree space and landscape in phylodynamic inference and assess its impacts on analysis difficulty and key biological estimates. By running extensive Bayesian analyses of 15 classic large phylodynamic datasets and carefully analyzing the posterior samples, we find that the posterior tree landscape is diffuse yet rugged, leading to widespread tree sampling problems that usually stem from sequences in a small part of the tree. We develop clade-specific diagnostics to show that a few sequences-including putative recombinants and recurrent mutants-frequently drive the ruggedness and sampling problems, although existing data-quality tests show limited power to detect them. The sampling problems can significantly impact phylodynamic inferences or distort major biological conclusions; the impact is usually stronger on "local" estimates (e.g., introduction history) associated with particular clades than on "global" parameters (e.g., demographic trajectory) governed by general tree shape. We evaluate existing Markov chain Monte Carlo diagnostics and diagnostics developed here, and offer strategies for optimizing phylodynamic analysis settings and mitigating sampling problem impacts. Our findings highlight the need and directions to develop efficient traversal over rugged tree landscapes, ultimately advancing scalable and reliable phylodynamics.}, }
@article {pmid41512237, year = {2026}, author = {Castellino, SM and Li, H and Herrera, AF and LeBlanc, M and Parsons, SK and Unger, JM and Punnett, A and Hodgson, D and Keller, FG and Drachtman, RA and Lamble, A and Forlenza, CJ and Doan, A and Rutherford, SC and Evens, AM and Little, RF and Smith, MA and Hoppe, BS and Song, JY and Smith, SM and Friedberg, JW and Kelly, KM}, title = {Three-Year Follow-Up of Nivolumab-AVD Versus Brentuximab Vedotin-AVD in Adolescents With Advanced-Stage Classic Hodgkin Lymphoma on S1826.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {6}, pages = {449-454}, doi = {10.1200/JCO-25-00203}, pmid = {41512237}, issn = {1527-7755}, support = {UG1 CA189955/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hodgkin Disease/drug therapy/pathology/mortality ; Adolescent ; Brentuximab Vedotin/administration &amp; dosage/adverse effects ; Female ; Male ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Child ; Nivolumab/administration &amp; dosage/adverse effects ; Doxorubicin/administration &amp; dosage/adverse effects ; Vinblastine/administration &amp; dosage/adverse effects ; Follow-Up Studies ; Dacarbazine/administration &amp; dosage/adverse effects ; Neoplasm Staging ; Progression-Free Survival ; Immunoconjugates/administration &amp; dosage/adverse effects ; }, abstract = {We present a subset analysis on the adolescent cohort of the S1826 randomized phase three trial, comparing nivolumab, doxorubicin, vinblastine, dacarbazine (N-AVD) to brentuximab vedotin-AVD (BV-AVD) in newly diagnosed advanced-stage (AS, stages III and IV) classic Hodgkin lymphoma (cHL). Among 994 patients enrolled, 24% (n = 240) were age 12-17 years. The 3-year progression-free survival (PFS) was significantly higher in the N-AVD group (93% [95% CI, 87 to 96]) compared with the BV-AVD group (82% [95% CI, 73 to 88]; hazard ratio, 0.37 [95% CI, 0.17 to 0.80]). One N-AVD and two BV-AVD patients received protocol-specified residual site radiotherapy (RT). Rates of febrile neutropenia and sepsis were low in both groups. Severe immune-related adverse events were infrequent, although thyroid dysfunction was seen in 7% with N-AVD. Sensory neuropathy (grade ≥2) was more frequent with BV-AVD (14% v 7%) by clinician report. Although premature discontinuation of therapy was reported in 12 N-AVD patients and four BV-AVD patients, no PFS events were noted in the N-AVD group. Patient-reported outcomes indicated less toxicity with N-AVD. N-AVD demonstrated high 3-year PFS in adolescents with AS cHL, with minimal RT use. S1826 exemplifies the benefits of harmonized clinical trial protocols, resulting in timely access to novel agents for adolescents.}, }
@article {pmid41513413, year = {2026}, author = {Segawa, I and Ortblad, KF and Kadama, H and Natukunda, D and Muwonge, TR and Laker, EAO and Nsubuga, R and Akello, S and Tamale, WJ and Kiragga, A and Mujugira, A}, title = {Optimising community pharmacy PrEP delivery for cisgender female sex workers in Uganda: Protocol for a mixed-methods study.}, journal = {BMJ open}, volume = {16}, number = {1}, pages = {e111220}, pmid = {41513413}, issn = {2044-6055}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Uganda/epidemiology ; *Sex Workers/statistics &amp; numerical data ; Female ; *HIV Infections/prevention &amp; control ; *Pre-Exposure Prophylaxis/methods ; *Health Services Accessibility ; *Community Pharmacy Services/organization &amp; administration ; Pharmacies ; Research Design ; }, abstract = {INTRODUCTION: Pre-exposure prophylaxis (PrEP) use among cisgender female sex workers (FSWs), a population at disproportionately high HIV acquisition risk in Uganda, remains suboptimal. Uptake and continued use are constrained by barriers, such as limited clinical hours, long distances to access facility-based PrEP services, and high mobility among FSWs. Community pharmacies may offer a more accessible PrEP delivery model due to extended operating hours and convenient locations. This study aims to evaluate the accessibility and capacity of pharmacies in Kampala, Uganda, to serve as potential sites for PrEP delivery.<br><br>METHODS AND ANALYSIS: We will conduct a concurrent mixed-methods study combining geospatial mapping, structured surveys, a discrete choice experiment (DCE), and in-depth interviews (IDIs). First, the study will compare the reach and accessibility of PrEP services through community pharmacies versus public healthcare facilities. To highlight PrEP service reach, we will use geospatial analysis to map pharmacies, PrEP clinics, FSW hotspots (i.e., areas where sex is exchanged), and HIV incidence. We will also calculate a PrEP facility needs ratio (number of PrEP facilities/HIV incidence) for each of Kampala's administrative divisions and estimate travel distance and time to access PrEP services using cost-distance analysis. Perceived accessibility of PrEP services will be assessed through FSW surveys (n=50) and IDIs (n=20-30), guided by Levesque's framework. Then, we will evaluate pharmacy capacity via surveys (n=274) and IDIs (n=20-30), exploring infrastructure, resources, and staff perspectives, informed by the Consolidated Framework for Implementation Research. Additionally, a DCE will be embedded in the pharmacy survey to elicit staff preferences for delivery approaches and analysed using mixed logit models. Finally, we will integrate quantitative and qualitative findings to provide a broad assessment of whether pharmacies are suitable venues for PrEP delivery to FSWs in Kampala. Enrolment will begin by April 2026 for FSWs and July 2026 for pharmacy staff.<br><br>ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Infectious Diseases Institute Research Ethics Committee (IDI-REC-2025-175) and the Uganda National Council for Science and Technology (HS6178ES). Written informed consent will be obtained from all participants. We will disseminate study findings through stakeholder meetings, scientific conferences, and peer-reviewed publications.}, }
@article {pmid41514580, year = {2025}, author = {Pettenger-Willey, CM and Laszlo, GS and Gang, M and Cole, FM and Godwin, CD and Erraiss, S and Chanana, P and Kehret, AR and Li, J and Barton, JW and Yochim, MM and Rodríguez-Arbolí, E and Walter, RB}, title = {DNA Damage Sensing and TP53 Function as Modulators of Sensitivity to Calicheamicin-Based Antibody-Drug Conjugates for Acute Leukemia.}, journal = {Cancers}, volume = {18}, number = {1}, pages = {}, pmid = {41514580}, issn = {2072-6694}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; U54-DK106829/DK/NIDDK NIH HHS/United States ; N/A//Pfizer/ ; T32-HL007093//National Heart Lung and Blood Institute/ ; }, abstract = {BACKGROUND/OBJECTIVES: Approved for treatment of acute leukemia, gemtuzumab ozogamicin (GO) and inotuzumab ozogamicin (InO) are antibody-drug conjugates (ADCs) that deliver a toxic calicheamicin (CLM) derivative. The resistance mechanisms to GO/InO remain incompletely understood.<br><br>METHODS: We performed a genome-wide clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 screen for CLM sensitivity genes, and then performed confirmatory cytotoxicity assays.<br><br>RESULTS: Several DNA damage pathway regulation genes were identified, most notably TP53. Across 13 acute leukemia cell lines, the six TP53-mutant cell lines (TP53[MUT]) were indeed 10- to 1000-fold less sensitive to CLM than the seven TP53[WT] cell lines. In five TP53[WT/KO] syngeneic cell line pairs we generated, TP53[KO] cells were significantly less sensitive to CLM than their TP53[WT] counterparts. In TP53[WT] but not TP53[MUT] cells, the MDM2 inhibitor and p53 activator, idasanutlin, enhanced CLM cytotoxicity, demonstrating that decoupling of cells from MDM2-p53 regulation sensitizes leukemia cells to CLM. The ATM inhibitors AZD1390 and lartesertib also significantly enhanced CLM efficacy but did so independent of the TP53 status. In contrast, neither an ATR inhibitor, Chk1/Chk2 inhibitor, Chk2 inhibitor, or a PARP inhibitor significantly impacted CLM-induced cytotoxicity across the thirteen cell lines. Together, our studies identify ATM, MDM2, and TP53-which are in the same cellular response to DNA damage pathway-as key modulators of CLM-induced cytotoxicity in acute leukemia cells.<br><br>CONCLUSIONS: These results support further evaluation of combination therapies with corresponding small-molecule inhibitors (currently pursued for therapy of other cancers) toward clinical testing as novel strategies to increase the efficacy of CLM-based ADCs such as GO and InO.}, }
@article {pmid41514630, year = {2025}, author = {Alban, J and Bowen, RC and Reichstein, DA and McKean, M and Lutzky, J and Weis, E and Carvajal, RD and Dulka, S and Morse, BG and Butler, MO and Rapisuwon, S and Kim, KB and Chandrasekaran, S and Warner, AB and Zager, JS and Chmielowski, B and Patel, SP and Hernandez-Aya, LF and Correa, ZM and Fecher, LA and Najjar, YG and Montazeri, K and Shoushtari, AN and Javed, A and Gombos, DS and Salama, AKS and Tsai, K and Miller, FH and Khushalani, N and Seedor, RS and Lipson, EJ and Reddy, SA and Buchbinder, E and Bhatia, S and Pavlick, A and Mehmi, I and Aaberg, T and Ikeguchi, AP and Kim, IK and Walter, SD and Singh, AD and Sullivan, RJ and Choi, JS and Williams, BK and Orloff, M and Mruthyunjaya, P and Schollenberger, MD and Gandhi, N and Harbour, JW and Chandra, S}, title = {Metastatic Uveal Melanoma Surveillance: A Delphi Panel Consensus.}, journal = {Cancers}, volume = {18}, number = {1}, pages = {}, pmid = {41514630}, issn = {2072-6694}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND/OBJECTIVES: Uveal melanoma is a rare but aggressive intraocular malignancy that metastasizes in up to half of patients, most commonly to the liver, despite effective local treatment. In the absence of robust evidence, there are no standardized guidelines for post-treatment surveillance, resulting in wide variation in imaging modalities, frequency, and duration across physicians and institutions. This study aimed to develop expert consensus recommendations for surveillance strategies in patients with uveal melanoma.<br><br>METHODS: A modified Delphi method was conducted across three iterative survey rounds between September 2024 and February 2025 using an online platform. Panelists included medical oncologists, ocular oncologists, radiologists, and surgical oncologists from North America. A multidisciplinary steering committee developed statements addressing risk-based surveillance using both molecular and clinical prognostic factors, including gene expression profiling (GEP) and PRAME status. Consensus was defined a priori as &#x2265;70% of panelists rating a statement 7-9 on a 9-point Likert scale.<br><br>RESULTS: Forty-nine experts were invited, and 41 completed at least one survey round. The panel represented 17 U.S. states, Washington, D.C., and two Canadian provinces. Twelve statements reached stable consensus, including recommendations for imaging modality, frequency, and duration in intermediate- and high-risk patients. Although there was agreement that low-risk patients warrant surveillance, no consensus was reached on the optimal approach for this group.<br><br>CONCLUSIONS: This is the first study to provide consensus-based guidance incorporating GEP and PRAME status into surveillance recommendations for uveal melanoma, offering a standardized framework to guide clinical practice and future research.}, }
@article {pmid41515121, year = {2025}, author = {Park, J and Kadro, ZO and Honvoh, GD and Domeniciello, AF and Ramsden, CE and Faurot, KR and Miller, VE}, title = {Associations Between Dietary Intakes of Omega-3 Fatty Acids, Blood Levels, and Pain Interference in People with Migraine: A Path Analysis of Randomized Trial Data.}, journal = {Nutrients}, volume = {18}, number = {1}, pages = {}, pmid = {41515121}, issn = {2072-6643}, support = {RO1-AT007813/AT/NCCIH NIH HHS/United States ; Intramural Program/AG/NIA NIH HHS/United States ; T32-AT003378/AT/NCCIH NIH HHS/United States ; Gift to the Department of Physical Medicine and Rehabilitation//Dr. John M. Davis/ ; }, mesh = {Humans ; *Migraine Disorders/diet therapy/blood ; Female ; Male ; *Docosahexaenoic Acids/blood/administration &amp; dosage ; *Eicosapentaenoic Acid/blood/administration &amp; dosage ; Adult ; *Fatty Acids, Omega-3/blood/administration &amp; dosage ; Middle Aged ; *Diet ; *Pain ; }, abstract = {Background/Objectives: Increasing evidence supports the hypothesis that dietary intervention can improve pain among individuals with headaches, including migraine, a highly prevalent condition that can be disabling. Non-pharmacologic treatments for migraine are particularly attractive. In this secondary analysis of 182 participants enrolled in a randomized controlled trial of a dietary intervention designed to increase omega-3 (n-3) compared with a control diet, we examined the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both thought to decrease inflammatory processes. Methods: Path models with two time points (baseline and 16 weeks after randomization), were used to test the relationships between exposures of n-3 blood levels and self-reported dietary intake on outcomes of pain interference using the PROMIS pain interference scale and the Headache Impact Test (HIT-6). Model building was based on our published conceptual model. Results: Good fit was demonstrated for both models (EPA model: CFI = 0.984, RMSEA = 0.039, and SRMR = 0.045; DHA model: CFI = 0.981, RMSEA = 0.040, and SRMR = 0.040). Both EPA and DHA in the blood at 16 weeks were associated with lower levels of pain interference, but the effect for EPA was stronger (B = -0.56, p < 0.001 for EPA, and B = -0.43, p = 0.057 for DHA). Conclusions: Our findings are consistent with an indirect pathway linking diet to pain interference through blood levels of EPA and DHA in migraine.}, }
@article {pmid41518882, year = {2026}, author = {Summers, C and Mallhi, K and Persinger, H and Fan, X and Gooley, TA and Dahlberg, AE and Burroughs, LM and Thakar, MS and Bhatt, NS and Petrovic, A and Hadland, B and Carpenter, PA and Baker, KS and Bleakley, M}, title = {Outcomes following hematopoietic cell transplantation for children, adolescents and young adults with relapsed acute lymphoblastic leukemia.}, journal = {Cytotherapy}, volume = {28}, number = {3}, pages = {102004}, doi = {10.1016/j.jcyt.2025.102004}, pmid = {41518882}, issn = {1477-2566}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Adolescent ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/mortality/pathology ; Female ; Male ; Child ; Young Adult ; Retrospective Studies ; Adult ; Treatment Outcome ; Recurrence ; Child, Preschool ; Neoplasm Recurrence, Local/therapy ; }, abstract = {BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) is a common consolidation therapy for recurrent acute lymphoblastic leukemia (ALL), reducing relapse risk but causing significant morbidity, mortality, and potential impairment of growth and development in children, adolescents, and young adults (CAYA). Avoiding or delaying HCT could prevent such complications. New targeted therapies, including CD19 chimeric antigen receptor (CAR) T cells, have increased the number of recurrent ALL patients who might achieve long-term remission without HCT. However, outcomes of delaying HCT beyond second complete remission (CR2) in the modern era remain unclear.<br><br>OBJECTIVE: To compare outcomes of HCT performed in CR2 versus third or later remission (CR3+) in CAYA with ALL.<br><br>METHODS: We retrospectively reviewed CAYA who underwent first HCT for ALL in CR2 (n = 81) or CR3+ (n = 44) at our institution from 2000-2020.<br><br>RESULTS: For all patients, estimated 1-year overall survival (OS), relapse, and nonrelapse mortality (NRM) were 76%, 20.8%, and 9.6%; 3-year estimates were 69%, 30%, and 9.6%, respectively. At 3 years, OS was 77% for CR2 versus 53% for CR3+, and NRM was 6% versus 16%. Adjusted hazard ratios (HR) for CR3+ versus CR2 were: overall mortality HR 1.87 (95% CI, 1.06-3.31), relapse HR 1.28 (95% CI, 0.66-2.50), and NRM HR 2.63 (95% CI, 1.08-6.39).<br><br>CONCLUSIONS: CAYA with ALL undergoing HCT in CR3+ experienced higher NRM and worse survival compared to those transplanted in CR2. Efforts to reduce NRM in multiply relapsed patients are required.}, }
@article {pmid41519253, year = {2026}, author = {Thornburgh, S and Farland, LV and Harris, HR and Sonneville, KR and Neblett, MF and Field, AE and Chavarro, JE and Missmer, SA and Gaskins, AJ}, title = {Disordered eating behaviors during adolescence and risk of endometriosis: a prospective cohort study.}, journal = {Fertility and sterility}, volume = {}, number = {}, pages = {}, pmid = {41519253}, issn = {1556-5653}, support = {U01 HL145386/HL/NHLBI NIH HHS/United States ; }, abstract = {OBJECTIVE: Disordered eating behaviors may impact the gynecologic health of adolescents through effects on menstrual cycle function and body size; however, few studies have evaluated these associations. This study aimed to prospectively investigate the associations between individual disordered eating behaviors during adolescence and the risk of subsequent endometriosis diagnosis.<br><br>DESIGN: Prospective, longitudinal cohort (1996-2021).<br><br>SUBJECTS: Female participants (n = 11,773) from the Growing Up Today Study.<br><br>EXPOSURE: Frequency of binge eating, laxative use, and self-induced vomiting over the past year was self-reported on repeated questionnaires during follow-up.<br><br>MAIN OUTCOME MEASURES: Physician-diagnosed endometriosis was reported on repeated questionnaires during follow-up. Multivariable logistic regression models with generalized estimating equations were used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).<br><br>RESULTS: Over 25 years of follow-up, we identified 269 incident cases of endometriosis (2.3%), 190 of which were reported as laparoscopically confirmed. A total of 32% of girls reported ever binge eating, 14% reported self-induced vomiting to lose weight, and 9% reported ever using laxatives to lose weight. The odds of a laparoscopically-confirmed endometriosis diagnosis were more than three-fold higher (aOR = 3.07; 95% CI 1.74, 5.40) for girls who cumulatively reported self-induced vomiting more than monthly during follow-up, compared with girls who never reported self-induced vomiting. A similar effect estimate (aOR = 2.41; 95% CI 1.40, 4.12) was noted for girls who reported weekly or more frequent self-induced vomiting at least once during follow-up compared with girls who reported never vomiting. Cumulative exposure to binge eating during follow-up was not associated with diagnosis of laparoscopically-confirmed endometriosis; however, girls who reported the highest ever engagement in binge eating of weekly or more had 52% lower (aOR = 0.47; 95% CI 0.25, 0.90) odds of laparoscopically-confirmed endometriosis, compared with girls who reported less than weekly binge eating. Laxative use was not strongly associated with endometriosis diagnosis, although estimates were imprecise.<br><br>CONCLUSION: We observed that females with a greater frequency of self-induced vomiting were more likely to be diagnosed with endometriosis during follow-up, whereas girls with a history of frequent binge eating had a lower likelihood of endometriosis diagnosis. We found no association between laxative use and endometriosis.}, }
@article {pmid41519271, year = {2026}, author = {Nicholas, JC and Alkis, T and Bis, JC and Boerwinkle, E and Brody, JA and Clish, CB and de Vries, PS and Gao, Y and Gerzsten, RE and Guo, X and Johnson, AD and Larson, MG and Lemaitre, RN and Psaty, BM and Vasan, RS and Reiner, AP and Rich, SS and Rodriguez, B and Rong, J and Rotter, JI and Simino, J and Smith, NL and Wilson, J and Yao, J and Morrison, AC and Yu, B and Raffield, LM}, title = {Fibrinogen-associated plasma metabolites and implications for coagulation, inflammation, and vascular diseases.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {24}, number = {4}, pages = {1523-1541}, pmid = {41519271}, issn = {1538-7836}, support = {R01 HL139553/HL/NHLBI NIH HHS/United States ; R01 HL141291/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Fibrinogen/metabolism/analysis ; *Inflammation/blood/diagnosis ; Male ; Female ; *Blood Coagulation ; Middle Aged ; Metabolomics ; Cross-Sectional Studies ; Biomarkers/blood ; *Vascular Diseases/blood/diagnosis ; Adult ; Aged ; United States ; Risk Factors ; }, abstract = {BACKGROUND: Fibrinogen is a critical coagulation factor that plays an essential role in thrombosis and is elevated in individuals with chronic inflammation.<br><br>OBJECTIVES: Here, we used fibrinogen as a representative quantitative measure of procoagulant risk and evaluated metabolites associated with fibrinogen levels using nontargeted plasma metabolomics profiling (Broad and Metabolon platforms).<br><br>METHODS: Our analysis included 10 533 individuals across 6 United States-based cohorts representing diverse population groups. The cross-sectional relationship between each of the 789 metabolites tested and plasma fibrinogen concentration was assessed after adjustment for relevant covariates, including age, cohort-reported sex, body mass index, and circulating lipoprotein levels.<br><br>RESULTS: Meta-analysis of per-cohort results revealed 270 metabolites significantly associated with fibrinogen levels (false discovery rate-adjusted P value < .05). Lipid species, such as glycerophospholipids, sphingolipids, and fatty acyls, were among the most significantly associated metabolites; some of these may capture effects of inflammation, as supported by sensitivity analyses adjusted for C-reactive protein. Significant associations between fibrinogen levels and serotonin, thyroxine, and sex hormone derivatives may capture endogenous influences on fibrinogen levels. Exogenous compounds and microbial cometabolites were significantly associated with fibrinogen, also implicating lifestyle and microbiome risk factors. Only a portion of fibrinogen-associated metabolites (30%) has been associated with cardiovascular disease outcomes in a prior study, suggesting that the associations discovered here may provide insights into vascular biology that case-control studies may not yet be powered to detect.<br><br>CONCLUSION: These findings contribute to the growing list of metabolite biomarkers that may influence coagulation and inflammation pathways and, thereby, vascular risk.}, }
@article {pmid41520058, year = {2026}, author = {Fuller, H and Agasaro, OP and Guevara, JM and Darst, BF}, title = {Pre-diagnostic circulating untargeted metabolomics and risk of overall and clinically significant prostate cancer: a systematic review and meta-analysis.}, journal = {British journal of cancer}, volume = {134}, number = {7}, pages = {1080-1091}, pmid = {41520058}, issn = {1532-1827}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA258808/CA/NCI NIH HHS/United States ; U54 HG013243/HG/NHGRI NIH HHS/United States ; R01 HL174378/HL/NHLBI NIH HHS/United States ; R00 CA246063/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R00 CA246063/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/blood/diagnosis/metabolism/pathology ; *Metabolomics/methods ; *Biomarkers, Tumor/blood ; Metabolome ; Risk Factors ; }, abstract = {BACKGROUND: Metabolomic dysregulation contributes to prostate cancer (PCa) pathogenesis, and studies suggest that circulating metabolites have strong potential to act as clinical biomarkers. However, evidence of associations between circulating metabolites with overall and clinically significant PCa risk has not been quantitively aggregated.<br><br>METHODS: We performed a systematic review and meta-analysis of untargeted pre-diagnostic circulating metabolomic studies across four clinically distinct outcomes: overall, low- to intermediate-risk, high- to very high-risk, and lethal PCa, each compared to controls.<br><br>RESULTS: Twelve studies were identified in the systematic review, and up to 408 metabolites were meta-analysed across the four PCa outcomes. Three, eleven, and nineteen metabolites were significantly associated with risk of overall, high- to very high-risk, and lethal PCa, respectively. Metabolites associated with high- to very high-risk PCa were significantly enriched for lipids. Limited evidence of correlation between metabolite effects across outcomes was identified, highlighting potentially unique metabolite drivers of high-risk and lethal PCa. In follow-up analyses, 13 of the significant metabolites were found to be modifiable by&#xa0;drugs and/or diet.<br><br>CONCLUSIONS: These findings suggest a strong potential for metabolites to inform risk of lethal PCa, which could inform risk-stratified screening strategies and facilitate the identification of targets for PCa prevention.}, }
@article {pmid41520338, year = {2026}, author = {Janssens, DH and Codomo, CA and Otto, DJ and Silberstein, L and Ahmad, K and Henikoff, S}, title = {Sequential RNA polymerase II activation drives human hematopoiesis.}, journal = {Cell reports}, volume = {45}, number = {1}, pages = {116802}, pmid = {41520338}, issn = {2211-1247}, support = {/HHMI/Howard Hughes Medical Institute/United States ; K22 CA272912/CA/NCI NIH HHS/United States ; R01 HG010492/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *RNA Polymerase II/metabolism/genetics ; *Hematopoiesis/genetics/drug effects ; Hematopoietic Stem Cells/metabolism/cytology ; Granulocyte Colony-Stimulating Factor/pharmacology ; Cell Lineage ; }, abstract = {Promoter-proximal pausing of RNA polymerase II (Pol II) primes genes for rapid activation, yet how Pol II dynamics are temporally organized in adult stem cells to enable fast and flexible responses to environmental cues remain unknown. To address this, we developed sciCUT&amp;Tag2in1 for joint profiling of Pol II and histone modifications in single cells. By profiling over 200,000 CD34[+] hematopoietic stem cells (HSCs) and progenitors, we identify a Pol II regulatory cascade that directs the response to granulocyte colony-stimulating factor (G-CSF)-induced inflammatory stress. HSCs are activated by elevated Pol II occupancy and reduced Polycomb repression of immune response genes. Lineage commitment proceeds through sequential modes of Pol II activation, beginning with rapid pause-and-release genes, followed by slower initiate-and-release of Polycomb-repressed targets. sciCUT&amp;Tag2in1 defines the temporal logic of how adult stem cells use paused Pol II to enable flexible lineage decisions, providing a powerful tool for studying the intersection of development, inflammation, and disease.}, }
@article {pmid41521011, year = {2026}, author = {Kanzaria, A and Arora, S and Naik, A and Dhanushkodi, N and Ho, CC and Kaur, N and Zhang, J and Ren, X and Fromm, JR and Shadman, M and Smith, S and Gopal, A and Roncador, G and Holland, E and Naresh, KN}, title = {Biomarkers Informed by Single-Cell and Spatial Transcriptomics-Biomarkers for Grade 3 Follicular Lymphoma.}, journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc}, volume = {39}, number = {3}, pages = {100958}, doi = {10.1016/j.modpat.2026.100958}, pmid = {41521011}, issn = {1530-0285}, mesh = {Humans ; *Lymphoma, Follicular/pathology/genetics ; *Biomarkers, Tumor/genetics/analysis ; Male ; Single-Cell Analysis ; *Transcriptome ; Female ; Neoplasm Grading ; Middle Aged ; Aged ; Receptors, CXCR4/analysis ; Gene Expression Profiling ; Prognosis ; Adult ; Immunohistochemistry ; }, abstract = {Follicular lymphoma (FL) patients have variable outcomes, underscoring the need for biomarkers for improved risk stratification. Current FL grading systems, based on subjective centroblast counts, suffer from poor reproducibility, despite evidence linking grade 3 FL to worse prognosis. We aimed to identify objective biomarkers for centroblasts and centrocytes to improve FL prognostication. We reanalyzed publicly available spatial and single-cell transcriptomic data from normal germinal centers and FL samples. Reanalysis revealed distinct gene expression profiles: AICDA (AID) and CXCR4 were highly expressed in germinal center dark zone cells (centroblasts) and CD40 and TFRC (CD71) in light zone cells (centrocytes). Single-cell RNA sequencing of FL samples further showed AID and CXCR4 overexpression in malignant grade 3A cells and CD40 and CD71 in grades 1 to 2 cells. We validated these findings using immunohistochemistry (single and multiplex) on tonsils and 59 FL specimens (42 grades 1 to 2, 17 grade 3). Grade 3 FL showed significantly higher expression of AID, CD71, and Ki67 compared to grades 1 to 2, with CXCR4 approaching significance. Receiver operating characteristic curve analysis identified optimal cutoffs for AID (1.54%), CXCR4 (21.9%), Ki67 (21.6%), and CD71 (7.57%) to distinguish grade 3 from grades 1 to 2 FL, with AID showing the best discriminatory ability. Crucially, AID expression evaluation showed reproducibility across 2 different digital algorithms and 2 independent visual observers. Furthermore, we observed a trend toward shorter disease-specific survival in patients with both FL grade 3 and high AID expression. This prognostic observation held true regardless of whether AID overexpression was assessed via digital evaluation (cutoff: 1.54%) or visual estimation (cutoff: 2%). In conclusion, AID, CXCR4, CD71, and Ki67 are promising biomarkers for objectively identifying FL grade 3, potentially enhancing the reproducibility of grading and serving as independent prognostic tools. Further clinical validation in uniformly treated FL cohorts is warranted.}, }
@article {pmid41521394, year = {2026}, author = {O'Keefe, GE and Navarro, SL and Zheng, Z and Randolph, TW and Shelton, M and Elizaga, N and Qiu, Q and Nagana, GGA and Raftery, D}, title = {Metabolic profiles in adults with trauma receiving enteral nutrition support: A metabolomic cohort study.}, journal = {JPEN. Journal of parenteral and enteral nutrition}, volume = {50}, number = {3}, pages = {385-393}, doi = {10.1002/jpen.70051}, pmid = {41521394}, issn = {1941-2444}, support = {R01GM127790/NH/NIH HHS/United States ; T32 GM121290/NH/NIH HHS/United States ; //NIDDK P30 DK035816 (Nutrition and Obesity Research Center)/ ; R01GM127790/NH/NIH HHS/United States ; T32 GM121290/NH/NIH HHS/United States ; }, mesh = {Humans ; *Enteral Nutrition/methods ; Female ; Male ; Adult ; Critical Illness/therapy ; Middle Aged ; Cohort Studies ; *Metabolomics ; *Wounds and Injuries/therapy/metabolism/blood ; Dietary Proteins/administration &amp; dosage ; *Metabolome ; Aged ; }, abstract = {BACKGROUND: We aimed to identify metabolic changes after injury and potential mechanisms whereby nutrition support may influence metabolites and pathways. We analyzed 45 metabolites in 67 trauma patients.<br><br>METHODS: We performed a metabolomic cohort study in critically ill adults with trauma using nuclear magnetic resonance to quantify 45 metabolites in plasma. We divided the cohort into two groups based on the median amount of protein intake calculated by averaging over the first 7 days of nutrition support. Using linear mixed models, we tested the hypotheses that metabolite concentrations would differ over time and the rate of change is altered by the amount of enteral protein intake.<br><br>RESULTS: Five metabolites in each of the low (median&#x2009;=&#x2009;0.6 [IQR, 0.4-0.8] gm/kg/day) and high (1.5 [1.1-1.7] gm/kg/day) protein intake groups were different by day 3 compared with baseline. Twenty metabolites in the low-protein intake group and 14 metabolites in the high-protein intake group were different by day 7 compared with baseline. There was no evidence that the rate of metabolite change over time differs by protein intake group. Quantitative enrichment analysis indicated that branched chain amino acid (BCAA) catabolism was one of the most altered pathways in both groups.<br><br>CONCLUSION: In critically ill trauma patients, metabolites, particularly those linked with BCAA metabolism, are altered over time but not influenced by the amount of enteral protein intake during the first week.}, }
@article {pmid41521409, year = {2025}, author = {Lindsay, J and Yeoh, D and Teh, BW and Reynolds, GK and Henden, A and McQuilten, Z and Wheeler, M and Hamilton, A and Nelson, A and Nakagaki, M and Sandhu, S and Slavin, MA and , }, title = {Consensus guidelines for antibacterial prophylaxis in patients with neutropenia.}, journal = {Internal medicine journal}, volume = {55 Suppl 7}, number = {}, pages = {115-135}, doi = {10.1111/imj.70250}, pmid = {41521409}, issn = {1445-5994}, mesh = {Humans ; *Anti-Bacterial Agents/therapeutic use ; *Antibiotic Prophylaxis/standards/methods ; Australia/epidemiology ; Neoplasms/drug therapy ; *Neutropenia/drug therapy/chemically induced ; }, abstract = {Since the publication of the Australian consensus guidelines in 2011, the routine use of prophylactic antibiotics in patients with neutropenia has remained controversial, because of concern that the risks of promoting antimicrobial resistance outweighed the level of evidence that their use reduced mortality. Populations at risk have changed over this period and now include a multitude of new cancer therapies, such as targeted cancer therapies and immunotherapies. Emerging understanding about the importance and role of the microbiome in defining treatment response and patterns of antibiotic resistance has also expanded. In addition, the management of neutropenic fever has improved significantly through the development and routine implementation of sepsis pathways. These updated consensus guidelines review recent evidence for the use of antibacterial prophylaxis in adults and children receiving cancer therapies associated with neutropenia. Recommendations presented in these guidelines were based on evaluating current evidence for the benefits and harms of antibacterial prophylaxis while considering the current Australian and New Zealand healthcare setting. In most circumstances, the potential harm of antibiotic resistance, adverse effects of antibiotics and disruption to the microbiome, outweighed the benefit of reducing the incidence of infection, without a benefit in mortality.}, }
@article {pmid41524253, year = {2026}, author = {Stolla, M and Bailey, SL and Chauhan, A and Byrne, DA and Ting, L and Klotz, P and Pulido, JN and Lehr, EJ and Youssef, S and Lawrence, J and Limanek, A and Alcorn, K and Ryan, P and Stout, DM}, title = {A pilot trial of long-distance shipped, extended- and cold-stored platelets in 100% plasma for cardiothoracic surgical bleeding.}, journal = {Transfusion}, volume = {66}, number = {3}, pages = {555-567}, doi = {10.1111/trf.70076}, pmid = {41524253}, issn = {1537-2995}, support = {W81XWH-12-1-0441//U.S. Department of Defense/ ; }, mesh = {Humans ; Pilot Projects ; Male ; Female ; *Platelet Transfusion/methods ; *Blood Preservation/methods ; Middle Aged ; Aged ; Double-Blind Method ; *Blood Platelets/cytology ; *Cardiac Surgical Procedures/adverse effects ; *Blood Loss, Surgical ; *Plasma ; }, abstract = {BACKGROUND: In this pilot trial, we tested the feasibility of conducting a randomized controlled trial in cardiac surgery patients using extended-, 100% plasma-, cold-stored, and long-distance-shipped platelets (CSPs).<br><br>STUDY DESIGN AND METHODS: We conducted a single center, controlled, double-blind pilot study in adult patients undergoing elective redo or complex cardiothoracic surgery. Patients were allocated in a week-based block randomization scheme to receive either room temperature-stored platelets (RTPs) or CSPs shipped from a Texas-based blood center and stored between 10 and 14&#x2009;days. The primary outcome was defined as the feasibility of recruitment and accrual. Several other secondary endpoints were assessed. All platelet units were screened for aggregates using RTP release criteria.<br><br>RESULTS: In a post-hoc "as treated" analysis, 15 patients received RTPs, and 9 received CSPs (including 3 who received both). We found that most CSPs (58%) were not usable for transfusion due to the presence of aggregates. This resulted in an excess of subjects receiving RTPs; consequently, the final nine transfused participants were allocated to receive CSPs without randomization. We accrued 0.7 evaluable subjects/month of active enrollment, which was below our desired primary outcome feasibility target of &#x2265;1.2. One death within 28&#x2009;days occurred in the RTP transfusion group, while none occurred in the CSPs group. In vitro testing yielded contradictory results.<br><br>CONCLUSION: Due to slow recruitment and the abundance of aggregates in CSPs, this pilot trial does not support the feasibility of the study protocol.}, }
@article {pmid41524276, year = {2026}, author = {Tan, Y and Kim, BJ and Mujal, AM and Chen, ACY and Weis, AM and Bergaggio, E and Micevic, G and Xie, H and Park, JS and Hor, JL and Papanicolaou, M and Shobaki, N and Domizi, P and Delconte, RB and Vendramin, R and Hegde, S and Han, S and Su, Y and Hacohen, N}, title = {Training Tomorrow's Leaders in Cancer Immunology.}, journal = {Cancer immunology research}, volume = {14}, number = {2}, pages = {186-193}, doi = {10.1158/2326-6066.CIR-25-1479}, pmid = {41524276}, issn = {2326-6074}, mesh = {Humans ; *Leadership ; *Neoplasms/immunology/therapy ; *Allergy and Immunology/education ; Mentors ; *Medical Oncology/education ; }, abstract = {The transition from trainee to independent investigator is one of the most challenging and formative phases of a scientific career. It requires not only scientific expertise but also the skills to lead, mentor, manage, and communicate effectively. The Arthur and Sandra Irving Cancer Immunology Symposium serves as a platform for established investigators to mentor trainees and early-career faculty as they navigate this transition to independence. Through sharing personal experiences and lessons from their own careers, senior leaders provide guidance on the scientific, professional, and personal challenges that shape a successful career in cancer immunology-emphasizing how curiosity, persistence, and a translational mindset can make a lasting real-world impact. This commentary highlights key themes, including leadership, communication, recruitment, and fundraising. Altogether, these insightful thoughts provide a framework for the next generation of cancer immunologists as they establish their independent careers as future leaders in the field.}, }
@article {pmid41526345, year = {2026}, author = {Strickler, JH and Cercek, A and Siena, S and André, T and Ng, K and Van Cutsem, E and Wu, C and Paulson, AS and Hubbard, JM and Coveler, AL and Fountzilas, C and Kardosh, A and Kasi, PM and Lenz, HJ and Ciombor, K and Elez, E and Bajor, DL and Cremolini, C and Sanchez, F and Nayeri, M and Feng, W and Bieda, M and Bekaii-Saab, TS}, title = {Tucatinib plus trastuzumab for chemotherapy-refractory, HER2 + , RAS wild-type metastatic colorectal cancer (MOUNTAINEER): final analysis.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {1068}, pmid = {41526345}, issn = {2041-1723}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Biomarkers, Tumor ; *Colorectal Neoplasms/drug therapy/genetics/mortality/pathology ; Drug Resistance, Neoplasm/drug effects ; *Erb-b2 Receptor Tyrosine Kinases/analysis/genetics/metabolism ; Neoplasm Metastasis ; *Oxazoles/administration &amp; dosage/therapeutic use/adverse effects ; Progression-Free Survival ; *Pyridines/administration &amp; dosage/therapeutic use/adverse effects ; *Quinazolines/administration &amp; dosage/therapeutic use/adverse effects ; *Trastuzumab/administration &amp; dosage/therapeutic use/adverse effects ; Treatment Outcome ; }, abstract = {MOUNTAINEER was a multicenter, open-label, phase 2 trial (NCT03043313) that evaluated the efficacy and safety of tucatinib plus trastuzumab, a dual HER2-targeted chemotherapy-free regimen. Patients were included if they had chemotherapy-refractory, HER2+, RAS wild-type unresectable or metastatic colorectal cancer. This final analysis reports updated efficacy and safety after a median follow-up of 32.4 months. Of the 84 patients who received tucatinib plus trastuzumab, the confirmed objective response rate was 39.3%; median duration of response was 15.2 months. Median progression-free survival was 8.1 months and overall survival was 23.9 months. Efficacy was relatively similar across central HER2+ testing methods. No clear association of treatment response with co-occurring biomarker alterations was seen. Few patients discontinued treatment due to adverse events; no treatment-emergent deaths occurred. Tucatinib plus trastuzumab showed clinically meaningful efficacy and favorable safety. Efficacy was observed irrespective of central HER2+ testing methods and in patients with heterogeneous tumor biomarker profiles.}, }
@article {pmid41528117, year = {2026}, author = {Johnson, M and Cai, Y and Vasconcelos, AG and Orchard, P and Auer, PL and Lettre, G and Wen, J and Franceschini, N and Kooperberg, C and Sun, W and Hsu, L and Raffield, LM and Reiner, AP}, title = {Whole Blood Transcriptomic Analysis of Sickle Cell Trait.}, journal = {European journal of haematology}, volume = {116}, number = {5}, pages = {535-544}, pmid = {41528117}, issn = {1600-0609}, support = {//Fred Hutchinson Cancer Center/ ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01HL146500/HL/NHLBI NIH HHS/United States ; phs001237/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; 3U54HG003067-13S1//Broad Institute of MIT and Harvard, and the Northwest Genomics Center (NWGC)/ ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; R01HL152439/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 HL163972/HL/NHLBI NIH HHS/United States ; X01HL153408//Broad Institute of MIT and Harvard, and the Northwest Genomics Center (NWGC)/ ; U01HG01172/HG/NHGRI NIH HHS/United States ; R01 HG013163/HG/NHGRI NIH HHS/United States ; phs001237/HL/NHLBI NIH HHS/United States ; R01HL152439/HL/NHLBI NIH HHS/United States ; R01HL146500/HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201500014C/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Gene Expression Profiling ; *Sickle Cell Trait/genetics/blood/diagnosis ; *Transcriptome ; Aged ; Middle Aged ; Gene Expression Regulation ; Biomarkers ; Erythropoiesis/genetics ; }, abstract = {Sickle cell trait (SCT) is the heterozygous carrier state for the HBB missense variant which causes sickle cell disease (SCD). SCT has been associated with increased risk of venous thromboembolism and chronic kidney disease as well as alterations in clinical laboratory parameters. To investigate differential gene expression in SCT, we used RNA sequencing of whole blood samples collected from 805 African American female participants (143 SCT; 660 controls) from the Women's Health Initiative Long Life Study (mean age = 76). We identified 226 differentially expressed genes (DEGs) in SCT compared to non-carriers (FDR < 0.05). Enriched pathways included those related to erythropoiesis, hemoglobin synthesis, and proteasomal degradation. Many of the SCT-associated DEGs were previously reported as differentially expressed in blood from individuals with SCD. Among the DEGs associated with SCT, we observed enrichment of upregulated ubiquitin-related genes normally downregulated during the later stages of erythroid differentiation, a pattern previously reported in SCD. Several of the SCT-associated DEGs highlight mechanisms that potentially link hemolysis or erythropoiesis to hypoxic kidney tubular injury. Future investigation of these genes using single cell transcriptomic analysis in relevant tissues may be useful in understanding mechanisms for adverse health outcomes in individuals with SCT.}, }
@article {pmid41530119, year = {2026}, author = {Ykema, MR and Davis, MA and Kasal, DN and Jennewein, MF and Lo, E and Singh, J and Beaver, S and Cross, N and Melief, E and Reed, S and Press, C and Brandt, DS and McClary, WD and Mohamath, R and Fusco, P and Bakken, J and Casper, C and Hartwig, AT and Gerhardt, A and Bowen, RA and Voigt, EA}, title = {Intranasal replicon vaccine establishes mucosal immunity and protects against H5N1 and H7N9 influenza.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {434}, pmid = {41530119}, issn = {2041-1723}, mesh = {Animals ; *Influenza Vaccines/immunology/administration &amp; dosage/genetics ; Administration, Intranasal ; *Immunity, Mucosal/immunology ; *Influenza A Virus, H5N1 Subtype/immunology/genetics ; Ferrets ; Mice ; *Orthomyxoviridae Infections/prevention &amp; control/immunology/virology ; *Replicon/immunology ; Female ; *Influenza A Virus, H7N9 Subtype/immunology/genetics ; Humans ; Mice, Inbred BALB C ; Antibodies, Viral/immunology ; *Influenza, Human/prevention &amp; control/immunology/virology ; Injections, Intramuscular ; Hemagglutinin Glycoproteins, Influenza Virus/immunology/genetics ; }, abstract = {Seasonal and pandemic influenza viruses are continuous threats to human health, requiring rapid development of vaccines to multiple evolving viral strains. RNA vaccine technologies have the adaptability and manufacturability to facilitate pandemic preparedness but have limited flexibility in their route of administration, reducing the ability to establish local protective immune responses such as respiratory mucosal immunity. Here, we describe monovalent and bivalent replicon vaccines against A/Vietnam/1203/2004 H5N1 and A/Anhui/PA-1/2013 H7N9. These replicon vaccines express either H5 or H7 hemagglutinin and are formulated with a nanostructured lipid carrier (NLC) that permits both intramuscular (IM) and intranasal (IN) dosing. In mice, IM vaccination established systemic humoral and cellular responses but no detectable mucosal response, while IN administration induced robust systemic and mucosal immunity. The replicon-NLC vaccines protected against morbidity and mortality in ferret challenge models, establishing this intranasally-administered replicon-NLC vaccine platform as a potential pandemic response tool.}, }
@article {pmid41530145, year = {2026}, author = {Brzoska, T and Kaminski, TW and Katoch, O and Menchikova, EV and Alagbe, AE and Tashbook, SE and Tofovic, SP and Jonassaint, JC and St Croix, CM and Watkins, SC and Howe, S and Field, JJ and Seyerle, AA and Pradhan-Sundd, T and Laurie, C and Pankratz, ND and Smith, NL and Goode, EL and Pankow, JS and Kooperberg, C and Kato, GJ and Zhang, Y and Novelli, EM and Gladwin, MT and Jackson, EK and Nouraie, SM and Sundd, P}, title = {CD39 polymorphism enables lung thrombosis in sickle cell disease.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {1693}, pmid = {41530145}, issn = {2041-1723}, support = {18TPA34170588//American Heart Association (American Heart Association, Inc.)/ ; 23TPA1074022//American Heart Association (American Heart Association, Inc.)/ ; R01HL141080//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL128297/HL/NHLBI NIH HHS/United States ; R01HL128297//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL166345//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL166345/HL/NHLBI NIH HHS/United States ; }, mesh = {*Anemia, Sickle Cell/genetics/complications/blood ; Humans ; Animals ; *Apyrase/genetics/metabolism ; *Thrombosis/genetics ; *Antigens, CD/genetics/metabolism ; Platelet Aggregation/drug effects/genetics ; Adenosine Diphosphate/metabolism ; Mice ; Male ; *Lung/pathology/metabolism ; Female ; Extracellular Vesicles/metabolism ; Polymorphism, Single Nucleotide ; *Lung Diseases/genetics ; Adult ; Blood Platelets/metabolism ; }, abstract = {Sickle cell disease (SCD) is the most common monogenic-hemolytic disorder affecting people of African ancestry. Adenosine diphosphate (ADP) released following intravascular hemolysis activates platelets by stimulating purinergic receptors to promote thrombosis. Despite brisk intravascular hemolysis, which releases high levels of ADP into plasma, and evidence of platelet and hemostatic activation, it remains elusive why only a subset of SCD patients develop lung thrombosis. Using real-time in vivo lung microscopy, we report a surprising finding that humanized SCD mice are protected from ADP-induced lung thrombosis, which is secondary to the degradation of ADP by CD39 present in circulating extracellular vesicles released by the lung endothelium. ADP-induced platelet aggregation is also impaired in the blood of SCD patients with elevated levels of CD39[+] extracellular vesicles. CD39 polymorphism rs3176891A→G is associated with the incidence of lung thrombosis in SCD patients but not healthy humans of African ancestry. Remarkably, CD39[+] extracellular vesicles are fewer and ADP-induced platelet aggregation is higher in the blood of SCD patients with rs3176891G allele. This study identifies a novel extracellular vesicle-dependent mechanism preventing lung thrombosis in SCD and reveals how CD39 polymorphisms may impair this protection to increase the risk for lung thrombosis in a subset of SCD patients.}, }
@article {pmid41531135, year = {2026}, author = {Hayek, H and Halasa, NB and Hill, JA}, title = {Establishing Permanence, Not Patchwork: Sustaining Coordinated Research Networks for Immunocompromised Populations.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {28}, number = {2}, pages = {e70168}, doi = {10.1111/tid.70168}, pmid = {41531135}, issn = {1399-3062}, }
@article {pmid41532388, year = {2026}, author = {Cassaday, RD and DeAngelo, DJ}, title = {Patients First: Navigating Asparaginase-Based Treatment in Young Adults With Acute Lymphoblastic Leukemia.}, journal = {American journal of hematology}, volume = {101}, number = {5}, pages = {937-938}, doi = {10.1002/ajh.70195}, pmid = {41532388}, issn = {1096-8652}, mesh = {Humans ; *Asparaginase/therapeutic use/adverse effects/administration &amp; dosage ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Young Adult ; Adult ; Female ; Male ; *Antineoplastic Agents/therapeutic use/adverse effects ; Drug Monitoring ; Adolescent ; }, abstract = {This CME/CE integrates real patient stories, current evidence, evolving guideline recommendations, and expert clinical experience to equip hematology/oncology clinicians with practical strategies for successful asparaginase-based therapy in young adults with acute lymphoblastic leukemia (ALL). The overarching goal is to improve outcomes for young adults with ALL through more consistent application of pediatric-inspired regimens, optimized asparaginase use, and comprehensive, patient-centered care. Leukemia experts synthesize the latest evidence on the efficacy and safety of asparaginase-based ALL treatment for young adults. Using a case-based approach, the curriculum provides structured guidance on mitigation, monitoring, and management of key asparaginase-related toxicities. Practical recommendations include therapeutic drug monitoring of asparaginase activity, detection of clinical and silent hypersensitivity reactions, and timely substitution of Escherichia coli-derived asparaginase with Erwinia-derived asparaginase to preserve therapeutic activity and efficacy after immune-mediated inactivation. Beyond treatment selection and toxicity management, the activity addresses system-level and psychosocial barriers that uniquely affect young adults with ALL, such as distance from specialty centers, employment and family responsibilities, lower rates of clinical trial participation, and survivorship concerns. To view this activity, and obtain CME/CE credit, visit www.cmeologyce.org/ajh-all.}, }
@article {pmid41533748, year = {2025}, author = {Boeckh, M and Xie, H and Stevens-Ayers, T and Sircy, L and Zamora, D and Goldman, JD and Woods, CW and Stapleton, RD and Rubenfeld, G and Kalil, A and Jerome, KR and Dasgupta, S and Limaye, AP}, title = {Cytomegalovirus DNAemia in Hospitalized Adults With SARS-CoV-2 Infection Requiring Supplemental Oxygen: Virologic and Clinical Characteristics and Association With Outcomes.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiaf649}, pmid = {41533748}, issn = {1537-6613}, support = {//Merck Investigator Study/ ; }, abstract = {BACKGROUND: Cytomegalovirus (CMV) reactivation occurs in the context of coronavirus disease 2019 (COVID-19); however, the viral kinetics, risk factors, and clinical outcomes are poorly defined.<br><br>METHODS: We examined the association of CMV DNAemia with clinical outcomes among participants of a randomized trial of remdesivir with or without baricitinib (National Institute of Allergy and Infectious Diseases [NIAID], Adaptive COVID-19 Treatment Trial 2 [ACTT-2]). Plasma CMV DNAemia from CMV-seropositive participants with COVID-19 (NIAID ordinal scale [OS] 5, 6, or 7 at entry) were assessed longitudinally by quantitative polymerase chain reaction. Factors associated with CMV DNAemia, and clinical outcomes were analyzed by Cox regression and proportional odds models.<br><br>RESULTS: Of 772 trial participants with available samples, 643 (83%) were CMV seropositive. Baseline CMV serostatus was not associated with COVID-19 outcomes. The cumulative incidence of CMV DNAemia among seropositive persons by day 28 was overall 11% (baseline OS 5, 6.3%; OS 6, 16.4%; OS 7, 24.7%), and was associated with older age, baseline OS, male sex, lymphopenia, and systemic corticosteroid use, while remdesivir and baricitinib did not affect risk. CMV DNAemia was associated with a lower probability of improvement by day 29 (adjusted hazard ratio, 0.3 [95% confidence interval, .17-.56]), with a more pronounced delay of recovery with higher CMV viral load. CMV DNAemia was also associated with higher severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and death.<br><br>CONCLUSIONS: In hospitalized adults with COVID-19 requiring oxygen, CMV viremia occurs within well-defined clinical risks and is independently associated with delayed recovery from illness, higher SARS-CoV-2 viral load, and increased mortality.}, }
@article {pmid41534004, year = {2026}, author = {Liang, EC and Jeon, Y and Qiao, Y and Wu, X and Huang, JJ and Portuguese, AJ and Basom, R and Torkelson, A and Kirchmeier, D and Braathen, K and Cowan, AJ and Shadman, M and Hirayama, AV and Till, BG and Kimble, EL and Wu, Q and Gauthier, J}, title = {Time-Series Clustering Captures Patterns of Early Immune Effector Cell-Associated Hematotoxicity That Are Predictable Using Tree-Based Models.}, journal = {JCO clinical cancer informatics}, volume = {10}, number = {}, pages = {e2500148}, pmid = {41534004}, issn = {2473-4276}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; T32 GM145449/GM/NIGMS NIH HHS/United States ; T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Cluster Analysis ; *Immunotherapy, Adoptive/adverse effects/methods ; Male ; Female ; Middle Aged ; Time Factors ; }, abstract = {PURPOSE: Immune effector cell-associated hematotoxicity (ICAHT) is a major cause of nonrelapse mortality after chimeric antigen receptor (CAR) T-cell therapy. We hypothesized that unsupervised time-series clustering could better identify archetypal patterns of early hematotoxicity compared to the early ICAHT (eICAHT) grading system.<br><br>METHODS: We applied unsupervised k-means time-series clustering based on Euclidean distances to longitudinal absolute neutrophil count (ANC) data from days +0 through +30 post-CAR T-cell infusion in 691 patients treated at our center (training set: n = 483, 70%; test set: n = 208, 30%).<br><br>RESULTS: Within our training set, we identified an optimal cluster solution based on four ANC recovery clusters, which were labeled as very good, good, poor, and very poor. We trained a random forest (RF) model including the top five most important features (day +3, +4, +5, +26, and +27 ANC values) to predict the cluster assignments. Within our test set, we applied the RF model to predict cluster assignments. Compared with the eICAHT criteria, the RF-predicted clusters were more compact and better separated (Dunn index: 0.078 v 0.034; average silhouette width: 0.12 v 0.010). In addition, the RF model identified patients in the good recovery cluster with intermediate overall survival (hazard ratio [HR], 1.70 [95% CI, 1.05 to 2.74]; P = .029; reference, very good), which was not captured by grade 2 eICAHT (HR, 1.37 [95% CI, 0.80 to 2.35]; P = .25; reference, grade 0-1).<br><br>CONCLUSION: Unsupervised time-series clustering identified distinct and clinically relevant patterns of hematotoxicity after CAR T-cell therapy. We trained and tested an RF model that accurately predicted cluster assignments using only five features. Predictions can be generated using our online web application.}, }
@article {pmid41535386, year = {2026}, author = {Li, J and Hu, J and Yun, H and Mei, Z and Wang, X and Luo, K and Guasch-Ferré, M and Han, X and Truong, B and Merino, J and Jia, C and Ruiz-Canela, M and Rebholz, CM and Moon, EH and Alkis, T and Liu, G and Yao, J and Zhang, X and Porneala, BC and Salas-Salvadó, J and Wang, TJ and Dupuis, J and Selvin, E and Guo, X and Bhupathiraju, SN and Brody, JA and Liu, Y and Wood, AC and North, KE and Jung, SY and Liu, CT and Sotoodehnia, N and Liu, S and Tinker, LF and Eliassen, AH and Manson, JE and Florez, JC and Gerszten, RE and Clish, CB and Liang, L and Lemaitre, RN and Tucker, KL and Rich, SS and Rotter, JI and Martínez-González, MA and Rexrode, KM and Meigs, JB and Boerwinkle, E and Kaplan, RC and Hu, FB and Yu, B and Qi, Q}, title = {Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.}, journal = {Nature medicine}, volume = {32}, number = {2}, pages = {660-670}, pmid = {41535386}, issn = {1546-170X}, support = {R00DK122128//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01DK119268; R01DK126698; U01DK140761; R01DK120870//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01DK081572//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01AG085320//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01HL060712//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 23POST1020455//American Heart Association (American Heart Association, Inc.)/ ; NNF24OC0095435//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; K24HL152440//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 EY036258/EY/NEI NIH HHS/United States ; R01HL136266//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U01DK140761//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01DK134672//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01HL060712; R01HL170904//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL153178//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/genetics/blood/metabolism ; *Life Style ; Female ; Male ; *Metabolome/genetics ; Risk Factors ; Middle Aged ; Adult ; Obesity/genetics ; Insulin Resistance/genetics ; Metabolomics ; Diet ; }, abstract = {The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.}, }
@article {pmid41535474, year = {2026}, author = {Cheng, H and Su, Y and Pan, X and Xu, Y and Xie, E and Du, J and Chen, DG and Dai, X and Gottardo, R and Greenberg, PD and Li, G}, title = {The ubiquitin ligase KLHL6 drives resistance to CD8[+] T cell dysfunction.}, journal = {Nature}, volume = {651}, number = {8105}, pages = {451-461}, pmid = {41535474}, issn = {1476-4687}, support = {//Juno Therapeutics/ ; }, mesh = {Animals ; Female ; Humans ; Male ; Mice ; *CD8-Positive T-Lymphocytes/immunology/cytology/metabolism/pathology/enzymology ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice, Inbred C57BL ; Mitochondria/metabolism/pathology ; Mitochondrial Dynamics ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Receptors, Antigen, T-Cell/metabolism ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Ubiquitination ; *Carrier Proteins/metabolism ; }, abstract = {The multifaceted dysfunction of tumour-infiltrating T cells, including exhaustion and mitochondrial dysfunction, remains a major obstacle in cancer immunotherapy[1-6]. Transcriptomic and epigenomic regulation of T cell dysfunction have been extensively studied[7-9], but the role of proteostasis in regulating these obstacles remains less defined. Here we combined computational analyses of atlases of T cell exhaustion and mitochondrial fitness with performed targeted in vivo CRISPR screens, which identified the E3 ubiquitin ligase KLHL6 as a dual-negative regulator of both T cell exhaustion and mitochondrial dysfunction. Mechanistically, KLHL6 expression promoted TOX poly-ubiquitination and subsequent proteasomal degradation, thereby attenuating the transition of progenitor exhausted T cells towards terminal exhaustion. Simultaneously, KLHL6 maintained mitochondrial fitness by constraining the excessive mitochondrial fission that occurs during chronic T cell receptor stimulation by means of post-translational regulation of the PGAM5-Drp1 axis. However, KLHL6 is naturally downregulated by T cell receptor ligation, mitigating its potentially beneficial ubiquitin ligase activities during exposure to chronic stimulation. Enforcing KLHL6 expression in T cells markedly improved efficacy and long-term persistence against tumours and during viral infections in vivo. These findings uncover KLHL6 as a multifunctional, clinically actionable target for cancer immunotherapy, and highlight the potential of modulating proteostasis and ubiquitin modification to improve immunotherapy.}, }
@article {pmid41535609, year = {2026}, author = {Gottimukkala, KSV and Lane, DD and Cunningham, R and Malik, HS and Jwa, Y and Cassidy, ME and Castelli, JMP and Enstrom, MR and Poljakov, K and Gastelum, G and Ho, SH and Tassa, C and Adair, JE}, title = {CRISPR-AuNP: physicochemical optimization of a gold nanoparticle platform for cost-effective and modular non-viral gene editing in HSPCs.}, journal = {Gene therapy}, volume = {33}, number = {2}, pages = {188-202}, pmid = {41535609}, issn = {1476-5462}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI158728/AI/NIAID NIH HHS/United States ; R01 AI167009/AI/NIAID NIH HHS/United States ; U54 DK106829/DK/NIDDK NIH HHS/United States ; }, mesh = {*Gene Editing/methods/economics ; *Gold/chemistry ; *CRISPR-Cas Systems ; *Metal Nanoparticles/chemistry ; Humans ; *Hematopoietic Stem Cells/metabolism ; Cost-Benefit Analysis ; Polyethylene Glycols/chemistry ; }, abstract = {Efficient delivery of CRISPR ribonucleoproteins into primary hematopoietic stem and progenitor cells (HSPCs) is essential for durable gene editing therapies but remains challenging. Here, we advance a modular, benchtop-assembled gold-polymer hybrid nanoparticle (CRISPR-AuNP) platform that enables non-viral delivery of multiple CRISPR systems into HSPCs. Guided by a mechanistic understanding of Cas9's interaction with gold surfaces, we engineered the formulation by conjugating pre-formed RNP-polymer complexes, assembled using thiolated polyethyleneimine-polyethylene glycol, to gold nanoparticles. This system achieved efficient editing in primary CD34+ HSPCs for Cas9, Cas12a, and Cas12a-M29-1 without compromising cell viability. Notably, the nanoformulation can be assembled in under 2 h in a PCR tube for less than $70/million HSPCs treated. This work establishes a scalable, cost-effective, and accessible gene editing system with the potential to democratize CRISPR applications in HSPC research and therapy.}, }
@article {pmid41536779, year = {2026}, author = {Martinelli, G and Solomon, SR and Mukherjee, S and Santoro, A and Strickland, SA and Vives, S and Ravandi, F and Walter, RB and Cook, RJ and Lech-Maranda, E and Calbacho, M and Wierzbowska, A and Marconi, G and Acuña-Cruz, E and Cano-Ferri, I and Bertolini, F and Rzymski, T and Paoli, A and Merlo, GM and Auriol, FK and Zicari, S and Galleu, A and Gupta, I and Montesinos, P}, title = {Dual FLT3/PIM inhibitor dapolsertib in acute myeloid leukemia: results from the phase 1/2 DIAMOND-01 trial.}, journal = {Blood neoplasia}, volume = {3}, number = {1}, pages = {100178}, pmid = {41536779}, issn = {2950-3280}, abstract = {Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer with poor survival outcomes. Despite improvements with recent FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance is common, and responses are short. Dapolsertib (MEN1703) is a novel, first-in-class dual inhibitor of PIM (proviral integration site for Moloney murine leukemia virus) and FLT3 kinases, with activity in both FLT3-mutated and wild-type cells. A phase 1/2 open-label, multicenter, dose-escalation study (DIAMOND-01) investigated the maximum tolerated dose (MTD) of single-agent dapolsertib and assessed its safety, efficacy, pharmacokinetic (PK) profile, pharmacodynamic biomarkers, and genomics in patients with AML with no standard therapeutic options available. Seventy-three patients received oral doses of dapolsertib ranging from 25 to 150 mg per day (14 consecutive days over 21-day cycles). In the dose-escalation phase, the MTD was 125 mg and was selected for dose expansion. The most common grade ≥3 adverse events in patients receiving 125 mg were pneumonia (38%), thrombocytopenia (30%), and anemia (27%); most of these events were deemed not treatment related. For patients receiving 125 mg dapolsertib (n = 55), the overall response rate was 9%, with a median 2.07-month duration of response, and 4 of 5 responses were observed in patients with isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations. PK analysis indicated rapid absorption of oral dapolsertib, an elimination half-life suitable for once daily dosing and a PK independent of formulation and IDH mutational status. Pharmacodynamic activity was confirmed in 50% of evaluable patients. Overall, dapolsertib demonstrated modest single-agent activity in patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT03008187.}, }
@article {pmid41537347, year = {2026}, author = {Yeung, CCS and Eacker, SM and Sala-Torra, O and Wood, M and Beppu, L and Woolston, DW and Liachko, I and Malig, M and Stirewalt, D and Muratov, A and Fang, M and Radich, J}, title = {Evaluation of acute myeloid leukemia using genomic proximity mapping-based next generation cytogenomics.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.288461}, pmid = {41537347}, issn = {1592-8721}, support = {R44 CA278140/CA/NCI NIH HHS/United States ; }, abstract = {Cytogenetic analysis encompasses a suite of standard-of-care diagnostic testing methods that is applied routinely in cases of acute myeloid leukemia (AML) to assess chromosomal changes that are clinically relevant for risk classification and treatment decisions. In this study, we assess the use of Genomic Proximity Mapping® (GPM) for cytogenomic analysis of AML diagnostic specimens for detection of cytogenetic risk variants included in the European Leukemia Network (ELN) risk stratification guidelines. Archival patient samples (n = 48) from the Fred Hutchinson Cancer Center (FH) leukemia bank with historical clinical cytogenetic data were processed for GPM and analyzed with the CytoTerra cloud-based analysis platform. Genomic proximity mapping showed 100% concordance for all specific variants that have associated impacts on risk stratification as defined by ELN 2022 criteria and 78% concordance when considering all variants reported by the FH Cytogenetics Lab. Notably, the percentage of blasts (ranging from 5- 96%) did not have a clear effect on the ability to detect these variants. In two cases, GPM identified a recurrent inv(9)(p13.3p13.1). These findings demonstrate GPM's effectiveness for the evaluation of known AML-associated risk variants and a source for biomarker discovery.}, }
@article {pmid41537594, year = {2026}, author = {Snow, JA and Hatzios, SK and Salama, NR}, title = {Managing dangerous liaisons: lessons from Helicobacter pylori for understanding bacterial carcinogenesis.}, journal = {Journal of bacteriology}, volume = {208}, number = {2}, pages = {e0045725}, pmid = {41537594}, issn = {1098-5530}, support = {R01 AI094839/AI/NIAID NIH HHS/United States ; R01 AI054423/AI/NIAID NIH HHS/United States ; R01AI136946//National Institute of Allergy and Infectious Diseases/ ; R01AI054423//National Institute of Allergy and Infectious Diseases/ ; R35 GM137952/GM/NIGMS NIH HHS/United States ; R35GM137952/GM/NIGMS NIH HHS/United States ; R01AI182086//National Institute of Allergy and Infectious Diseases/ ; R21CA270512/CA/NCI NIH HHS/United States ; R21 AI135381/AI/NIAID NIH HHS/United States ; R01 AI182086/AI/NIAID NIH HHS/United States ; }, mesh = {*Helicobacter pylori/pathogenicity/genetics/physiology ; *Helicobacter Infections/microbiology/complications ; Humans ; Animals ; *Carcinogenesis ; *Host-Pathogen Interactions ; Mice ; Disease Models, Animal ; Virulence Factors/metabolism/genetics ; Stomach Neoplasms/microbiology ; Bacterial Proteins/metabolism/genetics ; }, abstract = {As the first bacterium to be deemed a class I carcinogen by the World Health Organization in 1994, Helicobacter pylori has paved the way for studying complex host-pathogen interactions. While 1982 marked the discovery of this helical-shaped microorganism found in gastric biopsies by Drs. Robin Warren and Barry Marshall, it took years to link H. pylori infection to gastric inflammation, ulcers, and adenocarcinoma (recognized by a Nobel Prize in 2005). Further investigations into how H. pylori colonizes the stomach, the identification of key virulence factors (such as VacA, CagA, and outer membrane proteins), and global epidemiological studies solidified the impact of H. pylori on gastric disease. This review details the seminal discovery of H. pylori and subsequent work that cemented its status as a microbial carcinogen. Because chronic H. pylori infection and progressive changes to the tissue environment prior to cancer development can span years/decades, studying H. pylori pathogenesis has been challenging. We focus on the importance of using animal models, in particular mouse models, to recapitulate hallmarks of H. pylori-driven human disease. Finally, we highlight recent findings illustrating how H. pylori has adapted to survive and utilize oxidative stress induced during infection, which potentiates cancer development. Due to the long-lasting nature of H. pylori infection and associated remodeling of the host environment that, in turn, promotes carcinogenesis, H. pylori stands as a model organism for understanding other chronic bacterial infections in humans and pathogen-associated malignancies.}, }
@article {pmid41538162, year = {2026}, author = {Qureshi, S}, title = {A Completely Unfair Time of Ultimate Suffering.}, journal = {JAMA oncology}, volume = {12}, number = {3}, pages = {239-240}, doi = {10.1001/jamaoncol.2025.5921}, pmid = {41538162}, issn = {2374-2445}, }
@article {pmid41538746, year = {2026}, author = {Sepassi, A and Ramsey, SD and Fendrick, AM and Gabriel, N and Zell, JA and Mukamel, DB and Sullivan, SD}, title = {Potential Impact of the Medicare Prescription Payment Plan for Medicare Part D Beneficiaries With a Cancer Diagnosis.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {7}, pages = {598-606}, pmid = {41538746}, issn = {1527-7755}, abstract = {PURPOSE: To address high out-of-pocket (OOP) medication costs among Medicare Part D beneficiaries, the 2022 Inflation Reduction Act introduced the Medicare Prescription Payment Plan (M3P), a voluntary program that allows beneficiaries to spread OOP costs over the calendar year. We examined M3P's potential impact among beneficiaries with cancer, who frequently incur substantial early-year Part D medication costs.<br><br>MATERIALS AND METHODS: We evaluated a 2022 5% random sample of Medicare beneficiaries with a cancer diagnosis and &#x2265;1 fill for a cancer-indicated Part D medication. We estimated 2025-adjusted annual true OOP spending and median monthly beneficiary OOP payment obligations with and without M3P enrollment. Subgroup analyses were performed by demographics, nonadherence status in 2022, and Part D benefit phase.<br><br>RESULTS: Among 168,480 beneficiaries with cancer, most were diagnosed with breast (47.6%), dermatologic (17.6%), or prostate (13.3%) cancers. Overall, 46.7% were projected to reach catastrophic coverage in 2025, with 32.4% doing so in January. Breast (29.7%), prostate (21.20%), and hematologic (20.0%) cancers were most common among those reaching catastrophic coverage. Overall, 43.0% were nonadherent to cancer-indicated Part D medications, with 31.5% reaching catastrophic coverage in January 2025. M3P reduced beneficiary payment obligation variability, especially among those reaching the catastrophic phase in January (IQR, $1,798 US dollars [USD] no M3P v $118 USD M3P). Of those reaching catastrophic coverage with a cancer-indicated drug (58.6% overall), 89.2% did so in January.<br><br>CONCLUSION: Early-year entry into catastrophic coverage is common among beneficiaries with certain high-cost cancers. M3P may most effectively reduce financial burden when enrollment occurs before January. Targeted outreach from cancer care teams and Part D plans to nonadherent patients and those considering costly therapies could maximize program impact and improve treatment outcomes.}, }
@article {pmid41539205, year = {2026}, author = {Lee, J and Rodriguez, CJ and Daviglus, ML and Kaplan, R and Isasi, CR and Sotres-Alvarez, D and Blaha, MJ and Mok, Y and Perreira, KM and Oren, E and Elfassy, T and Telzak, A and Ejiri, K and Vu, TT and Matsushita, K}, title = {Electronic Cigarette Use and Risk of Hypertension: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {JACC. Advances}, volume = {5}, number = {2}, pages = {102525}, pmid = {41539205}, issn = {2772-963X}, support = {P30 ES027792/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Acute increases in blood pressure (BP) after electronic cigarette (e-cigarette) use have been reported, but its long-term association with hypertension is unclear.<br><br>OBJECTIVES: The purpose of this study was to assess whether e-cigarette use is associated with prevalent and incident hypertension.<br><br>METHODS: We analyzed visit 2 (2014-2017) and visit 3 (2020-2024) data from the HCHS/SOL (Hispanic Community Health Study/Study of Latinos), a population-based cohort study including 11,623 individuals aged 18 to 74 years across 4 U.S. communities. The primary exposure was ever e-cigarette use at visit 2. We also explored current use and dual use with combustible cigarette use. Hypertension was defined as measured BP &#x2265; 140/90 mm Hg or self-reported antihypertensive medication use. Multivariable Poisson and Cox regression were used for prevalent and incident hypertension, respectively. Longitudinal BP change from visit 2 to 3 was assessed using mixed-effects models. All analyses accounted for the complex survey design.<br><br>RESULTS: Of 11,593 participants with e-cigarette data (mean age 47 years; 52.2% female), 937 reported ever use (136 current users). Ever vs never e-cigarette use was not associated with prevalent hypertension. Over a median follow-up of 6.0 years, 1,409 participants developed hypertension. Ever vs never e-cigarette use was associated with incident hypertension (HR: 1.49; 95% CI: 1.14-1.95), as were current use (HR: 1.89; 95% CI: 1.12-3.18), former use (HR: 1.43; 95% CI: 1.07-1.93), and dual ever use (HR: 1.85; 95% CI: 1.37-2.49), compared to never use. Longitudinal BP change did not differ by e-cigarette use.<br><br>CONCLUSIONS: Ever e-cigarette use was associated with increased risk of incident hypertension, suggesting potential long-term cardiovascular harm.}, }
@article {pmid41539488, year = {2026}, author = {Markova, A and Lee, SJ and Modi, B and Baumrin, E and Rosenstein, RK and Tkaczyk, ER and Lehman, JS and Inamoto, Y and Carpenter, PA and Schultz, KR and Pidala, JA and Martin, P and Pusic, I and Goklemez, S and Stockmann, C and Pinal-Fernandez, I and Paczesny, S and Harris, A and Ponce, DM and Holtzman, NG and Jurdi, NE and Pavletic, SZ and Cowen, EW}, title = {Toward Better Response Assessment of Cutaneous Chronic Graft-Versus-Host Disease: A Report from the National Institutes of Health Consensus Project Task Force.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, pmid = {41539488}, issn = {2666-6367}, support = {IK2 CX001785/CX/CSRD VA/United States ; U54 CA163438/CA/NCI NIH HHS/United States ; K12 CA226330/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA118953/CA/NCI NIH HHS/United States ; K23 AR085191/AR/NIAMS NIH HHS/United States ; U01 CA118953/CA/NCI NIH HHS/United States ; R01 HL169944/HL/NHLBI NIH HHS/United States ; R01 HL164902/HL/NHLBI NIH HHS/United States ; I01 CX002721/CX/CSRD VA/United States ; U01 CA236229/CA/NCI NIH HHS/United States ; }, abstract = {The National Institutes of Health (NIH) chronic graft-versus-host disease (cGVHD) Consensus Project established response criteria that enabled clinical trials and facilitated regulatory approval of multiple therapies. Nonetheless, organ-specific assessments have limitations, particularly for severe sclerotic skin involvement. Cutaneous manifestations occur in approximately half of patients with chronic GVHD but are difficult to evaluate due to heterogeneous clinical features. To address these challenges, the NIH Consensus Skin Task Force convened from 2024 to 2025 to refine skin response measures for use in clinical trials. This report (1) summarizes current diagnosis and scoring of skin chronic GVHD, (2) reviews existing response assessments, (3) identifies gaps in their performance, (4) proposes refinements to the 2014 NIH skin response criteria, and (5) outlines future directions incorporating patient-reported outcomes, novel technologies, and biomarker research. Current NIH scoring relies on a 4-point body surface area (BSA) scale and a 3-point sclerosis features scale. While standardized, these measures have limited sensitivity to clinically meaningful change. Proposed refinements include: (1) separate BSA assessments for epidermal involvement and sclerotic features; (2) modification of sclerosis descriptors, with removal of impaired mobility and specification of GVHD-related ulceration, and addition of sclerosis-associated edema with or without erythema; and (3) replacement of the exploratory severity scale with two new clinician instruments. The Sclerosis Quality and Physical Signs scale (0 to 10) captures qualitative physical changes, while the Sclerosis Daily Function Impact scale (0 to 4) evaluates functional compromise. These proposed refinements aim to improve the accuracy, reproducibility, and clinical relevance of skin chronic GVHD assessments, strengthening trial endpoints and patient care.}, }
@article {pmid41540004, year = {2026}, author = {Chen, Z and Song, W and Li, Q and Li, C and Wen, W and Huyghe, JR and Law, PJ and Fernandez-Rozadilla, C and Timofeeva, MN and Thomas, M and Schmit, SL and Martin, V and Devall, M and Dampier, C and Moratalla-Navarro, F and Cai, Q and Wang, J and Shi, J and Kweon, SS and Tanikawa, C and Jia, WH and Shu, X and Long, J and Gao, J and Kim, J and Shin, A and Matsuo, K and Jee, SH and Jung, KJ and Wang, N and Kim, DH and Ping, J and Yang, G and Shin, MH and Ren, Z and Oh, JH and Oze, I and Ahn, YO and Gao, YT and Pan, ZZ and Kamatani, Y and Van Kaer, L and Wu, L and Li, B and Matsuda, K and Shu, XO and Hsu, L and Dunlop, MG and Gruber, SB and Houlston, R and Tomlinson, I and Li, L and Lau, KS and Moreno, V and Casey, G and Peters, U and Zheng, W and Guo, X}, title = {Mixed-model and transcriptome-wide association analyses identify transcription factors and genes associated with colorectal cancer susceptibility.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {1377}, pmid = {41540004}, issn = {2041-1723}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA269589/CA/NCI NIH HHS/United States ; R01 CA297582/CA/NCI NIH HHS/United States ; R37 CA227130/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics ; Genome-Wide Association Study ; *Genetic Predisposition to Disease/genetics ; *Transcription Factors/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; *Transcriptome/genetics ; Gene Regulatory Networks ; Polymorphism, Single Nucleotide ; Asian People/genetics ; White People/genetics ; Gene Expression Profiling ; Female ; Alternative Splicing ; Male ; }, abstract = {Susceptibility transcription factors (TF) whose DNA bindings are altered by genetic variants regulating colorectal cancer (CRC) risk genes remain poorly defined. Using generalized linear mixed models, we analyze 218 TF ChIP-Seq datasets alongside GWAS data from 100,204 CRC cases and 154,587 controls of East Asian and European ancestries. We identify 51 TFs and TF-cofactor interactions, including VDR-cofactors, as key regulators of CRC risk. Integrating these TF insights with transcriptome-wide association studies (TWAS), we further evaluate associations between genetically predicted gene expression, alternative splicing, and alternative polyadenylation with CRC risk, using RNA-seq data from 364 Asian-ancestry and 707 European-ancestry individuals. Multi-ancestry TWAS identify 222 risk genes, including 95 novel genes and 48 potentially druggable targets. Single-cell analysis provides additional functional evidence supporting ~45% of these genes, and experimental validation confirms oncogenic roles for RHPN2, IRS2, and TXN. Our findings elucidate key TF-gene regulatory networks and uncover novel CRC risk genes.}, }
@article {pmid41540901, year = {2026}, author = {Xu, P and Ueha, S and Aoki, H and Kitabatake, M and Mingyu, C and Shichino, S and Hara, A and Ouji-Sageshima, N and Ito, T and Motozono, C and Matsushima, K}, title = {Repeated mRNA vaccination and breakthrough infection reveal durable dominance but diminishing recall of vaccine-induced CD8[+] T-cell clones.}, journal = {International immunology}, volume = {}, number = {}, pages = {}, doi = {10.1093/intimm/dxag004}, pmid = {41540901}, issn = {1460-2377}, abstract = {Successive mRNA vaccinations preserve SARS-CoV-2-specific T-cell immunity, but how individual CD8[+] T-cell clones behave across repeated booster doses and breakthrough infection (BTI) remains poorly defined. We longitudinally tracked bulk CD8[+] TCRβ repertoires and spike-specific tetramer[+] CD8[+] T cells in adult participants across the third and fourth vaccine doses and subsequent BTI. Each booster continued to recruit previously unexpanded "new" responder clonotypes, but both the number and summed frequency of newly engaged clones declined with successive doses. In contrast, clones first recruited by the initial prime-boost doses-particularly those expanded after dose 2-formed a durable, hierarchically dominant memory pool that persisted for more than two years yet displayed progressively attenuated recall with later boosters. BTI revealed a complementary mode of repertoire remodeling: newly engaged clones that had not responded to prior vaccinations showed the strongest, but transient, expansion, broadening the antigenic targets beyond spike. On the other hand, vaccine-induced clones showed limited recall response while sustaining their dominance in the long term. Together, these findings indicate that repeated mRNA vaccination maintains a stable pool of early-established CD8[+] T-cell clones but progressively limits their recall capacity, whereas BTI mobilizes additional, partially distinct clonotypes that expand robustly and broaden antigenic coverage.}, }
@article {pmid41541220, year = {2026}, author = {Mishra, DK and Morris, SM and Popovski, D and Girard, EJ and Bondoc, A and Senthil Kumar, S and Andrade, AF and Zhu, X and Yao, F and Brusniak, MY and Umaru, B and Crotty, EE and Brasel, K and Pakiam, F and Russo, C and Zeinieh, M and Biery, MC and Coxon, M and Conti, H and Clarke, M and Lu, M and Rutka, J and Llivichuzhca-Loja, D and Konnikova, L and Fouladi, M and Jabado, N and Huang, A and Olson, JM and Drissi, R}, title = {Preclinical assessment of checkpoint blockade combined with DNA methyltransferase inhibition in high-risk pediatric brain tumors reveals limited therapeutic synergy.}, journal = {Neuro-oncology advances}, volume = {8}, number = {1}, pages = {vdaf241}, pmid = {41541220}, issn = {2632-2498}, abstract = {ABSTRACT: BackgroundDespite intensive therapies, outcomes for high-risk pediatric brain tumors (PBTs) remain dismal, prompting the search for novel treatments. DNA methyltransferase inhibitors (DNMTi) have been shown to prime tumors to improve response to checkpoint inhibition. The aim of this study was to investigate the potential of decitabine (DAC), in combination with a PD-1 inhibitor, to improve survival in pediatric high-risk brain tumor models.<br><br>METHODS: Analysis of human PBT datasets was performed to determine gene expression levels of immune cell markers. Tumor response to DAC, with or without a PD-1 inhibitor, was tested in murine models representing H3-wildtype diffuse intrinsic pontine glioma (DIPG), H3K27-mutant diffuse midline glioma (DMG), atypical teratoid rhabdoid tumor (ATRT), and medulloblastoma (MB). CyTOF analysis of allograft tumors was performed to characterize changes within the tumor microenvironment.<br><br>RESULTS: Analysis of PBT subtypes revealed heterogeneous expression of immune cell markers, checkpoint receptors, and MHC molecules. DAC treatment decreased DNA methylation and increased neoantigen expression in human and mouse tumor cells. DAC treatment resulted in prolonged survival in syngeneic mouse models of DIPG and ATRT but not DMG and MB models. However, no added survival benefit was observed when combined with a PD-1 inhibitor. CyTOF analysis of mouse tumors revealed changes in local immune cell infiltration.<br><br>CONCLUSIONS: DAC alone or in combination with a checkpoint inhibitor can alter the immune microenvironment in mouse tumor models. Changes were observed in H3-wildtype DIPG and ATRT models, suggesting that certain tumor subtypes may respond to immune priming with DNMTi.}, }
@article {pmid41541249, year = {2026}, author = {Pan, X and Pan, Y and Su, Y and Xu, Y and Du, J and Cheng, H and Li, G}, title = {Chronic TCR signaling-driven suppression of the FOXO1-KLHL6 axis promotes T cell exhaustion.}, journal = {Immunity &amp; inflammation}, volume = {2}, number = {1}, pages = {8}, pmid = {41541249}, issn = {3059-4774}, }
@article {pmid41542066, year = {2026}, author = {Montano-Campos, F and Heagerty, P and Haupt, E and Hahn, E and Radich, J and Bansal, A}, title = {A Framework for Locally Imputing and Predicting Biomarker Trajectories Under Irregular Monitoring: Application to Chronic Myeloid Leukemia.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41542066}, issn = {2693-5015}, support = {R37 CA218413/CA/NCI NIH HHS/United States ; }, abstract = {Irregular monitoring and missing data limit the utility of longitudinal biomarkers in real-world practice. We developed a generalizable framework that combines interval-aligned preprocessing, localized multiple imputation, and machine-learning forecasting to generate complete trajectories and predict future biomarker values under routine clinical conditions. Using BCR::ABL1 monitoring in chronic myeloid leukemia as a case study, we aligned measurements to 90-day intervals, applied a windowed, uncertainty-propagating imputation strategy, and trained recurrent neural network (RNN) and XGBoost models to forecast values three and six months ahead. Full Information models achieved RMSEs of 1.22-1.24 for 3-month predictions-well below the biomarker's observed variability-and maintained accuracy even when the most recent visit was intentionally omitted, simulating extended follow-up. This framework preserves local temporal structure, supports individualized monitoring decisions, and is directly adaptable to other continuous biomarkers measured under irregular real-world schedules.}, }
@article {pmid41542557, year = {2026}, author = {Ahn, JJ and Yu, TC and Dadonaite, B and Radford, CE and Bloom, JD}, title = {Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41542557}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {Hemagglutinins (HA) from different influenza A virus subtypes share as little as ~40% amino acid identity, yet their protein structure and cell entry function are highly conserved. Here we examine the extent that sequence constraints on HA differ across three subtypes. To do this, we first use pseudovirus deep mutational scanning to measure how all amino-acid mutations to an H7 HA affect its cell entry function. We then compare these new measurements to previously described measurements of how all mutations to H3 and H5 HAs affect cell entry function. We find that ~50% of HA sites display substantially diverged preferences for different amino acids across the HA subtypes. The sites with the most divergent amino-acid preferences tend to be buried and have biochemically distinct wildtype amino acids in the different HA subtypes. We provide an example of how rewiring the interactions among contacting residues has dramatically shifted which amino acids are tolerated at specific sites. Overall, our results show how proteins with the same structure and function can become subject to very different site-specific evolutionary constraints as their sequences diverge.}, }
@article {pmid41543300, year = {2026}, author = {Ko, YJ and Castor, J and Kuralt, TD and Goecker, EA and Pepper, G and Reed, JC and Greninger, AL}, title = {Analytical Performance Comparison of Three Quantitative Hepatitis B Surface Antigen Assays.}, journal = {Clinical chemistry}, volume = {}, number = {}, pages = {}, doi = {10.1093/clinchem/hvaf191}, pmid = {41543300}, issn = {1530-8561}, support = {//Department of Laboratory Medicine/ ; //University of Washington/ ; F208422001//Chosun University/ ; }, abstract = {BACKGROUND: Quantitative hepatitis B surface antigen (qHBsAg) assays are important tools for monitoring hepatitis B virus (HBV) infection and treatment response and constitute the primary endpoint in most HBV antiviral trials. To date, no qHBsAg assay has been authorized by the FDA for use in the United States, highlighting the need for performance evaluation and harmonization of available methods.<br><br>METHODS: We evaluated the analytical performance of three commercial assays for qHBsAg measurement: Architect HBsAg Qualitative (Abbott) adapted for quantitative use, Elecsys HBsAg II quant II (Roche), and LIAISON XL Murex HBsAg Quant (DiaSorin). Performance characteristics including precision, accuracy, analytical sensitivity, linearity, and lot-to-lot variability were assessed using World Health Organization (WHO) International Standards 12/226 and 03/262, following CLSI guidelines. Clinical accuracy was also evaluated using 72&#x2005;HBsAg-positive clinical specimens.<br><br>RESULTS: The lower limit of quantification was 0.02&#x2005;IU/mL for Architect, 0.07&#x2005;IU/mL for Elecsys, and 1.02&#x2005;IU/mL for LIAISON. The LIAISON exhibited limited linearity and significantly greater variability in samples with high HBsAg levels, as well as significant lot-to-lot variability. Ultimately, all three assays demonstrated acceptable precision and accuracy, though the LIAISON had to be recalibrated specifically with WHO International Standard 03/262.<br><br>CONCLUSIONS: The Architect and Elecsys qHBsAg assays demonstrated sufficient analytical performance for clinical use, while the LIAISON was limited by its linearity, lower limit of quantification, and lot-to-lot variability. Standardization is essential to ensure consistent and accurate quantification of HBsAg for effective clinical monitoring and the establishment of treatment goals.}, }
@article {pmid41543856, year = {2026}, author = {Barata, PC and Corrigan, JK and La, J and Culnan, JM and Akama-Garren, E and Dulberger, KN and Dumontier, C and Hansen, J and Bihn, JR and Bitting, RL and Brophy, MT and Cheng, HH and Cooperberg, MR and Do, NV and Dorff, T and Fojo, AT and Gaziano, JM and Goryachev, SD and Halabi, S and Hauger, RL and Nanus, DM and Rebbeck, TR and Pan, CX and Schoen, MW and Swinnerton, KN and Myrie, K and Ramoni, RB and Fillmore, NR and Paller, CJ and Rettig, MB}, title = {Docetaxel Rechallenge vs Cabazitaxel in Patients With Metastatic Castration-Resistant Prostate Cancer.}, journal = {JAMA network open}, volume = {9}, number = {1}, pages = {e2551231}, pmid = {41543856}, issn = {2574-3805}, support = {IK2 CX002218/CX/CSRD VA/United States ; }, mesh = {Humans ; Male ; *Docetaxel/therapeutic use/administration &amp; dosage ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/mortality/pathology ; Aged ; *Taxoids/therapeutic use ; Retrospective Studies ; *Antineoplastic Agents/therapeutic use ; Middle Aged ; Treatment Outcome ; Neoplasm Metastasis ; }, abstract = {IMPORTANCE: Docetaxel has been a standard treatment for metastatic castration-resistant prostate cancer (mCRPC) since 2004. Cabazitaxel, a related taxane, was approved in 2010 for patients with mCRPC who had been previously treated with docetaxel. The comparative effectiveness of docetaxel rechallenge vs switching to cabazitaxel after prior docetaxel for mCRPC remains unclear.<br><br>OBJECTIVE: To compare the clinical outcomes associated with docetaxel rechallenge vs cabazitaxel in patients with mCRPC who did not experience disease progression during prior administration of docetaxel in the mCRPC setting.<br><br>This retrospective cohort study was conducted in the nationwide Veterans Affairs health care system, using inverse probability of treatment weighting to control for potential confounders. Patients who were diagnosed with chemonaive mCRPC between January 1, 2010, and December 31, 2023, received initial docetaxel treatment, and did not experience disease progression were eligible to participate.<br><br>EXPOSURES: Treatment with docetaxel rechallenge or cabazitaxel.<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS) from the initiation of the second course of taxane, which was compared in patients treated with docetaxel rechallenge vs cabazitaxel using weighted Kaplan-Meier analysis and Cox proportional hazards regression models. Secondary outcomes included prostate-specific antigen response, time to next systemic treatment or death, and subsequent treatments received.<br><br>RESULTS: A total of 669 patients (407 receiving cabazitaxel and 262 receiving docetaxel rechallenge) with a median age of 72 (IQR, 67-77) years were included. Patients treated with docetaxel rechallenge had a significantly longer OS (median, 12.3 [IQR, 10.5-13.8] months) compared with those treated with cabazitaxel (median, 9.6 [IQR, 8.6-11.1] months), with a hazard ratio of 0.81 (95% CI,&#x2009;0.55-0.99; P&#x2009;=&#x2009;.04). Descriptive analysis of secondary outcomes was consistent with this finding, including prostate-specific antigen response (weighted 9.8% achieving reduction of 90% or more in the docetaxel rechallenge group vs 3.0% in the cabazitaxel group) and time to next treatment or death (median, 10.7 [IQR, 7.8-12.7] months in the docetaxel rechallenge group vs 8.9 [IQR, 7.1-10.5 months] in the cabazitaxel group). Use of platinum, immunotherapy, or poly (ADP-ribose) polymerase inhibitors was similar between patients treated with cabazitaxel and docetaxel rechallenge.<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of patients with mCRPC, docetaxel rechallenge was associated with improved OS compared with cabazitaxel among patients who did not experience disease progression during prior docetaxel for mCRPC. These findings support docetaxel rechallenge as a treatment option for patients in this scenario.}, }
@article {pmid41543884, year = {2026}, author = {Bryl, KL and Silverwood, S and Desai, K and Schobert, K and Li, X and Chimonas, S and Mao, JJ and Gillespie, EF}, title = {Benefits and Challenges of a Digital Exercise and Mind-Body Program During Active Cancer Treatment: Qualitative Study of Patients' Perceptions.}, journal = {JMIR cancer}, volume = {12}, number = {}, pages = {e80075}, pmid = {41543884}, issn = {2369-1999}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Neoplasms/therapy/psychology ; Qualitative Research ; Middle Aged ; Male ; *Mind-Body Therapies/methods ; *Quality of Life ; Aged ; *Exercise Therapy/methods ; *Exercise ; Telemedicine ; }, abstract = {BACKGROUND: Individuals undergoing cancer treatment often face a high symptom burden that impairs quality of life. Exercise and mind-body therapies have been shown to reduce symptoms but are underused. We developed a digital exercise and mind-body therapy program that effectively reduces symptoms while overcoming in-person delivery barriers. Understanding patient experiences can inform treatment mechanisms and guide digital health interventions in cancer care.<br><br>OBJECTIVE: This study aimed to explore patient experiences with Integrative Medicine at Home (IM@Home), a 12-week live digital program delivering exercise and mind-body therapies tailored to the needs of individuals undergoing cancer treatment.<br><br>METHODS: This qualitative study was embedded in a randomized clinical basket trial (NCT05053230) evaluating the effects of IM@Home versus enhanced usual care on symptoms and acute health care utilization in adults with solid tumors undergoing active treatment and experiencing moderate or greater fatigue. Using maximum variation sampling, 20 participants were selected for semistructured interviews. Interviews explored participants' experiences with the program, its impact on outcomes, unmet needs, and suggestions for improvement. Transcripts were analyzed using a combined inductive and deductive thematic analysis.<br><br>RESULTS: Twenty participants (mean age 63, SD 9.6 years; 18/20, 90% female) were interviewed. Five major themes emerged: (1) IM@Home alleviated symptom burden and supported symptom self-management; (2) IM@Home facilitated social support and information exchange; (3) IM@Home offered a flexible, tailored program in a group setting; (4) IM@Home facilitated accessible, cost-effective support; and (5) recommendations for program enhancement. IM@Home was perceived as an accessible, flexible, and supportive program that promoted physical and emotional well-being during treatment.<br><br>CONCLUSIONS: IM@Home demonstrates a promising model for delivering integrative supportive care during cancer treatment. Findings highlight patient-valued features such as real-time guidance, tailored content, and community support. These insights can inform future implementation, integration into clinical care, and efforts to enhance digital mind-body interventions in oncology.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT05053230; https://www.clinicaltrials.gov/study/NCT05053230.<br><br>RR2-10.1038/s41746-024-01387-z.}, }
@article {pmid41544105, year = {2026}, author = {Mayer-Blackwell, K and Minervina, A and Pogorelyy, M and Rawat, P and Shapiro, MR and Peters, LD and Ford, ES and Posgai, AL and Vegesana, K and Minot, S and Koelle, DM and Greiff, V and Bradley, P and Brusko, TM and Thomas, PG and Fiore-Gartland, A}, title = {TCR2HLA: Calibrated inference of HLA genotypes from TCR repertoires enables identification of immunologically relevant metaclonotypes.}, journal = {PLoS computational biology}, volume = {22}, number = {1}, pages = {e1013767}, pmid = {41544105}, issn = {1553-7358}, support = {P01 AI042288/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; 75N93019C00063/OD/NIH HHS/United States ; U01 AI144616/AI/NIAID NIH HHS/United States ; P01 AI165077/AI/NIAID NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; K99 DK140511/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Genotype ; *HLA Antigens/genetics/immunology ; Computational Biology/methods ; Alleles ; *Receptors, Antigen, T-Cell/genetics ; COVID-19/immunology/genetics ; *Software ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; SARS-CoV-2/immunology ; }, abstract = {T cell receptors (TCRs) recognize peptides presented by polymorphic human leukocyte antigen (HLA) molecules, but HLA genotype data are often missing from TCR repertoire sequencing studies. To address this, we developed TCR2HLA, an open-source tool that infers HLA genotypes from TCRβ repertoires. Expanding on work linking public TRBV-CDR3 sequences to HLA genotypes, we incorporated "quasi-public" metaclonotypes - composed of rarer TCRβ sequences with shared amino acid features - enriched by HLA genotypes. Using four TCRβseq datasets from 3,150 individuals, we applied TRBV gene partitioning and locality-sensitive hashing to identify ~96,000 TCRβ features strongly associated with specific HLA alleles from 71M input TCRs. Binary HLA classifiers built with these features achieved high balanced accuracy (>0.9) across common HLA-A (9/12), B (9/12), C (6/13), DRB1 (11/11) alleles and prevalent DPA1/DPB1 (6/10), DQA1/DQB1 (8/17) heterodimers. We also introduced a high-sensitivity calibration to support predictions in samples with as few as 5,000 unique clonotypes. Calibrated predictions with confidence filtering improved reliability. Beyond genotype imputation, TCR2HLA enables the discovery of novel HLA- and exposure-associated TCRs, as shown by the identification of SARS-CoV-2 related TCRs in a large COVID-19 dataset lacking HLA data. TCR2HLA provides a scalable framework for bridging the gap between TCRseq data and HLA genotype for biomarker discovery.}, }
@article {pmid41544219, year = {2026}, author = {Patel, K and Vose, JM and Nasta, SD and Brown, JR and Maddocks, KJ and Woyach, JA and Shah, NN and Fakhri, B and Tessoulin, B and Ma, S and Jagadeesh, D and Lech-Maranda, E and Coombs, CC and Patel, MR and Rhodes, JM and Ujjani, C and Hoffmann, MS and Cheah, CY and Munir, T and Lewis, D and Scarfò, L and Eyre, TA and Alencar, A and Cohen, JB and Zelenetz, AD and Tsai, DE and Li, M and Bian, Y and Abada, P and Balbas, M and Zinzani, PL}, title = {Pirtobrutinib, a highly selective, noncovalent (reversible) BTKi in R/R marginal zone lymphoma: phase 1/2 BRUIN study.}, journal = {Blood advances}, volume = {10}, number = {7}, pages = {2441-2451}, pmid = {41544219}, issn = {2473-9537}, mesh = {Humans ; *Lymphoma, B-Cell, Marginal Zone/drug therapy/mortality/pathology ; Male ; Female ; Middle Aged ; Aged ; *Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; *Protein Kinase Inhibitors/therapeutic use/adverse effects/pharmacology ; Adult ; Aged, 80 and over ; *Pyrimidines/therapeutic use/adverse effects/pharmacology ; Treatment Outcome ; Pyrazoles ; }, abstract = {Marginal zone lymphoma (MZL) is a group of indolent B-cell malignancies with a remitting and relapsing course. For systemic disease, available first-line therapies include anti-CD20 antibody as monotherapy or in combination with chemotherapy (chemoimmunotherapy), with second-line options including covalent Bruton tyrosine kinase inhibitors (cBTKi). However, management of relapsed and refractory (R/R) MZL remains challenging. Pirtobrutinib, a highly selective, noncovalent BTKi has shown promising efficacy and tolerability in poor-prognosis B-cell malignancies following prior therapy, including cBTKi. Here, we report the safety and efficacy of pirtobrutinib in MZL from the phase 1/2 BRUIN study. Endpoints included investigator-assessed objective response rate (ORR) by Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Among 36 patients with R/R MZL (extranodal [n = 6]; nodal [n = 17]; splenic [n = 13]), median age was 68 years (range, 22-83) and median prior lines of therapy were 3 (range, 2-10). The ORR was 55.6% (95% confidence interval [CI], 38.1- 72.1), including 3 (8.3%) complete responses and 17 (47.2%) partial responses. Median DOR was 17.8 months (95% CI, 7.4 to nonestimable [NE]), and median PFS was 16.6 months (95% CI, 9.0-22.1). With median follow-up of 32.4 months (IQR, 28.0-41.3), median OS was NE (95% CI, 29.5-NE). The ORR for patients with prior cBTKi therapy was 53.8% (95% CI, 33.4-73.4). Pirtobrutinib was well tolerated with dose reductions in 4 patients (11.1%) and permanent discontinuation due to treatment emergent adverse events in 4 patients (11.1%). Pirtobrutinib showed promising efficacy and safety in patients with heavily pretreated R/R MZL, including prior cBTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529.}, }
@article {pmid41544638, year = {2026}, author = {Duncombe, CJ and Hergott, DEB and Staubus, W and Balke-Buijs, M and Kublin, JG and Duffy, PE and Healy, SA and Talley, A and Jackson, L and Sim, BKL and Hoffman, SL and Sauerwein, RW and Roestenberg, M and Murphy, SC}, title = {Sex-based differences in Plasmodium infection in the control groups of controlled human malaria infection trials in malaria-naive populations in the USA and the Netherlands: a pooled analysis.}, journal = {The Lancet. Microbe}, volume = {7}, number = {2}, pages = {101265}, doi = {10.1016/j.lanmic.2025.101265}, pmid = {41544638}, issn = {2666-5247}, mesh = {Humans ; Male ; Adult ; Female ; *Plasmodium falciparum/genetics/isolation &amp; purification ; *Malaria, Falciparum/parasitology/epidemiology ; Young Adult ; Middle Aged ; Adolescent ; Netherlands/epidemiology ; United States/epidemiology ; Parasitemia/parasitology ; Sex Factors ; RNA, Ribosomal, 18S/genetics ; Liver/parasitology ; }, abstract = {BACKGROUND: Before infecting red blood cells and causing the clinical manifestations of malaria, the hepatotropic parasite Plasmodium falciparum completes a complex liver stage. Sex-based differences in pathogenesis by hepatotropic micro-organisms are well documented but unstudied for P falciparum in humans. We aimed to evaluate the effect of sex on the time to blood-stage positivity and initial blood-stage parasite densities as indicators of liver-stage dynamics and parasite replication.<br><br>METHODS: We conducted a pooled analysis of data from malaria-naive participants in control groups from controlled human malaria infection (CHMI) studies conducted between Jan 1, 2010, and Dec 31, 2024, in which samples were tested using Plasmodium 18S ribosomal RNA nucleic acid amplification tests (18S NAATs) at laboratories in Seattle (WA, USA) and Leiden (Netherlands). Participants aged 18-48 years were eligible for inclusion if they were in placebo or infectivity control groups in any CHMI study at the two laboratories and developed parasitaemia following CHMI. Patient demographics and 18S NAAT data were obtained from study leads at each centre and collated, standardised, and reviewed. Information on P falciparum strain, challenge route, and sampling schedule were extracted from study protocols or publications. The main outcome, time to positivity (TTP), was calculated as the study day of the first positive 18S NAAT of any density, measured during a 28-day monitoring period following CHMI. Using an interval-censored generalised gamma accelerated failure time model, we compared time to blood-stage positivity by sex, adjusting for challenge route, P falciparum strain, and study site. Odds of developing detectable infection after 7 days post-challenge was compared between male and female participants using a linear mixed-effects model adjusted for the same terms.<br><br>FINDINGS: Evaluable data were available from 102 control participants (48 [47%] female and 54 [53%] male) across 13 CHMI studies. There was moderate heterogeneity between studies (I[2]=31% [95% CI 0-57]). There were no notable demographic differences between male and female participants regarding age, challenge route, or strain. The mean time to first detectable parasitaemia was slightly longer in male participants (7&#xb7;59 days [SD 1&#xb7;15]) than in female participants (7&#xb7;17 days [0&#xb7;91]). Adjusted accelerated failure time analysis suggested that TTP occurred 8% later in male participants than female participants (time ratio 1&#xb7;08 [1&#xb7;03-1&#xb7;16]). Male participants were significantly more likely than female participants to have a detectable infection after day 7 (19 [35%] of 54 male participants vs six [13%] of 48 female participants), with adjusted odds of delayed infection 5&#xb7;20 times (95% CI 1&#xb7;52-17&#xb7;70) higher in male than female participants.<br><br>INTERPRETATION: Our findings suggest that male individuals are more likely to have a delayed detection of blood-stage parasites following CHMI with P falciparum compared with female individuals. Although the inability to directly measure liver-stage burden is a limitation, CHMI offers a controlled system to infer liver-stage dynamics. Thus, P falciparum infection is likely to involve a sex-specific host-pathogen interaction in the liver, emphasising the importance of considering sex as a biological variable in liver-targeting clinical interventions.<br><br>FUNDING: The Gates Foundation and the University of Washington.}, }
@article {pmid41544713, year = {2026}, author = {Prentice, RL and Tinker, LF and Neuhouser, ML and Lampe, JW and Raftery, D and Gowda, GN and Song, X and Navarro, SL and Huang, Y and Vasan, S and Orchard, TS and Brasky, TM and Manson, JE and Zheng, C}, title = {Biomarkers for dietary fatty acid densities among postmenopausal United States females derived using a habitual-diet human feeding study.}, journal = {The American journal of clinical nutrition}, volume = {123}, number = {3}, pages = {101197}, pmid = {41544713}, issn = {1938-3207}, support = {R01 CA119171/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Biomarkers/blood/urine ; Middle Aged ; *Postmenopause ; *Fatty Acids/blood/urine ; United States ; Aged ; *Diet ; *Dietary Fats/administration &amp; dosage ; *Feeding Behavior ; Phospholipids/blood ; }, abstract = {BACKGROUND: Although measures of blood and tissue fatty acid (FA) concentrations are available, objective measures of dietary FA densities (grams per kilocalories) are generally lacking.<br><br>OBJECTIVES: We aimed to explore the development of biomarkers for specific and composite dietary FA densities, not including contributions from dietary supplements, using metabolite profiles from serum and 24-h urine, along with separately measured serum phospholipid FA concentrations in the Women's Health Initiative.<br><br>METHODS: Potential biomarker equations were based on linear regression of feeding study dietary FA densities on metabolite concentrations, each log-transformed, among participants in a habitual-diet human feeding study (n = 153) within the Women's Health Initiative. Corresponding biomarker equations were also considered for total SFA, MUFA, and PUFA densities and for total n-3 and n-6 PUFA densities. Dietary FA density estimates derived from these equations were evaluated by correlation with feeding study intake densities, and by other important biomarker criteria.<br><br>RESULTS: Regression cross-validated R[2] values >30% for specific SFAs were 64.7 butyric, 60.9 caprioc, 48.7 caprylic, 53.0 capric, 39.9 lauric, 61.0 myristic, 42.2 palmitic, 34.2 stearic, 34.8 arachidic, 49.9 decosanoic; for specific MUFAs were 31.3 oleic; and for specific PUFAs were 51.7 linoleic, 50.1 &#x3b1;-linolenic, 39.7 arachidonic, 40.2 EPA, 53.5 decosapentaenoic acid, and 47.9 DHA. Corresponding values were 46.4, 52.8, 46.1, and 52.4 for total SFA, total PUFA, total n-3, and total n-6 densities. Many FA density equations had contributions from multiple metabolites, mostly serum metabolites, and from total energy expenditure. Sensitivity and specificity criteria are plausibly satisfied for proposed biomarkers, based on the feeding study design and on the sets of selected metabolites.<br><br>CONCLUSIONS: Combinations of log-transformed metabolite concentrations can lead to objective intake density estimates for multiple FAs in the diets of United States postmenopausal females, with relevance to the reliable study of dietary FA densities and chronic disease risk. This study was registered at clinicaltrials.gov as NCT00000611 https://clinicaltrials.gov/study/NCT00000611).}, }
@article {pmid41545094, year = {2026}, author = {Nowicka, Z and Grassberger, C and Beekman, C}, title = {The Challenges Discovering the Mechanisms Underlying Radiation-Induced Lymphopenia From Clinical Data.}, journal = {International journal of radiation oncology, biology, physics}, volume = {124}, number = {2}, pages = {484-487}, doi = {10.1016/j.ijrobp.2025.11.002}, pmid = {41545094}, issn = {1879-355X}, }
@article {pmid41545303, year = {2026}, author = {Huang, JJ and YousefiAsl, M and Singh, N and Grivas, P and Bhatia, S}, title = {Steroid-sparing strategies for managing immune-related adverse events.}, journal = {Journal for immunotherapy of cancer}, volume = {14}, number = {1}, pages = {}, pmid = {41545303}, issn = {2051-1426}, support = {K23 AR079588/AR/NIAMS NIH HHS/United States ; R03 AG082857/AG/NIA NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; T32 GM145449/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/drug therapy/immunology ; *Immune Checkpoint Inhibitors/adverse effects ; *Drug-Related Side Effects and Adverse Reactions/drug therapy/etiology ; *Steroids/therapeutic use ; *Immunotherapy/adverse effects/methods ; }, abstract = {Although immune checkpoint inhibitors (ICI) have greatly improved outcomes in several cancer types, their use is also associated with immune-related adverse events (irAEs) that can impact any organ system and lead to significant morbidity and even mortality. Current approaches to treatment of irAEs largely rely on the use of systemic corticosteroids, which can compromise antitumor immune responses and oncologic outcomes. Prolonged use of systemic corticosteroids is also associated with its own set of toxicities. Thus, there is a critical need for steroid-sparing treatment approaches for irAEs.In this article, we review the literature for alternative therapeutic approaches for irAEs, which include targeted delivery (alternate routes of administration) of steroids (eg, budesonide) as well as systemic non-steroidal strategies using other mechanisms of action, such as integrin/cytokine blockade, antibody depletion, disease-modifying antirheumatic drugs and fecal microbiota transplant, among others. Many of these approaches have shown significant promise in their ability to induce a clinical response and improve symptoms, even in the setting of steroid-refractory or steroid-dependent irAEs. These approaches are being increasingly used as primary and secondary prophylaxis in patients at high risk of irAEs. Importantly, these strategies may mitigate steroid-associated toxicities, preserve antitumor immune responses and allow continuation of ICI after development of irAEs, hence enabling the full potential of ICI against cancer.}, }
@article {pmid41546729, year = {2026}, author = {Karvonen, KA and McDougall, JA and Hohl, SD and Carosso, EA and Burrows, T and Mecham, SH and Stohr, E and Devine, A and Linden, H and Gopal, AK and Yu, EY and Cowan, AJ and Mendoza, JA}, title = {Perspectives on GUIDE (Guiding participation toward understanding, inclusion, diversity, and equity for cancer trials): a clinical trial access intervention.}, journal = {Cancer causes &amp; control : CCC}, volume = {37}, number = {2}, pages = {19}, pmid = {41546729}, issn = {1573-7225}, support = {FY23-IDCT-01//Andy Hill CARE Fund/ ; }, mesh = {Humans ; *Neoplasms/therapy/psychology ; Female ; Male ; *Clinical Trials as Topic/economics ; Middle Aged ; Adult ; *Health Services Accessibility ; Aged ; *Patient Participation ; Patient Selection ; Qualitative Research ; }, abstract = {BACKGROUND: We sought to examine key patient and provider perspectives to develop GUIDE (Guiding participation toward Understanding, Inclusion, Diversity, and Equity for Cancer Clinical Trials), an intervention aimed to improve access to clinical trials through reimbursement of trial-related out-of-pocket costs and navigation. We sought patient and provider perspectives to optimize future GUIDE implementation.<br><br>METHODS: Study team members conducted semi-structured 1:1 qualitative interviews with oncology patients (n&#x2009;=&#x2009;20) and providers (n&#x2009;=&#x2009;20) to identify influences on clinical trial participation and GUIDE acceptability, appropriateness, and feasibility. Data were analyzed using a deductive, rapid framework analysis. We applied a Consolidated Framework for Implementation Research and constructs of Proctor's taxonomy of implementation outcomes to organize themes and inform the development of GUIDE.<br><br>RESULTS: Patients reported clinical trial-related expenses as significant barriers for trial participation. Providers unanimously found GUIDE acceptable, appropriate, and feasible. Participants indicated program success would depend on establishing clarity around reimbursement and the role of the trial navigator ('Guide') within an existing multidisciplinary team and equipping the Guide with skills and affect to build trust with patients.<br><br>CONCLUSION: Health-related social needs (HRSN) are a critical influence on trial participation. Providers perceived the GUIDE program has potential to address HRSN and enhance trial diversity. For successful implementation, clear reimbursement protocols and infrastructure, integration of the Guide as part of the care team, and training for the Guide to screen for HRSN and connect patients to trial/institutional resources are needed.<br><br>IMPACT: We report patient and provider-identified elements critical for future trial navigator programs.}, }
@article {pmid41546844, year = {2026}, author = {Donzella, SM and VoPham, T and Weaver, MD and Patel, AV and Phipps, AI and Zhong, C}, title = {Sleep midpoint, social jetlag, and cancer risk in the Cancer Prevention Study-3.}, journal = {Cancer causes &amp; control : CCC}, volume = {37}, number = {2}, pages = {29}, pmid = {41546844}, issn = {1573-7225}, mesh = {Humans ; Female ; Middle Aged ; *Neoplasms/epidemiology/prevention &amp; control/etiology ; Male ; Adult ; *Sleep/physiology ; Prospective Studies ; Aged ; Risk Factors ; Incidence ; United States/epidemiology ; *Jet Lag Syndrome/epidemiology/complications ; Follow-Up Studies ; }, abstract = {PURPOSE: Sleep timing and regularity are associated with various health and performance outcomes, but limited research has investigated the relationship of these sleep dimensions with cancer incidence. The objective of this study was to investigate the associations of sleep midpoint and social jetlag with cancer risk among US adults.<br><br>METHODS: The Cancer Prevention Study-3 is a large prospective study of US adults aged 30-65&#xa0;years. At the first triennial follow-up (2015), participants were asked to report the average time they spent sleeping during a 24-h weekday and weekend, respectively. Sleep midpoint was calculated as the wake time minus half of sleep duration on a weekday and weekend to create a 5:2 weekday:weekend weighted average which was categorized as&#x2009;<&#x2009;2:30AM, 2:30-&#x2009;<&#x2009;3:30AM (referent), and&#x2009;&#x2265;&#x2009;3:30AM. Social jetlag measures were calculated to estimate the difference in sleep midpoint on the weekend and weekday and categorized as&#x2009;<&#x2009;1&#xa0;h (referent), 1-&#x2009;<&#x2009;2&#xa0;h, and&#x2009;&#x2265;&#x2009;2&#xa0;h. Cancer incidence was determined via linkage to state registries; follow-up time ended at the time of cancer diagnosis or death or end of follow-up (12/31/2020). We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals adjusted for socio-demographics, socioeconomic status, comorbidities, and lifestyle behaviors.<br><br>RESULTS: A total of 5,537 incident cancer cases were reported among 145,386 CPS-3 participants. We found no statistically significant associations of sleep midpoint or measures of social jetlag with overall cancer or breast cancer-specific risk.<br><br>CONCLUSION: Our findings suggest no significant associations of sleep midpoint and social jetlag with cancer risk.}, }
@article {pmid41547399, year = {2026}, author = {Pidala, J and Logan, B and Lee, SJ and Shaw, BE and Devine, S and Ciurea, SO and Horowitz, M and He, N and Pusic, I and Srour, SA and Arai, S and Juckett, M and Uberti, J and Hill, L and Vasu, S and Hogan, WJ and Hayes-Lattin, B and Westervelt, P and Bashey, A and Farhadfar, N and Grunwald, MR and Leifer, E and Symons, H and Saad, A and Vogel, J and Erickson, C and Buck, K and Dehn, JG}, title = {Donor Search and Selection Strategy to Facilitate Comparable Transplant Rates across Donor Search Prognosis Groups: A Report from the BMT CTN 1702 Trial.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, pmid = {41547399}, issn = {2666-6367}, support = {U24 HL138660/HL/NHLBI NIH HHS/United States ; UG1 HL109137/HL/NHLBI NIH HHS/United States ; }, abstract = {In a secondary analysis from the BMT CTN 1702 trial, we report on donor search and selection strategies according to baseline recipient search prognosis (SP). A total of 1751 patients in 3 SP groups-very likely, 958; less likely, 517; very unlikely, 276- were analyzed. The target time to HCT was most often 6 to 12 weeks (SP P = nonsignificant) and was associated with acute myelogenous leukemia remission status (P < .01). The baseline preferred alternative donor (across all SP groups was most commonly a haploidentical (haplo) donor (62.2% overall), whereas the use of mismatched unrelated donors (MMUDs) increased over time during the study period. Those in the less/very unlikely groups prioritized more alternative donor types at baseline and had more priority ranking changes (SP P < .01). While a comparable number of donors were typed (all SP: median, 3 donors; median time, 1.1 months), less/very unlikely SP had greater use of alternative donors (SP P < .01). Reasons for nonselection of typed donors varied by SP group. For less/very unlikely SP, the rates of HLA mismatching and donor-specific antibodies were higher, while for very likely SP, the use of other preferred donors was more common. Of 1751, 65% reached HCT: 94% of the very likely had an 8/8 matched unrelated donor (MUD) and 91% of the very unlikely had an alternative donor (haplo, 61%; MMUD, 22%; umbilical cord blood, 8%). HCT occurred within the initial desired timeline in 38% of all subjects. HCT delays occurred in 29%, mostly for disease or patient health overall, and of these 52% reached HCT after delay. In this prospective, multicenter evaluation of donor search and selection practices, we demonstrate that patients with poor likelihood of 8/8 MUD matching can reach HCT at comparable rates and with similar effort (time spent typing, number of donors typed) using an early alternative donor-centered strategy. Uniformly across SP groups, the target time to HCT is not commonly reached and is disrupted mostly by disease/patient health delays and not by donor unavailability.}, }
@article {pmid41547989, year = {2026}, author = {Xu, J and Halloran, ME and Moore, M and Zhang, L and Hyrien, O and Luedtke, A and El Sahly, HM and Baden, LR and Goepfert, PA and Gray, G and Grinsztejn, B and Sobieszczyk, ME and Falsey, AR and Robinson, ST and Garcia, NMG and Zhou, H and van Dromme, I and Truyers, C and Hirsch, I and Neuzil, KM and Corey, L and Kublin, JG and Follmann, D and Janes, HE and Gilbert, PB and Huang, Y}, title = {Association between COVID-19 vaccine efficacy and epidemic force of infection.}, journal = {NPJ vaccines}, volume = {11}, number = {1}, pages = {54}, pmid = {41547989}, issn = {2059-0105}, abstract = {The association between vaccine efficacy (VE) and force of infection (FoI) remains incompletely understood. Previous analyses have been primarily based on trial-level summary data-not accounting for the effect of time and constrained by the number of trials. Here, we leverage individual-level data from three phase 3 randomized, placebo-controlled COVID-19 vaccine trials-the COVE trial (Moderna, CoVPN3001), the AZD1222 trial (AstraZeneca, CoVPN3002), and the ENSEMBLE trial (Janssen/Johnson &amp; Johnson, CoVPN3003)-and contemporaneous geographic-location-specific SARS-CoV-2 surveillance data from the start of the pandemic through November 14, 2021 (including the blinded follow-up periods of the trials) to conduct five cohort- and vaccine-specific analyses: COVE (U.S.), AZD1222 overall (U.S. + non-U.S.), AZD1222 U.S., ENSEMBLE overall (U.S. + non-U.S.), and ENSEMBLE U.S. In AZD1222 U.S., higher VE was associated with higher FoI (p = 0.01). In ENSEMBLE overall, lower VE was marginally associated with higher FoI (p = 0.21), further supported by a region-specific analysis. In COVE, AZD1222 overall, and ENSEMBLE U.S., no VE-FoI association was found. These findings highlighted a new perspective: the VE-FoI association appears complex, potentially influenced by FoI levels, with patterns suggesting an inverted U-shaped relationship, showing a positive association at low FoI levels and a negative association at high levels.}, }
@article {pmid41549659, year = {2026}, author = {Okinaka, K and Schiffer, JT}, title = {Strategies for mitigating severe COVID-19 in patients with haematological malignancy during the omicron era.}, journal = {The Journal of antimicrobial chemotherapy}, volume = {81}, number = {2}, pages = {}, doi = {10.1093/jac/dkaf489}, pmid = {41549659}, issn = {1460-2091}, mesh = {Humans ; *COVID-19/prevention &amp; control/complications ; *Hematologic Neoplasms/complications/virology ; *SARS-CoV-2/drug effects ; *Antiviral Agents/therapeutic use ; Pre-Exposure Prophylaxis/methods ; Antibodies, Monoclonal/therapeutic use ; Immunocompromised Host ; COVID-19 Drug Treatment ; }, abstract = {Despite a decrease in disease severity since the emergence of the severe acute respiratory syndrome coronavirus 2 Omicron variant, coronavirus disease-2019 (COVID-19) continues to pose a significant threat to patients with haematological malignancies (HM). Although repeated booster vaccinations enhance protection against severe illnesses in immunocompromised individuals, they remain at heightened risk of adverse outcomes. This underscores the crucial need for effective pharmacologic strategies to prevent and treat infection. This review examines current strategies for preventing severe COVID-19 in patients with HM, focusing on pre-exposure prophylaxis and early treatment of COVID-19. New monoclonal antibodies have been developed, offering effective pre-exposure prophylaxis. Antiviral agents and monoclonal antibodies demonstrated efficacy in limiting severe COVID-19 outcomes in patients with HM, though some patients, particularly the elderly, remain at risk of critical illness and death. Prolonged infection over months is also common, particularly in patients with lymphoid malignancies. Sustained viral shedding and ongoing mutation may be associated with chronic symptoms and is the likely source of several novel variants of concern that prolonged the pandemic. While HM subtype and advanced age are risk factors for severe or persistent COVID-19, there are no accurate tools for predicting individual risk. Given this uncertainty, prompt medical consultation, timely prescription of antiviral agents, and close monitoring are essential to minimize the risk of adverse outcomes in this vulnerable population.}, }
@article {pmid41549755, year = {2026}, author = {Heitner, JA and Stansfield, SE and Mitchell, KM and Doyle, CM and Milwid, RM and Moore, M and Donnell, DJ and Xia, Y and Maheu-Giroux, M and Barnabas, RV and Boily, MC and Dimitrov, DT}, title = {Cost-effectiveness of leveraging long-acting injectable cabotegravir to expand PrEP coverage among MSM in two contrasting North American cities.}, journal = {Journal of the International AIDS Society}, volume = {29}, number = {1}, pages = {e70061}, pmid = {41549755}, issn = {1758-2652}, mesh = {Male ; Humans ; *Pre-Exposure Prophylaxis/economics/methods ; *Cost-Benefit Analysis ; *HIV Infections/prevention &amp; control/epidemiology/transmission ; Homosexuality, Male ; *Pyridones/economics/administration &amp; dosage ; *Anti-HIV Agents/economics/administration &amp; dosage ; Adult ; Georgia/epidemiology ; Middle Aged ; Injections ; Young Adult ; Canada ; Quebec/epidemiology ; Cities ; *Disease Transmission, Infectious/prevention &amp; control ; Diketopiperazines ; }, abstract = {INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) is superior to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) and could expand PrEP usage. Given price differentials between CAB-LA and TDF/FTC, evaluating the cost-effectiveness of potential PrEP coverage scenarios is warranted.<br><br>METHODS: We simulated PrEP coverage expansion among men who have sex with men (MSM) via introducing CAB-LA using two age- and risk-stratified HIV transmission models separately calibrated to local data from a high-incidence (Atlanta, USA) and a low-incidence (Montr&#xe9;al, Canada) North American setting. PrEP coverage of HIV-negative MSM was simulated to increase from 6% to 15%, 30%, 40% or 50% (Montr&#xe9;al) or from 29% to 40% or 50% (Atlanta), within 5 or 10 years, with 0%, 15%, 30%, 50% or 100% of current TDF/FTC users switching to CAB-LA. Costing took a healthcare payer perspective and included PrEP pharmaceuticals, PrEP programmatic costs and HIV-related care. Atlanta scenarios considered oral PrEP acquired at average recent market prices (primary analysis), and both settings modelled universal acquisition at the lowest available generic price (LAGP). Simulations were compared to baseline projections without CAB-LA-based expansions over 20 years, with costs and disability-adjusted life years (DALYs) discounted 3% annually. Incremental cost-effectiveness ratios (ICERs) of expansions were assessed against a $100,000 per DALY averted threshold.<br><br>RESULTS: In Atlanta, scenario median ICERs at recent prices ranged from $141,600 (90% CI $60,100-$256,000) to $203,800 ($99,300-$359,200) per DALY averted. All uncertainty intervals covered $100,000. Under universal LAGP TDF-FTC, median ICERs ranged from $255,800 ($112,900-$452,30) to $370,700 ($172,200-$669,100). The strongest expansion scenarios were expected to remain cost-effective until approximately $2800/dose, or approximately $1350 with universal LAGP TDF/FTC. In Montr&#xe9;al, scenarios had median ICERs from $920,000 to $2,540,000, excluding dominated runs.<br><br>CONCLUSIONS: In a high-incidence Atlanta MSM population, CAB-LA-based PrEP expansions are not projected to be cost-effective, though a minority of simulations achieved cost-effectiveness. However, lower prices could achieve cost-effectiveness. In a low-incidence Montr&#xe9;al MSM population, broad expansions are not expected to be cost-effective at modelled prices. Prioritizing CAB-LA to Montr&#xe9;al MSM facing access, adherence or persistence barriers to oral PrEP warrants a cost-effectiveness assessment.}, }
@article {pmid41550315, year = {2025}, author = {Chandrasekhar, S and Finberg, A and Jabbour, A and Dang, L and Hanson, J and Behnia, S and Goff, P and Nghiem, P}, title = {A single dose of neoadjuvant radiation for Merkel cell carcinoma: Complete pathologic response with minimal morbidity in a rapidly growing lesion of the eye.}, journal = {JAAD case reports}, volume = {66}, number = {}, pages = {137-140}, pmid = {41550315}, issn = {2352-5126}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, }
@article {pmid41553230, year = {2026}, author = {Shadman, M and Bouwmeester, W and Mohseninejad, L and Xu, S and Jevdjevic, M and Yang, K and Williams, R and Jansen, JP}, title = {Prolonged progression-free survival with zanubrutinib in relapsed/refractory CLL: an indirect treatment comparison versus other BTK inhibitors using multilevel network meta-regression.}, journal = {Journal of medical economics}, volume = {29}, number = {1}, pages = {180-192}, doi = {10.1080/13696998.2025.2609514}, pmid = {41553230}, issn = {1941-837X}, mesh = {Humans ; Adenine/analogs &amp; derivatives/therapeutic use ; Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; *Antineoplastic Agents/therapeutic use ; Benzamides/therapeutic use ; Clinical Trials, Phase III as Topic ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; *Piperidines/therapeutic use ; Progression-Free Survival ; *Protein Kinase Inhibitors/therapeutic use/economics ; Pyrazines/therapeutic use ; *Pyrazoles/therapeutic use/economics ; *Pyrimidines/therapeutic use ; Randomized Controlled Trials as Topic ; }, abstract = {BACKGROUND: Bruton tyrosine kinase inhibitors (BTKis) are therapeutic agents for relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Previous indirect treatment comparisons are limited in simultaneously comparing multiple interventions and adjusting for population differences. This study aimed to use a more rigorous approach called multilevel network meta-regression (ML-NMR) to estimate the relative treatment effects of zanubrutinib compared to acalabrutinib and ibrutinib in two target populations: a general R/R CLL population similar to the phase 3 ALPINE trial's intention-to-treat (ITT) population, and a high-risk population with del(17p) and/or del(11q), similar to the ITT population of the phase 3 ELEVATE-RR trial.<br><br>METHODS: The ML-NMR was conducted using data from three phase 3 randomized controlled trials: ALPINE (N&#x2009;=&#x2009;652), ELEVATE-RR (N&#x2009;=&#x2009;533), and ASCEND (N&#x2009;=&#x2009;310). Progression-free survival (PFS) and overall survival (OS) were the outcomes of interest. The ML-NMR integrated individual patient data from ALPINE with aggregate data from the other trials, incorporating important effect modifiers to estimate relative treatment effects for the target populations.<br><br>RESULTS: In the general R/R CLL population, zanubrutinib showed an improved PFS compared to ibrutinib (HR = 0.67, 95% Credible Interval [CrI]&#x2009;=&#x2009;0.52-0.87) and acalabrutinib (HR = 0.57, 95% CrI = 0.34-0.95). In the high-risk population, zanubrutinib maintained its PFS advantage over ibrutinib and acalabrutinib. OS was similar across BTKis in both populations, with wide CrIs that included an estimate of no difference between treatments.<br><br>CONCLUSION: This ML-NMR suggests that zanubrutinib offers improved PFS compared to ibrutinib and acalabrutinib in both general and high-risk R/R CLL populations. OS results were uncertain due to limited follow-up.}, }
@article {pmid41556483, year = {2026}, author = {Rosen, EA and Krantz, EM and Thibodeau, A and Kennedy, K and Yoke, LH and Tverdek, F and Kassamali Escobar, Z and Cooper, JP and Ueda Oshima, M and Hendrie, P and Mielcarek, M and Liu, C}, title = {Diagnostic Yield of Repeat Blood Cultures and Risk Factors for Bloodstream Infection in Persistent Febrile Neutropenia.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciag014}, pmid = {41556483}, issn = {1537-6591}, abstract = {BACKGROUND: The optimal frequency of repeat blood cultures in persistent febrile neutropenia (FN) remains unknown. This study aims to identify opportunities for blood culture diagnostic stewardship in persistent FN.<br><br>METHODS: This is a retrospective cohort study of patients with hematology/oncology diagnoses and an FN episode >3 days. Generalized estimating equation logistic regression models were used to evaluate risk factors for new bloodstream infection (BSI) after FN day 3.<br><br>RESULTS: Among 620 patients, median FN duration was 5 days and median blood culture bottles collected per patient was 12. On FN day 1, 25% of patients had a positive blood culture; on FN days 2-9, <5% of patients per day had a new organism isolated. Among 31 new organisms isolated after FN day 3, 8 (26%) were contaminants. Of 503 patients with &#x2265;1 blood culture collected after FN day 3, 19 (4%) had a new BSI after FN day 3. FN onset in the peri-hematopoietic cell transplant (HCT) period (day -7 to +30) was associated with lower odds of new BSI after FN day 3 (OR 0.18; 95%CI [0.04-0.71]; p=0.01).Thirty-six patients died within 30 days after FN day 3, including 4 with a new BSI after FN day 3; 1 death was attributable to BSI after FN day 3.<br><br>CONCLUSIONS: Detection of new BSI after FN day 3 was uncommon, demonstrating low diagnostic yield of repeat blood cultures after FN day 3. FN episodes in the peri-HCT period may be a potential focus for blood culture diagnostic stewardship initiatives.}, }
@article {pmid41556857, year = {2026}, author = {Tsai, YY and Thomas, CE and Law, PJ and Chen, Z and Gruber, SB and Schmit, SL and , }, title = {HLA Heterozygosity Influences Colorectal Cancer Risk and Survival Outcome.}, journal = {Gastroenterology}, volume = {170}, number = {3}, pages = {619-622}, pmid = {41556857}, issn = {1528-0012}, support = {R01 CA067941/CA/NCI NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; R01 CA097325/CA/NCI NIH HHS/United States ; U01 CA067941/CA/NCI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R03 CA153323/CA/NCI NIH HHS/United States ; R01 CA126895/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, }
@article {pmid41557352, year = {2026}, author = {Alagoz, O and Lu, Y and Gil Quessep, E and Kerlikowske, K and Mandelblatt, JS and Sprague, BL and Trentham-Dietz, A and Hampton, J and Groeneweg, R and de Koning, HJ and Miglioretti, DL and Schechter, CB and van Ravesteyn, NT and Tosteson, ANA and Stout, NK and Lowry, KP}, title = {Five-Year Absolute Risk-Based and Age-Based Breast Cancer Screening in the US.}, journal = {JAMA network open}, volume = {9}, number = {1}, pages = {e2552944}, pmid = {41557352}, issn = {2574-3805}, support = {R01 CA248068/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/diagnosis/diagnostic imaging/epidemiology/mortality ; Middle Aged ; *Early Detection of Cancer/methods/statistics &amp; numerical data ; *Mammography/methods/statistics &amp; numerical data ; Aged ; Adult ; United States/epidemiology ; Risk Assessment/methods ; Age Factors ; *Mass Screening/methods ; }, abstract = {IMPORTANCE: General mammography screening guidelines target women at average risk within a specified age range (age based) and do not consider absolute risk of individual women at a given age (risk based).<br><br>OBJECTIVE: To compare outcomes of mammography screening strategies that vary by 5-year risk of invasive breast cancer vs age-based strategies.<br><br>This decision analytical model used 2 established Cancer Intervention and Surveillance Modeling Network (CISNET) breast cancer models and simulated US women born in 1980 who were aged 40 years or older without a prior history of breast cancer. Modeling analyses were conducted from April 2023 to April 2025.<br><br>INTERVENTION: Digital breast tomosynthesis delivered via 50 screening strategies (3 age based and 47 risk based) vs a no-screening scenario. Five-year absolute invasive breast cancer risk was based on the validated Breast Cancer Surveillance Consortium, version 3 calculator. Women's 5-year breast cancer risk was categorized as low, average, intermediate, or high.<br><br>MAIN OUTCOMES AND MEASURES: Primary outcomes included lifetime number of breast cancer deaths averted and false-positive screening recalls. Lifetime outcomes were averaged across models and expressed per 1000 women screened.<br><br>RESULTS: Nine risk-based screening strategies were associated with a comparable or greater number of deaths averted than biennial age-based screening from ages 40 to 74 years (B40-74) (range across strategies for mean model estimates, 6.8-7.5 per 1000 women vs 6.8 per 1000 women) as well as reduced false-positive recalls by 8% to 23% (1050-1257 per 1000 women for risk-based screening strategies vs 1365 per 1000 women for B40-74). For example, a risk-based approach using a combination of biennial screening (for women at low risk aged 55-74 years, at average risk aged 50-59 years, at intermediate risk aged 45-54 years, and at high risk aged 40-49 years) and annual screening (for women at average risk aged 60-74 years, at intermediate risk aged 55-74 years, and at high risk aged 50-74 years) would be associated with 6% more breast cancer deaths averted than B40-74 (7.2 vs 6.8 per 1000 women) and 13% fewer false-positive recalls (1190 vs 1365 per 1000 women). Results were consistent across the 2 CISNET models, and the relative difference in breast cancer deaths averted between B40-74 and risk-based screening strategies was more pronounced than for life-years gained.<br><br>CONCLUSIONS AND RELEVANCE: In this decision analytical modeling study of breast cancer screening, population risk-based screening using 5-year invasive breast cancer risk was associated with similar or greater benefits than age-based screening as well as reduced false-positive recalls. As personalized medicine advances, risk-based screening is poised to become a cornerstone of breast cancer prevention, offering a more nuanced and tailored approach to patient care.}, }
@article {pmid41557789, year = {2026}, author = {Li, T and Ilano, A and Arias-Badia, M and Luong, D and Chang, H and Kwek, SS and Allaire, K and Chumber, A and Sakamoto, M and Clark, M and Lea, A and Bridge, M and Chen, B and Liu, E and Porten, S and Meng, MV and Erlich, LIR and Oh, DY and Fong, L}, title = {Functionally heterogeneous intratumoral CD4[+]CD8[+] double-positive T cells can give rise to single-positive T cells.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {4}, pages = {e2506168123}, pmid = {41557789}, issn = {1091-6490}, support = {P50 CA275741/CA/NCI NIH HHS/United States ; R35 CA253175/CA/NCI NIH HHS/United States ; P50CA275741//HHS | NIH | National Cancer Institute (NCI)/ ; 1R35CA253175//HHS | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Carcinoma, Renal Cell/immunology/pathology ; *CD8-Positive T-Lymphocytes/immunology ; *Kidney Neoplasms/immunology/pathology ; *CD4-Positive T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; }, abstract = {Conventional single-positive (SP) CD4[+] and CD8[+] T cells recognize tumor antigens and help mediate clinical responses with cancer immunotherapy. Double-positive CD4[+]CD8[+] (DP) T cells have also been described in human cancers, but their role in the tumor microenvironment remains unclear. By generating a multiomic single cell atlas of DP and SP T cells, we find that DP T cells possess phenotypic heterogeneity similar to SP T cells that includes multiple clonally expanded populations of cytotoxic DP T cells in human renal cell carcinoma (RCC). These intratumoral DP T cells can mediate both MHC class I- and class II-dependent killing of autologous tumor cells. In addition, transcriptional profiling of DP TCR-bearing T cells revealed a gene signature enriched for clinical responders to PD-1 blockade in advanced RCC. We confirm prior observations of SP T cells transitioning into DP T cells and more notably, demonstrate that intratumoral T cells are capable of bidirectional differentiation in which DP T cells serve as precursors to SP T cell sin vivo. In the latter scenario, intratumoral DP T cells are shown to express Rag2, suggesting that the tumor may act as an extrathymic site of T cell development. These findings reveal the multiple roles that DP T cells can possess in antitumor immunity.}, }
@article {pmid41557860, year = {2026}, author = {Desai, D and Sager, RA and Basin, M and Jacob, JM and Morris, GJ and Spiess, PE and Li, R and Cheng, L and Necchi, A and Kamat, AM and Grivas, P and Pavlick, D and Goldberg, H and Mollapour, M and Lin, D and Ross, JS and Bratslavsky, G and Basnet, A and Daneshvar, MA}, title = {Fanconi anemia complementation group C gene (FANCC) association with hereditary and sporadic renal tumors.}, journal = {The oncologist}, volume = {31}, number = {3}, pages = {}, pmid = {41557860}, issn = {1549-490X}, mesh = {Humans ; Male ; Female ; *Kidney Neoplasms/genetics/pathology ; Middle Aged ; *Fanconi Anemia Complementation Group C Protein/genetics ; Adult ; Aged ; Mutation ; Microsatellite Instability ; }, abstract = {BACKGROUND: Inactivating genomic alterations (GA) of the FANCC gene are associated with genomic instability, DNA cross-linking, and homologous DNA repair deficiency. Here, we evaluated the incidence of FANCC GA in renal tumors (RT).<br><br>METHODS: A total of 463&#x2009;546 clinically advanced cancer (CAC) cases underwent hybrid capture-based comprehensive genomic profiling using the FDA-approved F1CDx assay to detect all classes of GA. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity, prediction of germline status, and genomic signature were determined with algorithm-based analysis.<br><br>RESULTS: Clinically advanced cancers (0.43% of 1993) featured FANCC GA; 27 of these FANCC-mutated tumors (20 males, mean age 57) were RT (0.35% of 7668 RT). The primary tumor was sequenced in 9 cases and a metastatic site in 18 (5 lymph nodes, 4 soft tissues, 3 brains, 2 livers, 1 each lung, adrenal, eye, bone). Only 1 of 25 tested FANCC-mutated RT was MSI-high; 4 cases (15%) featured TMB &#x2265;10 mutations/Mb. The genomic signature could be assessed in 5 cases: 4 were MMR-deficient. The FANCC mutations included inactivating short variant mutations in 24 cases (10 nonsense, 10 frameshift, 2 non-frame, and 2 splice-site mutations) and 3 truncating rearrangements (FANCC: SUSD3, FANCC: FANCC, and FANCC: C20orf24). Interestingly, 14 (52%) of the FANCC-mutated RT were predicted to be germline.<br><br>CONCLUSIONS: Somatic and germline mutations in FANCC occur in an exceedingly small subset of clinically advanced RT but at a similar rate to other cancers, and the genomic landscape does not appear to be different from RT with wild-type FANCC. Germline testing is warranted, as we see a high frequency of germline FANCC mutations.<br><br>PATIENT SUMMARY: Our study highlights the rate of FANCC mutation in kidney cancer, which may be a therapeutic target and awaits further assessment and drug development. Also, it shows that FANCC mutations are more germline, requiring further genetic testing.}, }
@article {pmid41558886, year = {2026}, author = {Pichler, R and Subiela, JD and Scilipoti, P and Rehder, P and Grivas, P}, title = {Regional Node-positive Bladder Cancer: Therapeutic Decisions Based on Trial Results in Perioperative and Advanced Disease Settings.}, journal = {European urology}, volume = {89}, number = {4}, pages = {302-304}, doi = {10.1016/j.eururo.2026.01.013}, pmid = {41558886}, issn = {1873-7560}, mesh = {Humans ; Clinical Decision-Making ; *Cystectomy ; Lymphatic Metastasis ; Neoplasm Staging ; *Urinary Bladder Neoplasms/pathology/therapy ; }, abstract = {Optimal therapeutic management for cN1 M0 bladder cancer consists of perioperative systemic therapy and radical cystectomy. For patients with cN2-3 M0 disease, evidence supports upfront systemic therapy, preferably with enfortumab vedotin + pembrolizumab. Consolidative locoregional therapy may be an option in selected responders. Questions remain regarding the optimal duration of systemic therapy and the role of biomarkers. Multidisciplinary expert opinion can be critical for informed shared decision-making.}, }
@article {pmid41559522, year = {2026}, author = {Sassine, D and Huang, Y and Hur, C and Elkin, EB and Ferris, JS and Melamed, A and Kong, CY and Myers, ER and Bickell, NA and Hazelton, WD and Layne, TM and Heckman-Stoddard, B and Samimi, G and Havrilesky, LJ and Blank, SV and Xu, X and Wright, JD}, title = {Neoadjuvant Chemotherapy Versus Primary Cytoreductive Surgery for Metastatic Endometrial Cancer.}, journal = {Cancer medicine}, volume = {15}, number = {1}, pages = {e71539}, pmid = {41559522}, issn = {2045-7634}, support = {U01 CA265739/CA/NCI NIH HHS/United States ; 1U01 CA265739/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Endometrial Neoplasms/pathology/mortality/therapy/drug therapy/surgery ; *Cytoreduction Surgical Procedures/methods ; *Neoadjuvant Therapy ; Middle Aged ; Aged ; Neoplasm Staging ; Treatment Outcome ; Chemotherapy, Adjuvant ; Adult ; Neoplasm Metastasis ; }, abstract = {OBJECTIVE: To evaluate the pattern of use and clinical outcomes associated with neoadjuvant chemotherapy (NACT) compared with primary debulking surgery (PDS) in patients with stage IV endometrial cancer.<br><br>METHODS: We utilized the National Cancer Database to identify individuals diagnosed with stage IV endometrial cancer, and categorized them according to receipt of NACT or PDS. Propensity score weighting using inverse probability of treatment weighting was applied. Survival outcomes were evaluated using both an intention-to-treat (ITT) analysis, which included all eligible patients, and a per-protocol (PP) analysis restricted to those who underwent chemotherapy and surgery.<br><br>RESULTS: Among 18,205 patients, NACT utilization rose from 30.3% in 2010 to 73.8% in 2021 (p&#x2009;<&#x2009;0.0001). In the multivariable analysis, patients diagnosed in more recent years, Black and Hispanic race and ethnicity, Medicaid insurance, serous histology, and greater comorbidities were associated with NACT (p&#x2009;<&#x2009;0.05). In the ITT analysis, there was no mortality difference within 4&#x2009;months after diagnosis between NACT patients and PDS patients (aHR&#x2009;=&#x2009;1.03; 95% CI: 0.96-1.11); however, after 4&#x2009;months, patients treated with NACT experienced higher mortality than those undergoing PDS (aHR&#x2009;=&#x2009;1.58; 95% CI: 1.51-1.64). In the PP analysis, NACT patients had lower mortality compared to PDS patients within 24&#x2009;months after diagnosis (aHR&#x2009;=&#x2009;0.93; 95% CI, 0.88-0.99) but a 34% higher mortality after 24&#x2009;months (aHR&#x2009;=&#x2009;1.34; 95% CI, 1.23-1.47).<br><br>CONCLUSION: Utilization of NACT has expanded among patients with metastatic endometrial cancer. Primary debulking surgery with postoperative chemotherapy is linked to higher early mortality but improved long-term outcomes relative to treatment strategies beginning with NACT followed by surgery.}, }
@article {pmid41562022, year = {2026}, author = {Childs-Kean, LM and Azimi, SF and Beieler, AM and Castellino, L and Keller, SC and Pertzborn, M and Yamshchikov, A and Yoke, LH and Young, K and Mahoney, MV}, title = {A bundle of the top 10 OPAT publications in 2024.}, journal = {Antimicrobial stewardship &amp; healthcare epidemiology : ASHE}, volume = {6}, number = {1}, pages = {e20}, pmid = {41562022}, issn = {2732-494X}, abstract = {OBJECTIVE: Outpatient parenteral antimicrobial therapy (OPAT) is a mainstay of clinical infectious diseases practice, and OPAT-related publications continue to be prominent in journals. The objective of this article is to summarize ten clinically important OPAT-related publications from 2024.<br><br>DESIGN: Narrative review.<br><br>METHODS: Eighty-one articles were found in a literature search, and 56 met inclusion criteria. A survey containing 25 articles was sent to an email listserv of clinicians with OPAT experience.<br><br>RESULTS: This article summarizes the top 10 OPAT articles published in 2024, based on those survey results.<br><br>CONCLUSIONS: Common themes from the top 10 OPAT articles published in 2024 included OPAT clinician workload, patient perspectives of OPAT, tools for OPAT work, and dalbavancin use.}, }
@article {pmid41562706, year = {2026}, author = {Ganesh, N and Grady, WM and Kaz, AM}, title = {Epigenetic Alterations in Colitis-Associated Colorectal Cancer.}, journal = {Epigenomes}, volume = {10}, number = {1}, pages = {}, pmid = {41562706}, issn = {2075-4655}, support = {U54 CA274374/CA/NCI NIH HHS/United States ; U2 CCA271902/CA/NCI NIH HHS/United States ; }, abstract = {Colitis-associated colorectal cancer (CAC) represents a distinct subtype of colorectal malignancy that arises in the setting of chronic inflammatory bowel disease (IBD). Unlike sporadic colorectal cancer, CAC develops through inflammation-driven molecular pathways, in which epigenetic alterations play a pivotal role in tumor initiation and progression. This review highlights the major epigenetic mechanisms implicated in CAC, including DNA methylation, histone modifications, and microRNA (miRNA) dysregulation. Aberrant DNA methylation patterns, such as promoter hypermethylation of tumor suppressor genes and global hypomethylation, contribute to genomic instability and altered gene expression. In parallel, inflammation-induced changes in histone configuration modulate chromatin accessibility and transcriptional activity of key oncogenic and tumor-suppressive pathways. Furthermore, deregulated miRNAs influence multiple aspects of CAC pathogenesis by targeting genes involved in inflammation and tumor progression. Understanding these epigenetic processes provides valuable insights into the development of colorectal malignancy and identifies potential biomarkers for early detection and intervention in colitis-associated colorectal cancer.}, }
@article {pmid41563741, year = {2026}, author = {Babu, V and Shin, DB and Onstad, L and Pidala, JA and Chen, G and Lee, CJ and Kitko, CL and Carpenter, PA and Cutler, C and El Jurdi, N and Loren, AW and Gelfand, JM and Lee, SJ and Baumrin, E}, title = {Discordance in Treatment Response Assessment Between Clinicians and Patients With Skin Chronic Graft-vs-Host Disease.}, journal = {JAMA dermatology}, volume = {162}, number = {3}, pages = {245-254}, pmid = {41563741}, issn = {2168-6084}, mesh = {Humans ; *Graft vs Host Disease/therapy/mortality/drug therapy/diagnosis ; Male ; Female ; Middle Aged ; Adult ; Chronic Disease ; *Patient Reported Outcome Measures ; *Skin Diseases/therapy/mortality/drug therapy ; Longitudinal Studies ; Treatment Outcome ; Hematopoietic Stem Cell Transplantation/adverse effects ; }, abstract = {IMPORTANCE: Clinician-reported and patient-reported outcomes are critical measures of therapeutic efficacy in cutaneous chronic graft-vs-host disease (cGVHD) but are not always correlated. Discordance in treatment response between clinicians and patients hinders interpretation of outcomes in clinical trials and complicates therapeutic decision-making in clinical practice.<br><br>OBJECTIVE: To identify factors associated with discordance in clinician-reported and patient-reported treatment response assessments and to evaluate the association of clinician-reported and patient-reported responses with survival.<br><br>This multicenter longitudinal cohort study included adults 18 years and older with cutaneous cGVHD at study enrollment, assembled from 2 observational studies and 1 randomized clinical trial. Data were collected from August 2007 to March 2024, and data were analyzed from July 2024 to May 2025.<br><br>MAIN OUTCOMES AND MEASURES: A global 8-point cutaneous cGVHD treatment response assessment (with 1 indicating resolved and 8 indicating very much worse) was reported by clinicians and patients 3 to 6 months after study enrollment. Clinician-reported and patient-reported treatment responses were categorized into improved, stable, and worse from the 8-point scale, and discordance was defined as a difference in response between clinicians and patients. Positive clinician discordance indicates the clinician reported a better response than the patient, and negative clinician discordance indicates the clinician reported a worse response than the patient. The association of clinician-reported and patient-reported responses with survival was measured by nonrelapse mortality.<br><br>RESULTS: Of 489 adults with cutaneous cGVHD, 192 (39.3%) were female, 297 (60.7%) were male, and the median (IQR) age was 55 (43-62) years. A total of 321 adults (65.6%) had concordant responses and 168 (34.4%) had discordant responses between clinician-reported and patient-reported treatment responses. Patients with sclerotic cGVHD had greater odds of discordance compared with those without sclerosis, with clinicians reporting both better and worse treatment response than patients (positive clinician discordance: adjusted odds ratio, 3.14; 95% CI, 1.41-6.95; P&#x2009;=&#x2009;.005; negative clinician discordance: adjusted odds ratio, 2.33; 95% CI, 1.19-4.56; P&#x2009;=&#x2009;.01). Worsening compared with improved overall cutaneous cGVHD was associated with nonrelapse mortality when reported by clinicians (adjusted hazard ratio, 2.28; 95% CI, 1.46-3.54; P&#x2009;<&#x2009;.001) and patients (adjusted hazard ratio, 1.86; 95% CI, 1.12-3.08; P&#x2009;=&#x2009;.02), while only patient-reported worsening was significantly associated with nonrelapse mortality in patients with sclerotic disease (adjusted hazard ratio, 2.00; 95% CI, 1.02-3.90; P&#x2009;=&#x2009;.04).<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study, discordance in treatment response assessments between clinicians and patients was common in cutaneous cGVHD, yet clinician-reported and patient-reported treatment responses were both associated with survival. In patients with sclerosis who were more likely to experience discordance, patient-reported response was a critical treatment end point, and approaches should be developed to bridge discordance.}, }
@article {pmid41564387, year = {2026}, author = {Kelkar, AH and Abel, GA and Cutler, CS and Lee, SJ and Soiffer, RJ}, title = {Is It Time to Move Beyond Graft-Versus-Host Disease-Free, Relapse-Free Survival as a Primary End Point in Clinical Trials for Hematopoietic Cell Transplantation?.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2502130}, doi = {10.1200/JCO-25-02130}, pmid = {41564387}, issn = {1527-7755}, }
@article {pmid41565815, year = {2026}, author = {Sng, XYX and Voigt, V and Schuster, IS and Fleming, P and Deuss, FA and Abuwarwar, MH and van Dommelen, SLH and Neate, GEG and Arnold, RM and Horsnell, HL and Daly, S and Golzarroshan, B and Varelias, A and Lyman, SD and Scalzo, AA and Hill, GR and Mueller, SN and Wikstrom, ME and Berry, R and Rossjohn, J and Fletcher, AL and Andoniou, CE and Degli-Esposti, MA}, title = {Fibroblastic reticular cells direct the initiation of T cell responses via CD44.}, journal = {Nature}, volume = {651}, number = {8106}, pages = {752-762}, pmid = {41565815}, issn = {1476-4687}, support = {R01 AI175535/AI/NIAID NIH HHS/United States ; //National Health and Medical Research Council/ ; //NHMRC investigator awards/ ; }, mesh = {Animals ; *Hyaluronan Receptors/metabolism ; Mice ; *Fibroblasts/cytology/immunology/metabolism ; Dendritic Cells/immunology/cytology ; Muromegalovirus/immunology ; *CD8-Positive T-Lymphocytes/immunology/cytology ; Hyaluronic Acid/metabolism ; Mice, Inbred C57BL ; Spleen/cytology/immunology ; Viral Proteins/metabolism/immunology ; Female ; *T-Lymphocytes/immunology/cytology ; Cell Movement ; Male ; Protein Binding ; Ligands ; }, abstract = {The movement of dendritic cells and T cells within secondary lymphoid organs is critical for the development of adaptive immune responses[1,2]. Central to this process is the fibroblastic reticular cell (FRC) network, which forms a highly organized conduit system that facilitates the movement of and interactions between dendritic cells and T cells[3-6]. Previous studies have partly characterized how FRCs support these interactions[7,8]. However, the molecular mechanisms that operate under physiological conditions remain unknown. Here we show that the viral protein m11, encoded by the herpesvirus murine cytomegalovirus (CMV), inhibits antiviral immunity by targeting the FRC network and interfering with a critical function of cellular CD44. We found that m11 binds to CD44 and established that m11 perturbs the molecular interactions of CD44 with its natural ligand, hyaluronic acid. The interaction of m11 with CD44 impairs the trafficking of dendritic cells within the spleen, thereby impeding efficient priming of naive T cells and the initiation of antiviral CD8 T cell responses. The targeting of CD44 by CMV reveals CD44 as a molecule that is essential to the functioning of the FRC network and uncovers a previously unrecognized stroma-based mechanism that is critical for the generation of effective T cell responses.}, }
@article {pmid41567835, year = {2025}, author = {Blinka, S and Wong, RL and Holt, SK and Lo, E and Cheng, HH and Conrad, N and Loesch, H and Toulouse, AE and Lai, M and Hsieh, AC and Grivas, P and Yezefski, T and Wright, JL and Schweizer, MT and Montgomery, RB and Chen, DL and Zeng, J and Lin, DW and Yu, EY}, title = {Results from a prospective registry of [18]F-Fluciclovine PET/CT use in prostate cancer management: a cautionary lesson for implementation of PSMA PET.}, journal = {American journal of nuclear medicine and molecular imaging}, volume = {15}, number = {6}, pages = {262-271}, pmid = {41567835}, issn = {2160-8407}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: [18]F-Fluciclovine positron emission tomography (PET) was FDA-approved in the U.S. in 2016 and was the most sensitive imaging modality for prostate cancer (PC) until the approval of prostate-specific membrane antigen (PSMA) PET in 2020. However, providers' reasons for ordering [18]F-Fluciclovine PET/CT (FluPET) in practice and impact on patient care remain poorly defined. This prospective registry at a tertiary academic center describes patterns of FluPET use and outcomes prior to the FDA approval of PSMA PET in December 2020.<br><br>METHODS: Providers ordering FluPET for patients with PC were surveyed before, &#x2264;2 weeks after, and &#x2265;1 year after imaging to assess reasons for obtaining FluPET, projected treatment plan, changes in plan due to FluPET findings, and toxicity attributable to the change in treatment plan. Baseline patient characteristics, FluPET results, and longitudinal outcomes were collected.<br><br>RESULTS: Between 12/2018-09/2021, 62 patients with localized PC (8.1%), biochemical recurrence (BCR; 80.6%), non-metastatic castration-resistant PC (CRPC) (3.2%), metastatic castration-sensitive PC (3.2%), or metastatic CRPC (4.8%) were enrolled and underwent FluPET. Most scans (90.3%) were performed prior to the FDA approval of PSMA PET 12/2020. FluPET was most often obtained to guide local salvage or metastasis-directed therapies (90.3%); other reasons (non-exclusive) were initial staging (9.6%) or clarifying equivocal lesions from other imaging (9.6%). FluPET detected &#x2265;1 PC lesion in 74.2% of patients. After FluPET, 48.4% of providers reported changing treatment plans, which was more likely when FluPET was positive (60.9% vs 12.5%, P<0.001), and often involved initiation of systemic therapy (19.4%). Treatment changes were reported in 57% of patients with BCR1 and 48.2% of patients with BCR2. In contrast, only 20% of patients with distant metastatic disease had a change in treatment. Among patients in the BCR1 and BCR2 cohort, treatment plan changes were associated with a median time to next treatment that was not reached after a median follow-up of 67.6 months. There was no statistically significant difference in overall survival between patients with biochemical recurrence (BCR) who did and did not have a treatment plan change. A year after FluPET, reported potential toxicities from treatment plan changes were minimal.<br><br>CONCLUSION: FluPET was utilized across the disease spectrum of PC, primarily to guide local salvage or metastasis-directed therapies, given its improved sensitivity for detecting prostate bed recurrence due to the slow physiologic excretion of [18]F-fluciclovine. Notably, a positive FluPET frequently prompted initiation of systemic therapy; however, the clinical benefit of such management remains uncertain. Moreover, providers often selected multiple, sometimes conflicting, treatment plans following FluPET, reflecting uncertainty in translating imaging findings into definitive management decisions. A larger, prospective registry using PSMA PET with a requirement for providers to select a single post-scan treatment strategy is warranted to better assess whether imaging-guided treatment changes improve clinical outcomes.}, }
@article {pmid41571639, year = {2026}, author = {Nicholas, JC and Katz, DH and Tahir, UA and Debban, CL and Aguet, F and Blackwell, T and Bowler, RP and Broadaway, KA and Chen, J and Clish, CB and Coresh, J and Cornell, E and Cruz, DE and Deo, R and Doyle, MF and Durda, P and Ekunwe, L and Floyd, JS and Gill, D and Guo, X and Hoogeveen, RC and Johnson, C and Lange, LA and Li, Y and Manning, A and Meigs, JB and Mi, MY and Mychaleckyj, JC and Olson, NC and Pratte, KA and Psaty, BM and Reiner, AP and Ruan, P and Sevilla-Gonzalez, M and Shah, AM and Sun, Q and Tracy, RP and Wen, J and Wood, AC and Wilson, JG and Young, KL and Yu, B and Rooney, MR and Manichaikul, A and Dubin, R and Mohlke, KL and Rich, SS and Rotter, JI and Ganz, P and Gerszten, RE and Taylor, KD and Raffield, LM}, title = {Cross-ancestry comparison of aptamer and antibody protein measures.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {1054}, pmid = {41571639}, issn = {2041-1723}, support = {UL1 RR033176/RR/NCRR NIH HHS/United States ; R01 HL071259/HL/NHLBI NIH HHS/United States ; R01 DK072193/DK/NIDDK NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; U01 AG082042/AG/NIA NIH HHS/United States ; 75N98025D00027/OD/NIH HHS/United States ; R01 HL071205/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; R01 HL071258/HL/NHLBI NIH HHS/United States ; 75N98025D00026/OD/NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; 75N98025D00028/OD/NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; T32 GM135128/GM/NIGMS NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01 HL071251/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; 75N98025D00024/OD/NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; T32GM135128//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; K08 HL161445/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; R01 HL071250/HL/NHLBI NIH HHS/United States ; 75N98025D00025/OD/NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; F31 HL176194/HL/NHLBI NIH HHS/United States ; R01DK072193//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL146860/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 HL071051/HL/NHLBI NIH HHS/United States ; R01 HL159081/HL/NHLBI NIH HHS/United States ; R01HL133870//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; 75N98025D00022/OD/NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01 HL133870/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; R01 HL151855/HL/NHLBI NIH HHS/United States ; UM1 DK078616/DK/NIDDK NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; 1F31HL176194-01A1//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Proteomics/methods ; *Antibodies/genetics ; Genetic Variation ; *Proteins/genetics ; *Aptamers, Nucleotide ; Polymorphism, Single Nucleotide ; }, abstract = {Measures from affinity-proteomics platforms often correlate poorly, challenging interpretation of protein associations with genetic variants and phenotypes. Here, we examine 2157 proteins measured on both SomaScan 7k and Olink Explore 3072 across 1930 participants with genetic similarity to European, African, East Asian, and Admixed American ancestry references. Inter-platform correlation coefficients for these 2157 proteins follow a bimodal distribution (median r = 0.30). We evaluate protein measure associations with genetic variants, and find approximately 25-30% of the signals on each platform are likely driven by protein-altering variants. We highlight 80 proteins that correlate differently across ancestry groups likely in part due to differing protein-altering variant frequencies by ancestry. Furthermore, adjustment for protein-altering variants with opposite directions of effect by platform improves inter-platform protein measure correlation and results in more concordant genetic and phenotypic associations. Hence, protein-altering variants need to be accounted for across ancestries to facilitate platform-concordant and accurate protein measurement.}, }
@article {pmid41571919, year = {2026}, author = {Bot, A and Stephan, MT and Gill, S}, title = {The dawn of in vivo immune cell engineering in oncology.}, journal = {Nature biotechnology}, volume = {44}, number = {2}, pages = {177-180}, pmid = {41571919}, issn = {1546-1696}, }
@article {pmid41574991, year = {2026}, author = {Podgorsak, A and Kang, J and Zheng, D and Milano, M and Lo, S and Hardy, S}, title = {The Role of Artificial Intelligence for the Radiotherapeutic Management of Brain Metastases.}, journal = {Cancer journal (Sudbury, Mass.)}, volume = {32}, number = {1}, pages = {}, pmid = {41574991}, issn = {1540-336X}, mesh = {Humans ; *Brain Neoplasms/secondary/radiotherapy/diagnosis ; *Artificial Intelligence ; *Radiosurgery/methods ; Radiotherapy Planning, Computer-Assisted/methods ; Prognosis ; }, abstract = {As the radiotherapeutic management of brain metastases increasingly utilizes stereotactic radiosurgery (SRS) and repeated treatments, artificial intelligence (AI) applications are being investigated in treatment planning, prognostication, and evaluation of treatment effects versus tumor progression. The burden on radiation oncologists increases as more lesions are targeted with SRS. AI algorithms facilitate improved detection and segmentation of lesions, reduce interobserver variability, and save clinician time. Predictive analytics, based on large datasets, enable better prognostication and treatment strategies tailored to individual patients. There is also data for the differentiation between radiation necrosis and tumor progression, which is a difficult issue that comes up more and more in patient care. However, challenges remain regarding data standardization, model validation, and clinical integration. Continued research and interdisciplinary collaboration are essential to fully harness AI's potential in the radiotherapeutic management of brain metastases and improving patient outcomes in neuro-oncology.}, }
@article {pmid41575713, year = {2026}, author = {Pi, S and Rutter, CM and Pineda-Antunez, C and Chen, JH and Goldhaber-Fiebert, JD and Alarid-Escudero, F}, title = {Discrete-Event Simulation Modeling Framework for Cancer Interventions and Population Health in R (DESCIPHR): An Open-Source Pipeline.}, journal = {PharmacoEconomics}, volume = {44}, number = {4}, pages = {409-427}, pmid = {41575713}, issn = {1179-2027}, support = {T15LM007033//U.S. National Library of Medicine/ ; DGE-2146755//National Science Foundation Graduate Research Fellowship Program/ ; U01-CA253913//Division of Cancer Prevention, National Cancer Institute/ ; U01-CA265750//Division of Cancer Prevention, National Cancer Institute/ ; }, mesh = {Humans ; Bayes Theorem ; *Neoplasms/economics/therapy/epidemiology ; *Computer Simulation ; *Population Health ; Health Policy ; Uncertainty ; *Decision Support Techniques ; Colorectal Neoplasms ; Disease Progression ; }, abstract = {Simulation models inform health policy decisions by integrating data from multiple sources and forecasting outcomes when there is a lack of comprehensive evidence from empirical studies. Such models have long supported health policy for cancer, the first or second leading cause of death in over 100 countries. Discrete-event simulation (DES) and Bayesian calibration have gained traction in the field of decision science because they enable flexible modeling of complex health conditions and produce estimates of model parameters that reflect real-world disease epidemiology and data uncertainty given model constraints. This uncertainty is then propagated to model-generated outputs, enabling decision-makers to assess confidence in recommendations and estimate the value of collecting additional information. However, there is limited end-to-end guidance on structuring a DES model for cancer progression, estimating its parameters using Bayesian calibration, and applying the calibration outputs to policy evaluation. To fill this gap, we introduce the DES Modeling Framework for Cancer Interventions and Population Health in R (DESCIPHR), an open-source codebase integrating a flexible DES model for the natural history of cancer, Bayesian calibration for parameter estimation, and an example application of screening strategy evaluation. To illustrate the framework, we apply DESCIPHR to calibrate bladder and colorectal cancer models to real-world cancer registry targets. We also introduce an automated method for generating data-informed parameter prior distributions and increase the functionality of a neural network emulator-based Bayesian calibration algorithm. We anticipate that the adaptable DESCIPHR modeling template will facilitate the construction of future decision models evaluating the risks and benefits of health interventions.}, }
@article {pmid41577999, year = {2026}, author = {Oehler, VG and Sala-Torra, O and Gilderman, N and Beppu, L and Woolston, DW and Namaganda, P and Rynning, J and González, IG and Towlerton, A and Voutsinas, J and Wu, Q and Yeung, CCS and Radich, JP}, title = {Next-generation sequencing from chronic myeloid leukemia dried blood spots: insights and implications for global oncology.}, journal = {Leukemia}, volume = {40}, number = {3}, pages = {587-593}, pmid = {41577999}, issn = {1476-5551}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/diagnosis/blood ; *High-Throughput Nucleotide Sequencing/methods ; *Mutation ; *Dried Blood Spot Testing/methods ; Male ; Female ; Middle Aged ; Adult ; Fusion Proteins, bcr-abl/genetics ; Aged ; Prognosis ; Young Adult ; }, abstract = {The goal of the "Spot On CML" program is to provide diagnostic and monitoring tests to chronic myeloid leukemia (CML) patients in low- and middle-income countries (LMICs). Previously, we demonstrated reproducible BCR::ABL1 transcript quantification using dried blood spots (DBS). We have now optimized methods of DNA and RNA extraction from DBS, allowing the detection of myeloid gene variants, including ABL1 tyrosine kinase domain mutations. Among 177 CML patients from nine countries, ABL1 mutations were identified in 61 (34%) patients, with multiple mutations present in some cases. The most common ABL1 mutation was T315I (45.9% of patients with ABL1 mutations). Among 69 patients, 89 Tier I-II variants (pathogenic or likely pathogenic) were identified in other genes, including 52 ASXL1 variants in 49 patients. The detection of ASXL1 variants correlated strongly with the presence of ABL1 mutations (P = 3.51E-04). These methodologies are directly applicable to all assays used for the diagnosis, prognosis, and monitoring of CML and have important implications in bringing state-of-the-art genetic analysis to CML patients in LMICs.}, }
@article {pmid41579732, year = {2026}, author = {Beydoun, HA and Beydoun, MA and Tsai, J and Tinker, LF and Franceschini, N and Nudy, M and Gradidge, PJ and Haring, B and Jung, SY and Price, CA and Nakhoul, M and Manson, JE}, title = {Triglyceride-glucose index and cardiovascular disease by cardiovascular-kidney-metabolic syndrome and socioeconomic status among postmenopausal women.}, journal = {Atherosclerosis}, volume = {414}, number = {}, pages = {120645}, pmid = {41579732}, issn = {1879-1484}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UL1 TR002014/TR/NCATS NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; KL2 TR002015/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; Female ; *Metabolic Syndrome/blood/epidemiology/diagnosis ; *Postmenopause/blood ; *Cardiovascular Diseases/blood/epidemiology/diagnosis ; Middle Aged ; *Triglycerides/blood ; *Blood Glucose/analysis/metabolism ; Aged ; Biomarkers/blood ; *Social Class ; *Kidney Diseases/blood/epidemiology/diagnosis ; United States/epidemiology ; Prognosis ; Risk Assessment ; Incidence ; Risk Factors ; Prospective Studies ; }, abstract = {BACKGROUND AND AIMS: The triglyceride-glucose (TyG) index (ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]) is a novel, simple, and inexpensive biomarker of insulin resistance with growing evidence in support of its diagnostic and prognostic value for cardiovascular disease (CVD). We examined the relationship of baseline TyG index with incident CVD, coronary heart disease (CHD), and cerebrovascular disease during up to 32 years of follow-up among postmenopausal women, before and after stratifying by the cardiovascular-kidney-metabolic (CKM) syndrome and socioeconomic status (SES) at baseline.<br><br>METHODS: 11,769 participants from Women's Health Initiative (5074 with CKM vs. 6695 without CKM; 4149 low SES vs. 5958 medium SES vs. 1662 high SES) were analyzed.<br><br>RESULTS: On average, the TyG index increased with decreasing SES and was higher in women with vs. without CKM. Cox regression and multistate Markov models adjusting for demographic, lifestyle, and health characteristics at baseline were constructed to estimate hazard ratios (HR) and 95&#xa0;% confidence intervals (CI). A 1-unit increase in the TyG index was associated with greater CVD risk (CVD: HR&#xa0;=&#xa0;1.54, 95&#xa0;% CI: 1.39, 1.71; CHD: HR&#xa0;=&#xa0;1.74, 95&#xa0;% CI: 1.52, 1.99; Cerebrovascular disease: HR=1.32, 95% CI: 1.15, 1.53). The TyG index was positively associated with probabilities of transitions from a healthy state to CHD, cerebrovascular disease, and death, as well as transitions between CHD or cerebrovascular disease and death. These relationships did not vary by CKM syndrome or SES.<br><br>CONCLUSIONS: Among postmenopausal women, irrespective of CKM syndrome or SES, the TyG index is a valuable diagnostic and prognostic tool for CVD outcomes.}, }
@article {pmid41580163, year = {2026}, author = {Dhar, A and Siva, S and Tan, VS and Mahadevan, A and Bruynzeel, A and Tang, C and Cury, F and Corkum, M and Ali, M and Zaorsky, NG and Cheung, P and Hannan, R and Hudes, R and Morgan, S and Lo, S and Murthy, V and Correa, RJM and Swaminath, A}, title = {International Radiosurgery Oncology Consortium of the Kidney (IROCK) Contouring Guidelines for Renal Cell Carcinoma Treated With Stereotactic Ablative Radiation Therapy.}, journal = {International journal of radiation oncology, biology, physics}, volume = {125}, number = {1}, pages = {136-145}, doi = {10.1016/j.ijrobp.2026.01.008}, pmid = {41580163}, issn = {1879-355X}, mesh = {Humans ; *Carcinoma, Renal Cell/diagnostic imaging/radiotherapy/pathology/surgery ; *Kidney Neoplasms/diagnostic imaging/pathology/radiotherapy/surgery ; *Radiosurgery/methods/standards ; Neoplasm Recurrence, Local/diagnostic imaging ; Kidney/diagnostic imaging ; Vena Cava, Inferior/diagnostic imaging ; Tumor Burden ; Radiation Oncology/standards ; Algorithms ; Radiotherapy Planning, Computer-Assisted/methods/standards ; Nephrectomy ; }, abstract = {PURPOSE: Stereotactic ablative body radiation therapy (SABR) is an emerging indication for localized renal cell carcinoma (RCC), yet there is a need for standardizing contouring practices, as accurate target delineation is essential to ensure optimal outcomes. Our objective was to develop consensus guidelines for target volume contouring for RCC SABR.<br><br>METHODS AND MATERIALS: An international panel of RCC SABR experts affiliated with IROCK was convened. All were asked to contour target volumes for 4 relevant clinical scenarios: a large tumor (>10 cm) with inferior vena cava tumor thrombus; a central tumor abutting the renal hilum; a local recurrence following nephrectomy; and an ablation cavity recurrence after radiofrequency ablation. Participants also contoured 2 investigational renal substructures: renal cortex and renal hilum. Contours by case were analyzed using a Simultaneous Truth and Performance Level Estimation algorithm (95% CI). Consensus contours and guidelines statements were discussed and refined over 2 consensus meetings. Measures of variance and agreement, including dice similarity coefficients (DSCs), Mean Distance to Agreement, and Hausdorff Distance, were measured for each case.<br><br>RESULTS: In total, 16 radiation oncologists participated. The median DSC was 0.85, and the median Mean Distance to Agreement/Hausdorff Distance were 2.17 mm/9.00 mm, respectively. The median DSC was greater than 0.70 for each case, suggesting "good agreement" among participants. Based on the consensus discussion, any tumor thrombus or ablation cavity should be included in the target volume; organ at risk dose constraints should take priority over target coverage in planning; and the ipsilateral renal cortex should be defined as the ipsilateral renal parenchyma, excluding the target volume, the renal pelvis, renal vasculature, and proximal ureter.<br><br>CONCLUSIONS: We present the first international consensus contouring guideline for RCC SABR. There was strong agreement among experts, yielding high-fidelity consensus contours and guidance statements for each scenario. These results can be used as a guide for radiation oncologists interested in using SABR to treat patients with localized RCC.}, }
@article {pmid41581152, year = {2026}, author = {Jagana, HL and Shabar, MM and Jackson, TS and Johnson, DE and Hemenway, JM and Mukkamala, V and Lukasik, A and Hathaway, MR and Pattwell, SS}, title = {Oncogenic influences of neurotrophin receptors: Shedding light on Trk biology.}, journal = {Cell reports}, volume = {45}, number = {2}, pages = {116928}, doi = {10.1016/j.celrep.2026.116928}, pmid = {41581152}, issn = {2211-1247}, support = {K22 CA258953/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Neoplasms/metabolism/pathology/genetics ; Signal Transduction ; *Receptors, Nerve Growth Factor/metabolism/genetics ; *Carcinogenesis/metabolism ; }, abstract = {During critical stages of neurodevelopment, tropomyosin receptor kinase receptors, encoded by NTRK genes, exhibit temporally driven differential peaks of expression to properly guide the establishment of the peripheral and central nervous systems. In addition, these neuronal systems exhibit non-canonical regulation of surrounding tissues, impacting organogenesis, homeostasis, plasticity, and regeneration. The same processes that guide neurodevelopment, such as differentiation, plasticity, and neuronal survival, are also hijacked in cancer, making the NTRK family an ideal candidate to study. The Trk receptor family plays a critical role in both normal development and several cancer hallmark pathways such as anti-apoptotic signaling, abnormal cellular proliferation, metastasis, and stemness. It is paramount to understand the molecular underpinnings that Trk receptors play in driving malignancy and the specificity of current therapeutics. This review explores key implications of the NTRK gene family in the pathophysiological mechanisms driving cancers within and outside the central nervous system.}, }
@article {pmid41581332, year = {2026}, author = {Duong, A and Fritzsche, D and Indorf, AL}, title = {Practical Considerations for the Use of Antiemetics in Pregnant Patients With Breast Cancer.}, journal = {Clinical breast cancer}, volume = {26}, number = {2}, pages = {80-86}, doi = {10.1016/j.clbc.2025.12.012}, pmid = {41581332}, issn = {1938-0666}, mesh = {Humans ; Female ; Pregnancy ; *Antiemetics/therapeutic use ; *Breast Neoplasms/drug therapy ; *Pregnancy Complications, Neoplastic/drug therapy ; *Nausea/chemically induced/drug therapy/prevention &amp; control ; *Vomiting/chemically induced/prevention &amp; control/drug therapy ; *Antineoplastic Agents/adverse effects ; Practice Guidelines as Topic ; }, abstract = {Early breast cancer treatment commonly includes highly emetogenic chemotherapy and immunotherapy regimens. Both pregnancy and chemotherapy treatment are associated with nausea and vomiting, and many agents used to treat pregnancy-associated nausea have limited data for CINV. Guidelines recommend a 4-drug antiemetic regimen for highly emetogenic chemotherapy regimens. Designing antiemetic regimens for pregnant women undergoing treatment for early breast cancer remains a challenge because of a lack of safety data for commonly used antiemetics as well as physiologic changes that occur throughout pregnancy This review aims to discuss current literature and guideline recommendations and provide practical considerations for agents used in chemotherapy-induced nausea and vomiting prevention in pregnant patients with breast cancer. A literature search on nausea pathophysiology, treatment of pregnant breast cancer patients, antiemetic use in pregnancy and chemotherapy-induced nausea and vomiting was conducted. Primary and tertiary literature sources were reviewed and cited. An overview of nausea pathophysiology and general treatment principles of treatment and supportive care in pregnant breast cancer patients is outlined. Five major antiemetic drug classes are reviewed in this article. When designing antiemetic regimens for pregnant patients undergoing chemotherapy treatment, clinicians must consider the current evidence, including safety, side effects, and pharmacokinetics of various agents, as well as pregnancy trimester and associated physiologic changes. Optimal management and prevention of chemotherapy-induced nausea and vomiting is crucial to avoid treatment delays and hospitalization, and to maximize patient quality of life.}, }
@article {pmid41582039, year = {2026}, author = {Tawagi, K and Khaki, AR and Chablani, PV and Hoffman-Censits, J and Koshkin, VS and Plimack, ER and Galsky, MD and Gupta, S and Rosenberg, JE and Grivas, P and O'Donnell, PH}, title = {Preferred Treatment Sequencing for Metastatic Urothelial Carcinoma (mUC) in the Era of Perioperative and First-Line (1L) Checkpoint Inhibitor: Results From a National Survey of Genitourinary Oncologists.}, journal = {Clinical genitourinary cancer}, volume = {24}, number = {2}, pages = {102487}, doi = {10.1016/j.clgc.2025.102487}, pmid = {41582039}, issn = {1938-0682}, mesh = {Humans ; *Carcinoma, Transitional Cell/drug therapy ; *Immune Checkpoint Inhibitors/therapeutic use ; *Practice Patterns, Physicians'/statistics &amp; numerical data ; *Urinary Bladder Neoplasms/drug therapy/pathology ; *Oncologists/statistics &amp; numerical data ; Surveys and Questionnaires ; Antibodies, Monoclonal, Humanized/therapeutic use ; United States ; Male ; Female ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Antibodies, Monoclonal ; }, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICI) are commonly used in urothelial carcinoma. We sought to understand provider preferences for subsequent treatment of patients after prior ICI.<br><br>MATERIALS AND METHODS: We comprised a group of 11 expert genitourinary medical oncologists in the United States and created a survey regarding treatment sequencing. We present the final responses to this survey, using descriptive statistics.<br><br>RESULTS: We received 78 responses (34%) from 227 genitourinary oncologists between May and August 2024; most were practicing for >5 years (62%) and were seeing >25 patients with metastatic urothelial carcinoma (mUC) yearly (72%). For patients with progression while receiving adjuvant ICI, 51% of respondents were somewhat/very likely to use enfortumab vedotin/pembrolizumab (EVP) as next therapy line. For patients with progression after prior ICI, 1/3 of respondents would consider first-line (1L) EVP irrespective of the interval from prior ICI completion. For ICI given in nonmuscle invasive bladder cancer and muscle-invasive bladder cancer, 43% and 45%, respectively would consider EVP > 6 months post-ICI completion. After progression on EVP, 77% were somewhat/very likely to give platinum-based chemotherapy, and most would not include combination or switch maintenance ICI. Similarly, 80% were somewhat/very likely to recommend non-ICI clinical trials in the second-line setting after EVP, and 87% were somewhat/very likely to offer erdafitinib for susceptible FGFR3 alterations.<br><br>CONCLUSION: Survey-based opinions can effectively capture treatment selection preferences for mUC and could inform future clinical trial design. Additional data, including the impact of residual toxicity from 1L EVP, are needed to better understand real-world treatment sequencing patterns.}, }
@article {pmid41583128, year = {2026}, author = {Cabre, HE and Marlatt, KL and Fernández-Verdejo, R and Beyl, R and Redman, LM and Ainslie, PN and Alemán-Mateo, H and Andersen, LF and Anderson, LJ and Arab, L and Bedu-Addo, K and Bonomi, AG and Bouten, CV and Bovet, P and Brage, S and Buchowski, MS and Butte, NF and Camps, SG and Casper, R and Close, GL and Colbert, LH and Cooper, JA and Cooper, R and Das, SK and Deb, S and Forrester, T and Gillingham, M and Goris, AH and Gurven, M and Hambly, C and Hu, S and Joosen, AM and Katzmarzyk, P and Kempen, KP and Kimura, M and Kraus, WE and Kriengsinyos, W and Kushner, RF and Lessan, N and Löf, M and Martin, CK and Matsiko, E and Medin, AC and Morehen, JC and Morton, JP and Neuhouser, ML and Prentice, RL and Racette, SB and Raichlen, DA and Reynolds, RM and Roberts, SB and Sardinha, LB and Schuit, AJ and Silva, AM and Urlacher, SS and Valencia, ME and Van Etten, LM and Verbunt, JA and Wilson, G and Wood, BM and Yoshida, T and Zhang, X and Murphy-Alford, AJ and Loechl, CU and Luke, AH and Pontzer, H and Rood, J and Sagayama, H and Schoeller, DA and Westerterp, KR and Wong, WW and Yamada, Y and Speakman, JR and Ravussin, E}, title = {Sex Differences in Measures of Energy Expenditure and Body Composition in Young, Middle-Aged, and Older Adults.}, journal = {Current developments in nutrition}, volume = {10}, number = {1}, pages = {107614}, pmid = {41583128}, issn = {2475-2991}, support = {R01 CA119171/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Total daily energy expenditure (TDEE) is vital for energy balance and cardiometabolic health, yet its trajectory across the lifespan, particularly in females, remains poorly understood.<br><br>OBJECTIVES: We sought to examine the effects of aging and sex on body composition and TDEE.<br><br>METHODS: In a cross-sectional analysis of data from research centers across 9 European Countries and the United States from the International Atomic Energy Agency database, TDEE and body composition measures of 2326 participants (1560W/766M; 50.7 &#xb1; 12 .6 y) were stratified across age groups: young (30-39 y; YOUNG), middle-aged (40-54 y; MID), and old (55-70 y; OLD). Doubly labeled water was used to estimate TDEE and fat-free mass (FFM). Fat mass (FM) was calculated as the difference between body mass and FFM, and %fat was ratio between FM and body mass as a percentage. Linear models were used for analysis.<br><br>RESULTS: Females demonstrated greater FM and lower FFM with each age group, compared with males (P < 0.001). In females, OLD had lower absolute TDEE than YOUNG (-217 kcal/d, P < 0.001) and MID (-208 kcal/d, P < 0.001). Male absolute TDEE was lowered across all age groups (OLD compared with YOUNG: -334 kcal/d; OLD compared with MID: -210 kcal/d; MID compared with YOUNG: -124 kcal/d; P < 0.001). Adjusted TDEE was similar within age groups between females and males.<br><br>CONCLUSIONS: These results suggest that age influences changes in body composition and energy expenditure similarly between males and females. The most significant change in TDEE occurs as individuals transition from middle age to older adulthood. Females generally have a higher percentage of %fat and FM, along with lower FFM, compared with males across all age groups. These findings are important for understanding how aging affects metabolism and body composition, which could inform sex-specific health strategies and interventions.}, }
@article {pmid41583333, year = {2026}, author = {Riviere, P and Morgan, KM and Nelson, T and Minarim, DS and Deshler, L and Banegas, MP and Stewart, TF and McKay, RR and Javier-DesLoges, J and Parsons, JK and Rose, BS}, title = {Natural History and Risk Stratification of Biochemically Recurrent Prostate Cancer Following Definitive Radiation Therapy.}, journal = {Advances in radiation oncology}, volume = {11}, number = {2}, pages = {101936}, pmid = {41583333}, issn = {2452-1094}, abstract = {PURPOSE: Among patients with biochemical recurrent (BCR) prostate cancer following radiation therapy, there is no validated method for identifying those at the highest risk for metastases or death from prostate cancer. We characterized the natural history of BCR after radiation therapy and validated the proposed European consensus guidelines for stratification.<br><br>METHODS AND MATERIALS: This retrospective, multicenter, nationwide cohort study used data from patients having postradiation BCR treated in the United States Veterans Administration Health System. High-risk BCR was defined as either Gleason score &#x2265;8 or BCR occurring within 18 months of radiation therapy, per guidelines.<br><br>RESULTS: Among 7126 patients who experienced BCR, 35.5% of patients developed metastatic disease and 17.4% died of prostate cancer at 10 years. 38.5% of patients had a high-risk BCR. High-risk BCR resulted in higher 10-year incidence of metastatic disease (56.2% vs 42.0%, adjusted hazard ratio [aHR] = 1.83, 95% CI: 1.69-1.98) and worse prostate cancer-specific survival (69.5% vs 81.6%, aHR = 1.82, 95% CI: 1.63-2.03, P < .001) and all-cause death (67.8% vs 65.0%, aHR = 1.18, 95% CI: 1.11-1.26, P < .001).<br><br>CONCLUSIONS: A simple, 2-element risk stratification tool using existing clinical data is the first validated tool for identifying patients at risk of metastases or prostate cancer-specific mortality following postradiation BCR. Most patients experiencing BCR in this context do not develop metastases or lethal prostate cancer, making such stratification essential for treatment decision-making and refinement of patient populations for clinical trials.}, }
@article {pmid41583700, year = {2026}, author = {Pernikoff, S and Clurman, A and Rötepohl, M and Galanter, N and Bibby, M and Harris, E and Stevens-Ayers, T and Xie, H and Ueda Oshima, M and Cheng, GS and Englund, JA and Boeckh, MJ and Boonyaratanakornkit, J}, title = {Respiratory Syncytial Virus in Hematopoietic Cell Transplant Recipients: Clinical and Humoral Risk Factors for Infection.}, journal = {Open forum infectious diseases}, volume = {13}, number = {1}, pages = {ofag005}, pmid = {41583700}, issn = {2328-8957}, abstract = {BACKGROUND: Respiratory syncytial virus (RSV) frequently causes upper respiratory tract infections, lung disease, and mortality in hematopoietic cell transplant (HCT) recipients. Currently, little is understood about what clinical and immunologic factors increase a patient's risk of infection or are protective against infection in immunocompromised populations.<br><br>METHODS: This study analyzed clinical and serologic data from a cohort of HCT recipients followed longitudinally with weekly blood draws and PCR surveillance for respiratory viruses to gain insight into clinical and antibody-based risk factors for RSV infection post-transplant. Serum was analyzed by a plaque reduction neutralization assay to determine neutralizing antibody titers to RSV.<br><br>RESULTS: Sixteen of 471 HCT recipients tested positive for RSV within the first 100 days post-transplant. A multivariate analysis of clinical factors revealed that prophylaxis with sirolimus for graft-versus-host disease (GVHD) was significantly correlated with increased risk of RSV infection. Moreover, higher levels of neutralizing antibody to RSV were associated with reduced risk for RSV infection, in a time-varying analysis.<br><br>CONCLUSIONS: GVHD prophylaxis with sirolimus and low serum neutralizing antibody titers were correlated with increased risk of RSV infection in the early post-transplant period. These results support the role of developing and implementing strategies that boost neutralizing antibody levels to prevent RSV infections in HCT recipients.}, }
@article {pmid41583981, year = {2026}, author = {Samorodnitsky, S and Campbell, K and Little, A and Ling, W and Zhao, N and Chen, YC and Wu, MC}, title = {Detecting clinically relevant topological structures in multiplexed spatial proteomics using TopKAT.}, journal = {Patterns (New York, N.Y.)}, volume = {7}, number = {1}, pages = {101456}, pmid = {41583981}, issn = {2666-3899}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {Multiplexed spatial proteomics profiling platforms expose the intricate geometric structure of cells in the tumor microenvironment (TME). The spatial arrangement of cells has been shown to have important clinical implications, correlating with disease prognosis and treatment response. These datasets require new statistical methods to test whether cell-level images are associated with patient-level outcomes. We propose the topological kernel association test (TopKAT), which combines persistent homology with kernel testing to determine whether geometric structures created by cells predict continuous, binary, or survival outcomes. TopKAT quantifies the topological structure of cells in each image using persistence diagrams and compares the similarities between persistence diagrams on the basis of the number and lifespan of the detected homologies among cells. We show that TopKAT can be more powerful than existing approaches, particularly when cells arise along the boundary of a ring and demonstrate its utility in breast cancer and colorectal cancer applications.}, }
@article {pmid41584692, year = {2026}, author = {Santiago-Torres, M and Mull, KE and Sullivan, BM and Fogel, CA and Hwang, SB and Keith, AR and David, SP and Bricker, JB}, title = {Overcoming Challenges to Remote Biochemical Verification of Smoking Status: Insights From Participant Interviews.}, journal = {Substance use : research and treatment}, volume = {20}, number = {}, pages = {29768357251414464}, pmid = {41584692}, issn = {2976-8357}, support = {R01 CA247156/CA/NCI NIH HHS/United States ; R01 CA253975/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVES: Remote biochemical verification of smoking abstinence is limited by low adherence rates and technical problems with test completion. Qualitative data from study participants about their experiences completing these remote tests is lacking. The objectives were to interview participants who provided biochemical verification in a randomized trial of a smoking cessation intervention to (1) learn about participants' actual experiences with cotinine saliva testing; (2) examine willingness to conduct smartphone app-based carbon monoxide (CO) breathalyzer testing; and (3) gather recommendations to minimize barriers and improve adherence.<br><br>METHODS: Participants who completed biochemical verification were invited to participate in semi-structured interviews that included watching an instructional video about the breathalyzer test. Audio recordings were professionally transcribed, and 2 independent coders applied an interactive inductive thematic analysis approach.<br><br>RESULTS: Ten participants, ages 38.7 (9.5) years (30% male) completed interviews. Barriers to successful saliva cotinine testing included: technical issues submitting results (56%), issues following written instructions (44%), saliva collection sponge discomfort (33%), confusion about invalid results (33%), and concerns with device safety/data usage (22%). While more participants said they would, in concept, prefer the CO test or had no preference, they reported more problems with completing the CO test, including potential inaccessibility for people with respiratory illness. Key recommendations for improving compliance included: increasing monetary incentives, diversifying reminders, amplifying reciprocity messaging, managing expectations, and embedding clear, concise in-app guidance.<br><br>CONCLUSION: Results suggest that compliance with remote biochemical verification can be improved through a comprehensive approach that includes increasing incentives, managing expectations, streamlining visual instructions, and diversifying reminders.}, }
@article {pmid41584860, year = {2026}, author = {Ko, LK and Rillamas-Sun, E and Kratz, M and Jimenez, E and Jang, SH and Mendoza, JA and Bishop, S and Xiao, L}, title = {A Multi-Level Intervention to Address Childhood Obesity in Rural Hispanic Communities.}, journal = {Obesity science &amp; practice}, volume = {12}, number = {1}, pages = {e70116}, pmid = {41584860}, issn = {2055-2238}, abstract = {OBJECTIVES: Pediatric obesity disproportionately affects children of lower socioeconomic status, racial and ethnic minorities, and rural communities, and is influenced by social and physical environments. Community-engaged interventions can address pediatric obesity and have been implemented in rural settings for other conditions, but few have specifically targeted rural childhood obesity. Together We STRIDE study is a community-based trial designed to test the effectiveness of a multi-level obesity prevention intervention in Hispanic children living in rural communities.<br><br>METHODS: The trial enrolled 653 children (8-12&#xa0;years old). The 13-month (March 2017-April 2018) multi-level intervention included comic books, nutrition and physical activity (PA) classes, media literacy education and PA breaks, and an open-street community program (Ciclov&#xed;a). The primary outcome was between-group differences in BMI z-score, measured at baseline, 6&#xa0;months, and 18&#xa0;months.<br><br>RESULTS: There were no significant between-group differences in BMI z-scores and BMI-for-age percentile relative to 95th percentile at 6&#xa0;months or 18&#xa0;months follow up. The mean difference in BMI z-score between intervention and comparison communities was -0.02 (95% CI -0.05, 0.02; p&#xa0;=&#xa0;0.31) at 6&#xa0;months and 0.03 (95% CI -0.03, 0.09; p&#xa0;=&#xa0;0.32) at 18&#xa0;months, respectively. BMI z-scores decreased progressively with increased exposure to intervention components (unadjusted p-trend&#xa0;=&#xa0;0.008 and adjusted p-trend&#xa0;=&#xa0;0.009).<br><br>CONCLUSIONS: Although this multi-level community-based intervention did not show an overall intervention effect on BMI z-scores, greater engagement with the intervention components was associated with higher reductions in BMI z-scores. The findings underscore both the promise and the challenges of community-based obesity prevention interventions in rural communities.<br><br>TRIAL REGISTRATION: NCT02982759 (Together We STRIDE) retrospectively registered during study recruitment.}, }
@article {pmid41585364, year = {2026}, author = {Wang, Z and Langevin, D and Chen, V and Bai, J}, title = {Reversible Chemogenetic Fluorescence Labeling with pFAST in C. elegans.}, journal = {microPublication biology}, volume = {2026}, number = {}, pages = {}, pmid = {41585364}, issn = {2578-9430}, support = {R01 NS109476/NS/NINDS NIH HHS/United States ; R01 NS115974/NS/NINDS NIH HHS/United States ; }, abstract = {The promiscuous fluorescence-activating and absorption-shifting tag (pFAST) enables reversible chemogenetic labeling with multiple fluorogens. We generated a single-copy tandem pFAST (td-pFAST) transgenic Caenorhabditis elegans strain expressed in pharyngeal muscle. In dissected worms, lime fluorogen produced rapid fluorescence that was efficiently quenched by the competing ligand darth, demonstrating reversibility. Amber and coral fluorogens also produced reversible signals with distinct emission spectra, supporting multicolor labeling. However, fluorogen delivery by soaking intact worms failed, indicating cuticle permeability remains a barrier. These findings establish td-pFAST as a functional probe for reversible, multicolor labeling in dissected C. elegans tissues.}, }
@article {pmid41586342, year = {2026}, author = {Patterson, S and Emerson, J and Brown, H and Alagesan, P and Labriola, C and Zuzul, R and Taylor, AO and Mebuge, DL and Salama, NR and Min Htike, WY and Wang, F and McCall, S and Garman, KS and Epplein, M}, title = {Iron Deficiency Anemia is Associated With Gastric Intestinal Metaplasia in Patients With Helicobacter pylori Infection.}, journal = {Gastro hep advances}, volume = {5}, number = {3}, pages = {100852}, pmid = {41586342}, issn = {2772-5723}, support = {T32 DK007568/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Despite acknowledgment of the relationship between iron deficiency anemia (IDA) and Helicobacter pylori, consensus is lacking on clinical practice implications. This study sought to examine the association of iron deficiency and anemia with the precancerous lesion gastric intestinal metaplasia (GIM) in a cohort of patients with active H. pylori infection.<br><br>METHODS: This retrospective cohort was assembled from adult patients diagnosed with H. pylori at endoscopy at Duke University between 2015 and 2019. Data were collected from pathology reports and electronic health records. The relationship between iron deficiency status and GIM prevalence among 422 H. pylori-positive individuals was examined using age-adjusted logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs), and stratified by diagnosis of H. pylori before the diagnosis at study enrollment.<br><br>RESULTS: Of these 422 H. pylori-positive patients, 48.6% had evidence of anemia and/or iron deficiency in the electronic health record. Compared to patients without anemia, those with IDA were more likely to have GIM (OR = 1.66; 95% CI, 1.02-2.69). Fifty-seven patients were previously positive for H. pylori, treated, and remained positive for H. pylori at the index endoscopy, of whom 40% had IDA. Among these patients, those with IDA had 4-fold increased odds of having GIM compared to patients without anemia (OR = 4.11; 95% CI, 1.10-15.32).<br><br>CONCLUSION: In a cohort of H. pylori-positive individuals at endoscopy, those with a history of IDA had greater odds of having GIM compared to patients without anemia. These results suggest the importance of close endoscopic evaluation and sampling of the gastric mucosa to evaluate for GIM in patients with IDA, and particularly those with a previous H. pylori diagnosis.}, }
@article {pmid41587071, year = {2026}, author = {Liu, Y and Ju, B and Dong, L and Loyd, M and Brady, SW and Ries, R and Feng, Y and Mulder, H and Plyler, E and Deardorff, C and McBride, A and Jones, T and Eckert, A and Kolekar, P and Fan, L and Li, H and Briviba, M and Zhao, H and Bennett, D and Neale, G and Chang, TC and Chen, W and Pounds, S and Wu, G and Mullighan, C and Geeleher, P and Ji, L and Yang, JJ and Meshinchi, S and Brown, PA and Carroll, WL and Zhang, J and Loh, ML and Easton, J and Ma, X}, title = {Uncovering the genomic complexity of PAX5 intragenic tandem multiplication via long-read and short-read sequencing.}, journal = {Blood}, volume = {147}, number = {13}, pages = {1498-1502}, pmid = {41587071}, issn = {1528-0020}, support = {U10 CA180899/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *PAX5 Transcription Factor/genetics ; Whole Genome Sequencing ; Genomics/methods ; Genome, Human ; *Gene Duplication ; Sequence Analysis, RNA ; }, abstract = {By integrating short-read whole-genome sequencing and RNA sequencing (RNA-seq) data with long-read RNA-seq, we dissect the complex genomic architecture of PAX5 intragenic tandem multiplication, revealing that these complex rearrangements result in in-frame transcripts that likely encode proteins with altered domains.}, }
@article {pmid41587417, year = {2026}, author = {Lu, B and Troyer, J and Krause, KJ and Lapite, A and Aviles, MM and Della-Moretta, S and Dobson, D and Farrokhi, K and Hasanali, ZS and Pillai, PM and Taborda, C and Villagomez, L and Vo, P and Wangondu, R and Yui, JC and Weyand, AC and Fingrut, WB}, title = {Understanding the impact of social determinants of health in hematology: a scoping review of trends across journals and over time.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025017559}, pmid = {41587417}, issn = {2473-9537}, abstract = {Addressing social determinants of health is increasingly recognized as a critical priority in medicine to optimize care delivery to all patients. To support healthcare providers, researchers, and the hematology field to process/synthesize the rapidly expanding hematology social determinants of health literature, we conducted a scoping review to catalogue/describe recent hematology social determinants works. Our goals were to highlight the state-of-the-art in hematology social determinants research, describe trends in this literature across journals/conferences and over time, identify gaps, and inspire efforts to improve health across populations. Our search returned 602 hematology articles and 153 abstracts. Most works examined racial or socioeconomic disparities among adults with hematologic malignancies or who are hematopoietic cell transplant/cell therapy recipients. In contrast, few explored basic science correlates of disparities, approaches to optimize collection/recording/reporting/use of social determinants of health data, or interventions/educational initiatives to address care inequities. Many vulnerable populations were understudied, including Indigenous peoples, people living with disabilities, transgender/gender non-binary peoples, and disparities across parity, religion, or immigration/legal status. Only a minority of works considered intersectionality across multiple dimensions of disparities. Although both the number and proportion of social determinants works increased over time, there were imbalances in where these works were published. Overall, this review is an important tool to advance hematology population health, highlight hematology social determinants of health research productivity, inform development of research agendas and priorities for societies/funders, and support researchers to address identified gaps. Closing these gaps will be essential to improve delivery of safe and effective hematologic care for all.}, }
@article {pmid41587482, year = {2026}, author = {Shadman, M and Tam, CS and Brander, DM and Lefebure, M and Yang, K and Xu, S and Tian, T and Kuptsova-Clarkson, N and Williams, R and Hirata, J and Munir, T}, title = {An indirect comparison of zanubrutinib vs acalabrutinib plus venetoclax in patients with treatment-naive CLL.}, journal = {Blood advances}, volume = {10}, number = {8}, pages = {2599-2607}, doi = {10.1182/bloodadvances.2025018536}, pmid = {41587482}, issn = {2473-9537}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; *Pyrazines/therapeutic use/administration &amp; dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Benzamides/therapeutic use/administration &amp; dosage/adverse effects ; *Piperidines/therapeutic use/administration &amp; dosage ; *Sulfonamides/therapeutic use/administration &amp; dosage ; Female ; Male ; *Pyrimidines/therapeutic use/administration &amp; dosage ; *Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/administration &amp; dosage ; Middle Aged ; Aged ; *Pyrazoles/therapeutic use/administration &amp; dosage ; Treatment Outcome ; }, abstract = {In the phase 3 randomized SEQUOIA study (NCT03336333), zanubrutinib (arm A) demonstrated superior progression-free survival (PFS) compared with bendamustine-rituximab (BR; arm B) in patients with treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) without del(17p). In the phase 3 AMPLIFY study (NCT03836261), acalabrutinib-venetoclax with or without obinutuzumab demonstrated prolonged PFS vs chemoimmunotherapy (investigator's choice of fludarabine, cyclophosphamide, and rituximab [FCR] or BR) in patients with treatment-naive CLL without del(17p) or TP53 mutations. Compared with AMPLIFY, the patient population in SEQUOIA was unsuitable for FCR and included patients with TP53 mutations. The aim of this post hoc analysis was to investigate the efficacy of zanubrutinib in patients from SEQUOIA vs a clinically similar patient population treated with acalabrutinib-venetoclax in AMPLIFY. A numerically greater 3-year investigator-assessed PFS (PFS-INV) was observed with zanubrutinib (84.3%) in the SEQUOIA population vs acalabrutinib-venetoclax in AMPLIFY (78.9%). When matching SEQUOIA to the AMPLIFY population by FCR eligibility, a greater PFS benefit with zanubrutinib was reported (89.2% vs 78.9%, respectively). To support the comparison of zanubrutinib vs acalabrutinib-venetoclax, an anchored matching-adjusted indirect comparison was performed, which showed that zanubrutinib was associated with prolonged PFS-INV vs acalabrutinib-venetoclax when adjusted for various baseline characteristics. Zanubrutinib also demonstrated longer PFS whether adjusted for age (PFS-INV hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.13-0.54; P< .0003) or unadjusted (PFS-INV HR, 0.45; 95% CI, 0.23-0.88; P = .0197). These results highlight zanubrutinib monotherapy as an effective treatment option for all patients with treatment-naive CLL/SLL, including patients who might otherwise be considered for more intensive fixed-duration combination regimens.}, }
@article {pmid41587559, year = {2026}, author = {Seshadri, C and Flynn, JL and Maiello, P and Schnappinger, D and Wilkinson, RJ and Gordon, SB and Mwandumba, HC and Jambo, KC and Hoft, DF and Rubin, EJ and Jamrozik, E and Fortune, SM and Kublin, JG}, title = {Controlled human infection with Mycobacterium tuberculosis: practical considerations for clinical trials.}, journal = {The Lancet. Microbe}, volume = {7}, number = {3}, pages = {101278}, pmid = {41587559}, issn = {2666-5247}, support = {75N93019C00071/AI/NIAID NIH HHS/United States ; P30 AI168034/AI/NIAID NIH HHS/United States ; R01 AI143788/AI/NIAID NIH HHS/United States ; R01 AI161013/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Mycobacterium tuberculosis/immunology/pathogenicity ; *Tuberculosis Vaccines/immunology ; *Tuberculosis/prevention &amp; control/microbiology/immunology ; *Clinical Trials as Topic/ethics ; Animals ; Vaccine Development/ethics ; *Tuberculosis, Pulmonary/prevention &amp; control/microbiology/immunology ; }, abstract = {Controlled human infection models (CHIMs) can accelerate vaccine development for infectious diseases. Mycobacterium tuberculosis is a human-adapted pathogen that is the leading infectious cause of death worldwide. M tuberculosis infection results in a spectrum of clinical outcomes that are incompletely modelled in animals. To date, the risks of infection, prolonged treatment, and sequelae related to CHIMs with M tuberculosis have been considered ethically unacceptable. However, recent advances in bacterial engineering have resulted in safe strains that could permit M tuberculosis CHIM studies with reduced risks. In this Personal View, we address the practical considerations for conducting a pulmonary M tuberculosis CHIM study. We summarise the ethical issues of M tuberculosis CHIM studies in tuberculosis-endemic and non-endemic settings; describe safety considerations, such as optimising the challenge dose and minimising risks to third parties; and outline and prioritise clinical, microbiological, immunological, and radiological endpoints that would render such a model useful for vaccine development.}, }
@article {pmid41588841, year = {2026}, author = {Peoples, AR and Damerell, V and Ose, J and Siegel, EM and Lin, T and Hardikar, S and Himbert, C and Ilozumba, MN and Schrotz-King, P and Crowder, SL and Toriola, AT and Shibata, D and Li, CI and Byrd, DA and Aßmann, ES and Jim, HSL and Figueiredo, JC and Ulrich, CM and Gigic, B}, title = {Association of Sleep Disturbance With Survival After Colorectal Cancer Diagnosis: Results From the ColoCare Study.}, journal = {Cancer medicine}, volume = {15}, number = {2}, pages = {e71576}, pmid = {41588841}, issn = {2045-7634}, support = {//Deutsches Krebsforschungszentrum/ ; //Matthias Lackas-Stiftung/ ; //Heidelberger Stiftung Chirurgie/ ; //Rahel-Goitein-Straus-Program Medical Faculty Heidelberg University/ ; //Huntsman Cancer Foundation/ ; //Claussen-Simon-Stiftung/ ; 01KD2101D//Bundesministerium f&#xfc;r Bildung und Forschung/ ; K07 CA222060/NH/NIH HHS/United States ; KL2TR002539/NH/NIH HHS/United States ; R01 CA189184/NH/NIH HHS/United States ; R01 CA207371/NH/NIH HHS/United States ; R01 CA211705/NH/NIH HHS/United States ; R03AG067994/NH/NIH HHS/United States ; T32 HG008962/NH/NIH HHS/United States ; U01206110/NH/NIH HHS/United States ; //German Consortium of Translational Cancer Research, (DKTK)/ ; //Stiftung LebensBlicke/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Colorectal Neoplasms/mortality/complications/diagnosis ; Neoplasm Recurrence, Local/epidemiology ; Neoplasm Staging ; Proportional Hazards Models ; Quality of Life ; *Sleep Wake Disorders/epidemiology/etiology/diagnosis ; }, abstract = {INTRODUCTION: Sleep problems are common among cancer patients. The relationship between sleep disruption and clinical outcomes after colorectal cancer (CRC) diagnosis remains poorly understood. We investigated associations of sleep disruption with survival and recurrence in patients with CRC.<br><br>METHODS: CRC patients with stages I-IV (N&#x2009;=&#x2009;895) were included in this study. Self-reported sleep disturbance was assessed presurgery using the sleep item from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core-30 and classified into "no/mild" or "moderate/severe" sleep disturbance. Cox-proportional hazard models were computed (HRs and 95% confidence intervals) to investigate associations of sleep disturbance with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusting for age, sex, body mass index, tumor stage and site, and study site.<br><br>RESULTS: Thirty percent of patients reported moderate/severe sleep disturbance. N&#x2009;=&#x2009;190 (21%) were deceased after a median follow-up of 31&#x2009;months, whereas 74 patients (15%) had a recurrence. Patients with moderate/severe vs. no/mild sleep disturbance had worse OS (HR&#x2009;=&#x2009;1.46; 95% CI&#x2009;=&#x2009;1.07-1.98; p&#x2009;=&#x2009;0.02). There were no significant associations for sleep disturbance with DFS and risk of recurrence. Stratified analyses indicated that the worse OS rates due to sleep disturbance were stronger in patients who were middle-aged and older, male, overweight/obese, diagnosed with rectal cancer and stage I-III.<br><br>CONCLUSIONS: Poor sleep is common among CRC patients and is associated with worse overall survival. These findings highlight the potential value of preoperative sleep screening as a way to identify patients at higher risk of poor outcomes, warranting further investigation in future studies.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02328677.}, }
@article {pmid41591383, year = {2026}, author = {Bernard, MJ and Gallardo, A and Ruiz, A and Diaz, JA and Nunley, NM and Dove, RN and Zhang, S and Lee, E and Heering, KY and Varuzhanyan, G and Bopardikar, S and Hashimoto, T and Agrawal, R and Smith, CM and Wilde, BR and Matulionis, N and Richards, HM and Lee, SCS and Sharifi, MN and Lang, JM and Zhao, SG and Witte, ON and Haffner, MC and Shackelford, DB and Boutros, PC and Christofk, HR and Goldstein, AS}, title = {OGDHL promotes prostate cancer progression and regulates neuroendocrine marker expression and nucleotide abundance.}, journal = {Molecular cancer research : MCR}, volume = {}, number = {}, pages = {}, pmid = {41591383}, issn = {1557-3125}, support = {T32 GM152342/GM/NIGMS NIH HHS/United States ; TL1 DK132768/DK/NIDDK NIH HHS/United States ; U2C CA271894/CA/NCI NIH HHS/United States ; R01 CA267721/CA/NCI NIH HHS/United States ; R01 CA270108/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; R01 CA208642/CA/NCI NIH HHS/United States ; P50 CA092131/CA/NCI NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; }, abstract = {As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL reduces nucleotide synthesis, induces accumulation of the DNA damage response marker ƔH2AX, and alters Androgen Receptor inhibition-induced plasticity. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer, and that knockdown of OGDHL impairs growth of cell line models of neuroendocrine prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer. Implications: OGDHL emerged as an unexpected metabolic dependency associated with lineage plasticity and neuroendocrine differentiation, implicating poorly studied metabolic enzymes as potential targets for treatment-resistant prostate cancer.}, }
@article {pmid41591647, year = {2026}, author = {Hsu, A and Fassett, T and Pallagi, S and Panch, SR}, title = {Patient and Physician Experiences in Immune Thrombocytopenia.}, journal = {Advances in therapy}, volume = {43}, number = {3}, pages = {935-947}, pmid = {41591647}, issn = {1865-8652}, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Purpura, Thrombocytopenic, Idiopathic/diagnosis/therapy/physiopathology/drug therapy ; }, abstract = {Immune thrombocytopenia (ITP) is a rare autoimmune disease that results in low platelet counts and an increased risk of spontaneous bleeding due to impaired blood clotting. Several therapeutic approaches can be used to treat patients with ITP. However, many patients either lose response in the long term or are unable to maintain a response after treatment discontinuation, necessitating chronic treatment and multiple lines of therapy. Here, two patients with ITP share their experience, each providing a firsthand description of their ITP diagnosis, symptoms, management, and perspectives on the future. These stories are complemented by a clinical review of ITP pathophysiology, symptoms, and treatments presented by two expert hematologists who care for patients with ITP. The physician perspective reinforces the challenges faced by patients in everyday life and highlights the remaining areas of concern regarding the treatment of chronic ITP.}, }
@article {pmid41591905, year = {2026}, author = {Traphagen, NA and Wheeler, E and Li, R and Akhshi, T and Ravindranathan, R and Alfieri, C and Lu, F and Ahmed, B and Tewari, AK and Balk, SP and Nelson, PS and Corey, E and Long, H and D'Andrea, AD and Qiu, X and Brown, M}, title = {Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {5}, pages = {e2515790122}, pmid = {41591905}, issn = {1091-6490}, support = {S10 OD036228/OD/NIH HHS/United States ; P50 CA272390/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; HT94252310910//DOD | MHS | Congressionally Directed Medical Research Programs (CDMRP)/ ; 5P01CA163227//HHS | NIH (NIH)/ ; }, mesh = {Male ; *Poly(ADP-ribose) Polymerase Inhibitors/pharmacology/therapeutic use ; Humans ; *Homologous Recombination/drug effects ; *Receptors, Androgen/metabolism/genetics ; Cell Line, Tumor ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/pathology/metabolism ; *Prostatic Neoplasms/drug therapy/genetics/metabolism ; DNA Repair/drug effects ; Animals ; *Androgen Receptor Antagonists/pharmacology ; Drug Synergism ; Mice ; }, abstract = {Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous recombination-proficient prostate cancer.}, }
@article {pmid41591908, year = {2026}, author = {Kuang, D and Hanchate, NK and Lee, CY and Heck, A and Ye, X and Erdenebileg, M and Mehta, C and Hassan, MM and Setty, M and Buck, LB}, title = {Olfactory inputs to appetite neurons in the hypothalamus.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {5}, pages = {e2524926123}, pmid = {41591908}, issn = {1091-6490}, support = {R01 DC015032/GF/NIH HHS/United States ; None//Millen Literary Trust/ ; R01 DC015032/DC/NIDCD NIH HHS/United States ; None//Stoneygate Trust (The Stoneygate Trust)/ ; None//HHMI (HHMI)/ ; R01 DC016941/GF/NIH HHS/United States ; MR/X003957/1//UKRI MRC New Investigator Research Grant/ ; UCL2021/1//Rosetrees Trust (Rosetrees)/ ; VS0321//Great Ormond Street Hospital Children's Charity/ ; R01 DC016941/DC/NIDCD NIH HHS/United States ; R35 GM147125/GM/NIGMS NIH HHS/United States ; R35GM147125//NIH / National Institute of General Medical Sciences/ ; VS2412//Great Ormond Street Hospital Children's Charity/ ; }, mesh = {Animals ; *Neurons/metabolism/physiology ; Mice ; *Appetite/physiology ; Agouti-Related Protein/metabolism/genetics ; Pro-Opiomelanocortin/metabolism/genetics ; *Hypothalamus/physiology/cytology/metabolism ; Male ; *Smell/physiology ; *Olfactory Cortex/physiology/metabolism ; *Olfactory Pathways/physiology ; Mice, Inbred C57BL ; *Arcuate Nucleus of Hypothalamus/physiology/cytology/metabolism ; }, abstract = {The sense of smell has potent effects on appetite, but the underlying neural pathways remain undefined. Here, we investigated how olfactory signals reach two subsets of appetite-linked ("appetite") neurons in the hypothalamic arcuate nucleus: Agouti-related peptide (AgRP) neurons, which stimulate appetite, and POMC (pro-opiomelanocortin) neurons, which suppress it. Using polysynaptic viral tracing, we show that AgRP and POMC neurons receive indirect input from partially overlapping but distinct areas of the olfactory cortex, indicating that they process different sets of olfactory information. We also identify different complements of neurons more directly upstream of AgRP and POMC neurons that could relay olfactory cortical signals to the appetite neurons. Single-cell transcriptomics shows heterogeneous expression of neuromodulator receptors among AgRP neurons, suggesting variations in the signals they receive. Integrated viral tracing and RNA localization further reveals selected brain areas where upstream neurons express cognate receptor ligands. Together, these findings outline multiple pathways by which distinct olfactory and modulatory signals are differentially routed to neurons that promote versus inhibit appetite.}, }
@article {pmid41592262, year = {2026}, author = {Banerjee, R and King, T and Faiman, B and Harding, S and Rosenberg, AS and Sanchorawala, V and Mikhael, JR and Cowan, AJ}, title = {Past, Present, and Future of Dexamethasone in Multiple Myeloma and AL Amyloidosis.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {10}, pages = {903-913}, doi = {10.1200/JCO-25-01713}, pmid = {41592262}, issn = {1527-7755}, mesh = {Humans ; *Multiple Myeloma/drug therapy ; *Dexamethasone/adverse effects/administration &amp; dosage/therapeutic use ; *Immunoglobulin Light-chain Amyloidosis/drug therapy ; }, abstract = {For over half a century, dexamethasone has been a backbone of treatment regimens for plasma cell disorders such as multiple myeloma (MM) and light-chain (AL) amyloidosis. Dexamethasone doses of approximately 40 milligrams (mg) once weekly are often continued for months or years despite accumulating evidence that they can cause dose-dependent toxicities such as cataracts and infections. Acute dexamethasone-related toxicities such as insomnia or pedal edema, even if low-grade by clinical criteria, can significantly interfere with patient quality of life. In the past 5 years, several trials have demonstrated the efficacy and improved tolerability of corticosteroid-sparing regimens in MM. In this review, we discuss these and other studies to comprehensively assess the role of dexamethasone in the modern era. In newly diagnosed MM, robust data support planned dexamethasone discontinuation after one to two cycles in older and frailer patients. In the maintenance setting, the risk-benefit ratio of prolonged dexamethasone is unfavorable. While randomized trials have shown that once-weekly dexamethasone adds value within doublet regimens in relapsed/refractory MM, its contribution to triplet and quadruplet regimens is uncertain. Furthermore, data suggest that indefinite dexamethasone may actually limit the feasibility and efficacy of subsequent postprogression therapies. In AL amyloidosis, dexamethasone 40 mg once weekly for 6 months is excessive and may predispose patients to volume overload. In our review, we also discuss dexamethasone as a premedication for CD38-targeted monoclonal antibodies (where it is no longer required after one to two cycles) and for supportive care (where lower doses of 4-8 mg as needed can often suffice). Despite the historical inertia of corticosteroid-containing regimens in clinical trials and practice guidelines, corticosteroid-sparing regimens warrant prospective investigation across the gamut of plasma cell disorders.}, }
@article {pmid41592768, year = {2026}, author = {Thompson, RN and Bansal, S and Clapham, H and Dyson, L and Gutierrez, MA and Hadley, L and Hart, WS and Heesterbeek, H and Hollingsworth, TD and House, T and Howerton, E and Isham, V and Lessler, J and Leung, K and Li, X and McBryde, E and McCaw, JM and Mollison, D and Pan-Ngum, W and Parag, K and Pellis, L and Scarabel, F and Swallow, B and Thumbi, SM and Tran-Kiem, C and Viboud, C and Plank, MJ}, title = {Infectious disease outbreak controllability: biological, social and public health factors.}, journal = {Proceedings. Biological sciences}, volume = {293}, number = {2063}, pages = {}, doi = {10.1098/rspb.2025.2848}, pmid = {41592768}, issn = {1471-2954}, support = {//Engineering and Physical Sciences Research Council/ ; }, mesh = {Humans ; *Disease Outbreaks/prevention &amp; control ; *Public Health ; *Communicable Disease Control/methods ; *Communicable Diseases/epidemiology ; Epidemiological Models ; }, abstract = {Early in an infectious disease outbreak, key policy questions include whether and how the outbreak can be brought under control. In the epidemiological modelling literature, analyses of outbreak controllability have often focused on metrics such as reproduction numbers (which quantify the number of infections generated by each infected individual). However, whether an outbreak can be controlled is a complex question, depending on both the precise definition of 'under control' used and numerous factors affecting decision-makers' ability to implement transmission-reducing measures. Here, based on discussions at the Isaac Newton Institute's 'Modelling and inference for pandemic preparedness' programme (5-30 August 2024), we describe a wide range of factors affecting outbreak controllability in practice. Programme participants came from institutions in ten countries, enabling discussions to reflect experiences of using models to inform policy in different settings. We divide the factors according to whether they relate predominantly to characteristics of the pathogen, host population or available interventions, and describe policy considerations when assessing whether an outbreak is controllable.}, }
@article {pmid41593091, year = {2026}, author = {LaBella, D and Schumacher, K and Mix, M and Leu, K and McBurney-Lin, S and Nedelec, P and Villanueva-Meyer, J and Raleigh, DR and Shapey, J and Vercauteren, T and Chia, K and Ivory, M and Barfoot, T and Al-Salihi, O and Leu, J and Halasz, LM and Velichko, Y and Wang, C and Kirkpatrick, JP and Floyd, SR and Reitman, ZJ and Mullikin, TC and Vaios, EJ and Bagci, U and Sachdev, S and Hattangadi-Gluth, JA and Seibert, TM and Farid, N and Puett, C and Pease, MW and Shiue, K and Anwar, SM and Faghani, S and Taylor, P and Warman, P and Albrecht, J and Jakab, A and Moassefi, M and Chung, V and Chai, R and Aristizabal, A and Karargyris, A and Kassem, H and Pati, S and Sheller, M and Maleki, N and Saluja, R and Kofler, F and Schwarz, CG and Lohmann, P and Vollmuth, P and Gagnon, L and Adewole, M and Hongwei B, L and Kazerooni, AF and Tahon, NH and Anazodo, U and Moawad, AW and Menze, B and Linguraru, MG and Aboian, M and Wiestler, B and Baid, U and Conte, GM and Rauschecker, AM and Nada, A and Abayazeed, AH and Huang, R and de Verdier, MC and Rudie, JD and Bakas, S and Calabrese, E}, title = {The 2024 Brain Tumor Segmentation Challenge Meningioma Radiotherapy (BraTS-MEN-RT) dataset.}, journal = {Scientific data}, volume = {13}, number = {1}, pages = {}, pmid = {41593091}, issn = {2052-4463}, support = {U01CA242871//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; U24CA279629//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; NCI/ITCR U01CA242871//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; NCI K08CA256045//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; }, mesh = {Humans ; *Meningioma/radiotherapy/diagnostic imaging ; Magnetic Resonance Imaging ; *Meningeal Neoplasms/radiotherapy/diagnostic imaging ; *Radiotherapy Planning, Computer-Assisted ; *Brain Neoplasms/radiotherapy/diagnostic imaging ; }, abstract = {Meningiomas are the most common primary intracranial tumors, frequently requiring radiotherapy as a part of management. Effective radiotherapy planning for meningiomas necessitates accurate and consistent segmentation of target volumes on MRI, a process that is complex, labor-intensive, and dependent on expert expertise. The 2024 Brain Tumor Segmentation Challenge Meningioma Radiotherapy (BraTS-MEN-RT) Dataset addresses this problem by providing the largest multi-institutional collection of systematically annotated radiotherapy planning MRIs for meningiomas. Publicly accessible, this dataset comprises 570 radiotherapy planning 3D T1-weighted post-contrast MRIs at native resolutions, with 500 cases featuring expert-annotated gross tumor volumes (GTV). Annotations follow standardized radiotherapy planning protocols and include both intact and postoperative meningioma cases, ensuring wide clinical relevance. Contributions from seven diverse medical centers across the United States and the United Kingdom enhance the dataset's generalizability. The dataset aims to accelerate the development of automated segmentation methods for radiotherapy planning, improving workflow efficiency, reducing interobserver variability, and ultimately enhancing patient outcomes.}, }
@article {pmid41602559, year = {2025}, author = {Mohtashemi, N and Spaczai, J and Guo, R and Tseng, CH and Cambou, MC and Emel, L and Ship, H and Zhang, TH and Chiu, SH and Stranix-Chibanda, L and Chipato, T and Kintu, K and Manji, KP and Moodley, D and Currier, JS and Thio, CL and Maldonado, Y and Bhattacharya, D}, title = {High HBV Seroprotection Rates in Infants Born to People with HIV and HBV Infection in Sub-Saharan Africa.}, journal = {Vaccine: X}, volume = {27}, number = {}, pages = {}, pmid = {41602559}, issn = {2590-1362}, support = {R01 AI100748/AI/NIAID NIH HHS/United States ; R01 HD085862/HD/NICHD NIH HHS/United States ; }, }
@article {pmid41603138, year = {2026}, author = {Guleria, I and Connelly-Smith, LS and Bapat, A and Klein, M and Alkhateeb, H and Jacob, EK and Mahanta, S and Anandappa, AJ and Cui, W and Reich-Slotky, R and Celluzzi, C and Spitzer, TR}, title = {Chimerism and a framework for clinical practice: A report from the Cellular Therapies Section Coordinating Committee (CTSCC) of Association for Advancement of Blood and Biotherapies (AABB).}, journal = {Transfusion}, volume = {}, number = {}, pages = {}, doi = {10.1111/trf.70095}, pmid = {41603138}, issn = {1537-2995}, }
@article {pmid41603726, year = {2026}, author = {Pareek, E and Pershad, Y and Zhao, K and Uddin, MM and Xue, L and Vlasschaert, C and Mack, TM and Haessler, J and Collins, JM and Glick, E and Glaser, V and Heise, R and Ling, W and Haring, B and Shadyab, A and Beydoun, H and Wallace, R and Jaiswal, S and Manson, JE and Natarajan, P and Honigberg, MC and Kooperberg, C and Whitsel, EA and Kitzman, JO and Bick, AG and Reiner, AR and Desai, P}, title = {Metformin does not significantly alter longitudinal dynamics of clonal hematopoiesis.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-3606}, pmid = {41603726}, issn = {1557-3265}, abstract = {PURPOSE: Early intervention in patients with Clonal Hematopoiesis (CH) is an area of intense investigation with no currently approved agents. With recent mechanistic data on metformin as a possible therapeutic agent in CH and its availability in clinical practice, we sought to investigate clonal dynamics of CH mutations in metformin users.<br><br>EXPERIMENTAL DESIGN: We analyzed longitudinal targeted deep sequencing of 1,104 CH mutations in 863 metformin-treated type 2 diabetic participants in two longitudinal cohorts: WHI and BioVu with blood collected at a median of 15.8 and 6.1 years apart respectively.<br><br>RESULTS: Metformin duration (per 6 months) was not significantly associated with overall CH growth rate in WHI (&#x3b2; = -0.05%/year; 95% confidence interval (CI): -0.11 to 0.01; P = 0.08; N = 543) and in BioVU (&#x3b2; = -0.09%/year; 95% CI: -0.22 to 0.05; P = 0.20; N = 561) . Inverse-variance weighted random-effect meta-analysis demonstrated a small, statistically significant association (&#x3b2; = -0.06%/year; 95% CI: -0.11 to -0.002; P = 0.04; N = 1,104) without significant heterogeneity (P = 0.60). These results were similar when only considering DNMT3A and DNMT3A R882 clones.<br><br>CONCLUSIONS: In our cohorts, duration of metformin use among diabetic users was associated with a small reduction in CH growth rate (-0.06%/year), which is modest compared to typical DNMT3A clonal growth rates of 5-7% annually. Metformin's clinical utility for modulating clonal dynamics in real-world settings appear limited and its clinical use for this indication requires further investigation in prospective studies.}, }
@article {pmid41604784, year = {2026}, author = {Kuhlmann, AS and Hamlin, DK and Li, Y and Wang, X and Li, L and Orvig, C and Kiem, HP and Sandmaier, BM and Wilbur, DS and Pincus, S and Harrington, RD}, title = {In vitro evaluation of anti-HIV radioimmunoconjugates labeled with astatine-211, thorium-227 and actinium-225.}, journal = {Nuclear medicine and biology}, volume = {154-155}, number = {}, pages = {109602}, pmid = {41604784}, issn = {1872-9614}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI136758/AI/NIAID NIH HHS/United States ; }, abstract = {UNLABELLED: We conducted an in vitro investigation of the selective cytotoxicity of alpha-emitting radioimmunoconjugates (α-RICs) directed against cells expressing HIV envelope (Env) proteins. It is well known that monoclonal antibody (mAb)-targeted α-emitting radionuclides can effectively kill antigen-expressing cells; however, the expected low-level expression of HIV antigens on latently infected cells poses an obstacle to all anti-HIV immune-based treatments, including α-RICs. This investigation tested the cytotoxicity of the HIV envelope antigen-binding mAbs, PGT126 (binding gp120) and 7B2 (binding gp41), conjugated with labeling chelators that bind the α-emitters astatine-211 ([211]At), actinium-225 ([225]Ac) or thorium-227 ([227]Th).<br><br>METHODS: High specific activity (SA) preparations of the &#x3b1;-RICs were made to increase the proportion of mAb conjugates carrying the &#x3b1;-emitting isotope. RIC cytolytic activity was evaluated against a cell line stably expressing the HIV envelope.<br><br>RESULTS: [211]At-labeled mAb conjugates did not demonstrate specific cell killing, while the longer lived radiometal &#x3b1;-RICs, [227]Th and [225]Ac, efficiently and specifically killed HIV envelope expressing cells.<br><br>CONCLUSIONS: Potential explanations for these differential effects include the longer half-lives of [225]Ac and [227]Th compared to [211]At and differences in the decay properties of radiometals compared to radiohalogens. These encouraging in vitro results suggest that in vivo evaluations of &#x3b1;-RIC in depleting the HIV harboring cells are warranted.}, }
@article {pmid41605126, year = {2026}, author = {Watanabe, R and Miura, N and Kikugawa, T and Saika, T and Haffner, MC and Nelson, PS}, title = {Molecular pathology of rare histologic variants and treatment-resistant lineages of prostate cancer.}, journal = {Urologic oncology}, volume = {44}, number = {4}, pages = {110987}, doi = {10.1016/j.urolonc.2025.110987}, pmid = {41605126}, issn = {1873-2496}, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/genetics ; Pathology, Molecular/methods ; }, abstract = {Rare histological variants of prostate cancer-including ductal adenocarcinoma, intraductal carcinoma of the prostate (IDC-P), neuroendocrine carcinoma, basal cell/adenoid cystic carcinoma, squamous cell carcinoma, sarcomatoid carcinoma, and stromal tumors-exhibit highly diverse biological behaviors and distinct molecular features. Accurate pathological recognition is essential, as these entities frequently diverge from conventional acinar adenocarcinoma in morphology, genomic alterations, therapeutic responsiveness, and clinical outcomes. Intraductal carcinoma of the prostate (IDC-P) and ductal adenocarcinoma often display genomic instability and aggressive clinical behavior, including enrichment for homologous recombination repair (HRR) defects and hypoxia-related pathways. Neuroendocrine subtypes, including de novo and treatment-related NEPC as well as double-negative prostate cancer (DNPC), are characterized by androgen receptor (AR) independence, RB1/TP53 loss, low prostate-specific antigen (PSA) production, and poor prognosis, reflecting lineage plasticity under therapeutic pressure. Other rare tumors-such as basal cell carcinoma/adenoid cystic carcinoma, squamous cell carcinoma, and stromal tumors (STUMP and prostatic stromal sarcoma)-demonstrate unique pathological patterns and limited responsiveness to standard systemic therapies, underscoring the importance of tailored diagnostic and management strategies. This review integrates the histopathological, molecular, and emerging spatial transcriptomic insights across this spectrum of rare and treatment-resistant prostate cancer subtypes. By highlighting shared mechanisms such as genomic instability, androgen receptor (AR) pathway bypass, and microenvironmental remodeling, we outline key diagnostic considerations and evolving therapeutic implications relevant to precision oncology.}, }
@article {pmid41605547, year = {2026}, author = {Roche, SD and Kamolloh, K and Thuo, N and Opiyo, M and Ogello, V and Odira, A and Owidi, E and Ochwal, P and Hewa, M and Adiema, L and Mogaka, F and Omollo, VO and Malen, RC and Harkey, K and Stewart, J and Ngure, K and Ortblad, KF and Bukusi, EA}, title = {Implementing long-acting injectable HIV pre-exposure prophylaxis services at private pharmacies in Kenya: client, pharmacy provider and key stakeholder perspectives on potential challenges and opportunities.}, journal = {BMJ global health}, volume = {11}, number = {1}, pages = {}, pmid = {41605547}, issn = {2059-7908}, support = {R00 MH121166/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *Pre-Exposure Prophylaxis/methods ; *HIV Infections/prevention &amp; control ; Female ; Adult ; Male ; *Pharmacies ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; Qualitative Research ; Young Adult ; Injections ; Pilot Projects ; Interviews as Topic ; Stakeholder Participation ; }, abstract = {INTRODUCTION: Maximising the impact of new and forthcoming long-acting injectable HIV pre-exposure prophylaxis (PrEP) products will require novel delivery approaches that widen accessibility and prioritise clients' needs and preferences. To understand the potential barriers and facilitators to delivering injectable PrEP via private pharmacies in Kenya, we conducted qualitative formative research.<br><br>METHODS: From July to September 2023, we interviewed pharmacy providers, pharmacy clients and other key stakeholders of HIV service delivery in Central and Western Kenya. Our purposive sample included some providers and clients with prior experience delivering or obtaining oral PrEP at a pharmacy as part of a pilot study and some without such experience. We analysed verbatim transcripts thematically using a combination of inductive and deductive approaches, the latter informed by the Consolidated Framework for Implementation Research.<br><br>RESULTS: We interviewed 25 pharmacy clients, 16 pharmacy providers and nine key stakeholders. Each group was ~50% female, and median age among clients was 25 (IQR 23-29). Overall, participants supported the idea of pharmacy-based injectable PrEP delivery. Anticipated facilitators included perceived benefits of injectable over oral PrEP; characteristics of pharmacies (eg, long operating hours) that could fulfil clients' need for accessible, fast and private injectable PrEP services; and existing skillsets of pharmacy providers, especially those already trained on injectable contraception. Anticipated barriers included gaps in enabling policy; pharmacies' lack of integration with the public health sector, such as its health information system; low client knowledge of and/or ability to pay for injectable PrEP and pharmacy staffing and compensation structures that could disincentivise providers.<br><br>CONCLUSIONS: Participants in this study expressed cautious optimism that private pharmacies could be an effective delivery channel for injectable PrEP in Kenya. If private pharmacies facilitate access to and use of injectable PrEP, they could play a pivotal role in ending HIV as a public health threat.}, }
@article {pmid41605897, year = {2026}, author = {Domingo-Domènech, E and Pro, B and Illidge, T and Horwitz, S and Trumper, L and Iyer, S and Advani, R and Bartlett, NL and Christensen, JH and Kim, WS and Feldman, T and Choi, I and Gritti, G and Belada, D and Shustov, A and Illes, A and Zinzani, PL and Hüttmann, A and Trneny, M and Le Gouill, S and Jagadeesh, D and Friedberg, JW and Little, M and Dong, C and Fanale, M and Fenton, K and Savage, KJ}, title = {Correction: Brentuximab vedotin plus chemotherapy for the treatment of front-line systemic anaplastic large cell lymphoma: subgroup analysis of the ECHELON-2 study at 5 years' follow-up.}, journal = {Blood cancer journal}, volume = {16}, number = {1}, pages = {21}, doi = {10.1038/s41408-025-01432-4}, pmid = {41605897}, issn = {2044-5385}, }
@article {pmid41608119, year = {2026}, author = {Brumm, VL and Kidd, SA and Logan, BR and Chunara, F and Heimall, J and Griffith, LM and Kohn, DB and Sanchez, L and Bednarski, JJ and Martinez, C and Lugt, MV and Kapoor, N and Wright, N and Spitzer, B and Oved, JH and Chandra, S and Chellapandian, D and Ebens, CL and Petrovic, A and Rayes, A and Haines, HL and Lust, H and Schofield, HT and Christopher, L and Harris, LL and Satter, LF and Burroughs, L and Dvorak, CC and Haddad, E and Leiding, JW and Marsh, RA and Notarangelo, LD and Pai, SY and Pulsipher, MA and Puck, JM and Cowan, MJ and Shah, AJ}, title = {Neurodevelopmental outcomes following hematopoietic cell transplantation for patients with severe combined immunodeficiency (SCID): A PIDTC study.}, journal = {Journal of human immunity}, volume = {2}, number = {1}, pages = {e20250163}, pmid = {41608119}, issn = {3065-8993}, support = {U01 AI184132/AI/NIAID NIH HHS/United States ; R13 AI094943/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U54 AI082973/AI/NIAID NIH HHS/United States ; R24 AI184316/AI/NIAID NIH HHS/United States ; U01 HL069294/HL/NHLBI NIH HHS/United States ; U54 NS064808/NS/NINDS NIH HHS/United States ; }, abstract = {Hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe combined immunodeficiency (SCID). Since the initiation of newborn screening (NBS), survival rates have improved significantly, but the impact of HCT upon neurodevelopment for patients with SCID requires more investigation. We performed a cross-sectional study of subjects with SCID in North America to assess the impact of NBS, transplant conditioning regimen, and genotype on neurodevelopmental outcomes after HCT. 69 subjects with SCID from 17 PIDTC centers (excluding those with ADA deficiency), ages 6-16 years, received comprehensive standardized neurodevelopmental testing of cognitive, behavioral, and emotional function. Compared with the normative population, our subjects performed in the average range. We found no impact of NBS, chemotherapy conditioning, or genotype. Multivariate analysis revealed a significant decrease in IQ in subjects whose families earned <$50,000 per year. We recommend that children treated by HCT for SCID be monitored with periodic cognitive and behavioral assessments for deficits that could potentially impact long-term ND outcomes.}, }
@article {pmid41609736, year = {2026}, author = {Omange, WR and Varco-Merth, BD and Fadeyi, O and Marenco, A and Takata, H and Duell, DM and Goodwin, WD and Armitage, P and Fennessey, CM and Kose, E and Immonen, TT and Kosmider, E and Bosche, WJ and Fast, R and Homick, C and Oswald, K and Shoemaker, R and Bochart, R and MacAllister, R and Labriola, CS and Smedley, JV and Axthelm, MK and Edlefsen, PT and Keele, BF and Lifson, JD and Gergen, J and Petsch, B and Rauch, S and Picker, LJ and Okoye, AA}, title = {Boosting SIV-specific CD8+ T cell responses prior to ART interruption extends time to SIVmac239 rebound.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {6}, pages = {}, pmid = {41609736}, issn = {1558-8238}, support = {P51 OD011092/OD/NIH HHS/United States ; }, mesh = {Animals ; *CD8-Positive T-Lymphocytes/immunology ; Macaca mulatta ; *Simian Immunodeficiency Virus/immunology/genetics ; *Simian Acquired Immunodeficiency Syndrome/immunology/drug therapy/virology ; *SAIDS Vaccines/immunology ; Viral Load ; Gene Products, gag/immunology/genetics ; *Anti-Retroviral Agents/therapeutic use ; Immunization, Secondary ; }, abstract = {HIV/SIV-specific CD8+ T cell responses are typically unable to control viral rebound following antiretroviral therapy (ART) interruption (ATI). To investigate whether enhancing the magnitude and activation of SIV-specific CD8+ T cells at the time of ATI can improve the immune interception of reactivating SIV infections, we vaccinated SIVmac239-infected rhesus macaques (RMs) on ART, boosting immediately prior to ATI, with a nucleoside-unmodified mRNA vaccine expressing SIVmac239 Gag (mRNA/SIVgag) alone or in combination with Nef (mRNA/SIVnef) and Pol (mRNA/SIVpol). The mRNA/SIVgag vaccine was effective in boosting Gag-specific CD8+ T cells in blood and lymphoid tissues. Following ATI, the mRNA/SIVgag vaccine group showed a significant delay in time to measurable viral rebound compared with controls and manifested lower plasma viral loads (PVLs) for up to 6 weeks after rebound. Similarly, RMs that received mRNA/SIVgag, mRNA/SIVnef, and mRNA/SIVpol also manifested a delay in SIV rebound compared with controls, suggesting that boosting SIV-specific CD8+ T cells during ATI can enhance early immune targeting of reactivating SIV infections. However, viral control was not sustained long term as PVLs were similar across vaccinees and controls by 24 weeks after rebound, highlighting the need for adjunctive therapies to improve the durability of virologic control elicited by CD8+ T cell-targeting vaccines.}, }
@article {pmid41611998, year = {2026}, author = {Kendra, KL and Bellasea, SL and Eroglu, Z and Hu-Lieskovan, S and Campbell, KM and Carson, WE and Wada, DA and Plaza, JA and In, GK and Ikeguchi, A and Hyngstrom, J and Brohl, AS and Chmielowski, B and Khushalani, NI and Markowitz, J and Monroe, M and Contreras, CM and Bowles, T and Norman, K and Medina, E and Gonzalez, CR and Baselga-Carretero, I and Garcilazo, IP and Vega-Crespo, A and Chen, JM and Deen, NNA and Patel, SP and Grossmann, KF and Sondak, VK and Sharon, E and Moon, J and Wu, MC and Ribas, A}, title = {Neoadjuvant PD-1 blockade in surgically resectable desmoplastic melanoma: cohort A of the phase 2 SWOG S1512 trial.}, journal = {Nature cancer}, volume = {7}, number = {2}, pages = {272-282}, pmid = {41611998}, issn = {2662-1347}, support = {P01 CA244118/CA/NCI NIH HHS/United States ; R35 CA197633/CA/NCI NIH HHS/United States ; P01 CA244118/CA/NCI NIH HHS/United States ; R35 CA197633/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/drug therapy/surgery/pathology/mortality ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects/therapeutic use ; *Neoadjuvant Therapy/methods ; Male ; Female ; Middle Aged ; Aged ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; Adult ; *Immune Checkpoint Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; Cohort Studies ; Treatment Outcome ; *Skin Neoplasms/drug therapy/surgery/pathology ; Aged, 80 and over ; }, abstract = {The phase 2 SWOG S1512 trial (NCT02775851) was designed to evaluate the response to pembrolizumab (anti-PD-1) in individuals with desmoplastic melanoma. Here we report the results of cohort A of the trial, evaluating the pathological complete response (pCR) rate of neoadjuvant PD-1 blockade in surgically resectable desmoplastic melanoma. Secondary endpoints included clinical response rate, overall survival and toxicities. Twenty-eight eligible individuals with resectable desmoplastic melanoma received intravenous pembrolizumab (200 mg) every 3 weeks three times, followed by excision. Tissue samples before treatment, at 3-5 weeks after treatment initiation and at the time of surgery were reviewed. The primary endpoint of pCR rate by local pathological review was 71% (95% confidence interval, 51-87%; P < 0.001), which met the prespecified endpoint. There were two (7%) grade 3 treatment-related adverse events. At three years of follow-up, four participants have died, none known to be from melanoma or adverse events. In conclusion, neoadjuvant pembrolizumab in individuals with resectable desmoplastic melanoma results in a high pCR rate with acceptable safety profile. Clinicaltrials.gov: NCT02775851 .}, }
@article {pmid41612517, year = {2026}, author = {Fladeboe, KM and Fredman, G and Maurer, SH and Zhou, C and Bradford, MC and Yi-Frazier, JP and Salsman, JM and Baker, KS and Mack, MC and Taylor, MR and Rosenberg, AR}, title = {Feasibility and proof-of-concept of a combined resilience and social connection intervention for adolescents and young adults with cancer: a pilot randomized trial protocol.}, journal = {Pilot and feasibility studies}, volume = {12}, number = {1}, pages = {}, pmid = {41612517}, issn = {2055-5784}, support = {R00CA267481/CA/NCI NIH HHS/United States ; R00CA267481/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Adolescents and young adults (AYAs) with cancer experience deficits in social connection that persist into survivorship; currently, few interventions target this unmet need. The current article describes the protocol for a pilot, parallel-group randomized controlled trial of a psychosocial intervention [Promoting Resilience in Stress Management (PRISM)] that includes a new skill-based module targeting AYA social needs (SN). The aims are to (1) establish the feasibility and acceptability of the PRISM-SN-adapted program; and (2) demonstrate proof-of-concept via clinically meaningful improvements in patient-reported outcomes (PROs).<br><br>METHODS: We anticipate 70 AYAs will enroll and complete data collection at two sites: Seattle Children's Hospital and UPMC Children's Hospital of Pittsburgh. Eligible AYAs are ages 12-25&#xa0;years old; diagnosed with a new malignancy&#x2009;<&#x2009;6&#xa0;months; treatment plan includes chemotherapy and/or radiation; and are English-speaking. Enrolled AYAs are randomized 1:1 to receive PRISM-SN or usual care and complete surveys at baseline and 12-week follow-up. PRISM-SN includes 5 sessions (4 standard PRISM modules&#x2009;+&#x2009;new SN module) teaching behavioral skills associated with psychosocial wellbeing. Sessions are delivered 1:1 by a trained coach, in person or virtually, 1-2&#xa0;weeks apart. Feasibility will be defined based on uptake, retention, and patient-reported intervention acceptability. Proof-of-concept will be defined based on clinically meaningful change and detectable differences in PROs at 12&#xa0;weeks, including social relationship coping efficacy (primary PRO of interest), social support, quality of life, resilience, anxiety, depression, and hope. Descriptive statistics and covariate-adjusted regression models will be used to assess feasibility outcomes and examine trends and between-group differences in PROs across study arms.<br><br>DISCUSSION: This pilot trial will determine feasibility of PRISM-SN in the context of a multi-site trial; provide proof-of-concept via effects of PRISM-SN on social connection outcomes; and represent an important step toward addressing an unmet need in AYA cancer care. Future directions include testing efficacy and effectiveness via larger multicenter trials.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT06242964.}, }
@article {pmid41615269, year = {2026}, author = {Montgomery, B and Lynch, JA and Brown, J and Maxwell, KN and Teerlink, CC and Kabilovic, N and Stoll, K and Simon, J and Kogan, M and Hassan, S and Whitbourne, SB and Muralidhar, S and Schoen, MW and Ramoni, R and Gaziano, JM and Sokolova, AO and Cheng, HH and Etzioni, R and Pritchard, CC}, title = {Remote delivery of cancer genetic testing in veterans with metastatic prostate cancer: A Million Veteran Program pilot study.}, journal = {Cancer}, volume = {132}, number = {3}, pages = {e70283}, pmid = {41615269}, issn = {1097-0142}, support = {//Institute for Prostate Cancer Research/ ; P50CA097186/CA/NCI NIH HHS/United States ; W81XWH-17-2-0043//Congressionally Directed Medical Research Programs/ ; W81XWH2220021//Congressionally Directed Medical Research Programs/ ; Challenge Award//Prostate Cancer Foundation/ ; Young Investigator Award//Prostate Cancer Foundation/ ; MVP031//US Department of Veterans Affairs/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/pathology/diagnosis ; *Genetic Testing/methods ; *Veterans/statistics &amp; numerical data ; Pilot Projects ; Middle Aged ; Aged ; Prospective Studies ; Genetic Predisposition to Disease ; Genetic Counseling ; Germ-Line Mutation ; Neoplasm Metastasis ; United States ; }, abstract = {BACKGROUND: Germline pathogenic variants can inform targeted therapy for metastatic prostate cancer (mPC), and improve cancer early detection and risk reduction for family members. Guidelines recommend germline genetic testing be offered to all men with mPC, yet uptake of testing is only 10%-12%.<br><br>METHODS: This prospective study enrolled veterans participating in the VA Million Veteran Program (MVP) with a diagnosis of mPC. Veterans were contacted by mail with option to opt-out of future contact. Eligible veterans who did not opt-out were mailed study information and received a follow-up phone call to establish interest in germline testing. Participants provided verbal consent and were mailed a saliva collection kit for a CLIA-level multigene cancer predisposition gene panel test. Results were disclosed to the patient and oncology provider. All steps were performed with genetic counseling support.<br><br>RESULTS: Of 2104 eligible patients, 1952 veterans with mPC did not opt out. Of these, 681 (35%) provided consent and 459 (24%) completed testing. Of those who were approached 63% were White and 25% were Black. Fifty-nine (13%) of those completing testing carried a germline pathogenic variant in a cancer risk gene. Of the 37 eligible for targeted therapy, 14 received targeted therapy, 18 did not yet have an indication for that therapy, and five were deceased without having received targeted therapy.<br><br>CONCLUSIONS: Participant completion of remote germline testing was facilitated at rates higher than the 10% previously reported. Remote genetic testing can augment uptake of testing in large, integrated health care systems.}, }
@article {pmid41616055, year = {2026}, author = {Mitchell, DK and Brewster, K and Jiang, L and Mang, H and Bessler, WK and Li, X and Lu, Q and Qian, S and York, E and Morrow, SK and Dixon, SAH and Davis, C and Chan, KK and Smith, A and Flint, AC and Le, VV and Geisinger, A and Enane, F and Nabet, B and Rhodes, SD and Angus, SP and Clapp, DW}, title = {Inhibition of focal adhesion kinase impairs tumor formation and preserves hearing in a murine model of NF2-related schwannomatosis.}, journal = {Science advances}, volume = {12}, number = {5}, pages = {eady8382}, pmid = {41616055}, issn = {2375-2548}, mesh = {Animals ; Mice ; Disease Models, Animal ; *Neurilemmoma/pathology/genetics/drug therapy/metabolism ; *Neurofibromatoses/pathology/genetics/drug therapy/metabolism ; *Skin Neoplasms/pathology/drug therapy/genetics/metabolism ; *Neurofibromatosis 2/genetics/pathology ; Neurofibromin 2/genetics/metabolism ; *Protein Kinase Inhibitors/pharmacology ; *Focal Adhesion Protein-Tyrosine Kinases/antagonists &amp; inhibitors/metabolism/genetics ; *Focal Adhesion Kinase 1/antagonists &amp; inhibitors/genetics/metabolism ; }, abstract = {NF2 (neurofibromatosis type 2)-related schwannomatosis (NF2-SWN) is a cancer predisposition syndrome characterized by the development of bilateral vestibular (VS) and spinal schwannomas. While benign, these tumors can cause substantial morbidity, and effective pharmacological treatments remain limited. Here, we demonstrate that genetic ablation of focal adhesion kinase (Fak/Ptk2) impairs tumor formation and preserves hearing in a murine model of NF2. Mechanistically, we show that Fak deletion decreases macrophage infiltration, attenuates nucleotide-binding oligomerization domain-containing protein 2-, leucine rich repeats (LRR)- and pyrin domain-containing protein 3 inflammasome activation, and suppresses the hepatocyte growth factor-MET axis. Pharmacological inhibition of FAK with single agent VS-4718 did not significantly reduce macroscopic tumor volume; however, its use in combination with the mitogen-activated protein kinase kinase (MEK) inhibitor selumetinib resulted in both a significant reduction in tumor volume and the preservation of dorsal root ganglion architecture. Our findings establish a critical role for FAK in schwannoma development and provide rationale for evaluation of combination FAK plus MEK inhibition in future clinical trials for NF2-associated SWN.}, }
@article {pmid41616239, year = {2026}, author = {Li, Y and Qiao, Y and Gao, F and Gauthier, J and Zhang, QE and Voutsinas, J and Leisenring, W and Gooley, T and Summers, C and Hirayama, A and Turtle, CJ and Gardner, R and Zee, J and Wu, QV}, title = {Novel R Shiny Tool for Survival Analysis With Time-Varying Covariate in Oncology Studies: Overcoming Biases and Enhancing Collaboration.}, journal = {JCO clinical cancer informatics}, volume = {10}, number = {}, pages = {e2500225}, pmid = {41616239}, issn = {2473-4276}, support = {U01 TR002487/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; Proportional Hazards Models ; Survival Analysis ; Immunotherapy, Adoptive/methods ; Bias ; Kaplan-Meier Estimate ; *Medical Oncology/methods ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/mortality ; *Neoplasms/mortality/therapy ; }, abstract = {PURPOSE: Our study is motivated by evaluating the role of hematopoietic cell transplantation (HCT) after chimeric antigen receptor T-cell (CAR-T) therapy for ALL, a debated topic. Because patients may receive HCT at different times after CAR-T infusion or never, HCT post-CAR-T should be considered as a time-varying covariate (TVC).<br><br>METHODS: Standard Cox models and Kaplan-Meier (KM) curves (na&#xef;ve method) assume that TVC status is known and fixed at baseline, which can yield biased estimates. Landmark analysis is a popular alternative but depends on a chosen landmark time. Time-dependent (TD) Cox model is better suited for TVC although visualizing survival curves is complex. The newly proposed Smith-Zee method generates appropriate survival curves from TD Cox models.<br><br>RESULTS: To address these challenges, we developed an open-source R Shiny tool integrating multiple models (na&#xef;ve Cox, landmark Cox, and TD Cox) and curves (na&#xef;ve KM, landmark KM, Smith-Zee, and Extended KM) to facilitate TVC analysis. Reanalysis of post-CAR-T HCT's effect on leukemia-free survival (LFS) showed consistent results between na&#xef;ve and TD Cox models, whereas landmark analyses varied by landmark time. A separate data analysis of chronic graft-versus-host disease and survival showed that substantial differences emerged across statistical methods. Simulations revealed increased bias in na&#xef;ve methods when TVC changed late and minimal bias when TVC changes occurred early relative to time to events.<br><br>CONCLUSION: We recommend TD Cox models and Smith-Zee curves for robust TVC analysis. Our R Shiny tool supports standardized analyses without requiring data sharing, thereby promoting collaboration across different institutions and providing a practical tool to advance survival analysis in oncology research.}, }
@article {pmid41616942, year = {2026}, author = {Keane, EP and Adri, FN and Larizza, IS and Monahan, JA and Song, MT and Boardman, AC and Schaefer, DA and Wu, JH and Conway, S and Brown, L and Baliousis, M and Lee, SJ and Gudenkauf, LM and Amonoo, HL}, title = {Caring for the Hematopoietic Stem Cell Transplantation Population: Clinician Perspectives on Challenges and Opportunities in Psychosocial Care Delivery.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.01.033}, pmid = {41616942}, issn = {2666-6367}, abstract = {Patients who receive hematopoietic stem cell transplantation (HSCT) undergo complex treatment regimens often accompanied by significant physical and psychological symptom burdens. However, patient access to psychosocial care is limited, likely in the context of persistent shortages of supportive care clinicians and services. Clinicians can offer valuable insights into psychosocial needs, barriers to accessing psychosocial support, and recommendations to improve psychosocial care for the HSCT population. This qualitative study aimed to explore the perspectives of HSCT clinicians to better understand the challenges HSCT recipients face accessing psychosocial support and how these barriers can inform strategies to enhance psychosocial care. Unlike existing literature that largely focuses on unmet needs in the HSCT population from patient perspectives and patient-reported outcomes, this study delves into the unique insights of HSCT clinicians. A purposive sampling strategy was employed to recruit clinicians across specialties in the United States, including mental health and oncology, involved in HSCT care. Semistructured individual interviews were conducted to explore psychosocial care within HSCT programs. Using a framework-guided rapid analysis, 2 coders analyzed the interviews for emergent themes. Participants (N = 21) shared perspectives on multiple emerging themes, including (1) patient psychosocial challenges (eg, isolation, psychological distress); (2) barriers to psychosocial care (eg, workforce shortage, gaps in integration and continuity of care); and (3) recommendations to improve care delivery (eg, adopting a holistic, team-based model that is proactive and tailored to the needs of HSCT patients throughout their treatment and recovery). Findings highlight critical gaps in psychosocial care for HSCT recipients and offer actionable clinician recommendations to improve psychosocial care delivery for the HSCT population.}, }
@article {pmid41618895, year = {2026}, author = {Shadman, M and Chanan-Khan, A and Campbell, D and Xue, M and Massoudi, M and Williams, R and Yang, K and Tam, CS}, title = {Number needed to treat to avoid progression and death and cost analysis: zanubrutinib versus acalabrutinib in relapsed/refractory chronic lymphocytic leukemia.}, journal = {Future oncology (London, England)}, volume = {22}, number = {3}, pages = {339-348}, pmid = {41618895}, issn = {1744-8301}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality/pathology/economics ; *Pyrazines/therapeutic use/economics/adverse effects ; *Benzamides/therapeutic use/economics/adverse effects ; *Pyrazoles/therapeutic use/economics/adverse effects ; Piperidines/therapeutic use/economics ; Disease Progression ; Pyrimidines/therapeutic use/economics ; Cost-Benefit Analysis ; *Neoplasm Recurrence, Local/drug therapy/mortality ; Drug Resistance, Neoplasm ; *Antineoplastic Agents/therapeutic use/economics ; Treatment Outcome ; Models, Economic ; Costs and Cost Analysis ; }, abstract = {AIMS: In the absence of head-to-head comparative trials, this study aimed to compare zanubrutinib versus acalabrutinib in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) by calculating number needed to treat (NNT) to avoid one disease progression or death and associated economic impact.<br><br>METHODS: A health-economic model was developed from US payer perspective using efficacy data from matching-adjusted indirect comparison for overall R/R CLL in base-case analysis, and network meta-analysis for high-risk R/R CLL in the subgroup analysis. The NNT analysis included costs of drug acquisition, adverse event management, medical resource utilization, and subsequent treatment over 24&#x2009;months. Deterministic sensitivity analyses assessed model uncertainty.<br><br>RESULTS: In the base case, zanubrutinib versus acalabrutinib avoided one progression for every 10 patients treated (NNT&#x2009;=&#x2009;10) and one death for every 15 patients treated (NNT&#x2009;=&#x2009;15), yielding per-patient cost savings of $7,335 over 24&#x2009;months. In high-risk R/R CLL subgroup, one progression was avoided per six patients treated (NNT&#x2009;=&#x2009;6) and one death per 18 patients treated (NNT&#x2009;=&#x2009;18), with cost savings of $11,533 per patient. Results were robust across sensitivity analyses.<br><br>CONCLUSIONS: The NNT analysis demonstrates that treatment with zanubrutinib versus acalabrutinib is associated with more favorable clinical and economic outcomes in R/R CLL, especially in high-risk CLL patients.}, }
@article {pmid41619356, year = {2026}, author = {Wittenauer, R and Shah, PD and Bacci, JL and Mooney, SJ and Stergachis, A}, title = {Pharmacy access and shingles vaccinations in the US: a propensity score matching analysis.}, journal = {Vaccine}, volume = {75}, number = {}, pages = {128256}, doi = {10.1016/j.vaccine.2026.128256}, pmid = {41619356}, issn = {1873-2518}, mesh = {Humans ; Propensity Score ; Middle Aged ; *Health Services Accessibility/statistics &amp; numerical data ; *Vaccination/statistics &amp; numerical data ; Female ; Male ; *Pharmacies/statistics &amp; numerical data ; Aged ; *Herpes Zoster Vaccine/administration &amp; dosage ; United States ; *Community Pharmacy Services/statistics &amp; numerical data ; Vaccination Coverage/statistics &amp; numerical data ; }, abstract = {IMPORTANCE: Community pharmacists provide many important healthcare services, including routine adult vaccinations. However, an estimated 15.8 million people in the US live in pharmacy deserts and may lack access to these services. The relationship between pharmacy deserts and adult vaccine receipt has yet to be thoroughly explored empirically.<br><br>OBJECTIVE: We evaluated the relationship between census tract-level pharmacy access and shingles vaccination receipt.<br><br>This propensity score matched analysis used 2022 vaccination data from seven collaborating State Departments of Health: Colorado, Louisiana, Massachusetts, Nevada, Oklahoma, Washington, and Wisconsin. Census tracts in those states were classified based on their access to community pharmacies in April 2022. The dataset for analysis contained 9652 census tracts representing 13.7 million adults aged 50+ years.<br><br>EXPOSURE: Our primary exposure was whether a census tract was a "pharmacy desert", defined as being both low-income and having low geographic access to pharmacies. Our secondary exposure was whether a tract had low geographic access to pharmacies regardless of income status of that tract.<br><br>MAIN OUTCOMES: The primary outcome was completed shingles vaccinations per 1000 population age 50+ years in 2022.<br><br>RESULTS: Pharmacy deserts had 0.4 fewer shingles vaccinations per 1000 population (p&#xa0;=&#xa0;0.83; 95% CI -3.8, 3.6) compared to matched non-pharmacy-desert tracts. Our secondary analysis indicated that low-access tracts had 2.4 fewer vaccinations per 1000 population (p&#xa0;=&#xa0;0.004, 95% CI: -3.9, -0.7).<br><br>CONCLUSIONS: Low pharmacy access is associated with lower rates of shingles vaccination. The definition of pharmacy desert that includes a low-income criterion may not add further precision in identifying areas with inadequate access to pharmacy-based vaccinations. Efforts at the state and national levels to prevent pharmacy closures and support pharmacists in delivering care may improve access to important pharmacy services such as vaccination.}, }
@article {pmid41620128, year = {2026}, author = {Bilen, MA and Shore, N and Burbage, S and Rossi, C and Diaz, L and Khilfeh, I and Wang, Y and Wong, G and Pilon, D and Brown, G and Lowentritt, B and Lin, DW}, title = {Homologous Recombination Repair Mutations, Next-generation Sequencing Testing, and Treatment Progression by Race Among Patients With Metastatic Castration-sensitive Prostate Cancer.}, journal = {Urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urology.2026.01.024}, pmid = {41620128}, issn = {1527-9995}, abstract = {OBJECTIVE: To describe next-generation sequencing (NGS) testing rates for deleterious homologous recombination repair (HRR) mutations and time-to-next-treatment (TTNT) among US patients with metastatic castration-sensitive prostate cancer (mCSPC).<br><br>METHODS: Data from oncology centers included in the nationwide (US-based) Flatiron Health-Foundation Medicine, Inc. Metastatic PC Clinico-Genomic Database (January&#xa0;1, 2011 to December&#xa0;31, 2022) and Core Registry (January&#xa0;1,&#xa0;2013 to December&#xa0;31,&#xa0;2023) were evaluated. Patients who initiated treatment for mCSPC (index date) after January&#xa0;1, 2018 and received an HRR alteration test were included. TTNT and NGS testing patterns were described overall and among White, non-White (ie, Black, Asian, Hispanic, other), and Black patient subgroups. TTNT was assessed using Kaplan-Meier analyses and annual NGS testing rates were assessed from 2018 to 2023 using the Core Registry.<br><br>RESULTS: In total, 1121 HRR-tested patients with mCSPC were included. HRR (BRCA1/2) alterations were observed among 17.4% (12.7%) of White patients, 16.5% (10.9%) of non-White patients, and 15.2% (9.7%) of Black patients. Non-White patients had the shortest median (months) TTNT (17.0; 60.6% with next treatment by 24 months), followed by White (19.2; 56.1% with next treatment by 24 months) and Black patients (21.2; 54.7% with next treatment by 24 months). Although Black patients had descriptively lower testing rates than White patients in 2018 (4.2%), the rates increased overall and became numerically comparable between racial groups by 2023 (29.8%).<br><br>CONCLUSION: Although NGS testing rates have increased, with less disparity in most recent years, the testing rates are unacceptable for patients with mCSPC, overall and across racial groups, with the majority of patients progressing to the next treatment by 24 months. Tweet (121/125 characters including spaces; required): Next-generation sequencing use for metastatic castration-resistant prostate cancer remains suboptimal, regardless of race.}, }
@article {pmid41622289, year = {2026}, author = {Richards, AR and Gomez, MF and Dowling, BI and Jean-Baptiste, E and Gigic, B and Figueiredo, JC and Li, CI and Shibata, D and Toriola, AT and Byrd, DA and Ulrich, CM and Stewart, PA and Siegel, EM and Kresovich, JK}, title = {Blood DNA methylation-predicted plasma protein levels and colorectal cancer survival.}, journal = {Clinical epigenetics}, volume = {18}, number = {1}, pages = {24}, pmid = {41622289}, issn = {1868-7083}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; P30-CA076292/GF/NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/blood/mortality ; *DNA Methylation/genetics ; Female ; Male ; Middle Aged ; Aged ; Case-Control Studies ; Biomarkers, Tumor/blood/genetics ; Prognosis ; Vascular Endothelial Growth Factor A/blood/genetics ; *Blood Proteins/analysis ; Disease-Free Survival ; Antigens, Neoplasm ; Extracellular Matrix Proteins ; }, abstract = {BACKGROUND: Protein EpiScores are a novel class of DNA methylation (DNAm)-based metrics proposed to measure peripheral immune system characteristics. Although Protein EpiScores have been associated with chronic disease risk, their relationship with colorectal cancer (CRC) survival has not been investigated.<br><br>METHODS: We generated new genome-wide DNAm data on pre-treatment whole blood samples from a case-control sample of 136 newly diagnosed CRC patients nested in the ColoCare Study and calculated 107 Protein EpiScores using the developer's algorithm. Over a median follow-up of 7.3 years (range: 0.3-13.8 years), 35 (26%) patients experienced disease recurrence, and 47 (35%) died. Protein EpiScore associations with disease-free and overall survival were tested using Cox regression models, adjusted for patient and clinical characteristics, and prognostic discrimination was assessed using Harrell's C-index.<br><br>RESULTS: In fully-adjusted models, HCII, VEGFA, CCL17, and LGALS3BP Protein EpiScores were associated with worse disease-free survival (HRs between 1.62 and 1.71, all FDR < 0.05). Adding these Protein EpiScores to traditional clinical prognosis risk factors significantly improved disease-free survival prediction (C-index: 0.64 vs 0.70, P-diff= 0.03). The LGALS3BP Protein EpiScore was associated with worse overall survival (HR: 1.80, 95% CI 1.29, 2.51,P = 0.0005, FDR= 0.056), and improved prediction (C-index: 0.70 vs 0.75, P-diff= 0.02). Protein EpiScores for HCII, LGALS3BP, MMP12, and VEGFA showed positive association with both disease-free and overall survival (HRs > 1.5).<br><br>CONCLUSIONS: Protein EpiScores are significantly associated with CRC survival. These findings highlight biological pathways underlying CRC prognosis and support the utility of Protein EpiScores for modeling survivorship.}, }
@article {pmid41623930, year = {2026}, author = {Le, CM and Chen, X and Kodaira, S and Othus, M and Gang, M and Davis, C and Basom, RS and Cherian, S and Walter, RB}, title = {Immunophenotypic abnormality quantification refines multiparameter flow cytometry-based measurable residual disease testing in adults allografted for acute myeloid leukemia in morphologic remission.}, journal = {HemaSphere}, volume = {10}, number = {2}, pages = {e70310}, pmid = {41623930}, issn = {2572-9241}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {Flow cytometry-based measurable residual disease (MRD) testing is routinely used in acute myeloid leukemia (AML), but methodologies need refinement to optimize assay characteristics. Here, we examined 1215 adults with AML or myelodysplastic syndrome/AML allografted in morphologic remission to study how the type(s) of leukemic blasts and degree/number of immunophenotypic abnormalities could improve MRD testing. Among 233 patients with pre-hematopoietic cell transplantation (pre-HCT) MRD, 80 (34%) had non-stem cell-like (NSC-like) leukemic blasts, 109 (47%) had stem cell-like (SC-like) leukemic blasts, and 44 (19%) had NSC- and SC-like leukemic blast cell populations. Across all MRD[pos] patients, a higher degree/number of immunophenotypic abnormalities was associated with increased relapse risk and worse relapse-free survival (RFS) and overall survival (OS). Maximally selected rank statistics estimated a total MRD immunophenotype score cut point of ≤4.5 (n = 63 [27% of MRD[pos] patients]) vs. >4.5 (n = 170 [73% of MRD[pos] patients]) as optimal for RFS discrimination. After multivariable adjustment, a high score was associated with a significantly increased relapse risk (hazard ratio [HR] = 4.99 [95% confidence interval: 3.92-6.36]; P < 0.001), shorter RFS (HR = 3.88 [3.15-4.78]; P < 0.001), shorter OS (HR = 2.99 [2.42-3.70]; P < 0.001), and higher risk of NRM (HR = 1.78 [1.07-2.81]; P = 0.014) relative to MRD[neg] patients. In contrast, there was no significant relapse risk or RFS difference between patients with low total MRD immunophenotype score and those without MRD. While requiring validation, our data suggest considering the type and degree/number of immunophenotypic abnormalities may refine MRD testing and identify a significant subset of MRD[pos] patients with outcomes like MRD[neg] patients.}, }
@article {pmid41627575, year = {2026}, author = {Abu-Raddad, LJ and Chemaitelly, H and Wald, A and Johnston, C}, title = {Herpes Simplex Virus Type 2 Screening in Persons with and Without HIV: Evidence, Challenges, and Future Directions.}, journal = {Current HIV/AIDS reports}, volume = {23}, number = {1}, pages = {3}, pmid = {41627575}, issn = {1548-3576}, abstract = {PURPOSE OF REVIEW: Herpes simplex virus type 2 (HSV-2) infection is one of the most prevalent sexually transmitted infections worldwide, with implications for HIV acquisition, transmission, and disease progression. This review synthesizes current evidence and guidance on HSV-2 serologic screening, emphasizing its relevance for HIV prevention and care.<br><br>RECENT FINDINGS: International guidelines advise against routine general population-level serologic screening for HSV-2 in asymptomatic persons. Key limitations include poor test specificity, the absence of potent antivirals or therapeutic vaccines, lack of curative therapy, no demonstrated population-level benefit, and psychosocial harms associated with diagnosis. Current practice instead emphasizes diagnostic testing in symptomatic persons and targeted screening in defined contexts&#x2014;such as among people with HIV in specific clinical situations, sex partners of those with HSV-2 infection, certain pregnant women, persons seeking sexual health care, and persons with recurrent or atypical symptoms&#x2014;where results may directly inform management. Emerging technologies, including highly specific assays, novel potent antivirals, therapeutic vaccines, and curative strategies, may eventually shift the cost&#x2013;benefit balance of general screening.&#xa0;<br><br>SUMMARY: Evidence supports targeted rather than general population-level screening to maximize clinical benefit while minimizing harm. New evidence demonstrating that interventions can achieve measurable population-level reductions in disease burden or transmission, together with future advances in diagnostics and therapeutics, may eventually justify integrating routine HSV-2 screening into broader contexts, including into HIV prevention and care.}, }
@article {pmid41632638, year = {2026}, author = {Zych, MG and Contreras, M and Mammel, AE and Hatch, EM}, title = {RCC1 depletion drives protein transport defects and rupture in micronuclei.}, journal = {The Journal of cell biology}, volume = {225}, number = {4}, pages = {}, doi = {10.1083/jcb.202510133}, pmid = {41632638}, issn = {1540-8140}, support = {R35GM124766/NH/NIH HHS/United States ; T32GM007270/NH/NIH HHS/United States ; T32CA009657/NH/NIH HHS/United States ; //Rita Allen Foundation/ ; P30CA015704//Fred Hutch/University of Washington Cancer Consortium/ ; }, mesh = {Humans ; *Nuclear Proteins/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; Nuclear Lamina/metabolism ; Chromatin/metabolism ; *Karyopherins/metabolism/genetics ; Protein Transport ; *Micronuclei, Chromosome-Defective ; Active Transport, Cell Nucleus ; Histones/metabolism ; Chromosomal Instability ; Euchromatin/metabolism/genetics ; Guanine Nucleotide Exchange Factors ; }, abstract = {Micronuclei (MN), a hallmark of chromosome instability, frequently rupture, leading to protumorigenic consequences. MN rupture requires nuclear lamina defects, yet their underlying causes remain unclear. Here, we demonstrate that MN lamina gaps are linked to excessive MN growth resulting from impaired protein export. This export defect arises from reduced levels of the transport protein RCC1 in MN. Overexpressing RCC1 increases protein export and protects MN from rupture. Differences in RCC1 levels linked to chromatin state also explain why high euchromatin content increases the stability of small MN. Additional RCC1 loss in euchromatic MN results in impaired protein import. For these MN, increasing RCC1, directly or through increasing histone methylation, accelerates rupture. Our findings define a new model of MN rupture, where defects in protein export drives continuous MN growth causing nuclear lamina gaps that predispose MN to membrane rupture and where chromatin-specific features can alter rupture of small MN by further impairing nuclear transport.}, }
@article {pmid41633487, year = {2026}, author = {Chen, L and Li, H and Zhu, Q and Xu, X and Liu, X and Dong, X and Yuan, C and Chen, W and Xiao, W and Ding, Z and Wu, K and Tu, B and Li, W and Zhu, X and Gong, W and Lu, G and Ji, D}, title = {Screening and identification of a novel PGAM5-specific inhibitor for attenuating multi-organ injury.}, journal = {Journal of advanced research}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jare.2026.01.075}, pmid = {41633487}, issn = {2090-1224}, abstract = {INTRODUCTION: The necroptosis regulator PGAM5 drives a pathological cycle of mitochondrial dysfunction and necroptotic signaling, contributing to multi-organ injury and representing a potential therapeutic target. Despite its clinical relevance, few PGAM5-specific small-molecule inhibitors have been developed.<br><br>OBJECTIVES: We aimed to identify a safe and effective natural small-molecule inhibitor targeting PGAM5 as a novel therapeutic strategy.<br><br>METHODS: Global PGAM5 knockout mice and pancreas-specific PGAM5 knockdown mice were used to clarify the regulatory role of PGAM5 in pancreatic injury in acute pancreatitis (AP). Subsequently, high-throughput screening of candidate compounds targeting PGAM5 was conducted based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combined with molecular docking, in vitro binding experiments, and functional verification experiments, Plantainoside D (PD) was finally identified as a natural small-molecule inhibitor targeting PGAM5. Finally, the protective effect of PD was evaluated using preclinical models of various organ injuries.<br><br>RESULTS: We identify PGAM5 as a critical mediator of pancreatic acinar cell (PAC) necrosis in AP. Genetic suppression of PGAM5 significantly mitigates PAC necrosis in both in vitro and in vivo AP models. Through high-throughput virtual screening of the TCMSP natural-product database, we identified PD, a phenylethanoid glycoside, as the first reported PGAM5-specific small-molecule inhibitor. By binding PGAM5, PD inhibits its phosphatase activity and prevents oligomerization, thereby restoring mitochondrial homeostasis and blocking necroptosis. Importantly, systemic PD administration demonstrated broad protective efficacy in multiple organ-injury models-including autoimmune hepatitis, acute kidney injury, myocardial ischemia - reperfusion, and lung fibrosis - as well as local efficacy in a pathological high intraocular pressure(ph-IOP) - induced retinal ganglion cell (RGC) injury model.<br><br>CONCLUSION: These findings establish PGAM5 as a druggable target in organ injury and identify PD as a natural compound with favorable safety and strong translational potential, providing a foundation for necroptosis-targeted therapeutic development.}, }
@article {pmid41634487, year = {2026}, author = {Gieselmann, L and DeLaitsch, AT and Rohde, M and Radford, C and Worczinski, J and Ashurov, A and Ahmadov, E and Burger, JA and Havenar-Daughton, C and Deshpande, S and Giovannoni, F and Corti, D and Kreer, C and Ercanoglu, MS and Schommers, P and Georgiev, IS and West, AP and Knüfer, J and Stumpf, R and Kroidl, A and Geldmacher, C and Maganga, L and William, W and Ntinginya, NE and Hoelscher, M and Yang, Z and Wei, Q and Renfrow, MB and Green, TJ and Novak, J and van Gils, MJ and Gristick, HB and Gruell, H and Bloom, JD and Seaman, MS and Bjorkman, PJ and Klein, F}, title = {Identification of a potent V3 glycan site broadly neutralizing antibody targeting an N332gp120 glycan-independent epitope.}, journal = {Nature immunology}, volume = {27}, number = {3}, pages = {572-585}, pmid = {41634487}, issn = {1529-2916}, support = {U01AI169385//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; ERC-stG639961//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; U54 AI170856/AI/NIAID NIH HHS/United States ; INV-002143/GATES/Gates Foundation/United States ; CRC1310//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; INV-036842/GATES/Gates Foundation/United States ; P01 AI100148/AI/NIAID NIH HHS/United States ; R01 AI140891/AI/NIAID NIH HHS/United States ; R01AI140891//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R01 AI162236/AI/NIAID NIH HHS/United States ; CRC1279//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; U01 AI169385/AI/NIAID NIH HHS/United States ; }, mesh = {*HIV-1/immunology ; Humans ; *Epitopes/immunology ; Animals ; *HIV Envelope Protein gp120/immunology/chemistry ; *HIV Antibodies/immunology ; *Polysaccharides/immunology/chemistry ; Mice ; *Antibodies, Neutralizing/immunology ; *HIV Infections/immunology ; *Broadly Neutralizing Antibodies/immunology ; AIDS Vaccines/immunology ; }, abstract = {Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels. 007 targets an N332gp120 glycan-independent V3 epitope, a site of the HIV-1 envelope protein (Env) vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryogenic electron microscopy structure revealed contacts with the V3 [324]GD/NIR[327] motif and interactions with N156gp120 and N301gp120 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332gp120 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs. Bivalent 007 IgG was more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1ADA-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure and vaccine design.}, }
@article {pmid41634669, year = {2026}, author = {Hailemariam, A and Han, K and Emerson, J and Batch, BC and McCall, S and Salama, N and Wang, F and Garman, KS and Epplein, M}, title = {Association between autoimmune thyroid disease and presence of CagA and gastric intestinal metaplasia among patients with H. pylori: a cross-sectional endoscopic study.}, journal = {BMC endocrine disorders}, volume = {26}, number = {1}, pages = {}, pmid = {41634669}, issn = {1472-6823}, support = {P30 CA014236/CA/NCI NIH HHS/United States ; P30 CA014236/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Autoimmune thyroid disease (AITD), specifically Graves’ disease and Hashimoto’s thyroiditis, has been seen to co-occur with Helicobacter pylori (H. pylori) infection. Some evidence suggests that the link is particularly strong with the H. pylori virulence factor cagA, though findings remain inconclusive. We sought to evaluate whether the presence of cagA and the pre-cancer lesion gastric intestinal metaplasia (GIM) differed by AITD status among patients with current H. pylori infection confirmed by histological assessment of endoscopic tissue biopsy.<br><br>METHODS: In a retrospective cohort of 478 Black and White adults with confirmed H. pylori infection on histological assessment from endoscopic gastric biopsy, AITD status was determined through electronic health records and patients were categorized into one of four mutually exclusive groups (no autoimmune disease, Graves&#x2019;, Hashimoto&#x2019;s, and other autoimmune disease). cagA status was identified using droplet digital PCR on gastric tissue samples. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between AITD and cagA, and GIM, separately.<br><br>RESULTS: Graves&#x2019; patients had an over 5-fold increased likelihood of cagA-positivity compared to individuals with no autoimmune disease (OR, 5.47; 95% CI: 1.06, &#x221e;, p&#x2009;=&#x2009;0.04). In contrast, Hashimoto&#x2019;s thyroiditis patients had a suggestive 63% decreased likelihood of having a cagA-positive H. pylori strain compared to individuals with no autoimmune disease (OR, 0.37; 95% CI: 0.12, 1.06; p&#x2009;=&#x2009;0.07). Neither AITD was associated with the presence of GIM. The seven cagA-positive Graves&#x2019; patients were grouped by treatment type, which revealed patterns showing that after eradication of H. pylori, patients who had thyroidectomy or those treated with RAI had stable thyroid hormone levels, while patients without definitive treatment had decreased thyroid stimulating hormone levels.<br><br>CONCLUSIONS: These findings suggest a higher prevalence of positivity to the virulence factor cagA in H. pylori-infected patients with Graves&#x2019; disease compared to H. pylori-infected patients without autoimmune conditions. This suggests a need for assessing H. pylori presence and the effect on eradication on thyroid antibody levels and management of Graves&#x2019;, to determine if incorporation of H. pylori screening into Graves&#x2019; care, as done in other autoimmune diseases, improves outcomes.<br><br>CLINICAL TRIAL NUMBER: Not applicable.}, }
@article {pmid41635086, year = {2026}, author = {Castelli, JMP and Poljakov, K and Jwa, Y and Cunningham, R and Cassidy, ME and Gray, MD and Sanchez Gaytan, JN and Enstrom, MR and Gastelum, G and Wang, Z and Linton, JD and Rongvaux, A and Taylor, JJ and Adair, JE}, title = {In vivo production of an anti-HIV antibody in mice by non-viral gene knockin in primate hematopoietic stem and progenitor cells.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, pmid = {41635086}, issn = {1525-0024}, support = {D43 TW013052/TW/FIC NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI158728/AI/NIAID NIH HHS/United States ; R01 AI167009/AI/NIAID NIH HHS/United States ; }, abstract = {Gene editing strategies that do not rely on viral vectors are being explored for their potential to support durable biologics production. While clinical trials have shown that adeno-associated virus encoding broadly neutralizing antibodies can protect against HIV, these interventions often yield limited, short-lived responses. The development of non-viral gene editing approaches in hematopoietic stem and progenitor cells holds promise for long-term antibody production. In this study, we evaluated CRISPR-Cas9 and CRISPR-Cas12a for gene knockin at the immunoglobulin heavy chain locus in non-human primate (NHP) hematopoietic stem and progenitor cells (HSPCs). Delivering the nuclease as a protein alongside a custom DNA template, we optimized editing with Cas12a and demonstrated higher knockin efficiency and fewer non-specific edits than with Cas9. Transplantation of edited NHP HSPCs into MISTRG mice led to engraftment, B cell differentiation, and transgene expression of a reporter transgene or anti-HIV antibody after gp120 antigen immunization with detectable titers in circulation. These findings demonstrate the feasibility of using non-viral knockin in HSPCs as a potential strategy for sustained biologics production in the treatment of chronic diseases. Future work will assess the efficacy of this approach in an NHP model of HIV infection.}, }
@article {pmid41636424, year = {2026}, author = {Gullà, A and Dhodapkar, MV and Einsele, H and Raab, MS and Solimando, AG and Botta, C and Turi, M and Sester, LS and Portuguese, AJ and Steinbrunn, T and Anderson, KC}, title = {Rethinking Multiple Myeloma Treatment: The Biological and Clinical Insights Guiding Immune-Based Combinations.}, journal = {Blood cancer discovery}, volume = {7}, number = {2}, pages = {176-194}, doi = {10.1158/2643-3230.BCD-25-0107}, pmid = {41636424}, issn = {2643-3249}, support = {27750//Fondazione AIRC per la ricerca sul cancro ETS (AIRC)/ ; EMAGEN//Fondazione Piemontese per la Ricerca sul Cancro/ ; Ricerca corrente 2025//Ministero della Salute (Italy Ministry of Health)/ ; SPORE P50-CA100707//National Cancer Institute (NCI)/ ; //Paula and Rodger Riney Foundation/ ; //Leukemia and Lymphoma Society (LLS)/ ; //Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF)/ ; 442740310//Deutsche Forschungsgemeinschaft (DFG)/ ; 24534//Fondazione AIRC per la ricerca sul cancro ETS (AIRC)/ ; PRIN- 2022ZKKWLW//Ministero della Salute (Italy Ministry of Health)/ ; PNRR-POC-2022-12375862//European Union Next Generation EU/ ; P01-CA155258//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Multiple Myeloma/therapy/immunology/pathology ; *Immunotherapy/methods ; }, abstract = {UNLABELLED: The standard of care for multiple myeloma has rapidly evolved to include immune-based therapies. However, achieving durable immune control and long-term survival, particularly in high-risk patients, remains difficult. In this article, we review the immune effects of existing and emerging therapies, dissect key drivers of resistance, highlight rational combinations and treatment-sequencing strategies, and summarize ongoing clinical trials that aim to optimize durable immune control. We discuss how the application of these biological and clinical insights may help us rethink multiple myeloma treatment to fully eradicate residual disease and elicit sustained natural and/or synthetic tumor-specific immunity.<br><br>SIGNIFICANCE: Preclinical and clinical insights are reshaping how immune-based therapies are used in multiple myeloma. This review explores how optimizing the integration of natural and synthetic immunity can support a shift from disease control to deep, durable immune eradication, paving the way for personalized immune strategies tailored to individual immune profiles.}, }
@article {pmid41637641, year = {2026}, author = {Olivieri, D and Othus, M and Vo, P and Walter, RB and Manjappa, S and Basom, R and Storb, R and Keel, S}, title = {Allogeneic hematopoietic cell transplantation for aplastic anemia: a single institution experience across 6 decades.}, journal = {Blood advances}, volume = {10}, number = {8}, pages = {2661-2675}, doi = {10.1182/bloodadvances.2025018548}, pmid = {41637641}, issn = {2473-9537}, mesh = {Humans ; *Anemia, Aplastic/therapy/mortality ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Adult ; Transplantation, Homologous ; Graft vs Host Disease/prevention &amp; control/etiology ; Child ; Transplantation Conditioning/methods ; Female ; Male ; Adolescent ; Retrospective Studies ; Child, Preschool ; Middle Aged ; Young Adult ; Treatment Outcome ; }, abstract = {Since the introduction of allogeneic bone marrow transplantation (BMT) as a treatment for aplastic anemia (AA), major advances have occurred, such as refinements in conditioning regimens, graft-versus-host disease (GVHD) prophylaxis, high-resolution HLA typing, pretransplant transfusion practices, and general supportive care. We present a comprehensive retrospective single-center cohort study of 607 children and adults who underwent allogeneic transplantation for AA over 6 decades at a single BMT center. We highlight key temporal changes in conditioning strategies for related donor transplantation, GVHD prophylaxis, and HLA matching that correspond with improved nonrelapse mortality, reduced GVHD rates, and better overall survival among HLA-matched related and unrelated donor transplants. This work provides a historical perspective on the evolution of BMT for AA among HLA-matched related and unrelated donor recipients and identifies persistent barriers to curative therapy, including patient age and donor availability. Further studies are needed to clarify the role of antithymocyte globulin in conditioning regimens, improve GVHD prevention and management, and expand the use of alternative donors.}, }
@article {pmid41638872, year = {2026}, author = {Schmitt, TM and Furiya, K and Black, C and Vazquez, A and Sharma, J and Hailemariam, M and Paushter, DH and Trieu, L and Lam, J and Lee, B and Rakhra, K and Whalen, KA and Mehta, NK and Sauer, K and Baeuerle, PA and Michaelson, JS and Greenberg, PD and Chapuis, AG}, title = {Dysregulated expression of the tumor suppressor p14ARF in cancer provides an effective target for TCR-T cell therapeutics.}, journal = {Journal for immunotherapy of cancer}, volume = {14}, number = {2}, pages = {}, pmid = {41638872}, issn = {2051-1426}, mesh = {Humans ; *Tumor Suppressor Protein p14ARF/genetics/metabolism/immunology ; Animals ; Mice ; *Receptors, Antigen, T-Cell/metabolism/immunology ; Cyclin-Dependent Kinase Inhibitor p16/metabolism/genetics ; HLA-A2 Antigen/immunology ; *Neoplasms/therapy/immunology/genetics ; Cell Line, Tumor ; *Immunotherapy, Adoptive/methods ; CD8-Positive T-Lymphocytes/immunology ; }, abstract = {BACKGROUND: The CDKN2A gene encodes two canonical tumor suppressors, p16INK4A and p14ARF, which safeguard cells from malignant transformation by inducing cell cycle arrest and apoptosis in response to aberrant growth signals. Paradoxically, many cancers overexpress these proteins when downstream effectors that enforce negative feedback regulation are lost or inactivated. For example, p14ARF, which regulates p53 activation, is aberrantly expressed in more than 50% of tumors with inactivating p53 mutations. Here, we evaluated the feasibility of targeting dysregulated p16INK4A and p14ARF expression using TCR-T cell therapeutics.<br><br>METHODS: We analyzed a panel of p16INK4A- and p14ARF-derived peptides for HLA-A*02:01-associated presentation and recognition by CD8[+] T cells. Antigen-specific T cell receptors were isolated from healthy donor repertoires and expressed in primary T cells to assess specificity, functional avidity, tumor recognition, and safety using in vitro T cell functional assays, in vivo tumor models, and an in vivo safety model.<br><br>RESULTS: We identified a unique and well-presented p14ARF epitope that was consistently detected in the HLA-A*02:01-associated immunopeptidome of cancer biopsies but not in normal tissues. High-avidity ARF-specific TCRs were isolated from the peripheral repertoire of healthy donors, and TCR-transduced T cells mediated potent tumor cell killing in vitro and in vivo in preclinical models. Furthermore, targeting p14ARF-expressing cells did not result in detectable on-target toxicity in an in vivo safety model.<br><br>CONCLUSIONS: These findings demonstrate the feasibility of targeting dysregulated tumor suppressor proteins with TCR-T cell therapeutics and identify p14ARF as a promising target for future therapies.}, }
@article {pmid41639379, year = {2026}, author = {Besse, B and Lin, JJ and Bazhenova, L and Goto, K and de Langen, AJ and Kim, DW and Wolf, J and Springfeld, C and Popat, S and Lim, DWT and Nagasaka, M and Hong, JY and Baik, CS and Hervieu, A and Moreno, V and Yang, N and Kollengode, K and Yang, H and Xu, Y and Calvet, CY and Yuan, Y and Hammell, AB and Drilon, A and Solomon, BJ}, title = {Repotrectinib in NTRK fusion-positive advanced solid tumors: a phase 1/2 trial.}, journal = {Nature medicine}, volume = {32}, number = {2}, pages = {682-689}, pmid = {41639379}, issn = {1546-170X}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Neoplasms/drug therapy/genetics/pathology ; Adult ; Aged ; *Protein Kinase Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; *Oncogene Proteins, Fusion/genetics ; *Receptor, trkA/genetics/antagonists &amp; inhibitors ; *Pyrazoles/therapeutic use/adverse effects/administration &amp; dosage ; Protein-Tyrosine Kinases/genetics ; *Pyrimidines/therapeutic use/adverse effects ; Proto-Oncogene Proteins/genetics/antagonists &amp; inhibitors ; Young Adult ; Receptor, trkC/genetics ; Progression-Free Survival ; }, abstract = {Early-generation TRK tyrosine kinase inhibitors (TKIs) approved for treating NTRK fusion-positive (NTRK[+]) solid tumors provide clinical benefit; however, resistance emerges. Repotrectinib is a next-generation ROS1/TRK TKI with a compact macrocyclic structure designed to improve durability of response. TRIDENT-1 is a registrational phase 1/2 trial assessing repotrectinib, a next-generation ROS1/TRK TKI, in adults with advanced solid tumors, including NTRK[+] disease. The primary endpoint was confirmed objective response; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival and safety. Median follow-up ranged between 21.3 months and 25.7 months. In the TKI-naive cohort (n = 51; 95% confidence interval (CI)), the response rate was 59% (44-72); the median DOR was not estimable (NE); and the median PFS was 30.3 months (9.0-NE). In the TKI-pretreated cohort (n = 69; 95% CI), the response rate was 48% (36-60); the median DOR was 9.8 months (7.4-13.0); and the median PFS was 7.4 months (3.9-9.7). Of 30 TKI-pretreated patients with NTRK solvent front mutations, 16 had a response (53%; 95% CI: 34-72). Intracranial responses were observed in two of three TKI-naive patients and in four of six TKI-pretreated patients with measurable intracranial disease at baseline. Among all treated patients (n = 565), the most common any-grade treatment-related adverse event (TRAE) was dizziness (57%); most TRAEs were low grade; and 4% discontinued repotrectinib due to a TRAE. Here repotrectinib demonstrated durable systemic and intracranial responses with generally low-grade adverse events in patients with NTRK[+] solid tumors, including those with previous TRK TKI treatment and solvent front mutations. These results support the use of repotrectinib to treat patients with NTRK[+] solid tumors. ClinicalTrials.gov identifier: NCT03093116 .}, }
@article {pmid41639460, year = {2026}, author = {Natarajan, SK and Lum, J and Skeans, JH and Nenwani, M and Eyunni, S and Mota, M and Bayliss, JM and Deogharkar, A and Hamanishi, ET and Pun, M and Sweha, SR and Hoffman, S and Young, E and Zhang, Q and Mehta, R and Animasahun, O and Narayanan, P and Sunil, S and Parolia, A and Sajjakulnukit, P and Panwalkar, P and Doherty, R and Clausen, M and Dang, D and Hawes, D and Yang, F and Santi, M and Judkins, AR and Wilson, Y and Vigil, T and Franson, A and Mortensen, RM and Ozawa, T and Griesinger, A and Holland, EC and Foreman, NK and Michealraj, KA and Agnihotri, S and Taylor, M and Gilbertson, RJ and Koschmann, C and Chinnaiyan, AM and Lyssiotis, CA and Nagrath, D and Venneti, S}, title = {ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression.}, journal = {Nature}, volume = {}, number = {}, pages = {}, pmid = {41639460}, issn = {1476-4687}, abstract = {ZFTA-RELA[+] ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA[1]. Here we show that ZFTA-RELA[+] cells produce itaconate, a key macrophage-associated immunomodulatory metabolite[2]. Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA[+] tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA[+] ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA[+] ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.}, }
@article {pmid41641558, year = {2026}, author = {Hoffman, AM and Cocciardi, JM and Manna, P and Alvarado-Serrano, DF and Cavender-Bares, J and Groffman, PM and Hall, SJ and Hobbie, SE and Lerman, SB and Padullés Cubino, J and Pataki, DE and Trammell, TLE and Avolio, ML}, title = {Genetic Diversity and Population Structure in Cities Is Not Consistent Among Cosmopolitan Plant Species.}, journal = {Molecular ecology}, volume = {35}, number = {3}, pages = {e70261}, doi = {10.1111/mec.70261}, pmid = {41641558}, issn = {1365-294X}, support = {DEB-1836034//National Science Foundation/ ; DEB-1638519//National Science Foundation/ ; DEB-163872//National Science Foundation/ ; DEB-1637590//National Science Foundation/ ; DEB-1832016//National Science Foundation/ ; DEB-1638560//National Science Foundation/ ; DEB-1638648//National Science Foundation/ ; DEB-1638606//National Science Foundation/ ; EF-1638676//National Science Foundation/ ; DEB-2110351//National Science Foundation/ ; }, mesh = {*Genetic Variation ; *Genetics, Population ; Cities ; Gene Flow ; *Asteraceae/genetics ; *Poaceae/genetics ; United States ; }, abstract = {Urbanisation has led to increasing homogenization of plant communities across cities. However, it is unclear whether these patterns extend to cosmopolitan plant species at the genetic level. We examined genome-wide genetic patterns in six widespread plant species (three Poaceae and three Asteraceae) across five cities in the USA (Boston, Baltimore, Minneapolis-St. Paul, Phoenix, and Los Angeles) using reduced-representation sequencing. We assessed genetic structure, differentiation, and patterns of isolation by distance (IBD) and environment (IBE) to determine if species were genetically homogeneous or differentiated by city, percentage of impervious surface, or both. Most species exhibited limited population structure overall, with Poa annua (annual bluegrass), Taraxacum officinale (dandelion), and Cynodon dactylon (Bermuda grass) showing no significant genetic differentiation among cities, a pattern consistent with high gene flow mediated by human activity. Notable exceptions included city-level differences in Erigeron canadensis (horseweed) and Lactuca serriola (prickly lettuce), especially in Phoenix. We also observed low genetic diversity in Digitaria sanguinalis (crabgrass) from Phoenix, suggesting recent founder effects or selection via environmental filtering. Erigeron canadensis, the only native species studied, displayed stronger differentiation by city, along with significant isolation by temperature and distance. Among all species, we found no evidence for population structure by impervious surface. Our findings indicate that widespread population genetic structure patterns of cosmopolitan plants are likely to depend more on species attributes (e.g., self-compatibility) and human-mediated dispersal than on urbanisation per se.}, }
@article {pmid41641624, year = {2026}, author = {Xiong, Y and Chan, KCG and Gorfine, M and Hsu, L}, title = {Assessing the Benefits and Burdens of Preventive Interventions.}, journal = {Statistics in medicine}, volume = {45}, number = {3-5}, pages = {e70410}, doi = {10.1002/sim.70410}, pmid = {41641624}, issn = {1097-0258}, support = {S100D028685/RI/ORIP NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; /HL/NHLBI NIH HHS/United States ; R01 CA195789/NH/NIH HHS/United States ; R01 CA189532/NH/NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; U01 CA86368/NH/NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 CA236558/NH/NIH HHS/United States ; P30 CA015704/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; Colorectal Neoplasms/prevention &amp; control/mortality/diagnosis ; Middle Aged ; Computer Simulation ; Models, Statistical ; Early Detection of Cancer ; Risk Assessment ; Neoplasms/prevention &amp; control ; Mass Screening ; }, abstract = {Cancer prevention is recognized as a key strategy for reducing disease incidence, mortality, and the overall burden on individuals and society. However, determining when to begin preventive interventions presents a significant challenge: starting too early may lead to more interventions and increased lifetime burdens due to repeated administrations, while delaying may miss opportunities to prevent cancer. Evidence-based recommendations require a benefit-burden analysis that weighs life-years gained against the burden of interventions. With the growing availability of large-scale observational data, there is now an opportunity to empirically evaluate these trade-offs. In this paper, we propose a causal framework for assessing the benefit and burden of cancer prevention, using an illness-death model with semi-competing risks. Extensive simulations demonstrate that the proposed estimators are unbiased, with robust inference across realistic scenarios. We apply this approach to a benefit-burden analysis of the preventive screening for colorectal cancer, utilizing data from the large-scale Women's Health Initiative. Our findings suggest that initiating screening at age 50 years achieves the highest life-year gains with an acceptable incremental burden-to-benefit ratio compared to no screening, contributing valuable real-world evidence to the field of preventive cancer interventions.}, }
@article {pmid41641636, year = {2026}, author = {Chen, G and Banerjee, R}, title = {Post-CAR-T lymphocytosis in multiple myeloma: too much of a good thing?.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.300428}, pmid = {41641636}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid41642079, year = {2026}, author = {Billingsley, B and DiBello, AM and Farris, SG and Lee, HC and Chmielewski, M and Bricker, JB and Selby, EA and Steinberg, ML}, title = {Examining the psychometric properties of the Multidimensional Experiential (MEAQ) Questionnaire in combustible cigarette smokers.}, journal = {Cognitive behaviour therapy}, volume = {}, number = {}, pages = {1-13}, doi = {10.1080/16506073.2026.2622944}, pmid = {41642079}, issn = {1651-2316}, abstract = {The aim of the study was to validate the 30-item version of the Multidimensional Experiential Avoidance Questionnaire (MEAQ-30) in a sample of individuals who smoke combustible cigarettes and to examine the relationship between nicotine dependence, cigarette smoking, and experiential avoidance. Confirmatory factor analysis (CFA) was used to verify the structure of the MEAQ-30 and to test measurement invariance in a general population sample (n = 1040) and a sample of individuals who smoke combustible cigarettes (n = 550). Correlation and regression analyses were performed in a sample of individuals who smoke combustible cigarettes (n = 242) to evaluate the stability, dependability, convergent validity, discriminant validity, predictive validity and incremental predictive validity of the measure. The MEAQ-30 demonstrated adequate model fit and met criteria for measurement invariance. It exhibited good internal consistency, good stability, good discriminant validity, weak incremental predictive validity, and lower than expected levels of dependability. Based on our findings, the MEAQ-30 appears to be a valid measure of experiential avoidance in individuals who smoke combustible cigarettes.}, }
@article {pmid41642627, year = {2026}, author = {El-Bassel, N and Shoptaw, S and Skalland, T and Hanscom, B and Clarke, W and Marzinke, MA and Fogel, JM and Richardson, P and Choudhury, RP and Denis, C and Goodman-Meza, D and Kuo, I and Lake, JE and Morrison, EAB and Richards, AM and Harris-Wisecarver, J and Cummings, M and Chandler, R and Andrew, P and , }, title = {Prevalence of Illicit Drug Detection in 5 US Cities Among Out-of-Treatment People Who Inject Drugs.}, journal = {JAMA network open}, volume = {9}, number = {2}, pages = {e2555882}, pmid = {41642627}, issn = {2574-3805}, mesh = {Humans ; Male ; Adult ; Female ; Cross-Sectional Studies ; *Substance Abuse, Intravenous/epidemiology ; Prevalence ; *Illicit Drugs/analysis ; Middle Aged ; United States/epidemiology ; *Substance Abuse Detection/statistics &amp; numerical data/methods ; Cities/epidemiology ; New York City/epidemiology ; }, abstract = {IMPORTANCE: In the US, the overdose crisis continues to be driven by fentanyl, xylazine, and stimulant-involved polysubstance use among people who inject drugs, especially those who are not engaged in medical care.<br><br>OBJECTIVE: To estimate the overall prevalence of illicit drugs detected among people who inject drugs in 5 US cities by city and sociodemographic characteristics and assess trends in drug detection over a 2-year period.<br><br>This cross-sectional study included data from individuals enrolled in HIV Prevention Trials Network (HPTN) 094, a randomized clinical trial to evaluate an integrated mobile unit engaging adults aged 18 years or older who inject drugs in HIV services between June 2021 and September 2023 in New York City; Houston, Texas; Los Angeles, California; Philadelphia, Pennsylvania; and Washington, DC. All analyses were completed between August 2021 and August 2025.<br><br>MAIN OUTCOMES AND MEASURES: Baseline prevalence of toxicologic detection was assessed using liquid chromatography-high-resolution mass spectrometry. Differences in toxicologic detection by sociodemographic characteristics (age, race and ethnicity, housing status, and incarceration history), study site, and illicit drug type over time were analyzed using generalized linear models.<br><br>RESULTS: Across 444 participants, 303 (68.2%) were male, 267 (60.1%) were aged 30 to 49 years, 203 of 440 (46.1%) were unhoused, and 91 of 442 (20.6%) had a recent incarceration history. In all, 414 participants (93.2%) tested positive for fentanyl, 328 (73.9%) for cocaine, 299 (67.3%) for amphetamine-type stimulants, and 234 (52.7%) for xylazine. Nearly all participants (421 [94.8%]) tested positive for polysubstance drugs (fentanyl or opioids with stimulants, benzodiazepines, cocaine, and/or xylazine). Fentanyl detection was high across all sites; xylazine was most common in New York City (68 of 94 [72.3%]), Philadelphia (111 of 112 [99.1%]), and Washington, DC (31 of 41 [75.6%]). Every 6 months, xylazine detection increased in New York City by 10.3% (95% CI, 4.0%-16.5%; P&#x2009;=&#x2009;.001), and its prevalence stayed high in Philadelphia. Amphetamine-type stimulant detection increased in Washington, DC, by 15.0% (95% CI, 2.9%-27.1%) every 6 months over the enrollment period (P&#x2009;=&#x2009;.02). Across all sites, cocaine prevalence was higher among unhoused than housed participants (difference, 11.4%; 95% CI, 3.6%-19.2%; P&#x2009;=&#x2009;.004), and stimulant detection was elevated among those recently incarcerated vs not (difference, 9.9%; 95% CI, 1.4%-18.5%; P&#x2009;=&#x2009;.02).<br><br>CONCLUSIONS AND RELEVANCE: This cross-sectional study found widespread fentanyl and polysubstance detection, with rising xylazine and stimulant detection that varied by sociodemographic and structural vulnerabilities and may be due to adulteration within the unregulated drug supply. These findings highlight urgent public health needs for real-time drug supply surveillance, targeted harm-reduction services, and integrated treatment approaches to reduce overdose risk and address social and structural vulnerabilities.}, }
@article {pmid41642628, year = {2026}, author = {Chow, EJ and Chen, Y and Yasui, Y and Baldwin, LM and Hudson, MM and Muller, TM and Nathan, PC and Ngai, SL and Ohlsen, TJD and Snyder, C and Syrjala, KL and Tonorezos, ES and Armstrong, GT and Oeffinger, KC}, title = {Counseling and Cardiovascular Disease Risk Factor Control in Long-Term Cancer Survivors: A Randomized Clinical Trial.}, journal = {JAMA network open}, volume = {9}, number = {2}, pages = {e2555863}, pmid = {41642628}, issn = {2574-3805}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; U01 CA301480/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA204378/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Female ; Male ; Adult ; *Cardiovascular Diseases/prevention &amp; control ; *Counseling/methods ; Heart Disease Risk Factors ; Middle Aged ; *Neoplasms ; }, abstract = {IMPORTANCE: Survivors of childhood cancer have an increased risk of cardiovascular disease (CVD). However, many survivors at high risk do not receive recommended CVD screening tests as young adults.<br><br>OBJECTIVE: To assess whether a survivorship care plan (SCP)-based counseling intervention improves CVD risk factor control in high-risk survivors.<br><br>The Communicating Health Information and Improving Coordination With Primary Care (CHIIP) Study was a randomized clinical trial that enrolled eligible participants from the Childhood Cancer Survivor Study cohort in 9 US metropolitan areas between August 2017 and April 2020, with follow-up completed July 2022. Participants included adult survivors of childhood cancer exposed to cardiotoxic cancer therapies with undertreated CVD risk factors (hypertension, dyslipidemia, and glucose intolerance defined by standard guidelines); of 1840 survivors approached, 842 consented to participate, and 347 met all eligibility requirements and were randomized after a baseline home assessment. Data analysis was completed March 18, 2025.<br><br>INTERVENTION: The intervention consisted of a single remote session to review measurements and a SCP with personalized CVD risk information and to develop a CVD risk factor management plan, with a booster session 4 months later. Enhanced care controls received measurements with abnormal findings noted and written encouragement to follow up with their primary care clinician (PCC). PCCs received all materials sent to participants.<br><br>MAIN OUTCOMES AND MEASURES: Blood pressure, lipid profile, and glucose and hemoglobin A1c levels collected by a trained home examiner at baseline and 1-year follow-up, with undertreatment defined by standard guidelines.<br><br>RESULTS: A total of 347 cancer survivors (mean [SD] age, 40.5 [9.4] years; 182 [52.4%] male) were randomized, 175 to the intervention group and 172 to the enhanced care control group. Of these, 194 participants (53.0%) participants had undertreated hypertension at baseline; 180 (51.9%), undertreated dyslipidemia; and 170 (49.0%) undertreated glucose intolerance. After 1 year, 45 of 173 surviving intervention participants (26.0%) and 52 of 172 enhanced care control participants (30.2%) had less undertreatment, with lower percentages for each condition vs baseline. Although the intervention did not reduce undertreatment compared with the control condition (odds ratio, 1.31; 95% CI, 0.84-2.05), greater engagement was associated with less undertreatment at 1 year among intervention participants (odds ratio, 0.31; 95% CI, 0.18-0.72). The intervention group had improved PCC documentation of CVD risk vs controls after 1 year (14.8% improvement vs 0.9%; P&#x2009;=&#x2009;.002).<br><br>CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of long-term survivors of childhood cancer, the addition of survivorship-based self-management counseling did not reduce undertreatment beyond simply providing CVD risk assessments to survivors and PCCs. Additional strategies to mitigate CVD risk in high-risk survivors should be examined in the future.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03104543.}, }
@article {pmid41642668, year = {2026}, author = {Takenaka, R and Albanese, EH and Simmerman, SM and Verghese, S and Maddox, MAE and de la Cruz, AF and Young, JM and Schmidt, CA and Rieder, LE and Malik, HS}, title = {The Drosophila maternal-effect gene abnormal oocyte (ao) does not repress histone gene expression.}, journal = {Genetics}, volume = {232}, number = {4}, pages = {}, pmid = {41642668}, issn = {1943-2631}, support = {T32 GM007270/GM/NIGMS NIH HHS/United States ; //NIH IRACDA/ ; F32GM140778//NIH NRSA/ ; R00HD092625//NIH NRSA/ ; R35GM142724//NIH NRSA/ ; R01GM074108//NIH NRSA/ ; /HHMI/Howard Hughes Medical Institute/United States ; }, mesh = {Animals ; *Histones/genetics/metabolism ; *Drosophila Proteins/genetics/metabolism ; *Drosophila melanogaster/genetics ; Female ; Heterochromatin/genetics/metabolism ; CRISPR-Cas Systems ; *Oocytes/metabolism ; Maternal Inheritance ; Male ; }, abstract = {The abnormal oocyte (ao) gene of Drosophila melanogaster is a maternal-effect lethal gene previously identified as encoding a transcriptional regulator of core histones. However, background genetic mutations in existing ao mutant strains could compromise their utility in manipulating histone levels. To distinguish the true ao phenotype from background effects, we created 2 new ao reagents: a CRISPR/Cas9-mediated knockout of the ao allele for genetic and molecular analyses and an epitope-tagged ao allele for cytological experiments. Using these reagents, we confirm previous findings that loss of ao causes maternal-effect lethality, which can be rescued by either a decrease in the histone gene copy number or by Y chromosome heterochromatin. Our data indicate that ao genetically interacts with the heterochromatin, as previously suggested. However, contrary to a prior study, we detected neither Ao localization to histone genes nor ao repression of core histone transcript levels. Thus, the molecular basis for ao-associated maternal-effect lethality remains unknown.}, }
@article {pmid41642921, year = {2026}, author = {McClave, MK and Wan, YH and White, EM and Gálvez Martínez, B and Karimian Shamsabadi, M and Aldridge, N and Poudel, B and Sperl, AW and McGuire, AT and Heldwein, EE}, title = {Isolation and characterization of broadly-neutralizing anti-HCMV-gB antibodies from human donors using a prefusion-stabilized HCMV gB variant.}, journal = {PLoS pathogens}, volume = {22}, number = {2}, pages = {e1013950}, pmid = {41642921}, issn = {1553-7374}, support = {F31 AI179031/AI/NIAID NIH HHS/United States ; R01 AI164698/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Cytomegalovirus/immunology ; *Viral Envelope Proteins/immunology/genetics ; *Antibodies, Viral/immunology/isolation &amp; purification ; *Antibodies, Neutralizing/immunology/isolation &amp; purification ; *Cytomegalovirus Infections/immunology ; *Antibodies, Monoclonal/immunology/isolation &amp; purification ; Epitopes/immunology ; }, abstract = {Human cytomegalovirus (HCMV) poses a significant risk to immunocompromised individuals and is the leading cause of congenital birth defects worldwide. There is no cure or robust treatment options, although neutralizing antibodies (nAbs) derived from patient sera are being explored as prophylactics with limited success. Glycoprotein B (gB) is a viral membrane fusogen and a major target of the anti-HCMV humoral response in humans. Here, we engineered a soluble, prefusion-stabilized HCMV gB ectodomain variant and used it to isolate twelve new human monoclonal antibodies (mAbs). Seven of these mAbs strongly neutralized at least one strain of HCMV in vitro, whereas six mAbs neutralized both lab-adapted and minimally passaged clinical strains (were broadly neutralizing, bnAbs). All nAbs bound different epitopes within antigenic regions AD-4 or AD-5, and most targeted new sites. Despite being isolated using prefusion-stabilized HCMV gB variant, nAbs varied in their conformational specificity. Only one nAb preferentially bound the prefusion form, and most preferentially bound the intermediate form. The seven nAbs were separated into three classes based on their putative neutralization mechanisms, which were deduced from their conformational specificity, reactivity with gB on the cell surface, and epitope location. Our stabilized prefusion-gB construct provides a tool for isolating potent new nAbs, including prefusion-specific ones, and studying HCMV immunogenicity. Long term, these potent nAbs that arose during natural infections could be developed into potent prophylactics and therapeutics against HCMV diseases.}, }
@article {pmid41643192, year = {2026}, author = {Srinagesh, HK and Gupta, VK and Zhang, A and Grunwald, MR and Connor, MP and Kota, VK and Boccucci, J and Ulrickson, ML and Pradeep, R and Hill, LC and Tsai, SB and O'Connor, TE and Sandhu, KS and Advani, AS and Reshef, R and Gordillo, CA and Luskin, MR and Chen, EC and Lin, C and Cassaday, RD and Kopmar, NE and Majhail, NS and Battiwalla, M and Strickland, SA and Lee, CJ and Odstrcil Bobillo, S and Hilal, T and Park, JH and Valtis, YK and Faramand, RG and Solh, MM and Guzowski, C and Vasu, S and Leonard, JT and Tan, V and Wang, ES and McCauley, R and Sasine, JP and Tang, K and Miller, K and Sutherland, KC and Daunov, M and Mohty, R and Jamy, O and Kumaran, M and Hoeg, RT and Dykes, KC and Logan, AC and Othman, T and Stock, WA and Schwartz, MS and Byrd, K and Yalniz, FF and Bachanova, V and Tracy, SI and Yaghmour, G and Irizarry Gatell, V and Jackson, C and Oluwole, OO and Dholaria, B and O'Dwyer, KM and Moore, J and Roloff, GW and Frey, NV and Aldoss, I and Shah, BD and Oliai, C and Muffly, LS}, title = {Blinatumomab Nonresponse Correlates with Poor Survival After Brexucabtagene.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025031734}, pmid = {41643192}, issn = {1528-0020}, abstract = {In a real-world analysis of brexucabtagene autoleucel (brexu-cel) recipients with relapsed/refractory B-ALL (n = 278), lack of response to prior blinatumomab correlates with significantly worse post CAR-T outcomes.}, }
@article {pmid41643197, year = {2026}, author = {Rouse, KJ and Hazelton, WD and Frotscher, A and Chen, L and Prest, MT and Ferris, JS and Xu, X and Melamed, A and Hur, C and Heckman-Stoddard, BM and Samimi, G and Bickell, NA and Layne, TM and Blank, SV and Elkin, EB and Myers, ER and Havrilesky, LJ and Kong, CY and Wright, JD}, title = {Comparative Modeling of Recent and Projected Trends in the Incidence and Mortality of Uterine Cancer.}, journal = {Obstetrics and gynecology}, volume = {147}, number = {4}, pages = {585-595}, pmid = {41643197}, issn = {1873-233X}, support = {1U01 CA265739//Division of Cancer Prevention, National Cancer Institute/ ; }, mesh = {Humans ; Female ; *Uterine Neoplasms/mortality/epidemiology ; Incidence ; Middle Aged ; United States/epidemiology ; Adult ; SEER Program ; Aged ; Forecasting ; }, abstract = {OBJECTIVE: To aid in cancer control and prevention activities by developing, calibrating, and validating three distinct natural history simulation models of uterine cancer, a growing public health concern.<br><br>METHODS: To perform comparative analyses, we developed two state-transition microsimulation models and a multistage clonal expansion model of uterine cancer. The models simulate uterine cancer incidence and mortality. All three models were calibrated to common data on the incidence of uterine cancer from the Surveillance, Epidemiology, and End Results (SEER) 18 database. Each model accounts for changing trends in hysterectomy and obesity over time and simulates incidence and mortality for endometrioid and nonendometrioid tumors and uterine sarcoma. After calibration, we projected the incidence and mortality of uterine cancer to 2050.<br><br>RESULTS: The three uterine cancer models were well calibrated to population data and produced comparable results for projecting the burden of disease through 2050. Among non-Hispanic White women aged 40 years or older, the models project that by 2050 the incidence of uterine cancer will rise to 76.1-81.8 per 100,000 woman-years, up from 2018 SEER incidence of 60.0 per 100,000 woman-years. Among non-Hispanic Black women, new cases will rise to 90.3-107.2 per 100,000 woman-years, up from 2018 SEER incidence of 61.3 per 100,000 woman-years. Within these populations, incidence-based mortality will increase to 11.3-12.3 deaths per 100,000 woman-years for non-Hispanic White women and to 28.2-35.7 deaths per 100,000 woman-years for non-Hispanic Black women.<br><br>CONCLUSION: Three distinct mathematical simulation models of uterine cancer have been calibrated to observed population-based incidence and mortality. All three models project substantial and continued increases in the incidence and mortality of uterine cancer.}, }
@article {pmid41644089, year = {2026}, author = {Alam, R and Menon, AA and Ch'en, PY and Jabbour, AJ and Gooley, TA and Hippe, DS and Bhakuni, R and Miller, N and Lachance, K and Park, SY and Nghiem, P}, title = {Clinical benefit of adding radiation for immune checkpoint inhibitor-refractory Merkel cell carcinoma: A 27-patient analysis.}, journal = {The Journal of investigative dermatology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jid.2026.01.021}, pmid = {41644089}, issn = {1523-1747}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {Merkel cell carcinoma (MCC) recurs in 40% of patients, and 30% will require systemic therapy. Although PD-L1 immune checkpoint inhibitors (ICIs) have improved outcomes for advanced MCC, over half of patients do not experience long-term disease control. MCC is radiosensitive, and there is evidence that radiation therapy (RT) can promote antitumor immunity. We performed an analysis of 27 prospectively followed patients whose MCC progressed on ICI use and who then received RT while continuing ICI use. The median progression-free survival on ICI alone was 2.8 months. After disease progression, continuation of ICI, and addition of RT, these same patients had median progression-free survival of 5.1 months (P = .09). Patients with acquired ICI resistance had lower risk of progression than those with primary resistance (hazard ratio = 0.35, 95% confidence interval = 0.14-0.89, P = .02). Patients who received a single dose of RT (8 Gy; n = 13) had a risk of disease progression similar to those of patients who received multiple fractions (≥20 Gy, n = 14) (hazard ratio = 0.87, 95% confidence interval = 0.37-2.00, P = .73). RT to all disease sites (n = 10) was associated with longer post-RT progression-free survival versus RT to a subset of sites (5.3 vs 2.8 months). RT was well-tolerated without significant toxicity and is a clinically useful salvage option for ICI-refractory MCC.}, }
@article {pmid41644291, year = {2026}, author = {O'Steen, S and Lee, SY and Comstock, ML and Kehret, AR and Lin, Y and Hamlin, DK and Dexter, SL and Hippe, DS and Gooley, TA and Wilbur, DS and Li, Y and Walter, RB and Till, B and Orozco, JJ and Green, DJ}, title = {CD20-Targeted α-Radionuclides Synergize with Immune Checkpoint Inhibition to Treat Murine Lymphoma.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.125.270515}, pmid = {41644291}, issn = {1535-5667}, abstract = {Treatment-refractory and relapsed disease remain leading causes of death for patients with lymphoma. Virtually all lymphomas are exquisitely sensitive to radiation, and α-particle radiation therapies are notably suited to targeting microcluster disease common in the setting of early relapse. Refractory or relapsed lymphoma may also involve the loss of therapeutic targets, but radiation may stimulate antitumor immune effects against disease with incomplete target expression. Such effects make immune checkpoint inhibition a compelling candidate for combination treatment. Methods: We evaluated the therapeutic efficacy of [211]At-labeled antihuman CD20 monoclonal antibodies combined with immune checkpoint inhibition in human CD20 transgenic mice bearing murine lymphomas on opposing flanks that were either positive or negative for human CD20 expression (hCD20[(+)] and hCD20[(-)], respectively). Results: In the absence of [211]At-hCD20, the antimurine checkpoint inhibitors PD1, CTLA4, CD47, and TIM3 had no efficacy given alone or in doublets. [211]At-hCD20 given alone suppressed growth of both hCD20[(+)] and hCD20[(-)] tumors in a dose-dependent fashion, with predictably stronger suppression of hCD20[(+)] tumors. Strikingly, the addition of PD1 alone or the PD1 plus CTLA4 doublet to low-dose [211]At-hCD20 significantly strengthened suppression of both tumors and increased mouse survival. Conclusion: Future translation of this synergistic combination of α-radiotherapy and immune checkpoint inhibition holds promise for the treatment of high-risk aggressive lymphomas, including cases with postinduction minimal residual disease or antigen loss after targeted therapies.}, }
@article {pmid41644316, year = {2026}, author = {Jang, A and Jindal, T and Khaki, AR and Jiang, CY and Alhalabi, O and Nguyen, CB and Tsung, I and Oh, E and Epstein, I and Bakaloudi, DR and Jaime-Casas, S and Nizam, A and Glover, M and Mabey, H and Taylor, A and Evans, S and Shin, D and Pywell, C and Abuqayas, B and Barata, PC and Zakharia, Y and Basu, A and Kilari, D and Bilen, MA and Emamekhoo, H and Milowsky, M and Hoimes, CJ and Davis, N and Shah, S and Gupta, S and Tripathi, A and Grivas, P and Bellmunt, J and Alva, A and Campbell, MT and Chen, Z and Fu, P and Koshkin, VS and Brown, JR}, title = {Real-World Outcomes of Patients With Baseline Neuropathy and/or Diabetes Mellitus Receiving Enfortumab Vedotin-Based Regimens for Advanced Urothelial Carcinoma in the UNITE Database.}, journal = {Clinical genitourinary cancer}, volume = {24}, number = {2}, pages = {102501}, doi = {10.1016/j.clgc.2026.102501}, pmid = {41644316}, issn = {1938-0682}, mesh = {Humans ; Male ; Female ; Aged ; Retrospective Studies ; Middle Aged ; *Peripheral Nervous System Diseases/epidemiology ; Databases, Factual ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Diabetes Mellitus/epidemiology ; *Carcinoma, Transitional Cell/drug therapy/mortality/pathology ; Aged, 80 and over ; Treatment Outcome ; Progression-Free Survival ; *Urologic Neoplasms/drug therapy ; }, abstract = {INTRODUCTION: Enfortumab vedotin (EV)-based regimens have become standard treatments for advanced urothelial carcinoma (aUC). However, clinical trials excluded clinically significant peripheral neuropathy or uncontrolled diabetes mellitus. Therefore, we characterized real-world outcomes of patients with aUC and pre-existing peripheral neuropathy and/or diabetes mellitus receiving EV-based therapies.<br><br>PATIENTS AND METHODS: In the multicenter retrospective UNITE database, patients with documented baseline neuropathy and diabetes mellitus were identified. Observed response rate (ORR) and duration of response (DOR) were compared using Fisher's exact test. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Multivariable Cox models were used to adjust for confounding variables, including treatment duration.<br><br>RESULTS: Comparing 268 patients with baseline neuropathy to 586 patients without neuropathy, median PFS was 7.2 versus 6.3 months (HR 0.87 [0.73-1.04]; P = .11), and median OS 14.4 versus 13.0 months (HR 0.88 [0.73-1.07]; P = .21), Although discontinuation rate due to intolerance was significantly higher for patients with baseline neuropathy (26% vs. 18%; P = .008), these patients did not have shorter survival. Comparing 157 patients with baseline diabetes mellitus to 697 patients without diabetes mellitus, median PFS was 5.3 versus 6.7 months (HR 1.24 [1.01-1.52]; P = .04), and median OS 13.7 versus 13.3 months (HR 1.06 [0.84-1.34]; P = .62).<br><br>CONCLUSION: Patients with known baseline neuropathy and/or diabetes mellitus did not have worse survival outcomes receiving EV-based regimens. Patients with baseline neuropathy who discontinued EV early due to intolerance also did not exhibit worse survival. Our findings suggest despite these relevant underlying comorbidities, patients with aUC can derive benefit from EV-containing regimens, with very close monitoring.}, }
@article {pmid41645050, year = {2026}, author = {Applebaum, AJ and Manschot, C and Kuhn, E and Laber, E and Walsh, LE and Somers, TJ and Syrjala, KL and Smith, SK}, title = {Assessing the utility of the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5) as a screening tool among caregivers of hematopoietic stem cell transplantation survivors.}, journal = {Cancer}, volume = {132}, number = {4}, pages = {e70285}, doi = {10.1002/cncr.70285}, pmid = {41645050}, issn = {1097-0142}, support = {//Duke University School of Nursing/ ; T32CA225617/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Stress Disorders, Post-Traumatic/diagnosis/etiology/psychology ; *Hematopoietic Stem Cell Transplantation/psychology/adverse effects ; Female ; *Caregivers/psychology ; Male ; Middle Aged ; Adult ; Primary Health Care ; Diagnostic and Statistical Manual of Mental Disorders ; *Cancer Survivors/psychology ; Aged ; Mass Screening/methods ; }, abstract = {BACKGROUND: Hematopoietic stem cell transplantation (HCT) is an intensive and invasive procedure used in cancer treatment that depends heavily on the involvement of caregivers and places them at high risk for posttraumatic stress disorder (PTSD) symptoms. These symptoms are frequently overlooked in oncology and general health care settings. The suitability and utility of the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5) within cancer caregivers remains uncertain. This study sought to evaluate its performance as a brief (five-item) case finding screening alternative to the longer (20-item) PTSD Checklist for DSM-5 (PCL-5) in caregivers of survivors who received an HCT 1-5 years ago.<br><br>METHOD: A total of 106 caregivers completed the PC-PTSD-5 and PCL-5 during recruitment for a randomized clinical trial. Optimal cut scores for identifying probable PTSD and item performance were determined using indices correcting for chance and item response theory analyses.<br><br>RESULTS: Of the caregivers evaluated, 33% screened as positive for probable DSM-5 PTSD using the PCL-5. The PC-PTSD-5 exhibited acceptable internal consistency and significant associations with PCL-5 scores (total, r&#xa0;=&#xa0;0.79; items r [range] [0.60-0.69]). A cutoff score of 3 provided optimal sensitivity for screening (&#x3ba;[Se] = 1). Item response theory analyses indicated the need for the complete PC-PTSD-5 items to provide the greatest information across varying levels of PTSD.<br><br>CONCLUSION: Although not an instrument validation study, these findings provide preliminary support for using the PC-PTSD-5 as a succinct, effective screening tool among cancer caregivers in a clinical context.}, }
@article {pmid41645200, year = {2026}, author = {Peoples, AR and Obón-Santacana, M and Kim, AE and Kawaguchi, ES and Fu, Y and Qu, C and Moratalla-Navarro, F and Morrison, J and Lin, Y and Arndt, V and Berndt, SI and Bien, SA and Bishop, DT and Bouras, E and Brenner, H and Buchanan, DD and Campbell, PT and Chan, AT and Chang-Claude, J and Conti, DV and Corley, DA and Devall, MA and Dimou, N and Drew, DA and Gruber, SB and Gunter, MJ and Harlid, S and Harrison, TA and Hoffmeister, M and Hsu, L and Huyghe, JR and Keku, TO and Kundaje, A and Lewinger, JP and Li, L and Lynch, BM and Le Marchand, L and Martín, V and Murphy, N and Newton, CC and Ogino, S and Hardikar, S and Ose, J and Pai, RK and Palmer, JR and Papadimitriou, N and Pardamean, B and Pellatt, AJ and Pinchev, M and Platz, EA and Potter, JD and Rennert, G and Ruiz-Narvaez, EA and Sakoda, LC and Schoen, RE and Shcherbina, A and Stern, MC and Su, YR and Thomas, CE and Tian, Y and Tsilidis, KK and Um, CY and van Duijnhoven, FJB and Van Guelpen, B and Visvanathan, K and Wang, J and White, E and Wolk, A and Woods, MO and Wu, AH and Ulrich, CM and Peters, U and Gauderman, WJ and Moreno, V}, title = {Genetic risk factors modulate the association between physical activity and colorectal cancer.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41645200}, issn = {1741-7015}, support = {R01 CA273198/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; U01 CA137088, R01 CA059045, U01 CA164930, R01 CA201407, R01 CA244588/CA/NCI NIH HHS/United States ; R21 CA191312/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/epidemiology ; Male ; Female ; *Exercise/physiology ; Middle Aged ; Risk Factors ; Aged ; *Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Intercellular Signaling Peptides and Proteins/genetics ; }, abstract = {BACKGROUND: Physical activity is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-physical activity interaction analysis.<br><br>METHODS: Using logistic regression (1-d.f), two-step screening and testing method (EDGE), and joint tests (3-d.f), we analyzed interactions between common genetic variants across the genome and physical activity in relation to CRC risk. Self-reported physical activity levels were categorized as active (&#x2265;&#x2009;8.75 MET-h/wk) vs. inactive (<&#x2009;8.75 MET-h/wk; 39,992 participants) and as study- and sex-specific quartiles of activity (42,602 participants).<br><br>RESULTS: Physical activity was inversely associated with CRC risk overall (OR [active vs. inactive]&#x2009;=&#x2009;0.85; 95% CI&#x2009;=&#x2009;0.81-0.90). The two-step EDGE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and physical activity for CRC risk (p-interaction&#x2009;=&#x2009;2.6&#x2009;&#xd7;&#x2009;10[-8]). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR&#x2009;=&#x2009;0.80; 95% CI&#x2009;=&#x2009;0.75-0.85), but no significant physical activity-CRC associations among CT or TT carriers. When physical activity was modeled as quartiles, the 1-d.f. test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between physical activity and CRC (p-interaction&#x2009;=&#x2009;3.5&#x2009;&#xd7;&#x2009;10[-8]). Stratification at this locus showed that an increase in physical activity (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR&#x2009;=&#x2009;0.77; 95% CI&#x2009;=&#x2009;0.72-0.82).<br><br>CONCLUSIONS: In summary, we identified two genetic variants that modified the association between physical activity and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be involved in the protective association between physical activity and colorectal carcinogenesis.}, }
@article {pmid41646481, year = {2025}, author = {Klempner, SJ and Pazo-Cid, RA and Lonardi, S and Swanson, L and Arango, MJ and Enzinger, P and Ko, AH and Vaccaro, GM and Yamaguchi, K and Saeed, A and Lee, KW and Shitara, K and Ilson, D and Ajani, JA and Fuldeore, R and Braun, S and Broder, MS and Shah, MA}, title = {Consensus guidance for prevention and management of nausea and vomiting in patients treated with zolbetuximab + chemotherapy: a RAND/UCLA modified Delphi panel study.}, journal = {ESMO gastrointestinal oncology}, volume = {7}, number = {}, pages = {100131}, pmid = {41646481}, issn = {2949-8198}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: This study aims to develop consensus-based guidelines to prevent and manage nausea and vomiting in patients treated with zolbetuximab plus chemotherapy.<br><br>MATERIALS AND METHODS: An international Delphi panel included 15 experts who were involved in phase II or III clinical studies of zolbetuximab. A rating survey was developed, informed by literature and clinical experience, consisting of hypothetical scenarios of patients and interventions to prevent and manage nausea and vomiting during treatment with zolbetuximab plus chemotherapy. In April 2024, panelists rated the appropriateness of interventions on a scale of 1-9, discussed areas of disagreement in a virtual meeting, and repeated ratings following the meeting. The consensus was summarized based on responses to the second-round survey.<br><br>RESULTS: Areas of agreement were broader in the second-round survey than in the first-round survey, with panelists agreeing on 84.8% of ratings (second round) compared with 55.9% (first round). Agreement was reached on at least one management strategy for before and during the first zolbetuximab infusion and subsequent infusions. The Delphi panel endorses using the National Comprehensive Cancer Network&#xae; (NCCN&#xae;)-recommended regimens for high emetic risk prophylactically. During infusions, the Delphi panel suggested modifying the zolbetuximab infusion rate, interrupting zolbetuximab infusions temporarily for 30-60 min, administering antiemetic medications not used for prophylaxis, and/or providing intravenous hydration.<br><br>CONCLUSIONS: These consensus-based guidelines can be utilized by clinicians to guide the prevention and management of nausea and vomiting in patients treated with zolbetuximab plus chemotherapy so that patients can continue receiving treatment and achieve benefits.}, }
@article {pmid41646741, year = {2026}, author = {Carr, LL and Sankaranarayanan, A and Ha, K and Rawlani, M and Kazerouni, AS and Specht, J and Kennedy, LC and Reiter, D and Dintzis, S and Hippe, DS and Kilgore, MR and Symonds, L and Partridge, SC and Mittal, S}, title = {TILseg: Automated Whole Slide-Level Spatial Scoring of Tumor-Infiltrating Lymphocytes Reveals Prognostic Patterns in Triple Negative Breast Cancer.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41646741}, support = {K99 CA293004/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA248192/CA/NCI NIH HHS/United States ; }, abstract = {Stromal tumor-infiltrating lymphocytes (sTILs) are promising biomarkers for predicting therapeutic outcomes in triple-negative breast cancer (TNBC), with higher sTIL levels correlating with improved chemotherapy response and survival outcomes. Currently, sTILs are manually evaluated by pathologists, which is prone to inter-reader variability. In this study, we have developed an AI-driven TIL segmentation pipeline to process entire diagnostic hematoxylin-and-eosin-stained whole slide images for reproducible scoring (global TILseg scoring) and reliable prognostication. This pipeline was optimized and tested using two independent TNBC patient cohorts (n = 57 in the discovery cohort, n = 43 in the validation cohort) with clinical outcomes and follow-up data. The global scores generated by TILseg showed moderate to high concordance with expert scoring (Spearman R = 0.84-0.89) and improved patient stratification (p-value = 0.0191) as compared to manual scoring (p-value = 0.0663). Additionally, we investigate how the spatial localization of sTILs (spatial TILseg) impact survival outcomes by identifying TILs in selected stromal subsets (0.02-2 mm from the epithelial clusters). Our findings have shown that TILs up to 50 μm from epithelial regions prove to be most prognostic in predicting recurrence-free survival post-neoadjuvant chemotherapy with higher statistical significance than both manual and global TILseg scoring. Further, spatial TILseg scoring was more significantly associated with pathological complete response status in both patient cohorts. In summary, we present an AI-based digital tool for robust sTIL scoring and spatial mapping to enhance its potential as both a diagnostic and prognostic biomarker, particularly in TNBC patients.}, }
@article {pmid41646762, year = {2026}, author = {Ravindra, N and Lack, J and Dalgard, CL and vanCollenburg, E and Corner, A and Beppu, L and Erba, H and Othus, M and Radich, JP and Dillon, LW and Hourigan, CS}, title = {Whole Genome Sequencing Informed Patient Personalized Measurable Residual Disease Assays for Acute Myeloid Leukemia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41646762}, abstract = {Post-treatment measurable residual disease (MRD) in acute myeloid leukemia (AML) patients is associated with adverse clinical outcomes. Validated molecular methods for AML MRD are preferable to flow cytometry assays but are not available for all patients. The limit of detection (LOD) of next-generation sequencing (NGS) assays for single nucleotide variants is restricted by technical error rates. Structural alterations are common genetic features of AML, but MRD approaches for detecting this class of variants have primarily relied on RNA. However, RNA has suboptimal stability, not all structural alterations are expressed as transcripts, and the impact of anti-leukemic therapy on transcription may make leukemic disease burden quantification inaccurate. In this study, we demonstrate a whole genome sequencing (WGS)-based approach to identify genomic DNA breakpoints of chromosomal rearrangements that allowed design of highly sensitive patient-personalized digital droplet PCR (ddPCR) MRD assays. Acute myeloid leukemia (AML) is an aggressive malignancy of the hematopoietic precursor cells that predominantly affects older individuals. Oncogenic transformation occurring through the acquisition of structural chromosomal aberrations is noted in 35% of AML cases, and can result in the formation of fusion proteins that confer proliferation and survival advantages (1). When compared to classical cytogenetics for the identification of structural variants at diagnosis, newer techniques such as optical genome mapping can identify clinically pertinent aberrations that may be cryptic or smaller than the resolution of conventional karyotyping and FISH (2). Similarly, short-read whole genome sequencing (WGS) has been shown to increase diagnostic yield and better refine risk stratification when compared to traditional cytogenetic testing in myeloid malignancies (3). Additionally, WGS can be utilized to identify genomic breakpoints of chromosomal rearrangements at a basepair (bp) resolution.}, }
@article {pmid41648215, year = {2026}, author = {Darnell, AM and Chidley, C and Paradise, V and Cui, DS and Davidsen, K and Lincoln, SC and Abbott, KL and Elbashir, R and Vander Heiden, CP and Sorger, PK and Sullivan, LB and Davis, JH and Vander Heiden, MG}, title = {Ribosome-associated quality control of aberrant protein production during amino acid limitation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41648215}, issn = {2692-8205}, support = {R00 AG050749/AG/NIA NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA014051/CA/NCI NIH HHS/United States ; R35 CA242379/CA/NCI NIH HHS/United States ; R35 GM147118/GM/NIGMS NIH HHS/United States ; }, abstract = {Amino acids can become limiting for protein synthesis through depletion of charged tRNAs, leading to ribosome stalling and disruption of translation elongation at specific codons. To assess whether this is a mechanism by which amino acid availability can directly influence gene expression, we designed a reporter library to measure translation disruption across all sense codons in the context of amino acid limitations. We found that arginine limitation consistently impairs translation at the arginine codon AGA, resulting in synthesis of proteins from endogenous transcripts. In contrast, GCN2 pathway activation suppresses translation disruption following depletion of most other amino acids. Genome-wide screens revealed that the ribosome quality control trigger (RQC-T) and RQC pathways, which resolve ribosome collisions on defective mRNAs, catalyze ribosome splitting and premature fall-off in response to arginine depletion. Additionally, the E3 ubiquitin ligase RNF14, recently shown to clear ribosome A-site obstructions, promotes translation disruption through both ribosome fall-off and frameshifting during arginine limitation. Together, these data show that the RQC machinery is engaged by tRNA-limited ribosomes and identify a new role for RNF14 as a regulator of translation upon arginine limitation.}, }
@article {pmid41648379, year = {2026}, author = {Hartweger, H and Ruprecht, C and Yao, KH and Laffont, P and Lima Dos Reis, G and Zhou, P and Hägglöf, T and Binet, L and Loewe, M and Hong, JP and Xiao, T and Sefik, E and Hernandez, B and Gazumyan, A and Jankovic, M and Seaman, MS and Costa, G and Nelson, SA and Clark, J and Kanatani, S and Wilson, PC and Krammer, F and Levashina, EA and Julien, JP and Wardemann, H and Sinnis, P and Stamatatos, L and Flavell, RA and Nussenzweig, MC}, title = {B Lymphocyte Protein Factories produced by Hematopoietic Stem Cell Gene Editing.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41648379}, issn = {2692-8205}, support = {UM1 AI144462/AI/NIAID NIH HHS/United States ; T32 AI070084/AI/NIAID NIH HHS/United States ; P01 AI100148/AI/NIAID NIH HHS/United States ; INV-036842/GATES/Gates Foundation/United States ; INV-002777/GATES/Gates Foundation/United States ; R01 AI132359/AI/NIAID NIH HHS/United States ; INV-008866/GATES/Gates Foundation/United States ; UM1 AI191237/AI/NIAID NIH HHS/United States ; }, abstract = {Long-term in vivo production of therapeutic proteins and development of vaccines that elicit protective levels of broadly neutralizing antibodies (bNAbs) against major pathogens face challenges. Here we report on an alternative gene-editing approach using small numbers of hematopoietic stem and progenitor cells (HSPCs) to direct long-term, high-level expression of antibodies or cargo proteins. Edited B lymphocyte offspring can be activated by cognate antigen to undergo clonal expansion and develop into specific antibody or cargo protein-synthesizing plasma cells. These cells produce long-lasting, therapeutic levels of serum antibody against HIV-1 or malaria and an anti-influenza virus bNAb that mediated universal protection from heterologous lethal challenge. Our data provide a paradigm for cell therapy approaches to prevent or treat disease using self-amplifying B cell protein factories.}, }
@article {pmid41648398, year = {2026}, author = {Colegrove, HL and Dubard-Gault, ME and Marshall, H and Kohrn, BF and Smith, TH and Norgaard, ZK and Lo, FY and Schmidt, EK and Higgins, JE and Valentine, CC and Marshall, DA and Clark, JI and Konnick, EQ and Salk, JJ and Horwitz, MS and Rahbari, R and Feder, AF and Risques, RA}, title = {Ultra-deep duplex sequencing reveals unique features of somatic evolution in the normal tissues of a family with Li-Fraumeni syndrome.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41648398}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; R01 CA259384/CA/NCI NIH HHS/United States ; }, abstract = {Li-Fraumeni Syndrome (LFS) is caused by germline pathogenic variants in TP53 which predispose carriers to early onset cancer across multiple tissues. While genomically profiling those cancers has revealed factors contributing to their formation, little is understood about how LFS impacts clonal evolution in healthy tissues preceding cancer. Here, we use ultra-deep duplex sequencing (mean ~15,000× depth) to investigate somatic mutation and selection in a family carrying the germline TP53 p.R181H pathogenic variant and a cohort of non-carrier controls. In blood samples, the germline variant was associated with more mutations in a panel designed to capture genomewide mutagenesis, and with reduced positive selection on somatic TP53 mutations, despite confounding by chemotherapy treatment in one individual. DNMT3A and TET2 mutations were positively selected and GATA2 mutations were negatively selected across the cohort, independent of the p.R181H status. Extensive multi-tissue sampling of 22 non-cancerous and 6 cancerous samples was also performed at autopsy in one individual with LFS who succumbed to esophageal cancer. Cross-tissue analysis revealed excess mutations in sun-exposed skin, esophagus and chronically-inflamed stomach tissue, and highly parallel emergence of mutations in the p.R248 hotspot of TP53 across most (18/28) tissue samples. Most somatic TP53 mutations in LFS that could be assessed for phase arose on the chromosomal copy lacking the p.R181H variant. Our study reveals how the germline p.R181H variant reshapes baseline somatic mutation and selection in normal tissues and highlights the importance of understanding early somatic evolution in LFS prior to cancer development and treatment.}, }
@article {pmid41648419, year = {2026}, author = {Mallett, DR and Jiang, M and Minnuto, GM and Biggins, S}, title = {Kinetochore clustering is mediated by Mps1 phosphorylation of conserved MELT motifs in Stu1.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41648419}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Unattached kinetochores promote microtubule capture while preventing cell cycle progression during mitosis. The Mps1 kinase controls these events by mediating kinetochore assembly of the fibrous corona in animal cells and by triggering the spindle checkpoint. In budding yeast, which does not assemble a fibrous corona, the Stu1 and Slk19 spindle proteins promote microtubule capture by clustering unattached kinetochores, but the underlying mechanism is unclear. Here, we show that Mps1 controls this pathway. We identify two conserved MELT motifs in Stu1 that are directly phosphorylated by Mps1 to recruit Slk19 and mediate kinetochore clustering. Structural analysis of the Stu1:Slk19 complex reveals long, string-like filaments and offers mechanistic insight into how kinetochores might cluster. Our findings reveal parallels between the Mps1-Stu1-Slk19 pathway and the fibrous corona and suggest the regulation of kinetochore capture is a conserved Mps1 function across eukaryotes.}, }
@article {pmid41648436, year = {2026}, author = {Collienne, L and Richman, H and Rich, DH and Barker, M and Jennings-Shaffer, C and Matsen, FA}, title = {Unifying phylogenetic traversal and deep learning to guide tree exploration.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41648436}, issn = {2692-8205}, support = {R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Deep learning offers hope for more efficient phylogenetic inference methods. However, it has yet to have the transformative effect on phylogenetics that it has had in other fields. Here we present a novel approach that combines deep learning with concepts behind current successful phylogenetic algorithms. Specifically, we give the deep learning algorithm access to the output of a phylogenetic dynamic program on the sequence alignment, rather than the raw sequence alignment. The algorithm then learns features based on these phylogenetically processed versions of the sequence data, which provides information that could inform local tree search. For this paper, our goal is simple: predict for each edge in a tree whether it is in a maximum parsimony tree or not. Our model consists of a recurrent neural network that learns features while traversing the input tree, which are used to classify the edge. The model makes high-quality predictions for this NP-complete problem on simulated and empirical datasets for trees of various sizes, and we believe is a stepping stone towards efficient phylogenetic inference using deep learning.}, }
@article {pmid41648631, year = {2026}, author = {Pan, T and Shiau, CK and Lu, L and Wang, C and Wang, M and He, Y and Bhimaraj, A and Brat, D and Huse, J and Jessica Li, J and Gao, R}, title = {Hypatia: Comparative Isoform Profiling Across Cell Populations from Long-Read Single-Cell Transcriptomes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41648631}, issn = {2692-8205}, support = {P50 CA221747/CA/NCI NIH HHS/United States ; R35 GM142539/GM/NIGMS NIH HHS/United States ; }, abstract = {High-throughput long-read single-cell RNA-sequencing enables isoform-level study across single cells, yet methods for systematically assessing cell-to-cell variations remain limited. Here, we develop Hypatia, a comprehensive platform for dissecting isoform complexities across cell populations, devising Tsallis entropy and Cramer's V to facilitate robust comparative profiling. Hypatia revealed prominent isoform species variations and usage shifts across cell-types in glioblastoma, renal cell carcinoma, and heart, highlighting clinically relevant applications for studying isoform-derived, cell-specific functions.}, }
@article {pmid41649471, year = {2026}, author = {Karunanandaa, K and Knoche, EM and Montgomery, RB and Pickett, C and Doherty, J and Gruber, J and Raychaudhuri, R and Eaton, D and Garraway, IP and Rettig, MB and Maxwell, KN and Schoen, MW}, title = {Tumor suppressor genes, treatments, and survival in US veterans with prostate cancer.}, journal = {The oncologist}, volume = {31}, number = {4}, pages = {}, pmid = {41649471}, issn = {1549-490X}, support = {I01 CX002946/CX/CSRD VA/United States ; W81XWH-22-1-0602//Department of Defense/ ; //Prostate Cancer Foundation Igor Tulchinsky/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/mortality/pathology/drug therapy/therapy ; Veterans/statistics &amp; numerical data ; Aged ; Middle Aged ; United States/epidemiology ; *Genes, Tumor Suppressor ; PTEN Phosphohydrolase/genetics ; Prognosis ; }, abstract = {BACKGROUND: Tumor suppressor gene (TSG) alterations prognosticate inferior survival in metastatic hormone-sensitive prostate cancer (mHSPC) and may affect response to therapy. We evaluated the association of TSG alterations with overall survival (OS) in mHSPC, stratified by initial treatment.<br><br>METHODS: We identified veterans with de novo mHSPC diagnosed from 2017 to 2023 within the Veterans Health Administration. TSG alterations included loss-of-function alterations in RB1, TP53, and PTEN identified by somatic sequencing through the National Precision Oncology Program. Treatments within 4&#x2009;months of diagnosis included androgen deprivation therapy (ADT), docetaxel, and androgen receptor pathway inhibitors (ARPIs). Kaplan-Meier and Cox models evaluated relationships between TSG alterations, clinical factors, and OS.<br><br>RESULTS: Among 1842 veterans who met criteria, 865 had sequencing within 6 months. TSG alterations were found in 935 veterans, with the most common alterations being TP53 (36.7%), PTEN (23.4%), and RB1 (4.5%). In veterans sequenced within 6&#x2009;months, RB1, TP53, and PTEN alterations were associated with mortality with a hazard ratio (95% CI) of 2.86 (1.94-4.21) (P&#x2009;<&#x2009;.001), 1.64 (1.30-2.05) (P&#x2009;<&#x2009;.001), and 1.52 (1.20-1.91) (P&#x2009;<&#x2009;.001), respectively. In the same cohort, median OS (95% CI) was 40.7&#x2009;months (37.5-NR) with no alterations, 34.1&#x2009;months (30.3-37.3) with 1, and 19.7&#x2009;months (16.5-25.5) with &#x2265;2 TSG alterations. In veterans with &#x2265;1 alteration and sequencing within 6 months, combination therapy with ARPIs was associated with decreased mortality, aHR (95% CI) of 0.65 (0.48-0.88, P&#x2009;=&#x2009;.005).<br><br>CONCLUSION: TSG alterations were associated with inferior OS in veterans with mHSPC. In this real-world observational study, ARPI-based combination therapy in veterans with TSG alterations was associated with the longest survival.}, }
@article {pmid41649948, year = {2025}, author = {Piedvache, A and Rashed, WM and Petridou, ET and Mueller, BA and Bonaventure, A and Clavel, J and de Smith, AJ and Scheurer, ME and Dockerty, JD and Metayer, C and Wiemels, J and Kang, AY and Heck, JE and Hansen, J and Mejia-Arangure, JM and Sepúlveda-Robles, OA and Pombo-de-Oliveira, MS and Infante-Rivard, C and Roman, E and Erdmann, F and Schüz, J and Hangai, M and Morisaki, N and Doody, DR and Flores-Lujano, J and Chow, EJ and Sergentanis, TN and Polychronopoulou, S and Spector, LG and Urayama, KY and , }, title = {Maternal prenatal infection and childhood leukaemia: a Childhood Cancer and Leukemia International Consortium (CLIC) meta-analysis.}, journal = {International journal of epidemiology}, volume = {54}, number = {5}, pages = {}, doi = {10.1093/ije/dyaf167}, pmid = {41649948}, issn = {1464-3685}, support = {R21 CA175959/CA/NCI NIH HHS/United States ; 26253041//MEXT-Japan Society for the Promotion of Science/ ; }, mesh = {Humans ; Pregnancy ; Female ; Child ; *Pregnancy Complications, Infectious/epidemiology ; Risk Factors ; Case-Control Studies ; *Prenatal Exposure Delayed Effects/epidemiology ; Child, Preschool ; Infant ; Male ; Leukemia, Myeloid, Acute/epidemiology ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology ; *Leukemia/epidemiology ; Infant, Newborn ; }, abstract = {BACKGROUND: Maternal prenatal infections may affect fetal development, increasing the immunological vulnerability of offspring to childhood leukaemia (CL). The role of maternal infections in CL is unclear and might vary by subtype (lymphoblastic, ALL; myeloid, AML) or other characteristics. Understanding this potentially modifiable risk factor could inform prevention strategies.<br><br>METHODS: Seventeen hospital- and population-based case-control studies of children born in 1972-2019 within the Childhood Cancer and Leukemia International Consortium with self-questionnaires or health-registry data on maternal infection were included (13&#x2009;638 cases; 26&#x2009;870 controls). Meta-analyses assessed CL and maternal infection (overall, viral, bacterial, respiratory, influenza/cold, urinary, genital) stratified by subtype, infection timing, race and ethnicity, and diagnosis age.<br><br>RESULTS: The adjusted meta-analysis odds ratio (OR) for any maternal prenatal infection was 1.13 [95% confidence interval (CI) 0.91-1.40], with similar estimates for ALL and AML. Infection-specific estimates varied. ORs for first-trimester infections were highest for CL and ALL, but not AML, although all CIs contained one. We found modest risk differences between White and Hispanic/Latino children, most notably for CL diagnosed at <2&#x2009;years (White children: OR 1.25, 95% CI 1.02-1.53; Hispanic/Latino children: OR 0.79, 95% CI 0.34-1.81, subgroup difference P&#x2009;=&#x2009;.05), with similar differences for viral and respiratory/influenza/cold infections.<br><br>CONCLUSION: Although findings only modestly support an association between maternal prenatal infections and CL, some infections might increase the risk more markedly in young White children compared with Hispanic/Latino children. Risk patterns across race and ethnicity, type, and timing of maternal prenatal infection merit further investigation, as do studies with documented exposure information.}, }
@article {pmid41650190, year = {2026}, author = {Wang, Y and Wu, L and Zhang, L and Dong, Y and Pant, A and Liu, Y and Bai, J}, title = {Endocytic protein AP180 assembly domain regulates synaptic vesicle size and release in Caenorhabditis elegans.}, journal = {PLoS biology}, volume = {24}, number = {2}, pages = {e3003643}, pmid = {41650190}, issn = {1545-7885}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R01 GM127857/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Synaptic Vesicles/metabolism ; *Caenorhabditis elegans/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics/chemistry ; Synaptic Transmission/physiology ; *Monomeric Clathrin Assembly Proteins/metabolism/genetics/chemistry ; Protein Domains ; Presynaptic Terminals/metabolism ; Actins/metabolism ; Adaptor Proteins, Vesicular Transport/metabolism ; Endocytosis ; }, abstract = {Neuronal communication relies on neurotransmitter release from synaptic vesicles. The endocytic protein AP180 is critical for efficient vesicle recycling at presynaptic terminals, and its loss impairs neurotransmission, producing reduced release frequency, enlarged synaptic vesicles, and increased quantal amplitude. Yet how AP180 controls vesicle size and whether vesicle size influences release remains unclear. Here, we show that the C-terminal Assembly domain (AD) of AP180 determines vesicle size and thereby regulates release properties in Caenorhabditis elegans. An AP180 variant lacking the AD (AP180∆AD) increases release frequency, contrasting sharply with the reduced transmission in ap180 null mutants, yet fails to correct the vesicle size or quantal amplitude. These enlarged vesicles evade curvature-dependent inhibition by complexin, a presynaptic regulator of fusion, while remaining dependent on complexin for evoked responses. This selective escape reveals that vesicle size influences release dynamics through curvature-sensing proteins. Replacing the AP180 AD with actin-binding motifs restores normal vesicle size, quantal amplitude, and release frequency, indicating that actin interactions are both necessary and sufficient for AD function. Biochemically, we show that the intrinsically disordered AD forms condensates that enrich actin monomers and nucleate filament assembly, while full-length AP180 couples PIP2-rich membranes to actin filaments. Together, these findings reveal that the AP180 AD regulates synaptic vesicle size through actin binding, establishing vesicle morphology as a key influencer of curvature-dependent release control.}, }
@article {pmid41650235, year = {2026}, author = {Larsen, BB and Harari, S and Gen, R and Stewart, C and Veesler, D and Bloom, JD}, title = {Functional and antigenic constraints on the Nipah virus fusion protein.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {6}, pages = {e2529505123}, pmid = {41650235}, issn = {1091-6490}, support = {1U19AI181881//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI141707/AI/NIAID NIH HHS/United States ; 75N93022C00036/AI/NIAID NIH HHS/United States ; R01AI141707//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; DP1 AI158186/AI/NIAID NIH HHS/United States ; U19 AI181881/AI/NIAID NIH HHS/United States ; DP1AI158186//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {*Nipah Virus/immunology/genetics ; *Viral Fusion Proteins/immunology/genetics/chemistry ; Humans ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/immunology ; Mutation ; Antibodies, Monoclonal/immunology ; Animals ; *Antigens, Viral/immunology/genetics ; Virus Internalization ; Henipavirus Infections/immunology/virology ; Hendra Virus/immunology ; Viral Envelope Proteins ; }, abstract = {Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and host membranes. Here, we use nonreplicative pseudoviruses to safely measure the effects of all F single amino acid residue mutations on its cell entry function and neutralization by monoclonal antibodies. We compare mutational tolerance in F with previous experimental measurements for RBP and show that F is much more functionally constrained than the RBP. We also identify mutationally intolerant sites on the F trimer surface and core that are critical for proper function, and describe mutations that are candidates for stabilizing F in the prefusion conformation for vaccine design. We quantify how F mutations affect neutralization by six monoclonal antibodies, and show that the magnitude of mutational effects on neutralization varies among antibodies. Our measurements of mutational effects on Nipah virus F predict the ability of the antibodies to neutralize the related Hendra virus. Overall, our work defines the functional and antigenic constraints on the F protein from an important zoonotic virus.}, }
@article {pmid41650938, year = {2026}, author = {Cheng, S and Suger, AH and Goss, LB and Zhang, J and Fuller, H and Guo, B and Lindström, S and Darst, BF}, title = {Validation and context-dependent effects of a prostate cancer polygenic risk score in the All of Us Research Program.}, journal = {American journal of human genetics}, volume = {113}, number = {2}, pages = {392-398}, pmid = {41650938}, issn = {1537-6605}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; U01 CA261339/CA/NCI NIH HHS/United States ; R00 CA246063/CA/NCI NIH HHS/United States ; R03 CA287235/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/epidemiology/pathology ; *Multifactorial Inheritance/genetics ; Middle Aged ; *Genetic Predisposition to Disease ; Aged ; Risk Factors ; United States/epidemiology ; Genome-Wide Association Study ; Life Style ; Polymorphism, Single Nucleotide/genetics ; Case-Control Studies ; Adult ; Genetic Risk Score ; }, abstract = {Polygenic risk scores (PRSs) have demonstrated strong potential for improving prostate cancer risk stratification. However, it is unknown whether the clinical utility of prostate cancer PRS varies by demographic, lifestyle, and socioeconomic factors. We validated a previously developed multi-ancestry PRS of 451 prostate cancer risk variants and evaluated context-dependent effects using genetic and clinical data from the diverse All of Us Research Program, including 7,577 indivisuals with prostate cancer and 90,608 control individuals across six genetic ancestry groups. In ancestry-stratified testing, the PRS showed strong associations with prostate cancer risk, with odds ratios (ORs) per standard deviation (SD) increase ranging from 1.61 (95% confidence interval [CI] = 1.02-2.64, p = 0.05) in Middle Eastern to 2.19 (95% CI = 1.98-2.42, p = 2.2 × 10[-51]) in American populations. Age-stratified analyses showed reduced PRS effects with increasing age. Across modifiable lifestyle and healthcare access factors, PRS effects were larger in those with a higher body mass index (OR = 2.15 vs. 1.96 in individuals with obesity and normal weight, respectively, p = 0.03), in never or former smokers vs. current smokers (OR = 2.06, 2.37, and 1.93, respectively, p = 0.06), and in those recently accessing healthcare (OR = 2.21 vs. 1.88, p = 0.05), highlighting important context-specific modifiers. We did not observe context-dependent effects of other socioeconomic factors, such as income, education, and insurance. In a phenome-wide association study (PheWAS), the PRS was associated with 14 clinical outcomes, including known prostate cancer-related conditions. These findings confirm the predictive strength of the multi-ancestry prostate cancer PRS across diverse populations and underscore the importance of accounting for demographic-, lifestyle-, and healthcare-related contexts when applying PRSs in clinical and public health settings.}, }
@article {pmid41653436, year = {2026}, author = {Zhang, Y and Zhao, C and Zhao, Y and Wang, S and Guo, Z and Guo, W and Wen, P and Hao, Y and Li, W and Wang, Y and Li, Y}, title = {SERPINA3 mediates liver cancer cells escape from chemotherapy-induced neutrophil extracellular trap killing.}, journal = {Cell reports}, volume = {45}, number = {2}, pages = {116956}, doi = {10.1016/j.celrep.2026.116956}, pmid = {41653436}, issn = {2211-1247}, mesh = {Humans ; *Extracellular Traps/metabolism/drug effects ; *Liver Neoplasms/metabolism/drug therapy/pathology ; *Serpins/metabolism/genetics ; Irinotecan/pharmacology ; Cell Line, Tumor ; Cathepsin G/metabolism ; Apoptosis/drug effects ; *Neutrophils/metabolism/drug effects ; NF-kappa B/metabolism ; *Antineoplastic Agents/pharmacology ; 14-3-3 Proteins/metabolism ; Drug Resistance, Neoplasm/drug effects ; Signal Transduction/drug effects ; }, abstract = {Although many chemotherapeutic agents induce neutrophil extracellular trap (NET) formation, how NETs affect therapeutic efficacy across different cancer types remains poorly understood. Here, we report that irinotecan-induced NETs exhibit differential cytotoxicity against cancer cells through the proteolytic activity of cathepsin G (CTSG), with colon cancer cells exhibiting high sensitivity while liver cancer cells demonstrating marked resistance. Through bioinformatic analysis and siRNA-mediated knockdown validation, we identified SERPINA3, a serine protease inhibitor, as a key factor in this resistance. Mechanistically, SERPINA3 inhibits CTSG-mediated cleavage of the anti-apoptotic protein 14-3-3ε, thereby protecting cells from NET-induced apoptosis. Interestingly, the NF-κB signaling pathway governs SERPINA3 expression in liver cancer cells, with activated p65 directly binding to its promoter. Targeting SERPINA3 with antisense oligonucleotides successfully sensitized liver cancer cells to irinotecan therapy. These findings elucidate a critical mechanism of chemoresistance in liver cancer and propose targeting SERPINA3 as a promising therapeutic strategy to enhance chemotherapy efficacy.}, }
@article {pmid41654664, year = {2026}, author = {Goodsell, KE and Olapo, J and Sham, JG}, title = {Margins in Context: How Pathologic Response Reframes Surgical Success in CRLM.}, journal = {Annals of surgical oncology}, volume = {33}, number = {5}, pages = {3784-3786}, pmid = {41654664}, issn = {1534-4681}, }
@article {pmid41659404, year = {2026}, author = {Zhang, Y and Zhao, X and Wang, H and Hu, YM and Sun, XX and Zhao, F and Du, S and Dai, RS and Andeen, NK and Sears, RC and Corey, E and Brody, JR and Alumkal, JJ and Mills, GB and Nelson, PS and Dai, MS and Xia, Z}, title = {Global mRNA 3'UTR lengthening in small-cell neuroendocrine carcinoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41659404}, issn = {2692-8205}, support = {R01 CA251245/CA/NCI NIH HHS/United States ; R01 GM147365/GM/NIGMS NIH HHS/United States ; P01 CA298991/CA/NCI NIH HHS/United States ; S10 OD034224/OD/NIH HHS/United States ; R01 CA282005/CA/NCI NIH HHS/United States ; R01 CA262104/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA280056/CA/NCI NIH HHS/United States ; }, abstract = {Small-cell neuroendocrine carcinoma (SCNC) is a rare but highly malignant tumor subtype that primarily arises in the lung, also rarely in other organs, and as a consequence of treatment induced lineage transdifferentiation of prostate adenocarcinomas. The molecular convergence of SCNC across diverse tissues enables its identification through conserved SCNC-specific molecular markers, facilitating tumor subtype classification. As a critical post-transcriptional regulatory mechanism, alternative polyadenylation (APA) modulates 3'UTR length and significantly impacts tumor progression. However, its role in SCNC remains largely unclear. Here, we report a global 3'UTR lengthening pattern driven by APA in SCNC. We identified a set of conserved 3'UTR lengthening events across SCNCs of different tissue origins, which are strongly associated with neural development and related signaling pathways. Furthermore, we developed a neural network-based prediction model to classify SCNC by leveraging these specific APA signatures. Our study provides new insights into the post-transcriptional landscape of SCNCs and highlights APA signatures as promising biomarkers for SCNC identification.}, }
@article {pmid41659500, year = {2026}, author = {Lieberman, NAP and Garcia, LN and Bakhash, SAKM and Furlong, JC and Nunley, BE and Rabinovich, A and Pardal, PF and Leiro, V and Xie, H and Aghakhanian, F and Passos, MRL and Arze, WNC and Andrade, HB and Vargas, SK and Konda, KA and Diaz, MR and Caceres, C and Klausner, JD and Parr, JB and Seña, A and Manathunge, A and Giacani, L and Altcheh, J and Greninger, AL}, title = {Lineage-specific tprK diversification and Treponema pallidum transmission dynamics in Buenos Aires, Argentina.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41659500}, issn = {2692-8205}, support = {INV-036560/GATES/Gates Foundation/United States ; R01 AI139265/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Syphilis rates are rising globally, with increases in congenital syphilis in South America particularly concerning. The characterization of contemporary South American Treponema pallidum (Tp) strains is crucial to syphilis vaccine development, yet few genomic epidemiology studies have focused on this region. Here, we performed whole genome sequencing (WGS) of Tp from Buenos Aires, Argentina, as well as deep sequencing of the hypervariable tprK locus, which is critical to Tp immune evasion.<br><br>METHODS: People with primary, secondary, or congenital syphilis were enrolled at two clinics in Buenos Aires between October 2018 and January 2023, including individuals associated with intra-household transmission. Hybrid capture WGS was performed and a core genome phylogeny generated. K-mer-based methods using full-length tprK PacBio long reads were used to uncover differences in diversity and detect Tp transmission.<br><br>FINDINGS: Tp genomes were recovered from 70 individuals in Buenos Aires and primarily belonged to globally dominant SS14 sublineage-1 and Nichols sublineage-8, as did Tp from Brazil (n=8). Peruvian samples (n=3) all belonged to sublineage-1. Two individuals from Argentina had co-infections with Nichols- and SS14-lineage strains. Macrolide resistance via A2058G occurred in 27/70 (38.6%) samples. Across 56 samples, tprK allelic diversity was significantly increased in secondary syphilis, oral lesions, and SS14-lineage strains compared to primary syphilis, anogenital lesions, and Nichols-lineage strains, respectively. Increased diversity in SS14-lineage strains is driven by an enhanced repertoire of V7-specific donor sequences. tprK sequences from intra-household transmissions were more similar than unrelated samples with identical core genomes.<br><br>INTERPRETATION: Tp circulating in South America is closely related to dominant global sublineages. Increased tprK diversity in the SS14 lineage may influence Tp's ability to escape host immunity. tprK profiling is a promising tool to elucidate syphilis transmission networks. This study underscores the utility of genomics to yield insights into Tp pathogenesis.<br><br>FUNDING: Gates Foundation INV-036560 (A.S.); NIH/NIAID R01AI139265 (J.D.K).}, }
@article {pmid41659542, year = {2026}, author = {Jiang, M and Hu, C and Hedouin, S and Latino, AA and Arimura, Y and Stergachis, AB and Biggins, S}, title = {Native yeast kinetochore structures identify an essential inner kinetochore interaction.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41659542}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Kinetochores must accurately assemble on centromeres every cell cycle for faithful chromosome segregation. Although a conserved centromeric histone variant is essential for inner kinetochore formation, the budding yeast centromeric DNA is a poor template for nucleosome formation in vitro, possibly due to a resistance to bend. To better understand how the yeast inner kinetochore is assembled, we developed a one-step protocol to purify de novo assembled native inner kinetochore subcomplexes for structural studies. We performed cryoelectron microscopy on the purified complexes and generated medium to high resolution density maps of four separate inner kinetochore complexes, two of which had not previously been visualized. We detected differences between native and previously reconstituted structures, suggesting that the de novo assembly assay generated intermediate assemblage states. A strong extra structural density, which corresponds to an Ndc10 trimerization domain, associated with centromeric DNA and a pair of CBF3 complexes to induce significant centromere bending. Its deposition on the CBF3-CEN complex is essential for kinetochore assembly and chromosome segregation. We propose that Ndc10 trimerization facilitates bending of the centromeric DNA, leading to assembly and stabilization of the centromeric nucleosome and inner kinetochore.}, }
@article {pmid41659606, year = {2026}, author = {Barnett, EE and Castillo, A and Du Plessis, IA and Kistler, K and Carrillo, L and Leon, AS and Liu, T and Rutherford, MG and Ploug, J and McCrone, JT and Ávila-Arcos, MC and Blanco-Melo, D}, title = {Recovery of an 18[th] Century Rhinovirus Genome through Ancient RNA Isolation of Human Lungs.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41659606}, issn = {2692-8205}, support = {DP2 AI177896/AI/NIAID NIH HHS/United States ; }, abstract = {RNA viruses cause substantial global morbidity, yet their impact prior to the twentieth century remains obscured. While ancient DNA studies have transformed our understanding of past pathogens, ancient RNA (aRNA) isolation is largely restricted to exceptionally preserved samples. Here, we simultaneously recover aDNA and aRNA from non-formalin-fixed human lung specimens and reconstructed an 18th-century Human Rhinovirus (HRV) A genome-the oldest human RNA virus identified to date. The RNA is highly fragmented, with distinctive terminal misincorporations and coverage patterns consistent with double-stranded RNA. Phylogenetic analyses indicate that this historical HRV genome is an extinct lineage related to contemporary genotypes, providing a unique perspective on rhinovirus evolution. These findings demonstrate that centuries-old medical specimens can retain informative aRNA, expanding the temporal scope of paleovirology.}, }
@article {pmid41659627, year = {2026}, author = {Sackey, SA and Schrum, JE and Mangalanathan, UM and Fish, RS and Sola, E and Selehi, A and Pi, R and Zack, JA and Kim, JT and Lehman, DA and Davis, MM and Blish, CA}, title = {Modeling HIV infection, treatment, rebound, and intervention in human immune organoids.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41659627}, issn = {2692-8205}, support = {R01 AI161803/AI/NIAID NIH HHS/United States ; S10 OD032300/OD/NIH HHS/United States ; R01 AI183381/AI/NIAID NIH HHS/United States ; T32 AI007502/AI/NIAID NIH HHS/United States ; T32 AI007290/AI/NIAID NIH HHS/United States ; }, abstract = {Targeting the HIV-infected reservoir in lymphoid tissues (LT) will be critical to developing a cure for people living with HIV (PLWH). LT explants used to study HIV infection enable the evaluation of human-specific disease progression and treatment response; however, their short lifespan makes it challenging to assess long-term treatment interventions. We therefore established an immune organoid model of HIV infection using human tonsil or spleen cells, demonstrating productive HIV infection and viral integration into CD4[+] T cells. Treatment with a protease inhibitor fully suppressed ongoing viral production, with virologic rebound occurring within days of treatment interruption. The transfer of healthy allogeneic NK cells to target the reservoir upon treatment interruption reduced the number of infected cells, intact viral genomes, and production of de novo infectious viral particles. Adoption of this immune organoid platform will accelerate the evaluation of cure-based strategies to eliminate the HIV reservoir in tissues for PLWH.}, }
@article {pmid41661513, year = {2026}, author = {Zvolensky, MJ and Clausen, BK and Bizier, A and Wein, PY and Pathak, N and Redmond, BY and Garey, L and Weinberger, AH and Santiago-Torres, M and Bricker, JB}, title = {Anxiety disorder status among black adults who smoke: relations to cessation processes and smoking characteristics.}, journal = {Journal of behavioral medicine}, volume = {49}, number = {1}, pages = {66-78}, pmid = {41661513}, issn = {1573-3521}, support = {U54MD015946/MD/NIMHD NIH HHS/United States ; U54MD015946/MD/NIMHD NIH HHS/United States ; }, abstract = {Black/African American (hereafter Black) adults in the United States (US) who smoke cigarettes experience tobacco disparities. Although there are established associations between smoking and anxiety in the general population, past work has not explored these associations among Black adults who smoke. The present investigation examined Black adults who smoke combustible cigarettes who did and did not screen positive for an anxiety disorder (defined as a score of > 8 on the Overall Anxiety Severity and Impairment Norman et al., (J Psychiatric Res 45:262-268, 2011) in terms of perceived barriers for smoking cessation, severity of symptoms when trying to quit, and smoking abstinence expectancies. Exploratory tests were also conducted on secondhand smoke exposure. The current sample included 517 Black individuals who reported daily cigarette smoking (five or more cigarettes per day; mean age of 45 years, 51.5% identified as female). In the primary tests, results indicated a positive screen for an anxiety disorder (versus not) was associated with higher levels of perceived barriers for smoking cessation, severity of symptoms when quitting, and negative abstinence expectancies for smoking (negative mood, somatic symptoms, and harmful consequences). No group differences were evident for positive abstinence expectancies. Exploratory tests also indicated that a positive screen for an anxiety disorder (versus not) was related to higher degrees of secondhand smoke exposure. Overall, the present investigation found that screening positive for an anxiety disorder may be associated with a variety of cigarette smoking processes and beliefs among US Black adults who smoke.}, }
@article {pmid41662631, year = {2026}, author = {Takahashi, S and Inoue, T and Ensbey, KS and Legg, SR and Sekiguchi, T and Nelson, EL and Nemychenkov, NS and Joshi, T and Minnie, S and Yeh, AC and Zhang, P and Headley, M and Paik, J and Amory, JK and Hill, GR and Koyama, M}, title = {Targeting donor XCR1+ and CD11b+ dendritic cells prevents Th1 and Th17-dependent GVHD within the Gastrointestinal Tract.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025029431}, pmid = {41662631}, issn = {1528-0020}, abstract = {Acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is a primary cause of early transplant mortality after bone marrow transplantation (BMT), driven by local antigen presentation and T-cell expansion. We sought to clarify the role of various donor dendritic cell (DC) subsets in this process in order to define therapeutic strategies to prevent gut GVHD. Donor plasmacytoid DC (pDC) were prominent in the ileum of BMT recipients without GVHD but were largely absent in gut during GVHD. In contrast, donor XCR1+ conventional DC (cDC) were dramatically increased in the mesenteric lymph nodes (mLN) of BMT recipients with GVHD. We utilized Xcr1-DTR mice and Clec4c-DTR mice to enable highly efficient XCR1+ cDC versus pDC depletion. Donor XCR1+ cDC but not pDC deletion attenuated lethal GVHD, depleting most cDC presenting alloantigen, which inhibited α4β7 and the expansion of alloantigen-specific donor Th1 cells in the gut. Aldehyde dehydrogenase 1A (ALDH1A) expression by cDC is known to modulate GVHD and we thus examined the effect of a pan-ALDH1 inhibitor, WIN18,446, on this axis. WIN18,446 administration improved survival and these effects were ALDH1A1-specific but mediated by inhibition of CD11b+ rather than XCR1+ cDC, inhibiting alloantigen-specific Th17 cell differentiation in the gut. These findings highlight the limited role of pDC in the induction of gut GVHD and identify differential and dominant roles for XCR1+ and CD11b+ donor cDC in controlling Th1 and Th17 mediated gut aGVHD. The targeting of donor cDC subsets represents an effective strategy to prevent lethal gut GVHD.}, }
@article {pmid41663013, year = {2026}, author = {Munshi, PN and Yuen, C and Al-Juhaishi, T and Jensen, E and Nemecek, ER and Sandmaier, BM and Davies, SM and Auletta, JJ and Chakrabarty, JH}, title = {Breaking Access Barriers to Autologous Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy in Hematologic Malignancies-an ASTCT-NMDP ACCESS Initiative.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.02.001}, pmid = {41663013}, issn = {2666-6367}, abstract = {Autologous stem cell transplant (ASCT) and chimeric antigen receptor T cell therapy (CAR-T) are approved treatments with curative potential and excellent response rates in patients with aggressive hematologic malignancies. However, multiple barriers hinder the delivery of these treatments, affecting access to patients. Minority patients are less likely to receive ASCT and, when they do, outcomes may not match those of non-minority patients, highlighting the need for accountability and targeted interventions to prevent further widening of disparities. Patient, physician, product, and logistics-related barriers further make lifesaving treatments inequitable. Medicaid and public insurance coverage gaps, as well as social determinants of health, continue to limit access and worsen outcomes for ethnically diverse populations. Additionally, delays and lack of referral from physicians to cellular therapy specialists add to the problem, risking relapse and missed opportunity for these treatments. Addressing these barriers with a sense of urgency, especially in the era of expanding cell therapy indications, could save many patients from succumbing to disease. The American Society of Transplantation and Cellular Therapy (ASTCT) and NMDP (formerly known as the National Marrow Donor Program) collaborate to investigate and address these barriers at a national level. This article highlights treatment barriers and potential strategies to reduce them at individual program and ecosystem levels.}, }
@article {pmid41663621, year = {2026}, author = {Mehta, RS and McCurdy, SR and Milano, F and Nawas, M and Aljawai, Y and Rimando, JC and Al-Juhaishi, T and Im, A and Kanakry, JA and Lazaryan, A and Kanakry, CG}, title = {Challenging a clinical dogma with multimodal machine learning: a retrospective analysis of transplant mismatched donor selection.}, journal = {Leukemia}, volume = {40}, number = {3}, pages = {689-693}, pmid = {41663621}, issn = {1476-5551}, }
@article {pmid41665694, year = {2026}, author = {Hill, CM and Malen, RC and Reedy, AM and Kahsai, O and Curtis, K and Ma, N and Randolph, TW and Ma, J and Thomas, CE and Ogino, S and Potter, JD and Buchanan, DD and Newcomb, PA and Hullar, MAJ and Phipps, AI}, title = {Associations of epidemiologic risk factors with Fusobacterium nucleatum and bacterial alpha diversity in the colorectal tumor-associated microbiota.}, journal = {Cancer causes &amp; control : CCC}, volume = {37}, number = {3}, pages = {45}, pmid = {41665694}, issn = {1573-7225}, support = {R01CA217970/CA/NCI NIH HHS/United States ; U01CA167551/RC/CCR NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01CA076366/CA/NCI NIH HHS/United States ; C10674/A27140//Cancer Research UK Grand Challenge Award/ ; T32 CA094880/CA/NCI NIH HHS/United States ; T32CA094880/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R01 CA217970/CA/NCI NIH HHS/United States ; CRP-24-1185864-01-PROF//American Cancer Society/ ; }, mesh = {Humans ; Female ; *Fusobacterium nucleatum/isolation &amp; purification/genetics ; Male ; *Colorectal Neoplasms/microbiology/epidemiology ; Risk Factors ; Middle Aged ; Aged ; *Fusobacterium Infections/epidemiology/microbiology ; *Gastrointestinal Microbiome ; RNA, Ribosomal, 16S/genetics ; Adult ; Microbiota ; }, abstract = {BACKGROUND: Aspects of the gut microbiome, including presence of specific bacterial species and overall community structure, have been linked to the etiology and prognosis of colorectal cancer (CRC). Less is known about the epidemiologic risk factors that are associated with the composition of the microbiota in invasive colorectal tumors.<br><br>METHODS: Using tumor and paired normal colorectal tissue samples from a subset of participants in the population-based Seattle Colon Cancer Family Registry, we compared the presence of Fusobacterium nucleatum (F. nucleatum) (n&#x2009;=&#x2009;898) measured via droplet digital PCR and alpha diversity (Shannon index) (n&#x2009;=&#x2009;611) measured via 16S rRNA gene sequencing in colorectal tissue across demographics, health behaviors, and neighborhood socioeconomic status (nSES).<br><br>RESULTS: Normalized counts of F. nucleatum were consistently higher in tumor tissue than in patient-matched normal tissue across all risk factors, while alpha diversity was lower. Female sex was associated with high presence and enrichment of F. nucleatum in tumor tissue (odds ratio [OR] 1.61; 95% confidence interval [CI] 1.02, 2.54 and OR 1.58, 95% CI 1.10, 2.27, respectively). Relative to those aged 40-49&#xa0;years, the youngest age group (<&#x2009;40&#xa0;years) had lower alpha diversity in tumor tissue (OR for highest vs. lowest tertile: 0.33; 95% 0.13, 0.83). Other factors, including diet, were not related to F. nucleatum presence or tumor tissue alpha diversity.<br><br>CONCLUSION: By uncovering epidemiologic risk factors for F. nucleatum presence and bacterial diversity in the intratumoral microbiota, this work informs our understanding of associations of the gut microbiota with CRC etiology and outcomes.}, }
@article {pmid41665993, year = {2026}, author = {Chan, M and Zhu, S and Russell, ZR and Arora, S and Arakaki, AKS and Vaz, JM and Kumasaka, D and Szulzewsky, F and Michealraj, A and Holland, EC and Gujral, TS}, title = {A systems approach identifies MERTK as a therapeutic vulnerability in ZFTA-RELA-driven ependymomas.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {7}, pages = {e2514518123}, pmid = {41665993}, issn = {1091-6490}, support = {NA//Ben and Catherine Ivy Foundation (BCIF)/ ; NA//Ben and Catherine Ivy Foundation (BCIF)/ ; }, mesh = {*Ependymoma/genetics/drug therapy/metabolism/pathology ; *c-Mer Tyrosine Kinase/genetics/metabolism/antagonists &amp; inhibitors ; Humans ; Animals ; Mice ; Signal Transduction ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Transcriptome ; }, abstract = {Ependymomas (EPN) are rare central nervous system tumors that account for approximately 10% of intracranial tumors in children and 4% in adults. Despite their clinical and molecular heterogeneity, spanning supratentorial, posterior fossa, and spinal subtypes, treatment remains limited to surgery and radiotherapy, with chemotherapy offering minimal benefit. Here, we performed transcriptomic analysis of 370 human ependymoma samples and identified two distinct molecular subgroups: EPN-E1 and EPN-E2. The EPN-E1 cluster is enriched for supratentorial tumors harboring ZFTA-RELA fusions (ZFTA-RELA[fus]), which occur in over 70% of cases and are associated with poor prognosis. To identify targeted therapies for this aggressive subtype, we validated a ZFTA-RELA[fus] mouse model that recapitulates the human EPN-E1 transcriptome and used it for target discovery. Through Kinome Regularization, a machine learning-driven polypharmacology approach, we identified MERTK as a critical regulator of tumor cell viability. Genetic depletion or pharmacologic inhibition of Mertk reduced cell growth ex vivo, and treatment with a clinical-grade MERTK inhibitor significantly suppressed tumor proliferation in vivo. Both human EPN-E1 tumors and ZFTA-RELA[fus] mouse tumors exhibited elevated expression of MERTK and its ligand GAS6, and MERTK inhibition led to suppression of pro-survival signaling pathways including MEK/ERK (Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase) and PI3K/AKT (Phosphoinositide 3-Kinase/Protein Kinase B). Notably, over 80% of genes upregulated in ZFTA-RELA[fus] tumors were downregulated following MERTK inhibition, indicating a strong dependency on this pathway for tumor maintenance. These findings define a signaling vulnerability in ZFTA-RELA-driven ependymomas and support the clinical development of MERTK-targeted therapies for patients with the high-risk EPN-E1 subtype.}, }
@article {pmid41666504, year = {2026}, author = {Dolatkhah, R and Erdmann, F and Bouaoun, L and Mueller, BA and Petridou, ET and Schraw, JM and Kane, E and Marcotte, EL and Force, LM and Dockerty, JD and Moissonnier, M and Olsson, A and Roman, E and Clavel, J and Metayer, C and Magnani, C and Mora, AM and Rashed, WM and Chow, EJ and Bonaventure, A and Kang, AY and Miligi, L and Scheurer, ME and Spector, LG and Schüz, J}, title = {Associations of maternal education with suggested childhood cancer risk factors: Findings from the Childhood Cancer and Leukemia International Consortium (CLIC).}, journal = {Cancer epidemiology}, volume = {101}, number = {}, pages = {103014}, doi = {10.1016/j.canep.2026.103014}, pmid = {41666504}, issn = {1877-783X}, mesh = {Humans ; Female ; Risk Factors ; *Educational Status ; Case-Control Studies ; Child ; *Neoplasms/epidemiology/etiology ; Male ; Child, Preschool ; Infant ; Adult ; *Mothers/education ; Infant, Newborn ; Pregnancy ; Adolescent ; }, abstract = {BACKGROUND: Causes of childhood cancer remain poorly understood. Using data from the case-control studies of the Childhood Cancer and Leukemia International Consortium (CLIC), we explored how maternal education as a key socioeconomic status (SES) indicator, varies across studies/countries and contributes to understanding of potential environmental and lifestyle risk factors.<br><br>METHODS: Control group data from cancer-free children matched by diagnosis date of cases from 16 studies were included, using both interview-based and health registry sources. Maternal education, the primary SES measure used in previous analyses with pooled CLIC data, was categorized as low, medium, or high according to the International Standard Classification of Education. Multinomial logistic regression assessed associations between maternal education and perinatal/lifestyle factors, calculating crude and adjusted odds ratios (ORs) and 95&#x202f;% confidence intervals (CIs) for high vs. low education.<br><br>RESULTS: Maternal education levels varied across studies and over time, with the highest proportions of highly educated mothers in the U.S. and lowest in Costa Rica, Italy, and Egypt. Higher maternal education was generally positively associated with higher birthweight, breastfeeding, daycare attendance, and maternal prenatal alcohol consumption. Higher maternal education was generally inversely associated with lower birthweight, younger maternal age, paternal occupational pesticide exposure, maternal prenatal smoking, and having more siblings. The direction of associations for older maternal age and for caesarean delivery differed substantially across regions. Exclusion of mothers <&#x202f;21 years at birth of the index child had little effect on the results.<br><br>CONCLUSION: This multi-country analysis supports the use of maternal education for adjustment as a proxy for SES, showing largely consistent associations with various behaviors and exposures. While the direction of associations was generally consistent, the strengths varied sometimes considerably by geographical region. These findings support the inclusion of maternal education as a covariate in analyses of childhood cancer risk when pooling CLIC studies.}, }
@article {pmid41667953, year = {2026}, author = {Guccione, C and Sfiligoi, I and Gonzalez, A and Shaffer, JP and Kazachkova, M and Weng, Y and McDonald, D and Shah, SC and Minot, SS and Paulson, TG and Grady, WM and Alexandrov, LB and Knight, R and Curtius, K}, title = {Community assembly modeling of the microbiome within Barrett's esophagus and esophageal adenocarcinoma.}, journal = {BMC genomics}, volume = {27}, number = {1}, pages = {}, pmid = {41667953}, issn = {1471-2164}, support = {AGA2022-13-05//AGA Research Foundation/ ; 2019-67013-29137//National Institute of Food and Agriculture/ ; RG103468//University of California, San Diego/ ; P30 CA023100/NH/NIH HHS/United States ; ICX002027A//U.S. Department of Veterans Affairs/ ; 5K12GM068524-17/NH/NIH HHS/United States ; IK2 CX002027/CX/CSRD VA/United States ; R01 CA270235/NH/NIH HHS/United States ; R01 CA270235/CA/NCI NIH HHS/United States ; P30 DK120515/DK/NIDDK NIH HHS/United States ; }, abstract = {UNLABELLED: Computational modeling of somatic evolution, a process shaped by ecology and impacting both host cells and microbial communities in the human body, can capture important dynamics driving carcinogenesis. Here we considered models for esophageal adenocarcinoma (EAC), a cancer that has dramatically increased in incidence over the past few decades in Western populations, with high case fatality rates due to late-stage diagnoses. Despite advancements in genomic analyses of the precursor Barrett’s esophagus (BE), prevention of late-stage EAC remains a significant clinical challenge. Previous microbiome studies in BE/EAC have focused on quantifying static microbial abundance differences rather than determining population dynamics. Using whole genome sequencing data from a total of 505 esophageal samples, we first applied a robust bioinformatics pipeline to extract non-host DNA reads, mapped these putative reads to microbial taxa, and retained those taxa with high genomic coverage. When applying mathematical models of demographic stochasticity to sequential stages of progression to EAC, we observed evidence of neutral dynamics in community assembly within normal esophageal tissue and BE, but not EAC. In a large case–control study of BE patients who progressed to EAC versus BE patients with non-cancer outcomes (NCO) during follow-up (mean = 10.5 years), we found that Helicobacter pylori deviated significantly from the neutral expectation in BE NCO only, suggesting that factors related to H. pylori or H. pylori infection itself may influence EAC risk. Additionally, stochastic simulations incorporating selection recapitulated non-neutral behaviors observed. Formally modeling dynamics during progression holds promise in clinical applications by offering a deeper understanding of microbial involvement in cancer development.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12864-026-12545-w.}, }
@article {pmid41668175, year = {2026}, author = {Karasaki, S and Iyer, HS and Phipps, AI and VoPham, T}, title = {Per- and polyfluoroalkyl substances in drinking water and cancer prevalence in the United States.}, journal = {Environmental health : a global access science source}, volume = {25}, number = {1}, pages = {}, pmid = {41668175}, issn = {1476-069X}, support = {K01 ES035734/ES/NIEHS NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; K01 DK125612/DK/NIDDK NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; K01 ES035734/ES/NIEHS NIH HHS/United States ; K01 DK125612/DK/NIDDK NIH HHS/United States ; }, mesh = {United States/epidemiology ; Humans ; *Drinking Water/analysis/chemistry ; *Water Pollutants, Chemical/analysis/adverse effects ; *Fluorocarbons/analysis ; Prevalence ; *Neoplasms/epidemiology/chemically induced ; Female ; Male ; Middle Aged ; Adult ; Aged ; *Environmental Exposure ; Young Adult ; Adolescent ; }, abstract = {BACKGROUND: Research concerning the adverse health effects of per- and polyfluoroalkyl substances (PFAS) continues to grow. With the recent releases of nationwide data on PFAS in drinking water and public drinking water system service boundaries, it is now possible to conduct nationwide geospatial analyses on the relationships between PFAS in drinking water and aspects of health.<br><br>OBJECTIVE: To examine associations between PFAS in drinking water and cancer history prevalence in the United States.<br><br>METHODS: We examined cancer history prevalence, at the census tract level, among adults aged&#x2009;&#x2265;&#x2009;18 years diagnosed with any cancer in or prior to 2022 using the United States Population Level Analysis and Community EStimates dataset. We obtained data for PFAS in public drinking water from the Fifth Unregulated Contaminant Monitoring Rule (UCMR 5, 2023-ongoing). We used geographic information systems to spatially join water system boundaries (n&#x2009;=&#x2009;9,733) with census tracts applying population-weighted areal interpolation. We calculated prevalence ratios (PRs) and 95% confidence intervals (CIs) for the associations between PFAS in drinking water and prevalence of cancer history, adjusted for census tract-level sociodemographics, health conditions and behaviors, and environmental factors.<br><br>RESULTS: This analysis included 76,606 census tracts with an average cancer history prevalence of 7.8%. We observed positive associations of cancer history prevalence with PFAS levels in drinking water for 6:2-FTS, PFBA, PFBS, PFHpA, PFHxA, PFHxS, PFNA, PFOA, PFPeA, and PFPeS (p&#x2009;<&#x2009;0.01). For example, for 6:2-FTS, the adjusted PR comparing the highest quintile (0.0182-0.663&#xa0;&#xb5;g/L, population-weighted) to samples below the minimum reporting level (<&#x2009;0.005&#xa0;&#xb5;g/L) was 1.04 (95% CI 1.02-1.07, p&#x2009;<&#x2009;0.001). No associations were observed for HFPO-DA and PFOS. Models mutually adjusted for correlated PFAS showed generally similar results.<br><br>SIGNIFICANCE: Higher levels of certain PFAS in drinking water were independently associated with higher cancer history prevalence. Future research should examine the relationships between individual-level cancer outcomes and individual-level exposure to PFAS in drinking water.}, }
@article {pmid41669866, year = {2026}, author = {McKay, RR and Maughan, BL and Morgans, AK and Shore, ND and Yu, EY and Madan, RA and Berchuck, JE and Carthon, BC and Finkelstein, SE and Gomella, L and Gorin, MA and Hahn, AW and Loeb, S and Narayan, VK and Petrylak, DP and Ryan, CJ and Tawagi, K and Tran, PT and Dorff, T}, title = {Evolving strategies in prostate cancer: Emerging approaches and unmet needs from the Bridging the Gaps in Prostate Cancer expert panel.}, journal = {Cancer}, volume = {132}, number = {4}, pages = {e70304}, pmid = {41669866}, issn = {1097-0142}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U54 CA273956/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/therapy/diagnosis/genetics/pathology ; Biomarkers, Tumor/genetics ; Precision Medicine/methods ; Prognosis ; Quality of Life ; Artificial Intelligence ; Neoplasm Recurrence, Local ; }, abstract = {BACKGROUND: The expansion of treatment options for prostate cancer (PC) has improved disease-specific and overall survival outcomes but has also raised questions about the optimal level of treatment needed for patients based on their individual prognosis and accounting for potential toxicity, incorporating quality of life considerations.<br><br>METHODS: A panel of experts met to discuss current controversies in the care of patients with PC across the disease continuum. Multidisciplinary experts review advances and persistent uncertainties in biomarker-guided assessment, imaging, and systemic therapy for prostate cancer. The discussion outlines priority gaps in evidence that must be addressed to optimize individualized patient care.<br><br>RESULTS: Workshop topics included use of genomic biomarkers and artificial intelligence-guided tools to identify and manage high-risk and very-high risk localized disease, management of biochemical recurrence, identification of patients with metastatic hormone-sensitive PC who warrant treatment escalation, radiopharmaceutical therapy for metastatic castration-resistant PC including optimal sequencing of approved therapies, role of imaging in identification and management of extraprostatic disease, and lifestyle interventions to optimize survivorship.<br><br>CONCLUSIONS: Many questions remain about management of PC related to biomarker-based risk stratification to guide treatment selection, use of prostate-specific membrane antigen-positron emission tomography, and balancing the risk for PC-related death with risks for treatment-related toxicity. Ongoing research efforts are needed to optimize risk-based treatment, sequence of therapies throughout the disease continuum, and survivorship care.}, }
@article {pmid41671442, year = {2026}, author = {DeZern, AE and Gillis, N and Otterstatter, M and Abel, G and Padron, E and Deeg, HJ and Al Baghdadi, T and Liu, J and Xie, Z and Zhang, L and Moscinski, L and Kroft, S and Harrington, A and Foran, J and Komrokji, R and Starczynowski, D and Gore, S and Saber, W and Bejar, R and Lindsley, RC and Sherman, S and Lee, C and DiFronzo, N and Walter, M and Sekeres, MA}, title = {A novel approach to defining progression in MDS and precursor myeloid conditions in the MDS Natural History Study.}, journal = {Blood advances}, volume = {10}, number = {8}, pages = {2743-2753}, doi = {10.1182/bloodadvances.2025018770}, pmid = {41671442}, issn = {2473-9537}, mesh = {Humans ; *Myelodysplastic Syndromes/diagnosis/pathology/epidemiology/therapy ; Male ; Female ; Disease Progression ; Aged ; Middle Aged ; Prospective Studies ; Aged, 80 and over ; Risk Factors ; }, abstract = {Patients at risk for progression from myeloid precursor states (idiopathic cytopenia of undetermined significance [ICUS] and clonal cytopenia of undetermined significance [CCUS]) to myelodysplastic syndrome (MDS) are not well defined. Epidemiologic risk factors, clonal changes for MDS development, and evolution from one MDS state to another were available in the MDS Natural History Study (NHS), a prospective cohort enrolled at diverse US sites. Extensive clinical data and biospecimens were collected at baseline and follow-up. A total of 1177 (56%) individuals with MDS or MDS-related precursor conditions (ICUS/idiopathic dysplasia of undetermined significance [IDUS], CCUS, and MDS/myeloproliferative neoplasm overlap) were enrolled and diagnosed in the MDS NHS. The median age was 74 years, with 89% aged ≥60 years, and most were male patients. Median follow-up time was 1.6 years and was similar among ICUS/IDUS, CCUS, and MDS. During follow-up period, 68% of participants terminated the study, 35% died, and 38% had disease progression. Using a refined clinical definition of progression, the greatest proportion of progression was observed among higher-risk-MDS (116 [73%]), followed by lower-risk-MDS (170 [52%]); fewer progression events were observed among participants with CCUS (65 [22%]) and ICUS/IDUS (46 [17%]). Predictors of progression are delineated, including female sex, higher quantity of mutations, the presence of TP53 mutation, and poor/very poor cytogenetic score. Based on these prospective data, guidelines for clinical management including monitoring and surveillance are outlined. The MDS NHS provides real-world data to illustrate how clinical and genotypic differences inform the classification, disease course, and approach to therapy, with informed monitoring guidelines for patients. This trial was registered at www.ClinicalTrials.gov as NCT02775383.}, }
@article {pmid41671449, year = {2026}, author = {Hagen, MW and Setiawan, NJ and Dexter, S and Woodruff, KA and Gaerlan, FK and Billings, TM and Orozco, JJ and Termini, CM}, title = {The bone marrow niche and hematopoietic system are distinctly remodeled by CD45-targeted astatine-211 radioimmunotherapy.}, journal = {Blood advances}, volume = {10}, number = {7}, pages = {2452-2469}, pmid = {41671449}, issn = {2473-9537}, mesh = {Animals ; *Radioimmunotherapy/methods ; Mice ; *Leukocyte Common Antigens/metabolism ; *Astatine/therapeutic use/pharmacology ; *Bone Marrow/radiation effects/metabolism/pathology ; Hematopoietic Stem Cells/metabolism/radiation effects ; *Hematopoietic System/radiation effects/metabolism ; Humans ; *Stem Cell Niche/radiation effects ; Whole-Body Irradiation ; }, abstract = {Radioimmunotherapy (RIT) is used to treat patients with hematologic malignancies known to infiltrate the bone marrow (BM) microenvironment. RIT uses target-specific monoclonal antibodies stably conjugated to radionuclides to deliver cytotoxic radiation to cells of interest. Although RIT is effective at delivering radiation to cancer cells, normal tissue is also exposed to radiation during RIT, the consequences of which are largely unknown. Here, we studied the cellular and molecular effects of CD45-targeted astatine-211 (211At) RIT, immunoglobulin G (IgG) nontargeted 211At RIT, and Cesium-137 total-body irradiation (TBI) on hematopoietic cells and their BM niche in wild-type immunocompetent mice. Relative to nontargeted RIT or TBI, CD45-targeted RIT significantly delayed hematopoietic regeneration overall in the peripheral blood and BM and reduced hematopoietic stem/progenitor cell recovery and colony-forming ability. Although BM endothelial cells (ECs) do not express the CD45 antigen, CD45-targeted RIT significantly depleted BM ECs compared to nontargeted RIT or TBI. RNA sequence analysis revealed significantly different transcriptomic profiles of BM ECs from CD45-RIT-treated mice compared to nontargeted RIT or TBI. ECs from CD45-RIT-treated mice, but not TBI- or IgG-RIT-treated mice, were transcriptionally enriched for growth factor signaling pathways compared to untreated mice. BM soluble growth factor expression remained upregulated in CD45-RIT-treated mice 28 days after treatment compared to nontreated mice. Collectively, our study indicates that CD45-targeted RIT severely affects hematopoietic and EC niche recovery compared to nontargeted approaches. Future studies are required to determine the long-term consequences of such RIT-driven effects on BM niche physiology and how BM niche reprogramming by RIT affects cancer cells.}, }
@article {pmid41671463, year = {2025}, author = {Davis, KL and Yao, CC and Zimmerman, JAO and Rau, RE}, title = {Immunotherapy in B-Cell Acute Lymphoblastic Leukemia.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {12}, pages = {}, doi = {10.6004/jnccn.2025.7067}, pmid = {41671463}, issn = {1540-1413}, mesh = {Humans ; *Immunotherapy/methods ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/immunology ; Immunoconjugates/therapeutic use ; *Antineoplastic Agents, Immunological/therapeutic use ; Immunotherapy, Adoptive/methods ; Child ; }, abstract = {In recent years, immunotherapy has been increasingly incorporated into the clinical care of both pediatric and adult patients with B-cell acute lymphoblastic leukemia (B-ALL) to improve outcomes. Four main categories of immunotherapies are used in B-ALL: (1) unconjugated monoclonal antibodies (mAbs), (2) antibody-drug conjugates (ADCs), (3) T-cell-engaging antibodies, and (4) CAR T cells. Although mAbs such as rituximab are primarily used in adults, the other modalities have demonstrated efficacy in both pediatric and adult patients with B-ALL. Among ADCs, inotuzumab ozogamicin (InO) has proven effective as monotherapy for relapsed disease, leading to FDA approval for patients aged >1 year with relapsed/refractory B-ALL. InO is also being investigated in the upfront setting in combination with chemotherapy. Although results in adults have been promising, increased rates of infectious complications in chemotherapy courses post-InO have hampered progress of trials in children, adolescents, and young adults. T-cell-engaging antibodies are now a standard component of therapy for most patients with newly diagnosed and relapsed B-ALL, following the successful integration of the bispecific T-cell-engager blinatumomab into chemotherapy regimens for both adults and children. Recent studies support the possibility of using blinatumomab to replace some or even most of the intensive chemotherapy traditionally used in B-ALL treatment. CAR T-cell therapy has revolutionized the treatment of relapsed/refractory B-ALL by targeting CD19, but challenges remain due to the loss of CAR T-cell persistence and antigen escape. Newer CAR T cells targeting CD22 or the combination of CD19 and CD22 are being studied to address the issue of antigen escape. Overall, immune-based therapies are now a mainstay of B-ALL therapy. This article reviews the efficacy and safety data of several immune-based therapies in B-ALL and discusses a number of outstanding questions and possible future directions for the use of immune-based approaches in the treatment of B-ALL.}, }
@article {pmid41671529, year = {2026}, author = {Hendifar, AE and Krishna, V and Krishna, V and Zhang, H and Tarsode, A and Nimgaonkar, V and Smith, K and Abdilleh, K and Sonawane, S and Neema, A and Tiu, E and Larson, BK and Kazarov, V and Moshayedi, N and Hutchinson, S and Bevacqua, D and Doss, S and Alvarez, A and Watson, D and Abuzeid, WM and Grünwald, BT and Noel, M and Samdani, R and Keith, D and Sears, RC and Sohal, D and Fountzilas, C and O'Kane, GM and Grant, RC and Osipov, A and Collisson, EA and Kiedrowski, LA and Royce, TJ and Joshi, AR and Singhi, AD and Knox, JJ}, title = {Development and Validation of a Computational Histology Artificial Intelligence-Powered Predictive Biomarker for Selection of Chemotherapy in Advanced Pancreatic Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2502199}, doi = {10.1200/JCO-25-02199}, pmid = {41671529}, issn = {1527-7755}, abstract = {PURPOSE: Predictive biomarkers to guide selection of first-line chemotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) are an unmet clinical need. This study used the Computational Histology Artificial Intelligence (CHAI) platform to develop and validate a histomorphology-based G-chemo versus F-chemo (GvF) biomarker that predicts benefit from first-line fluoropyrimidine-based (F-chemo) versus gemcitabine-based (G-chemo) regimens.<br><br>METHODS: The CHAI platform extracted quantitative histomorphologic features from whole-slide images of hematoxylin and eosin-stained diagnostic biopsies. In a multi-institutional development cohort, features associated with differential outcomes as measured by time to next treatment or death (TNTD) between F-chemo-treated and G-chemo-treated patients produced continuous biomarker scores, which were dichotomized into G-pref or F-pref results. The biomarker and threshold were locked. An independent validation cohort from the prospective COMPASS and Know Your Tumor studies assessed differential treatment outcomes by TNTD and overall survival (OS).<br><br>RESULTS: There were 477 patients (development: 178; validation: 299). In validation, among 173 F-pref patients, those treated with F-chemo had significantly better outcomes than G-chemo for both TNTD (P = .035; median TNTD: F-chemo 8.6 months; G-chemo 7.5 months) and OS (P = .003; median OS: F-chemo 14.4 months; G-chemo 11.7 months). Among 126 G-pref patients, G-chemo had significantly superior TNTD (P = .038; median TNTD: F-chemo 7.2 months; G-chemo 9.6 months), but no difference in OS (P = .5; median OS: F-chemo 12.4 months; G-chemo 14.3 months). In propensity score-weighted analysis, the biomarker predicted treatment effect (biomarker-treatment interaction TNTD P < .001; OS P = .005). RNA subtypes were associated with TNTD and OS but did not predict differential treatment effects (P = .3).<br><br>CONCLUSION: The histomorphology-based GvF biomarker predicted differential treatment benefit of first-line GvF. This biomarker can guide optimal treatment selection for first-line therapy in advanced PDAC.}, }
@article {pmid41671533, year = {2026}, author = {Pemmaraju, N and Marconi, G and Montesinos, P and Lane, AA and Mazzarella, L and Sallman, DA and Ulrickson, ML and Schiller, GJ and Erba, HP and Wang, ES and Walter, RB and Deconinck, E and Aribi, A and Legrand, O and Lebon, D and Maisano, V and Martinelli, G and DeAngelo, DJ and Derenzini, E and Du, Y and Lakshmikanthan, S and Potluri, J and Kantarjian, HM and Daver, NG}, title = {Pivekimab Sunirine in Blastic Plasmacytoid Dendritic Cell Neoplasm.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {10}, pages = {861-873}, pmid = {41671533}, issn = {1527-7755}, mesh = {Humans ; Middle Aged ; Male ; Female ; Aged ; *Dendritic Cells/pathology/drug effects ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Hematologic Neoplasms/drug therapy/pathology/mortality ; Interleukin-3 Receptor alpha Subunit/antagonists &amp; inhibitors ; Blastic Plasmacytoid Dendritic Cell Neoplasm ; }, abstract = {PURPOSE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a unique myeloid malignancy with CD123 interleukin-3 receptor-α overexpression and poor prognosis.<br><br>METHODS: This phase I/II, open-label, multicenter study evaluated pivekimab sunirine (PVEK), a novel CD123 antibody-drug conjugate, 0.045 mg/kg once every 3 weeks, in adults with frontline (no previous systemic therapy and de novo BPDCN or coexisting hematologic malignancy) or relapsed/refractory BPDCN (ClinicalTrials.gov identifier: NCT03386513) The primary end point in the primary analysis population (PAP; frontline de novo) was composite complete response (CCR; CR+ clinical CR) rate.<br><br>RESULTS: Of 84 patients, 33 had frontline BPDCN (22 de novo [20 in PAP]; 11 with previous or concomitant malignancy) and 51 had relapsed/refractory disease. The median (range) age was 72 (63-76) years. In the PAP (n = 20), the CCR rate was 75% (95% CI, 51 to 91; n = 15; median duration: 10.6 [95% CI, 3.8 to not reached] months) and the median overall survival (OS) was 16.6 (95% CI, 7.2 to not reached) months. Eight of these 15 (53%) patients proceeded to stem-cell transplant (SCT). The corresponding rate for relapsed/refractory disease was 14% (95% CI, 6 to 26; n = 7; median duration: 9.2 [95% CI, 2.4 to not reached] months), and the median OS was 5.8 (95% CI, 3.9 to 8.4) months. Adverse events (AEs) included peripheral edema (54%), fatigue (26%), and infusion-related reactions (26%). Grade &#x2265;3 events included neutropenia (16%), thrombocytopenia (14%), and peripheral edema (12%). Serious AEs included pneumonia (6%) and febrile neutropenia (5%). Two on-treatment cases of reversible veno-occlusive disease (VOD) occurred. Of the total 19 patients who proceeded to SCT, VOD was reported in five patients (four with relapsed/refractory BPDCN).<br><br>CONCLUSION: PVEK, with convenient dosing, led to high, durable responses, especially in frontline BPDCN, and a manageable safety profile.}, }
@article {pmid41672261, year = {2026}, author = {Kanwal, F and Lopez, C and Ning, J and Luster, M and Reddy, KR and Parikh, ND and Singal, AG and Marrero, JA and Chhatwal, J and Feng, Z and Page-Lester, S and Koay, EJ and El-Serag, HB}, title = {Validation of Texas Hepatocellular Carcinoma Consortium Risk Index in the Hepatocellular Carcinoma Early Detection Strategy Study.}, journal = {Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.cgh.2026.01.041}, pmid = {41672261}, issn = {1542-7714}, abstract = {BACKGROUND &amp; AIMS: We previously developed a hepatocellular carcinoma (HCC) risk stratification model, the Texas HCC Consortium Risk Index (THCC-RI), for patients with cirrhosis. In this cohort study, we aimed to externally validate THCC-RI in a prospective cohort of patients with cirrhosis.<br><br>METHODS: We used data from the Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study, a prospective cohort of patients with cirrhosis enrolled in regular HCC surveillance at 7 centers in the United States. Patients were followed from enrollment until HCC diagnosis, liver transplantation, death, or December 2023.<br><br>RESULTS: The analysis was conducted in 1560 patients who contributed a total of 5051 person-years of follow-up (mean age, 59 years; 47% women; 40% with hepatitis C; 16% alcohol-associated disease; and 22% metabolic dysfunction-associated steatotic liver disease). Over a median follow-up of 2.5 years, 114 patients developed HCC. The THCC-RI had a C-index of 0.77 (95% confidence interval [CI], 0.64-0.85), with area under the receiver operating characteristic curve estimates of 0.77 (95% CI, 0.65-0.85) at 1 year, 0.73 (95% CI, 0.66-0.79) at 3 years, and 0.71 (95% CI, 0.65-0.77) at 5 years. THCC-RI was well-calibrated, with good agreement between observed and predicted risk. Compared with the medium-risk group (deciles 3-8), the high-risk group (deciles 9, 10) had 3.5-fold (hazard ratio, 3.5; 95% CI, 2.4-5.1) higher risk of HCC. THCC-RI had similar discrimination as the Age, Male, Albumin-bilirubin, and Platelets (aMAP) score during the first 2 years of follow-up, but the areas under the receiver operating characteristic curve for aMAP dropped more than those for THCC-RI as the time horizon expanded beyond 3 years.<br><br>CONCLUSIONS: In an independent multi-center cohort, THCC-RI had good performance for predicting the future risk of HCC in patients with cirrhosis, with stable discrimination and calibration over a 5-year follow-up. Implementation of THCC-RI into clinical care pathways requires further research.}, }
@article {pmid41674613, year = {2026}, author = {Stefanovic, F and Robertson, I and Moloney, K and Edelson, J and Nguyen, S and Shinkawa, V and Uchimura, K and Lin, A and Le, L and Tokihiro, JC and Takezawa, MG and Phan, D and Schiffer, JT and Boeckh, M and Adams, KN and Waghmare, A and Errett, NA and Berthier, E and Lim, FY and Theberge, AB}, title = {Research In Your Mailbox: Remote Blood Self-sampling Enables Participation of Underserved Populations in Longitudinal Studies.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41674613}, support = {R35 GM128648/GM/NIGMS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, abstract = {IMPORTANCE: Remote sampling technologies are invaluable for protecting both participants and researchers when studying highly infectious diseases. When leveraged for longitudinal studies, remote sampling with transcriptomic readouts is a powerful tool for studying the host immune response. Additionally, remote study flexibility circumvents common barriers to research participation including length of commute, transportation, and scheduling, thereby expanding access to clinical research.<br><br>OBJECTIVE: In this work, we investigate the effectiveness of a remote study model for reaching women from underrepresented, underserved, and underreported (U3) populations. We sought to recruit individuals who qualify as underrepresented in clinical research, who are located in rural areas, or who come from disadvantaged backgrounds per the NIH definition.<br><br>DESIGN: In this longitudinal study, U3 women positive for COVID-19 were enrolled and followed over the course of 6 months. In the first month of the infection, participants (n = 40) self-collected a set of 5 nasal swabs, 5 homeRNA-stabilized blood samples, and 2 additional unstabilized blood samples at first and last sampling. Sampling time points were spaced 5 days apart, so that the total of the 5 time points was completed within 25 days. homeRNA is a platform for remote self-collection of blood samples with subsequent RNA stabilization. A subset of participants likely to develop post-acute sequelae of COVID-19 (PASC) and their age-matched controls were selected to self-collect an additional set of 5 nasal swabs and 5 homeRNA-stabilized blood samples during month 3 of study participation, with the same sampling frequency. All participants were resurveyed at months 4, 5, and 6 about their symptoms. Participants also completed surveys at each sampling and a more comprehensive survey about study experience after each set of 5 time points.<br><br>SETTING: This was a fully remote study with all sampling supplies and instructions shipped to the participants. Participants self-collected blood and nasal swabs at home and shipped these back to our lab for further processing. Surveys were administered electronically using REDCap.<br><br>PARTICIPANTS: For this study, we enrolled women who were 18 or older, met the NIH criteria for U3, and who had tested positive for SARS-CoV-2 within a week of enrollment. Further, we excluded protected populations including individuals who were pregnant and/or incarcerated. Of the 334 individuals who completed the screening process, 65 were invited into the study based on the eligibility criteria and balancing age, race/ethnicity, and state of residence to closely correspond to the demographics of the United States. Of the 65 invited individuals, 40 were fully enrolled in the study and 39 completed all study components.<br><br>MAIN OUTCOMES AND MEASURES: Prior to the study, we proposed that the increased flexibility of a remote study design would allow for participation of populations underrepresented in clinical research. The primary measurements planned for this study consisted of usability data and general experience in a longitudinal study. These data were collected by self report using electronically administered surveys. The Consolidated Framework for Implementation Research (CFIR), a well-established implementation science framework, was used to guide the development of questions about usability and study experience.<br><br>RESULTS: 40 women were recruited from 19 states, with diverse racial backgrounds (62% White, 15% Black or African American, 10% Asian, 5% American Indian or Alaska Native, 5% Other, 3% More than one race), a mostly even age distribution (26% ages 20 - 29, 15% ages 30 - 39, 31% ages 40 - 49, 28% ages 50+), and most of whom (80%) are categorized as having a disadvantaged background per the NIH. Survey responses show high satisfaction with the study, where all participants who completed the study (100%, n = 39/39) indicating that they would be willing to participate in a similar study again, with most (n = 32/39) indicating a willingness to participate for up to 4 years with around 15 samples collected per year. We note that 4 years was the longest time period that participants were able to select in their surveys, suggesting that participants may be willing to participate for even longer periods. Most (>90%) either agreed or strongly agreed that all components of the kit were easy to use.<br><br>CONCLUSIONS AND RELEVANCE: The high retention (98%, n = 39/40) and satisfaction of participants in this study indicates the utility of a remote study design for longitudinal research. We also find that study topic, flexibility of study, and positive interactions with the study team are important factors for participant recruitment and retention. This work suggests that the increased flexibility of a fully remote design enables engagement of individuals who may otherwise be excluded from clinical research.}, }
@article {pmid41674614, year = {2026}, author = {Kung, E and Deo, R and Choudhary, MC and Chew, KW and Evering, TH and Ignacio, RB and Jagannathan, P and Flynn, JP and Regan, J and Moser, C and Giganti, MJ and Hughes, MD and Ritz, J and Javan, AC and Greninger, AL and Singh, U and Fischer, W and Daar, ES and Wohl, DA and Eron, JJ and Currier, JS and Coombs, RW and Smith, DM and Li, JZ}, title = {Viral shedding and symptom severity across populations during acute COVID in the ACTIV-2 study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41674614}, support = {UM1 AI068634/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; UM1 AI106701/AI/NIAID NIH HHS/United States ; }, abstract = {To evaluate the impact of sex on acute SARS-CoV-2 infection, 668 participants from the ACTIV-2/A5401 study were followed over a 28-day period. A primary analysis was performed on the 469 participants who had quantifiable viral loads at baseline. Male and female participants had comparable nasal SARS-CoV-2 RNA levels at study entry and throughout follow-up. However, sex-specific differences in viral shedding emerged when stratified by duration of symptoms. In the first three days from symptom onset, female participants exhibited higher nasal SARS-CoV-2 RNA levels than males, but lower viral RNA levels thereafter. The higher viral RNA levels in females during the earliest phase of acute COVID-19 was seen even after adjusting for age, race and region of enrollment. Female participants also tended to have higher symptom scores across days since symptom onset but no significant correlation was observed between nasal SARS-CoV-2 RNA levels and symptom score regardless of sex. These findings highlight the impact of sex on both viral shedding and symptom dynamics and underscore the importance of considering time since symptom onset when evaluating respiratory virus antiviral therapies in clinical trials.}, }
@article {pmid41675299, year = {2026}, author = {Aung, YK and Jenkins, MA and Baxter, NN and Potter, JD and Schmit, SL and Samadder, JJ and Newcomb, PA and Buchanan, DD and Win, AK}, title = {Subsequent primary cancer risks for non-hereditary colorectal cancer survivors.}, journal = {EClinicalMedicine}, volume = {92}, number = {}, pages = {103716}, pmid = {41675299}, issn = {2589-5370}, abstract = {BACKGROUND: Colorectal cancer survivors have increased risks of subsequent primary cancers (SPCs), but most studies have included individuals with hereditary colorectal cancer syndromes. This study assessed SPC risks for colorectal cancer survivors without a known hereditary predisposition to colorectal cancer.<br><br>METHODS: We analyzed data from the Colon Cancer Family Registry Cohort, recruiting participants between 1998 and 2012 through population cancer registries in Australia, Canada and the United States, with follow-up every five years (until December 2022). Individuals with pathogenic germline mutations in APC, MUTYH, or DNA mismatch repair genes were excluded. Standardized incidence ratios (SIRs) were calculated by comparing observed cases with expected cases based on age-, sex-, country-, and calendar period-specific incidence rates.<br><br>FINDINGS: The study included 7202 (49.8% female) colorectal cancer survivors with a mean age at diagnosis of 55.1 (SD 11.5) years and a mean follow-up of 10.6 (SD 7.45) years. Overall, there was no evidence of increased SPC risk (SIR 1.04, 95% CI: 0.98-1.11). Elevated risks were observed for subsequent primary colorectal (SIR 1.34, 95% CI: 1.14-1.57), hematopoietic (SIR 2.49, 95% CI: 1.92-3.21), liver (SIR 2.25, 95% CI: 1.51-3.36), and thyroid (SIR 1.90, 95% CI: 1.20-3.02) cancer. Early-onset colorectal cancer cases (diagnosed before age 50) had increased SPC risks (SIR 1.43, 95% CI: 1.25-1.64) while those diagnosed at 50 and above did not (p < 0.001).<br><br>INTERPRETATION: In non-hereditary colorectal cancer survivors, overall SPC risks are not elevated, but early-onset cases have higher risks and therefore warrant targeted surveillance and follow-up.<br><br>FUNDING: National Institutes of Health (U01 CA167551) and National Health and Medical Research Council (1194392).}, }
@article {pmid41678147, year = {2026}, author = {Huang, SH and Cotler, J and Palis, B and Seethala, RR and Hosni, A and O'Sullivan, B and Vander Poorten, V and Bishop, JA and Glastonbury, CM and Beadle, B and Ha, P and Kakarala, K and Rodriguez, CP and Su, J and Xu, W and Alfaraj, F and Souied, O and Marta, GN and Kowalski, LP and Mierzwa, ML and Ho, AS and Eagan, A and Madera, M and Lydiatt, W and Patel, SG and Ganly, I}, title = {Proposed Version Nine of the AJCC and UICC TNM Classification for Salivary Gland Carcinoma.}, journal = {JAMA otolaryngology-- head &amp; neck surgery}, volume = {152}, number = {4}, pages = {366-375}, pmid = {41678147}, issn = {2168-619X}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Salivary Gland Neoplasms/pathology/mortality/classification/therapy ; Male ; *Neoplasm Staging ; Female ; Retrospective Studies ; Middle Aged ; Prognosis ; Aged ; Lymphatic Metastasis ; Survival Rate ; }, abstract = {IMPORTANCE: A unified salivary gland carcinoma (SGC)-specific tumor-node-metastasis (TNM) classification can enhance prognostic accuracy, support clinical decision-making, and improve the quality of patient care.<br><br>OBJECTIVE: To derive and validate an SGC-specific pTNM classification with improved prognostic accuracy and optimized stage distribution for version nine of the American Joint Committee on Cancer/Union for International Cancer Control staging protocol.<br><br>This retrospective prognostic cohort study derived a novel pTNM classification using data from the National Cancer Database (NCDB) of patients with surgically treated major SGC (2012-2017) and validated it in an international major SGC cohort (2008-2021) and a single-institution minor SGC cohort (Memorial Sloan Kettering Cancer Center; 1985-2016). Data were analyzed from June to November 2024.<br><br>EXPOSURES: Surgery with or without postoperative radiotherapy or chemoradiotherapy.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS). Cox proportional hazards multivariable analysis was used to confirm the prognostic importance of pathologically positive lymph node (LN) number and extranodal extension (pENE) and derive an optimal pTNM classification.<br><br>RESULTS: The NCDB dataset included 8409 patients with SGC: 7659 with M0 disease (5748 with pN0 disease and 1911 with pN+ disease) and 750 with M1 disease. Among the 7659 patients with M0 disease, the median (IQR) age was 60 (48-71) years, and 3861 (50.4%) were male. The median (IQR) follow-up was 88.4 (72.3-108.5) months. The 5-year OS was 87.2% (95% CI, 86.3-88.0) for N0 disease, 68.2% (95% CI, 63.9-72.8) for 1 positive LN without pENE, 60.2% (95% CI, 53.5-67.5) for 2 positive LNs without pENE, 68.4% (95% CI, 58.0-76.6) for 3 positive LNs without pENE, 47.5% (95% CI, 41.6-52.8) for more than 3 positive LNs without pENE, and 41.4% (38.1-44.8) for pENE-positive LNs. Multivariable analysis confirmed the independent prognostication of LN count compared with pN0 disease (1 positive LN: adjusted hazard ratio [aHR], 1.70; 95% CI, 1.44-2.01; 2 positive LNs: aHR, 1.61; 95% CI, 1.31-1.98; 3 positive LNs: aHR, 2.10; 95% CI, 1.65-2.68; 4 positive LNs : aHR, 2.46; 95% CI, 1.87-3.24; more than 4 positive LNs: aHR, 2.07; 95% CI, 2.08-2.91) and pENE-positive LNs compared with pENE-negative LNs (aHR, 1.27; 95% CI, 1.10-1.48). The proposed pN classification were pN1 for 1 to 3 positive LNs and pENE negativity and pN2 for more than 3 positive LNs or pENE positivity. Model fit improved with the proposed pN classification vs the current pN classification (Akaike Information Criterion, 26&#x202f;442 vs 26&#x202f;483). Based on the aHR model, the following stage groups were proposed: stage I: T1N0 (1 [reference]); stage II: T2N0 (aHR, 1.34; 95% CI, 1.11-1.61); stage IIIA: T1-2N1 or T3-4N0 (aHR, 2.36; 95% CI, 1.99-2.80); stage IIIB: T1-2N2 or T3-4N1-2 (aHR, 5.15; 95% CI, 4.38-6.06); and stage IV: M1 disease (aHR, 13.61; 95% CI, 11.37-16.29). The C index values were similar (proposed classification: 0.792; current classification: 0.790), while the AIC improved slightly (proposed classification: 26&#x202f;441; current classification: 26&#x202f;482). Stage-specific OS differences were evident in both the international major SGC cohort (n&#x2009;=&#x2009;1015) and Memorial Sloan Kettering Cancer Center minor SGC cohort (n&#x2009;=&#x2009;444).<br><br>CONCLUSIONS AND RELEVANCE: This unified, SGC-specific staging system improved prognostic accuracy and sample size balance and was applicable to both major and minor SGCs.}, }
@article {pmid41679770, year = {2026}, author = {Hanna, M and Sun, Q and Bell-Brown, A and Issaka, RB}, title = {Colorectal Cancer Test Completion among Adults Aged 45 to 75 in an Integrated Healthcare System: A Retrospective Analysis.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {35}, number = {4}, pages = {655-663}, pmid = {41679770}, issn = {1538-7755}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; Middle Aged ; Retrospective Studies ; Female ; Male ; Aged ; *Early Detection of Cancer/statistics &amp; numerical data/methods ; *Delivery of Health Care, Integrated/statistics &amp; numerical data ; Colonoscopy/statistics &amp; numerical data ; Occult Blood ; Sigmoidoscopy/statistics &amp; numerical data ; }, abstract = {BACKGROUND: In 2021, the US Preventive Services Task Force (USPSTF) lowered the recommended age for colorectal cancer screening from 50 to 45 years. This study examined colorectal cancer test completion and test modalities used among adults 45 to 49 years of age compared with those 50 years and older.<br><br>METHODS: We conducted a retrospective cohort study using electronic health records from an integrated academic-community health system that implemented organized screening. Adults 45 to 75 years of age eligible for colorectal cancer screening between 2021 and 2024 were included. Outcomes were colorectal cancer test completion and test modality: colonoscopy, fecal immunochemical test (FIT), FIT-DNA, CT colonography, or flexible sigmoidoscopy.<br><br>RESULTS: Approximately 80,000 adults were eligible for screening annually. Colorectal cancer test completion increased from 61.8% (2021) to 70.8% (2024), with the largest increase in the 45- to 49-year age group (25.6% to 51.7%). Colonoscopy and FIT were the most used modalities; among 45 to 49 year olds, FIT increased by 12.2% and colonoscopy by 14.2%. FIT-DNA use increased slightly, whereas flexible sigmoidoscopy use declined. Racial and ethnic disparities in colorectal cancer test completion decreased across groups.<br><br>CONCLUSIONS: Following the 2021 USPSTF recommendation, colorectal cancer test completion improved across all age groups, especially in adults 45 to 49 years of age. Colonoscopy and FIT use predominated. Ongoing efforts are needed to improve screening among younger adults to reach the 80% national screening goal.<br><br>IMPACT: This study demonstrated that expanding colorectal cancer testing to 45 to 49 year olds led to increased uptake of colonoscopy and FIT. It highlights how organized outreach and providing options in screening modalities can improve colorectal cancer test completion across several patient populations.}, }
@article {pmid41680141, year = {2026}, author = {Harris, ED and McGovern, M and Pernikoff, S and Ikeda, R and Kipnis, L and Hannon, W and Sobolik, EB and Gray, M and Greninger, AL and He, S and Chin, CN and Fu, TM and Pancera, M and Boonyaratanakornkit, J}, title = {Development of a potent monoclonal antibody for treatment of human metapneumovirus infections.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41680141}, issn = {2041-1723}, support = {Vaccine and Infectious Disease Division Faculty Initiative//Fred Hutchinson Cancer Research Center (Hutchinson Center)/ ; Evergreen Beyond Pilot Award//Fred Hutchinson Cancer Research Center (Hutchinson Center)/ ; R01-AI171186//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {*Metapneumovirus/immunology/drug effects/genetics ; Animals ; *Paramyxoviridae Infections/immunology/drug therapy/virology/therapy ; *Antibodies, Monoclonal/immunology/therapeutic use/pharmacology ; Humans ; *Antibodies, Neutralizing/immunology/therapeutic use ; Cryoelectron Microscopy ; *Antibodies, Viral/immunology/therapeutic use ; Epitopes/immunology ; Mice ; Cricetinae ; Female ; Viral Fusion Proteins/immunology ; Neutralization Tests ; }, abstract = {Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for treatment and prevention. We describe the discovery and characterization of 4F11, a highly potent neutralizing mAb with in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we define a unique mechanism of binding employed by 4F11. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry of Fab to trimer, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan. In vitro, 4F11 displays high neutralization potency across diverse HMPV strains. It also shows low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation have significantly decreased fitness in vitro. In male hamsters, 4F11 significantly reduces viral loads in the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development.}, }
@article {pmid41680482, year = {2026}, author = {Talla, A and Azevedo, JLLC and Latif, MB and Enriquez, AB and Sanchez, GP and Pelletier, AN and Bal, SK and Kumari, S and Schuch, V and Ghneim, K and Rhodes, A and Maldarelli, F and Yarchoan, R and Lurain, K and Ramaswami, R and Sharon, E and Hess, BW and D'Amico, L and Martinez-Picado, J and Chomont, N and Lewin, SR and Deeks, SG and Fling, SP and Cheever, MA and Uldrick, TS and Sharma, AA and Sekaly, RP}, title = {Innate antiviral and immune functions associated with the HIV reservoir decay after anti-PD-1 therapy.}, journal = {Nature medicine}, volume = {32}, number = {2}, pages = {505-517}, pmid = {41680482}, issn = {1546-170X}, support = {P30 AI050409/AI/NIAID NIH HHS/United States ; UM1AI164561//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; P01AI178376//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Humans ; Male ; *HIV Infections/drug therapy/immunology/virology ; Female ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors/immunology ; *HIV-1/drug effects/immunology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Adult ; *Immunity, Innate/drug effects ; Middle Aged ; CD8-Positive T-Lymphocytes/immunology/drug effects ; CD4-Positive T-Lymphocytes/immunology/drug effects/virology ; Viral Load/drug effects ; Virus Latency/drug effects ; Neoplasms/drug therapy/immunology ; Immune Checkpoint Inhibitors/therapeutic use ; }, abstract = {Antiretroviral therapy (ART) suppresses HIV but does not eliminate the latent viral reservoir, which persists in programmed cell death protein 1 (PD-1)-expressing CD4[+] T cells. Anti-PD-1 therapies have reduced the HIV reservoir in people living with HIV (PLWH) and cancer; however, the individuals who benefit and the mechanisms driving reservoir reduction remain unclear. We performed a prespecified exploratory, longitudinal multiomic profiling of 30 PLWH (29 males and one female) with cancer in the phase 1 CITN-12 clinical trial, in which pembrolizumab was evaluated for safety and preliminary antitumor activity. The therapy was generally well tolerated, with most adverse events graded 1-2 and objective antitumor response observed in five participants (one complete response and four partial responses). Within 24 hours of treatment, we observed an expansion of proliferating HIV-specific effector CD8[+] T cells and a decline in plasma TGFβ. Furthermore, among the 14 participants tracked to the end of treatment (ranging from 44 to 315 days after therapy initiation), nine display early induction and sustained expression of interferon-stimulated genes (ISGs), antiviral restriction factors and Toll-like receptor (TLR) signaling and a reduction in the HIV reservoir. Mapping these transcriptomic signatures across more than 1,000 public single-cell RNA sequencing datasets reveals that anti-PD-1-induced programs are present in subsets of across subsets of disease states, indicating that some people already display a heightened antiviral state. Together, these findings define immune pathways that help identify PLWH most likely to experience reservoir decay with anti-PD-1 therapy and suggest that sustained ISG activation may contribute to reservoir reduction and prevention of viral rebound upon ART interruption. ClinicalTrials.gov registration: NCT02595866 .}, }
@article {pmid41681979, year = {2026}, author = {Chiorean, EG and Damle, SR and Zhen, DB and Whittle, M and George, B and Hochster, H and Coveler, AL and Hendifar, A and Dragovich, T and Safyan, RA and King, GT and Harris, WP and Dion, B and Stoll D'Astice, A and Lee, A and Thorsen, S and Kugel, S and Rosenthal, A and Hingorani, S}, title = {Phase II Study of Pegvorhyaluronidase Alfa (PEGPH20) and Pembrolizumab for Patients with Hyaluronan-High, Pretreated Metastatic Pancreatic Ductal Adenocarcinoma: PCRT16-001.}, journal = {Cancers}, volume = {18}, number = {3}, pages = {}, pmid = {41681979}, issn = {2072-6694}, support = {R01 CA161112/CA/NCI NIH HHS/United States ; HALO 109-9902//Halozyme Therapeutics (United States)/ ; MISP 53041//Merck Pharmaceuticals/ ; 5P30CA015704-39//Fred Hutchinson Cancer Center Support Grant/ ; }, abstract = {Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60-73) and median two (range 1-4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2-11.8) and 1.5 months (95% CI 0.9-4.4), respectively. Prolonged survival (range 10.2-27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA.}, }
@article {pmid41685810, year = {2026}, author = {Stankiewicz Karita, HC and Magaret, AS and Doody, DR and Schouten, JT and Mao, C and Huh, WK and Grieco, VS and Seymour, MA and Varon, D and Shrader, KH and Xi, LF and Galloway, DA and Wald, A and Madeleine, MM}, title = {Nonavalent HPV vaccine to prevent recurrent anal or vulvar high-grade squamous intraepithelial lesions (VIVA trial): A randomized, double-blind, placebo-controlled trial.}, journal = {International journal of cancer}, volume = {158}, number = {11}, pages = {2983-2994}, pmid = {41685810}, issn = {1097-0215}, support = {R01 CA213130/CA/NCI NIH HHS/United States ; 6R01CA213130-06/CA/NCI NIH HHS/United States ; 6R01CA213130-06/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Papillomavirus Vaccines/administration &amp; dosage/therapeutic use ; Double-Blind Method ; Adult ; Middle Aged ; *Squamous Intraepithelial Lesions/prevention &amp; control/virology/pathology ; *Papillomavirus Infections/prevention &amp; control/virology ; *Vulvar Neoplasms/prevention &amp; control/virology/pathology ; *Neoplasm Recurrence, Local/prevention &amp; control/virology ; *Anus Neoplasms/prevention &amp; control/virology/pathology ; Aged ; Papillomaviridae/immunology ; }, abstract = {The nonavalent human papillomavirus (9vHPV) vaccine protects against HPV infection and high-grade squamous intraepithelial lesions (HSIL) when administered prior to exposure, but evidence supporting its potential therapeutic benefit has been inconsistent. This randomized, double-blind, placebo-controlled trial evaluated whether the 9vHPV vaccine reduces recurrence of HSIL or HPV persistence in 27-69-year-old persons previously treated for anal or vulvar HSIL. Participants were HSIL-free at enrollment and received 9vHPV or placebo at months 0, 2, and 6. High-resolution anoscopy or vulvoscopy was performed at months 18 and 36, and anal or vulvar swabs were collected at months 0, 18, 24, and 36 for HPV DNA detection. The primary endpoints were HSIL recurrence and HPV persistence (≥2 consecutive positive swabs for the same 9vHPV-type). Of 185 participants included in the intent-to-treat analysis, 91 received vaccine and 94 received placebo. The DSMB recommended early termination for futility. The 9vHPV vaccine was not more effective than placebo in preventing recurrent HSIL, with 16 HSIL among 9vHPV recipients versus 21 HSIL in placebo recipients (incidence 8.1 vs. 10.1/100 person-years; p = .54). HPV persistence was 21% in vaccine versus 31% in placebo recipients (p = .20). The 9vHPV vaccine delivered after treatment of anal or vulvar HSIL did not reduce HSIL recurrence or HPV detection. Our study underlines the importance of HPV vaccine administration prior to HPV exposure and the need for novel treatments for HSIL with high recurrence potential.}, }
@article {pmid41686056, year = {2026}, author = {Tam, CS and Shadman, M and Ong, SY and Wu, K and Salmi, T and Korde, R and Barnes, G and Brown, JR and Zhou, K and Qiu, L}, title = {Zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: health-related quality of life in a subgroup of Chinese patients in the ALPINE trial.}, journal = {Current medical research and opinion}, volume = {42}, number = {1}, pages = {139-146}, doi = {10.1080/03007995.2026.2623629}, pmid = {41686056}, issn = {1473-4877}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Piperidines/therapeutic use/adverse effects ; Adenine/analogs &amp; derivatives ; Female ; Male ; Middle Aged ; *Quality of Life ; *Pyrazoles/adverse effects/administration &amp; dosage/therapeutic use ; Aged ; *Pyrimidines/adverse effects/administration &amp; dosage ; Adult ; *Urea/analogs &amp; derivatives/adverse effects/administration &amp; dosage/therapeutic use ; Patient Reported Outcome Measures ; China ; Asian People ; Aged, 80 and over ; East Asian People ; }, abstract = {OBJECTIVES: Zanubrutinib demonstrated superiority to ibrutinib in the ALPINE (NCT03734016) phase 3 trial for relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). This post hoc analysis examined patient-reported outcomes (PROs) in the Chinese subgroup.<br><br>METHODS: Adults with R/R CLL/SLL and &#x2265;1 prior therapy were randomized 1:1 to zanubrutinib or ibrutinib. PROs, a secondary endpoint, were measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30. Differences between treatment arms from baseline to Cycles 7 and 13 for key PRO endpoints were assessed using a mixed model for repeated measures. Changes from baseline on the EQ visual analog scale (EQ-VAS) were examined descriptively.<br><br>RESULTS: As of February 28, 2024, 90 Chinese patients were randomized to zanubrutinib (n&#x2009;=&#x2009;47) or ibrutinib (n&#x2009;=&#x2009;43). Global health status/quality of life improved in both arms. Fatigue was reduced in both arms, with greater improvement in the zanubrutinib versus ibrutinib arm at Cycles 7 and 13. Nausea/vomiting scores generally remained unchanged, and all other symptoms showed similar improvement in both arms. Greater improvement in health status, measured by VAS score, was observed for the zanubrutinib arm at Cycle 13 (Cycle 7, 4.8 vs 4.1; Cycle 13, 5.7 vs 1.7).<br><br>CONCLUSIONS: In ALPINE, Chinese patients with R/R CLL/SLL treated with zanubrutinib showed better and faster PRO outcomes versus those treated with ibrutinib, particularly in fatigue. These results corroborate PRO findings in the intent-to-treat population and support the benefit of zanubrutinib as a valuable treatment option for Chinese patients with R/R CLL/SLL.<br><br>TRIAL REGISTRATION: NCT03734016. Registered 01 November, 2018 https://clinicaltrials.gov/study/NCT03734016.}, }
@article {pmid41686437, year = {2026}, author = {LaMonte, MJ and Hyde, ET and Nguyen, S and Castro, E and Seguin-Fowler, RA and Eaton, CB and Miller, CR and Di, C and Stefanick, ML and LaCroix, AZ}, title = {Muscular Strength and Mortality in Women Aged 63 to 99 Years.}, journal = {JAMA network open}, volume = {9}, number = {2}, pages = {e2559367}, pmid = {41686437}, issn = {2574-3805}, support = {T32 HL079891/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; Aged ; Aged, 80 and over ; Middle Aged ; Prospective Studies ; *Hand Strength/physiology ; *Muscle Strength/physiology ; *Mortality/trends ; Exercise/physiology ; Accelerometry ; Sedentary Behavior ; }, abstract = {IMPORTANCE: Muscular strength is an important resilience marker relevant to maintaining functional independence and longevity.<br><br>OBJECTIVE: To examine associations between muscular strength and mortality in women aged 63 to 99 years accounting for accelerometer-measured physical activity and sedentary behavior, systemic inflammation, and other markers of aging.<br><br>The Objective Physical Activity and Cardiovascular Health study was a prospective cohort study from baseline (March 2012 to April 2014) through February 19, 2023. Participants were ambulatory women aged 63 to 99 years who completed physical performance testing and 7 days of accelerometer wear.<br><br>EXPOSURES: Dominant hand grip strength,measured in kg by quartile (1: <14, 2: 14-19, 3: 19-24, and 4: >24) and time in seconds to complete 5 unassisted chair stands by quartile (standard criteria: 1: >16.7, 2: 16.6-13.7, 3: 13.6-11.2, and 4: &#x2264;11.1).<br><br>MAIN OUTCOME AND MEASURE: All-cause mortality.<br><br>RESULTS: The present study included 5472 women (mean [SD] age, 78.7 [6.7] years; 1851 [33.8%] Black; 915 [16.7%] Hispanic/Latina; 2706 [49.5%] White) followed up for a mean (SD) of 8.4 (2.4) years. There were 1964 deaths during the study period. Controlling for age and sociodemographic, lifestyle, and clinical factors, significant inverse trends in mortality were evident across quartiles 2 through 4 of grip strength (quartile 2: hazard ratio [HR], 0.94; 95% CI, 0.85-1.06; quartile 3: HR, 0.85; 95% CI, 0.75-0.97; quartile 4: HR, 0.67; 95% CI, 0.58-0.78; P for trend&#x2009;<&#x2009;.001) and chair stand time (quartile 2: HR, 0.79; 95% CI, 0.69-0.88; quartile 3: HR, 0.76; 95% CI, 0.67-0.87; quartile 4: HR, 0.63; 95% CI, 0.54-0.73; P for trend&#x2009;<&#x2009;.001). Further controlling simultaneously for sedentary time and moderate to vigorous physical activity attenuated associations (grip strength: quartile 2: HR, 0.95; 95% CI, 0.86-1.07; quartile 3: HR, 0.87; 95% CI, 0.76-0.99; quartile 4: HR, 0.70; 95% CI, 0.61-0.82; P for trend&#x2009;<&#x2009;.001; chair stands: quartile 2: HR, 0.82; 95% CI, 0.73-0.92; quartile 3: HR, 0.82; 95% CI, 0.71-0.93; quartile 4: HR, 0.69; 95% CI, 0.59-0.79; P for trend&#x2009;<&#x2009;.001). Similar inverse associations were observed when controlling for walking speed and the inflammatory marker C-reactive protein. Magnitudes of association did not differ across subgroups defined by age, race and ethnicity, body mass index, moderate-to-vigorous physical activity, sedentary time, or timed walk.<br><br>CONCLUSIONS AND RELEVANCE: In this study of ambulatory older women, greater muscular strength was associated with lower mortality even when controlling for accelerometer-measured PA and sedentary time, walking speed, and systemic inflammation. These findings suggest that assessing strength and promoting its maintenance are instrumental for optimal aging.}, }
@article {pmid41686454, year = {2026}, author = {Biernacki, MA}, title = {The TCXpress lane to T-cell receptor-engineered T cells.}, journal = {Blood advances}, volume = {10}, number = {4}, pages = {1233-1235}, pmid = {41686454}, issn = {2473-9537}, }
@article {pmid41686530, year = {2026}, author = {Grimm, LJ and Dodelzon, K and Bhole, S and Edmonds, CE and Mullen, LA and Parikh, JR and Daly, CP and Epling, JA and Christensen, S and Dontchos, BN}, title = {Patients Are Generally Supportive of Artificial Intelligence in Breast Imaging: A Multisite Survey of Breast Imaging Patients.}, journal = {Journal of breast imaging}, volume = {8}, number = {2}, pages = {169-177}, doi = {10.1093/jbi/wbaf066}, pmid = {41686530}, issn = {2631-6129}, support = {//Duke Health Scholars Award/ ; //Principal Investigator Lars Grimm/ ; }, mesh = {Humans ; Female ; *Artificial Intelligence ; *Breast Neoplasms/diagnostic imaging ; Middle Aged ; Surveys and Questionnaires ; United States ; Adult ; *Mammography/methods ; Health Literacy ; Aged ; Early Detection of Cancer/methods ; }, abstract = {OBJECTIVE: To understand the perspective of patients undergoing breast imaging on the use of artificial intelligence (AI) in breast cancer screening.<br><br>METHODS: A 36-item survey was administered to breast imaging patients at 6 academic and 2 private practice groups in the United States. The survey included questions regarding demographics, breast imaging history, and electronic health literacy. Respondents were asked Likert scale questions on the role of AI in breast cancer screening, the role of AI as an independent or complementary reader, and concerns regarding AI in breast imaging.<br><br>RESULTS: The survey yielded 3532 responses, a response rate of 69.9% (3532/5053). The median age was 55.9 years (SD, 12.3 years), and most respondents were White (73.0%, 2679/3532). Respondents indicated support for the role of AI to identify suspicious findings (70.6%, 2492/3532), triage findings for review (69.5%, 2382/3532), calculate breast density (73.2%, 2588/3532), and estimate breast cancer risk (61.9%, 2186/3532). Significantly higher support was noted among patients who were White, had more education, and had greater health literacy (all P <.05). There was strong agreement that it was necessary for radiologists to also review each examination (67.3%, 376/3532). Respondents were uncertain about whether AI (41.2%, 1456/3532) or radiologists (31.8%, 1124/3532) were responsible for errors. There was concern that AI will limit communication between patients and radiologists (75.7%, 2673/3532).<br><br>CONCLUSION: Breast imaging patients have an overall favorable view of AI in breast cancer screening, with variable support by demographics. Education and outreach efforts should target perceived challenges to AI adoption to improve patient acceptance.}, }
@article {pmid41686902, year = {2026}, author = {Rawat, P and Shapiro, MR and Peters, LD and Widrich, M and Mayer-Blackwell, K and Motwani, K and Pavlović, M and Al Hajj, G and Posgai, AL and Kanduri, C and Isacchini, G and Chernigovskaya, M and Scheffer, L and Motwani, K and Balzano-Nogueira, LO and Pettenger-Willey, CM and Valkiers, S and Jacobsen, LM and Haller, MJ and Schatz, DA and Wasserfall, CH and Emerson, RO and Fiore-Gartland, AJ and Atkinson, MA and Klambauer, G and Sandve, GK and Greiff, V and Brusko, TM}, title = {Identification of a type 1 diabetes-associated T cell receptor repertoire signature from the human peripheral blood.}, journal = {Science advances}, volume = {12}, number = {7}, pages = {eadx7448}, pmid = {41686902}, issn = {2375-2548}, support = {P01 AI042288/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 1/immunology/genetics/blood ; *Receptors, Antigen, T-Cell/genetics ; Male ; Female ; HLA Antigens/genetics/immunology ; Alleles ; *Receptors, Antigen, T-Cell, alpha-beta/genetics ; Adult ; Cross-Sectional Studies ; }, abstract = {Type 1 diabetes (T1D) is a T cell-mediated disease with a strong immunogenetic human leukocyte antigen (HLA) dependence. HLA allelic influence on the T cell receptor (TCR) repertoire shapes thymic selection and controls activation of diabetogenic clones yet remains largely unresolved in T1D. We sequenced the circulating TCRβ chain repertoire from 2250 HLA-typed participants across three cross-sectional cohorts, including individuals with T1D and healthy related and unrelated controls. We found that HLA risk alleles show higher restriction of TCR repertoires in individuals with T1D. We leveraged deep learning to identify T1D-associated TCR subsequence motifs that were also observed in independent TCR cohorts residing in pancreas-draining lymph nodes of individuals with T1D. Collectively, our data demonstrate T1D-related TCR motif enrichment based on genetic risk, offering a potential metric for autoreactivity and groundwork for TCR-based diagnostics and therapeutics.}, }
@article {pmid41687672, year = {2026}, author = {Mhlanga, FG and Szydlo, DW and Mayo, AJ and Bunge, K and Fairlie, L and Nakabiito, C and Musara, P and Mgodi, NM and Dadabhai, S and Scheckter, R and Anderson, PL and Marzinke, MA and Chappell, C and Gadama, LA and Richardson, BA and Piper, JM and Hillier, SL and , }, title = {Safety, acceptability, and adherence to dapivirine vaginal ring and oral pre-exposure prophylaxis for HIV prevention in the second trimester of pregnancy: a multicountry, open-label, phase 3b randomised trial.}, journal = {The lancet. HIV}, volume = {13}, number = {3}, pages = {e176-e184}, doi = {10.1016/S2352-3018(25)00307-8}, pmid = {41687672}, issn = {2352-3018}, support = {U01 AI068633/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Pregnancy ; *HIV Infections/prevention &amp; control ; Adult ; *Pre-Exposure Prophylaxis/methods ; Young Adult ; *Anti-HIV Agents/administration &amp; dosage/adverse effects/therapeutic use ; *Contraceptive Devices, Female ; Adolescent ; Pregnancy Trimester, Second ; Administration, Oral ; *Pregnancy Complications, Infectious/prevention &amp; control ; *Pyrimidines/administration &amp; dosage/adverse effects ; Uganda ; Tenofovir/administration &amp; dosage ; South Africa ; }, abstract = {BACKGROUND: Pregnant women are at a four times higher risk of HIV per coital act than non-pregnant women. MTN-042/DELIVER was a phase 3b randomised study of dapivirine vaginal ring (DVR) and oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate-emtricitabine to assess safety, adherence, and acceptability when used during pregnancy. Our hypothesis was that both DVR and oral PrEP would be safe and well tolerated when started early in the second trimester and continued until delivery.<br><br>METHODS: In MTN-042/DELIVER, an open-label, phase 3b randomised trial, healthy pregnant women without HIV and aged 18-40 years from Malawi, South Africa, Uganda, and Zimbabwe were enrolled and randomly allocated (4:1) to open-label monthly DVR PrEP or daily oral PrEP. Women were enrolled between 12 weeks' and 29 weeks' gestation. Product use continued until delivery or 42 weeks' gestation. The primary outcomes for safety following exposure to study product were a composite of all serious adverse events, including maternal deaths, all grade 3 or higher adverse events, and pregnancy outcomes stratified as term (&#x2265;37[+0] weeks), preterm (<37[+0] weeks), and pregnancy loss before 20 weeks' gestation. Pregnancy complications and adverse events were summarised with descriptive statistics. This study is registered with ClinicalTrials.gov, NCT03965923.<br><br>FINDINGS: Between July 12, 2022, and Jan 12, 2023, 251 mothers were enrolled, with 202 randomly allocated to receive DVR PrEP and 49 to receive oral PrEP. The median age was 24&#xb7;0 years (IQR 22&#xb7;0-29&#xb7;0) and the median gestational age was 23&#xb7;7 weeks (19&#xb7;9-26&#xb7;3). 28 mothers (11%) had safety events under the composite study primary outcome (all serious adverse events plus all grade 3 or higher adverse events), none of which was related to product use. No maternal deaths or HIV seroconversions occurred. There were 247 pregnancy outcomes of which 233 (94%) were at term (&#x2265;37[+0] weeks). Pregnancy complications were uncommon, and none was infectious.<br><br>INTERPRETATION: Adverse pregnancy outcomes related to DVR and oral PrEP use were uncommon among women starting PrEP in the second trimester. These findings support the use of these preventive approaches during pregnancy.<br><br>FUNDING: US National Institutes of Health.}, }
@article {pmid41688063, year = {2026}, author = {Neher, RA and Huddleston, J and Bedford, T and Lewis, NS and Harvey, R and Galiano, M and Byrne, AMP and James, S and Smith, D and Łuksza, M and Ruchnewitz, D and Laessig, M and Fujisaki, S and Watanabe, S and Hasegawa, H and Hassell, N and Wentworth, DE and Kondor, R and Deng, YM and Dapat, C and Subbarao, K and Barr, I}, title = {Nomenclature for Tracking of Genetic Variation of Seasonal Influenza Viruses.}, journal = {Influenza and other respiratory viruses}, volume = {20}, number = {2}, pages = {e70230}, pmid = {41688063}, issn = {1750-2659}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; //UK Medical Research Council/ ; /CRUK_/Cancer Research UK/United Kingdom ; }, mesh = {*Genetic Variation ; Humans ; *Influenza, Human/virology/epidemiology ; Phylogeny ; *Terminology as Topic ; *Influenza A Virus, H3N2 Subtype/genetics/classification ; *Influenza A Virus, H1N1 Subtype/genetics/classification ; *Influenza B virus/genetics/classification ; Seasons ; Genome, Viral ; Neuraminidase/genetics ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; }, abstract = {BACKGROUND: Genomic surveillance of human seasonal influenza viruses is an essential component of the Global Influenza Surveillance and Response system (GISRS) and informs the recommendations for the seasonal influenza vaccine composition. Phylogenetic analysis of viral genome sequences is used to identify groups of viruses sharing potential antigenic change, and computational models are used to predict which viral variants are likely to circulate at high levels in upcoming seasons. To facilitate discussion and reporting of genetic diversity, as well as to communicate antigen recommendations, up-to-date and sufficiently granular definitions of genetic clades are important.<br><br>METHODS: We implemented a nomenclature system for Segments 4 (haemagglutinin) and 6 (neuraminidase) of human Influenza A(H3N2), A(H1N1)pdm09, and Influenza B that dynamically adapts to the diversity of circulating viruses. New subclades were proposed by a clade suggestion algorithm based on criteria including (i) the number of sequences in the group, (ii) the distance from the direct parent clade, and (iii) the weighted number of amino acid substitutions on the branch leading to the common ancestor of the subclade.<br><br>RESULTS: Algorithmic clade proposals were reviewed and assigned a systematic hierarchical label consisting of a leading letter, followed by numbers (e.g., G.1.3). Names are kept short by aliasing that is collapsing prefixes into unique letters. Subclade definitions are shared openly to promote adoption and tool development. Nextclade is supporting this new nomenclature, and it is being used routinely by the GISRS network.<br><br>CONCLUSIONS: With increasing genomic surveillance, the need for up-to-date classification schemes is growing and we hope that the current dynamic proposal will adapt to growing data volumes and aid in simplifying the interpretation of these data.}, }
@article {pmid41688657, year = {2026}, author = {Tjader, NP and Ramroop, J and Gandhi, T and Dauch, C and Meadows, O and Stevens, P and Pearlman, R and Hampel, H and Aglago, EK and Berndt, SI and Bloomer, A and Brenner, H and Buchanan, DD and Campbell, PT and Cao, Y and Chan, AT and Cheng, I and Dimou, N and Drew, DA and French, AJ and Georgeson, P and Giannakis, M and Giles, GG and Gomez, M and Gruber, SB and Hoffmeister, M and Huang, WY and Hullar, MAJ and Huyghe, JR and Loroña, N and Moreno, V and Newton, CC and Nowak, JA and Obón-Santacana, M and Ogino, S and Pellatt, A and Peoples, AR and Permuth, JB and Schmit, SL and Schoen, RE and Siegel, EM and Steinfelder, RS and Sun, W and Teer, JK and Thomas, CE and Trinh, QM and Tsilidis, K and Ugai, T and Um, CY and Van Guelpen, B and Zaidi, SH and Figueiredo, J and Peters, U and Phipps, AI and McElroy, JP and Toland, AE}, title = {Association of germline variants with KRAS-mutation status in colorectal cancer.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41688657}, issn = {2045-2322}, support = {Pelotonia Postdoctoral Fellowship//Pelotonia/ ; U54 HG003067/HG/NHGRI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; Investigator Initiated Grant//American Institute for Cancer Research/ ; R50 CA274122/NH/NIH HHS/United States ; Undergraduate Research Fellowship//Pelotonia/ ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; R50 CA274122/CA/NCI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA155101/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; R01 CA176272/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; Faculty Career Development Award//Brigham and Women's Hospital/ ; R01 CA81488/NH/NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; Pelotonia Graduate Research Fellowship//Pelotonia/ ; CRP-24-1185864-01-PROF//American Cancer Society/ ; UM1 CA167552/CA/NCI NIH HHS/United States ; R01 CA155101/NH/NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; R01 CA248857/NH/NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA215151/CA/NCI NIH HHS/United States ; R01 CA81488/NH/NIH HHS/United States ; R01 CA248857/NH/NIH HHS/United States ; R50 CA274122/NH/NIH HHS/United States ; R01 CA155101/NH/NIH HHS/United States ; R01 CA215151/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/pathology ; *Germ-Line Mutation ; *Proto-Oncogene Proteins p21(ras)/genetics ; Male ; Female ; Middle Aged ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Aged ; Genetic Predisposition to Disease ; Adult ; }, abstract = {Somatic mutations in KRAS are a common driver of colorectal cancer (CRC) and present at different frequencies by race, sex, tumor site, ethnicity, and genetic similarity. Inherited germline variants may influence tumor somatic mutation frequency by altering mutation or DNA repair processes or altering cellular, immunological and/or microenvironmental responses after a mutation. We hypothesized that the germline genetic background modifies somatic KRAS mutation frequency in CRC. To test this, we performed a genome-wide association study (GWAS) in 7071 individuals with CRC, using KRAS mutation status as the phenotype. Single-nucleotide variants were chosen for validation analyses based on P values from the discovery GWAS, predicted in silico functional effects, and proximity to genes with potential cancer relevance. A validation analysis of 101 SNVs of interest was performed in 2482 individuals. No SNVs were significantly associated with KRAS-mutant CRC (P value < 0.0005). One variant rs73067863-T showed a non-significant exploratory association with fewer KRAS-mutant tumors in the combined sample (P value = 9.7 × 10[-7], OR = 0.75). Follow-up studies are needed to determine if these or other germline variants impact population differences in KRAS mutations in CRC.}, }
@article {pmid41689800, year = {2026}, author = {La, C and Detavernier, A and Papadopoulou, M and Sanchez Sanchez, G and Martens, V and Thomas, S and Nguyen, M and Acolty, V and Melchior, M and Venturoli, D and de Toeuf, B and Azouz, A and Rezwani, M and Tafesse, Y and Verdebout, I and Rongvaux, A and Boehme, L and Taghon, T and Venken, K and Elewaut, D and Goriely, S and Vermijlen, D}, title = {In vivo modeling of human γδ T cell ontogeny reveals terminal deoxynucleotidyl transferase as a key regulator of type 3 Vδ2 T cell development.}, journal = {Cell reports}, volume = {45}, number = {2}, pages = {116977}, doi = {10.1016/j.celrep.2026.116977}, pmid = {41689800}, issn = {2211-1247}, mesh = {Humans ; Animals ; *Receptors, Antigen, T-Cell, gamma-delta/metabolism ; Mice ; *DNA Nucleotidylexotransferase/metabolism ; Mice, Inbred NOD ; *T-Lymphocytes/immunology ; Hematopoietic Stem Cells/cytology ; Cell Differentiation ; }, abstract = {Profound differences in T cell receptor (TCR) repertoire and functional profiles between human and murine γδ T cells pose significant challenges for translational γδ T cell research. Therefore, we generated humanized immune system (HIS) NBSGW (NOD,B6.Prkdc[scid]Il2rγ[-/-]Kit[W41/W41]) mice reconstituted with human fetal liver CD34[+] hematopoietic stem and progenitor cells (HSPCs) enabling evaluation of human γδ T cells in vivo. The HIS mice accurately recapitulate the TCR-associated thymic programming of human γδ T cells-alongside αβ T cell development-and their peripheral effector functions, including the generation of phosphoantigen-reactive Vγ9Vδ2 T cells uniquely found in humans. Moreover, terminal deoxynucleotidyl transferase (TdT) is identified as a key regulator of type 3 Vδ2 T cell development. These findings demonstrate that HIS mice are a powerful model to screen human γδ T cell-targeting immunotherapies and to obtain mechanistic insights into human γδ T cell biology.}, }
@article {pmid41690558, year = {2026}, author = {Meyer, J and Zoberi, JE and Kim, H and Tran, A and Lowenstein, JR and Al-Hallaq, HA}, title = {A National Survey of Medical Physicists: Part 1-Practice Patterns for High-Dose-Rate Brachytherapy.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2026.01.044}, pmid = {41690558}, issn = {1879-355X}, abstract = {PURPOSE: High-dose-rate (HDR) brachytherapy (BT) is an effective but resource-intensive treatment modality, demanding a highly skilled workforce, team coordination, and logistics. This study presents findings from a comprehensive national survey conducted in 2023, targeting all registered IROC-Houston (Imaging and Radiation Oncology Core) sites in the United States.<br><br>METHODS AND MATERIALS: The primary objective was to analyze national BT practice patterns and workload dynamics among medical physicists involved in HDR BT treatments. A secondary aim, explored in a companion publication (part 2), examines work effort, job satisfaction, and challenges faced by medical physicists in this field.<br><br>RESULTS: The survey received 365 complete responses, revealing an experienced workforce, with 71% reporting over 10 years of BT service and 75% performing complex gynecologic treatments involving more than 3 channels. Two-thirds of respondents were employed at nonacademic institutions, and 53% indicated that the medical physics full-time equivalent was <1 at their clinic. The most frequently performed procedure was gynecologic BT (96%), followed by skin (34%), prostate (33%), and breast (23%). Adoption of advanced planning tools was variable, with 66% using inverse planning and 34% employing automatic catheter reconstruction. Additionally, 32% of all respondents performed magnetic resonance imaging (MRI) based planning, with 14% reporting frequent use. Of the subgroup performing complex gynecologic treatments, 38% reported the utilization of MRIs. Uptake of MRI-based planning appears to have increased only slightly over the past decade.<br><br>CONCLUSIONS: The survey demonstrated that medical physicists are involved in and responsible for nearly every technical aspect of the HDR BT process. This study presents one of the largest national surveys on medical physics practice patterns to date. The findings highlight ongoing challenges in allocating resources, varying procedure complexity, and logistical demands. Future initiatives should focus on developing improved resource allocation metrics to optimize staffing based on procedure complexity and caseload.}, }
@article {pmid41691093, year = {2026}, author = {Stephan, SB and Cummings, CL and Fitzgerald, K and Stephan, MT}, title = {Drinkable gene therapy foam for the treatment of constrictive esophageal carcinoma.}, journal = {Gene therapy}, volume = {33}, number = {2}, pages = {118-126}, pmid = {41691093}, issn = {1476-5462}, mesh = {*Genetic Therapy/methods ; *Esophageal Neoplasms/therapy/genetics ; Humans ; Animals ; Cell Line, Tumor ; Mice ; Nanoparticles/chemistry ; Apoptosis ; *Esophageal Stenosis/therapy ; }, abstract = {Patients diagnosed with esophageal cancer (EC) currently rely on treatments given at specialist care centers (surgery, chemotherapy, radiation), which despite their low cure rates are extremely life-disruptive, cause severe pain, and have strong side effects. In particular, dysphagia is one of the most distressing and debilitating symptoms in patients with cancer-related esophageal obstruction. There is clearly an urgent need for new effective and accessible therapies for EC patients that allow patients to continue normal activity as much as possible. Here, we describe a drinkable methylcellulose/xanthan gum-based gene therapy foam that coats the esophagus and accumulates an apoptosis-inducing gene therapy drug (mRNA lipid nanoparticles encoding Pseudomonas exotoxin A) at the tumorous esophageal stricture. In an in vitro EC tissue model, we show that gene therapy foam induces 110-fold higher tumor regression compared to suspension treatment. We also establish that gene therapy foam given prior to radiotherapy strongly enhances anti-tumor effects. Once implemented in the clinic, this treatment, which can be administered orally by a local family doctor or at home by the patient or caregiver, could maximize the time EC patients can live normal lives outside of the hospital and allow them to maintain their ability to swallow and eat.}, }
@article {pmid41691096, year = {2026}, author = {Bouley, C and Fang, M and Radich, J and Yeung, CC and Campbell, J and Kroeger, K and Beppu, L and Mielcarek, M and Storb, R and Ueda Oshima, M}, title = {Donor-derived del[20q] following allogeneic-hematopoietic cell transplantation: a case with 26-year follow-up and literature review.}, journal = {Bone marrow transplantation}, volume = {61}, number = {4}, pages = {445-451}, pmid = {41691096}, issn = {1476-5365}, support = {CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; CA175008, CA233338, CA233381//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; PO1 78902//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Follow-Up Studies ; Male ; *Chromosome Deletion ; *Tissue Donors ; Adult ; Allografts ; Female ; Transplantation, Homologous ; Middle Aged ; }, abstract = {Donor-derived cytogenetic abnormalities are a rare finding following allogeneic hematopoietic cell transplantation. Deletion of the long arm of chromosome 20 [del(20q)] is one of the more frequently observed structural abnormalities, but its significance in the post-transplant setting remains unclear. We describe a unique case of donor-derived del(20q) with 26 years of post-transplant follow-up, the longest reported to date. The recipient remains well with normal blood counts despite persistent del(20q) in both myeloid and lymphoid lineages and the presence of coexisting somatic mutations in DNMT3A and TP53. Retrospective analysis of the donor's marrow confirmed del(20q) and low-level DNMT3A and TP53 mutations at the time of transplant; the donor later developed therapy-related MDS after radiation therapy for thyroid cancer. To contextualize this case, we reviewed 20 published reports of donor-derived del(20q) post-transplant. The median time to detection was 16 months post-transplant, and 35% of cases progressed to donor-derived malignancy. Among those who progressed, the median time to malignancy diagnosis was 22 months post-transplant. Clinical outcomes across cases ranged from asymptomatic persistence and cytopenias to donor-derived myeloid malignancies, highlighting the need for long-term follow-up and potential use of molecular profiling to better define the neoplastic potential of donor-derived del(20q) after transplantation.}, }
@article {pmid41695294, year = {2026}, author = {Yorke, AA and Muramuzi, A and Lin, LL and Awusa, K and Kibudde, S and Twum, PT and Yorke, CK and Ford, EC}, title = {Quantifying cervical cancer radiotherapy care gap: Baseline assessment prior to implementation of a digital Health App.}, journal = {Technical innovations &amp; patient support in radiation oncology}, volume = {37}, number = {}, pages = {100381}, pmid = {41695294}, issn = {2405-6324}, abstract = {PURPOSE: Sub-Saharan Africa accounts for over one-third of global cervical cancer deaths, despite representing only 14% of the world's female population. Radiotherapy (RT) services are essential in the treatment of cervical cancer, and the Uganda Cancer Institute (UCI) is the only oncology center with RT in a country of 50 million. Prior studies show most of the cervical cancer (CxCa) patients do not complete RT within the recommended timeframe of 6-8 weeks, and some miss their brachytherapy boost. This study analyzes care gaps to establish a baseline before implementing a digital health patient navigation app GLOCASSA.<br><br>METHODOLOGY: We quantified radiotherapy care gaps among 104 cervical cancer patients (FIGO IB-IIIC) treated at the UCI between 2023 and 2024, representing 13% of the annual patient volume ethical approval was obtained. A mixed-methods approach was employed, combining retrospective review of radiotherapy charts with a custom mathematical framework for care gap assessment. Patient timelines were reconstructed from consultation through CT simulation, treatment initiation, completion, and follow-up, across three external beam radiotherapy regimens (45&#xa0;Gy/15 fractions; 50&#xa0;Gy/25 fractions; 50.4&#xa0;Gy/28 fractions). We developed a Radiotherapy Care Gap (RCG) model incorporating professional benchmarks (ASTRO, ACR, ARS) to quantify delays, weighted by their clinical importance. Scores were normalized to reflect adherence (<1 expedited/incomplete; =1 standard; >1 delayed). Geospatial analyses were performed using ArcGIS Pro to measure travel distance from patient residence to UCI.<br><br>RESULTS: Among 104 cervical cancer patients treated with three EBRT regimens followed by brachytherapy, biologically equivalent doses were comparable across schedules (EQD2 &#x2248; 85-86&#xa0;Gy). However, treatment completion within the recommended 6-8&#xa0;weeks was rare, with on-time completion rates of 11% or lower at 6&#xa0;weeks and&#xa0;&#x2264;&#xa0;17% at 8&#xa0;weeks. The majority of patients had Radiotherapy Care Gap Scores (RCGS)&#xa0;>&#xa0;1, indicating significant delays, while only a small fraction achieved timely care (RCGS&#xa0;<&#xa0;1). Extreme delays were observed, with some patients requiring over 30&#xa0;weeks to complete therapy. Most patients (58%) were treated with 2D/3D techniques, though delays persisted across all modalities. Geospatial analysis showed a median travel time of 4&#xa0;h to the radiotherapy center, and more than half of patients (53%) missed the recommended 6-week follow-up visit, highlighting substantial geographic and continuity-of-care barriers.<br><br>CONCLUSION: Our findings suggest that patient navigation and follow-up support are major unmet needs. Digital health platforms that provide real-time reminders, enable remote symptom reporting, and facilitate coordination between patients and care teams offer promising solutions. Future directions include the implementation of the GLOCASSA-App as a targeted intervention to mitigate identified care gaps.}, }
@article {pmid41695969, year = {2026}, author = {Bazzell, AF and Madsen, LT and Bandini, L and Harrington, T and Siman, J and Stein, CE and Greenlee, H and Fleming, JB and Huffman, A}, title = {Integrative Oncology Models of Care: Practice Patterns From NCCN Member Institutions.}, journal = {Journal of the advanced practitioner in oncology}, volume = {}, number = {}, pages = {1-10}, pmid = {41695969}, issn = {2150-0878}, support = {P30 CA142543/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Patients with cancer frequently desire to incorporate integrative oncology (IO) practices into their care. However, patients are often uncertain about how to best access safe and effective IO practices and providers. The National Comprehensive Cancer Network (NCCN) Best Practices Committee (BPC), in collaboration with a National Cancer Institute (NCI)-Designated Comprehensive Cancer Center, sought information regarding IO practices of NCCN Member Institutions.<br><br>METHODS: The BPC conducted a survey of NCCN Member Institution IO practices, which was distributed via a web-based survey tool to a representative at each center. Results were compiled using descriptive statistics.<br><br>RESULTS: Twenty-nine centers responded to the survey, with 100% of the responding institutions offering IO services. Services provided included nutritional/dietary services (97%), stress and anxiety management services (76%), mind-body practices (72%), physical therapy/occupational therapy (72%), acupressure/acupuncture (69%), and massage therapy (59%). While the mechanism for patient access varied, the most common was provider referral with some services available by self-scheduling. Twenty-one percent of centers used institutionally designed algorithms for referrals. Significant variation in funding for services existed between institutions, including combinations of self-pay, insurance-based, and philanthropically funded models.<br><br>CONCLUSIONS: There was substantial variation in how NCCN Member Institutions deliver IO services. These results provide guidance for health-care organizations seeking to develop IO services and an opportunity to align best practices. As data were compiled solely from sites providing comprehensive cancer services, non-academic community settings may find similar implementation challenging. However, this information provides cancer providers insight into IO services most often sought by patients with cancer.}, }
@article {pmid41697969, year = {2026}, author = {Rutter, CM and Maerzluft, CE and Matrajt, L and Nascimento de Lima, P and Issaka, RB and Marsh, TL}, title = {CRC-SPIN version 3.0: an updated policy model for colorectal cancer screening that includes the serrated pathway.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag037}, pmid = {41697969}, issn = {1460-2105}, abstract = {BACKGROUND: Microsimulation models use empirical evidence about cancer epidemiology and screening test performance to predict the long-term effectiveness of screening regimens and are essential for developing cancer screening guidelines. Colorectal cancer (CRC) provides a clear example. CRC arises through two pathways, the adenoma-carcinoma pathway and the serrated pathway. Sessile serrated lesions (SSLs) are the primary serrated precursor lesion. SSLs are more difficult to detect and remove than adenomas.<br><br>METHODS: We describe version 3.0 of the Colorectal Cancer Simulated Population model for Incidence and Natural history (CRC-SPIN), which adds new information about the serrated pathway and CRC risk in adults under 50, then estimate the effectiveness of decennial colonoscopy from 45 to 75 years old. The model was calibrated using a Bayesian approach to estimate 95% credible intervals (CIs) that reflect uncertainty in predictions.<br><br>RESULTS: The model validated well to studies of the effect of one-time screening and outcomes from surveillance colonoscopy. In the absence of screening, SSLs accounted for 10.6% (95% CI: 3.3-21.6) of CRC, increasing to 23.5% (95% CI: 7.7%-46.0%) with screening due to selective removal of adenomas. Screening was predicted to prevent 93.9% (95% CI: 92.0%-94.3%) of CRC and 95.3% (95% CI: 93.8%-96.5%) of CRC mortality.<br><br>CONCLUSIONS: Although SSLs are less common than adenomas, they likely make up a large fraction of CRC that arises in people who participate in screening. This points to the importance of improving the ability to detect SSLs, especially large SSLs, at colonoscopy.}, }
@article {pmid41697970, year = {2026}, author = {Pocobelli, G and Del Vecchio, NJ and Cushing-Haugen, K and Kamineni, A and Corley, DA and Rendle, KA and Halm, EA and Li, CI and Oshiro, CES and Carroll, NM and Silver, MI and Greenlee, RT and Neslund-Dudas, C and Breslau, ES and Chubak, J}, title = {Up-to-date prevalence at recommended ages for discontinuing routine colorectal, cervical and lung cancer screening.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag044}, pmid = {41697970}, issn = {1460-2105}, abstract = {Cancer screening guidelines specify ages at which routine screening should be discontinued and, except for cervical cancer screening, do not require specific screening history criteria be met for discontinuation. We estimated the prevalence of being up to date with average-risk screening guidelines for colorectal, cervical, and lung cancer as of the recommended ages for discontinuation of routine screening. We conducted a descriptive study among several U.S. healthcare systems during 2010-2019. Up-to-date screening prevalence, based on U.S. Preventive Services Task Force guidelines, was ascertained prior to 76th, 66th, and 81st birthdays among persons eligible for colorectal (N = 316,756 persons), cervical (N = 20,282 persons), and lung cancer (N = 1,151 persons) screening, respectively. Up-to-date screening prevalence was 84.4% for colorectal, 58.9% for cervical, and 6.3% for lung cancer screening. Up-to-date screening prevalence at the ages recommended for discontinuing routine colorectal, cervical, and lung cancer screening varied appreciably, and was particularly low for lung cancer screening.}, }
@article {pmid41697987, year = {2026}, author = {Chhetri, R and Modi, ND and Menz, BD and Cornelisse, E and Postma, D and Kuderer, NM and Lyman, GH and Swain, SM and Li, LX and Abuhelwa, AY and McKinnon, RA and Vatandoust, S and Kichenadasse, G and Rowland, A and Sorich, MJ and Hopkins, AM}, title = {Sex-based prognosis in industry-sponsored advanced solid tumour trials: an individual participant data meta-analysis of survival and adverse events.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag046}, pmid = {41697987}, issn = {1460-2105}, abstract = {BACKGROUND: Sex is a recognised modifier of physiology, immunity, and social exposures, yet its independent association with survival and adverse event (AE) prognosis in contemporary anticancer therapy remains poorly defined. The aim of the present study was to assess the association between patient sex and OS, PFS, and grade ≥3 AEs across a pooled individual participant data (IPD) meta-analysis.<br><br>METHODS: IPD supporting FDA approval of anticancer medicines for solid tumours between 2011 and 2021 were accessed via the Vivli and YODA data sharing platforms. A two-stage random-effects meta-analysis approach was employed, using Cox proportional hazards regression to estimate sex-based prognostic differences in overall survival (OS), progression-free survival (PFS), and grade &#x2265;3 AEs. Analyses were adjusted for key baseline covariates.<br><br>RESULTS: In a pooled cohort of 20,806 participants from 39 phase II-III trials supporting US FDA approvals of anticancer medicines for advanced solid tumours, across 12 tumour types, female sex was associated with significantly improved OS (HR 0.79, 95% CI 0.73-0.85; P&#x2009;<&#x2009;0.001) and PFS (HR 0.84, 95% CI 0.79-0.89; P&#x2009;<&#x2009;0.001). Conversely, females experienced a higher risk of grade &#x2265;3 AEs (HR 1.12, 95% CI 1.07-1.18; P&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: In the largest analysis of IPD from trials supporting FDA drug approvals, we found that females had a 21% lower risk of death and a 16% lower risk of progression, but a 12% higher risk of severe adverse events. These findings highlight the value of the IPD sharing and the importance of sex-stratified evidence for risk stratification, dose optimisation and patient counselling.}, }
@article {pmid41697998, year = {2026}, author = {Huang, BZ and Chen, F and Bogumil, D and Han, S and Paik, A and Wan, P and Sheng, X and Siegmund, KD and Peters, U and VoPham, T and Wang, L and Alderete, T and Salhia, B and Lenz, HJ and Stram, DO and Wilkens, LR and Le Marchand, L and Conti, DV and Haiman, CA}, title = {Interaction of genetic and lifestyle risk scores on colorectal cancer risk across five racial and ethnic populations.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag045}, pmid = {41697998}, issn = {1460-2105}, support = {R01 ES035035/ES/NIEHS NIH HHS/United States ; R01 ES035056/ES/NIEHS NIH HHS/United States ; }, abstract = {BACKGROUND: Integrating genetic and lifestyle information has the potential to greatly improve the prediction of colorectal cancer (CRC) risk. However, racial and ethnic minorities are generally underrepresented in gene-environment studies of CRC risk.<br><br>METHODS: We investigated the interplay of genetics and lifestyle on CRC risk in a prospective analysis of 68,397 African American, Japanese American, Latino, Native Hawaiian, and White individuals from the Multiethnic Cohort Study. Genetic predisposition was assessed using a 205-variant polygenic risk score (PRS). Lifestyle was assessed using a lifestyle risk score based on smoking, alcohol consumption, body mass index, physical activity, and diet. The independent and joint associations of the PRS and lifestyle risk score on CRC risk were evaluated using Cox regression.<br><br>RESULTS: We identified 1,303 incident CRC cases (median 15.1-year follow-up). The highest quintile of the PRS was associated with a 2.4-fold increase in CRC risk compared to the lowest quintile (HRQ5vQ1 2.40, 95% CI 1.99-2.89). The highest quintile of the lifestyle risk score was associated with a 54% increased risk (HRQ5vQ1 1.54, 95% CI 1.26-1.88). This association was stronger among those with high genetic risk (PRS&#x2265;50%) (HRQ5vQ1 1.82, 95% CI 1.41-2.35) and non-significant among those with low genetic risk (PRS<50%) (HRQ5vQ1 1.20, 95% CI 0.88-1.64; p-interaction=0.01). Results were similar across race and ethnicity.<br><br>CONCLUSIONS: Our study suggests that lifestyle modification may offer greater risk reduction among those at higher genetic risk. Future research is warranted to enhance the integration of genetics and lifestyle in CRC risk stratification and screening approaches across populations.}, }
@article {pmid41698311, year = {2026}, author = {Heng, F and Magaret, CA and Rouphael, NG and Branche, AR and Fong, Y and Carpp, LN and Yu, C and Chen, S and Zhang, B and Diemert, DJ and Falsey, AR and Graciaa, DS and Baden, LR and Frey, SE and Whitaker, JA and Little, SJ and Kamidani, S and Walter, EB and Novak, RM and Rupp, R and Jackson, LA and Babu, TM and Kottkamp, AC and Luetkemeyer, AF and Immergluck, LC and Presti, RM and Bäcker, M and Winokur, PL and Mahgoub, SM and Goepfert, PA and Fusco, DN and Atmar, RL and Posavad, CM and Mu, J and Makowski, M and Makhene, MK and Nayak, SU and Simon, V and van Bakel, H and Roberts, PC and Gilbert, PB and , }, title = {The neutralizing antibody titer correlate of COVID-19 risk in the COVID-19 variant immunologic landscape (COVAIL) trial was not modified by SARS-CoV-2 amino acid sequence distances.}, journal = {Vaccine}, volume = {76}, number = {}, pages = {128348}, pmid = {41698311}, issn = {1873-2518}, support = {R37 AI054165/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/blood/immunology ; *COVID-19/immunology/prevention &amp; control/epidemiology/virology ; *SARS-CoV-2/immunology/genetics ; *Antibodies, Viral/blood/immunology ; *Spike Glycoprotein, Coronavirus/immunology/genetics/chemistry ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Female ; Male ; Amino Acid Sequence ; Middle Aged ; Immunization, Secondary ; United States/epidemiology ; Adult ; }, abstract = {In the Coronavirus Variant Immunologic Landscape Trial (COVAIL) conducted in the United States in 2022-2023, 985 participants received a second COVID-19 booster with one of twelve monovalent or bivalent mRNA inserts. Pseudovirus serum inhibitory dilution 50% neutralizing antibody titer (nAb titer) measured two-weeks post booster significantly associated with lower COVID-19 incidence over six months follow-up in this trial. COVAIL investigators sequenced SARS-CoV-2 Spike amino acid sequences for all COVID-19 cases, with a sequence successfully obtained from 129 of 195 cases. For COVID-19 endpoint cases we calculated five distances of the case-causing sequence to a reference sequence, the first two physico-chemical weighted Hamming distances of Spike or receptor binding domain (RBD) to a participant's nearest Spike or RBD vaccine-insert sequence, and the other three estimated degrees of neutralizing antibody escape from the XBB.1.5 RBD strain calculated with deep mutational scanning. Hypothesizing that the nAb titer correlate of risk may have a stronger association with COVID-19 when focusing on COVID-19 infections more closely matched to the vaccine insert in Spike or RBD amino acid sequence or with lower RBD antibody escape score, we tested this hypothesis for the combined group receiving a monovalent Prototype (ancestral strain) booster (n = 143) and for the combined group receiving an Omicron-containing booster (n = 744). For both combined groups, the nAb titer correlate of risk did not significantly vary across any of the assessed sequence distances from the vaccine insert (all p-values >0.10), although RBD Hamming distance had point estimates consistent with a weakening correlate with distance, motivating further exploration in settings with greater antigenic heterogeneity. Indeed, statistical power was bounded by the limited antigenic variability of viruses infecting trial participants over the follow-up period (April 21, 2022 to May 25, 2023), which spanned only a 3.02-fold nAb titer range of differential sensitivity to sera from XBB.1.5-infected individuals. ClinicalTrials.gov Identifier: NCT05289037.}, }
@article {pmid41698677, year = {2026}, author = {de la Calle, CM and Baras, AS and Lotan, TL}, title = {Digital pathology-based artificial intelligence algorithms in prostate cancer: inside the 'black box'.}, journal = {BJU international}, volume = {137}, number = {4}, pages = {596-604}, doi = {10.1111/bju.70164}, pmid = {41698677}, issn = {1464-410X}, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/diagnosis ; *Artificial Intelligence ; *Algorithms ; Prognosis ; }, abstract = {Artificial intelligence (AI) algorithms leveraging digital pathology slides are currently transforming the way urological cancers are diagnosed and graded, and they add additional prognostic, predictive and molecular subtyping information beyond traditional pathological risk stratification. This review explores recent advances in histopathology-based AI systems for prostate cancer. We examine how these algorithms perform relative to pathologists for tumour diagnosis and grading, and the ways in which they surpass pathologists with respect to reducing inter-observer variability and providing quantified tumour metrics. We particularly focus on prognostic algorithms that have been benchmarked against 'gold standard' patient outcomes such as metastasis or death, and we highlight the emerging role of digital pathology-enabled AI for predicting response to therapy or underlying tumour molecular alteration status. Finally, we touch on the advantages of, and barriers to, implementation of digital pathology and histopathology-based AI algorithms in clinical practice. Through this synthesis of current literature, we underscore the emerging potential of AI for standardising pathological assessment, guiding clinical management, and improving patient outcomes in prostate cancer.}, }
@article {pmid41700320, year = {2026}, author = {Smith, D and Weir, IR and Ramirez, S and Coelho, CH and Manne-Goehler, J and Aziz, M and Benson, CA and Wu, X and Hyer, R and Dhillon, PK and Faraji, F and Bloom, N and Myers, A and Ramezani-Rad, P and Lopez, PG and Parikh, UM and Heaps, AL and Javan, AC and Bender Ignacio, RA and Li, JZ and Greninger, AL and Daar, ES and Wohl, DA and Crotty, S and Sieg, SF and Chew, KW}, title = {Impact of COVID-19 Monoclonal Antibody Therapy on Subsequent Vaccine-elicited SARS-CoV-2 Immune Responses.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiag091}, pmid = {41700320}, issn = {1537-6613}, support = {UM1 AI069424/AI/NIAID NIH HHS/United States ; UM1 AI069432/AI/NIAID NIH HHS/United States ; UM1 AI068634/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; U54 CA267776/CA/NCI NIH HHS/United States ; UM1 AI106701/AI/NIAID NIH HHS/United States ; U01 AI069424/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: How anti-SARS-CoV-2 monoclonal antibodies (mAbs) change subsequent vaccine responses remains uncertain.<br><br>METHODS: We conducted a prospective, phase IV, open-label study of adults who received mRNA-1273 or BNT162b2. Cohort 1 included outpatients with acute COVID-19 previously randomized to mAbs (tixagevimab/cilgavimab or amubarvimab/romlusevimab), camostat, or placebo in ACTIV-2/A5401. Cohort 2 included unvaccinated adults without reported prior COVID-19 and was analyzed as na&#xef;ve or non-na&#xef;ve by baseline neutralizing antibodies (nAbs). We measured binding IgG, nAbs, spike-specific memory B cells, and CD4+/CD8+ T cells at baseline and days 28, 56, and 140.<br><br>RESULTS: Forty-three participants were analyzed. At day 140, nAb titers were lower among prior mAb recipients and COVID-19-na&#xef;ve participants than among placebo/camostat recipients and those with evidence of prior infection (overall p=0.018). RBD-specific, but not spike-specific, memory B cells were reduced after prior mAb therapy at days 56 and 140. Frequency of spike-specific CD4+ and CD8+ T-cell responses did not differ by prior mAb exposure. Adverse events were mostly grade 1-2 and consistent with vaccine trials.<br><br>CONCLUSIONS: Prior anti-SARS-CoV-2 mAb treatment limits endogenous RBD-focused B-cell responses to later mRNA vaccination without measurably affecting T-cell immunity. Timing of vaccination after mAb therapy may matter and warrants study.<br><br>TRIAL REGISTRATION: NCT04952402.}, }
@article {pmid41701126, year = {2026}, author = {Carter, JA and Dickerson, LK and Stephanou, A and Damle, SR and Goodsell, KE and Daniel, SK and Sullivan, KM and Shui, B and Jiang, X and Kenerson, HL and van den Bijgaart, RJE and Farghli, AR and Liu, Y and Beirne, E and Labadie, KP and Cernak, J and Chauhan, SSB and Bello Pineda, JM and Long, AN and Elz, AE and Newell, EW and Kim, TS and Riehle, KJ and Yeung, RS and Akilesh, S and Crispe, IN and Barry, KC and Sethupathy, P and Pillarisetty, VG}, title = {Overcoming CXCR4-Mediated T-Cell Exclusion Potentiates Antitumor Cytotoxicity in Fibrolamellar Carcinoma.}, journal = {Gastroenterology}, volume = {170}, number = {4}, pages = {787-802}, doi = {10.1053/j.gastro.2025.10.006}, pmid = {41701126}, issn = {1528-0012}, mesh = {Humans ; *Receptors, CXCR4/antagonists &amp; inhibitors/metabolism/immunology ; *Liver Neoplasms/immunology/pathology/genetics/drug therapy ; Tumor Microenvironment/immunology/drug effects ; *Carcinoma, Hepatocellular/immunology/genetics/pathology/drug therapy ; *T-Lymphocytes/immunology/drug effects/metabolism ; Immune Checkpoint Inhibitors/pharmacology/therapeutic use ; Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors/metabolism/immunology ; Signal Transduction ; *Lymphocytes, Tumor-Infiltrating/immunology/drug effects/metabolism ; Myofibroblasts/immunology/metabolism ; Female ; Cell Line, Tumor ; Chemokine CXCL12/metabolism ; Male ; *Tumor Escape/drug effects ; }, abstract = {BACKGROUND &amp; AIMS: Fibrolamellar carcinoma (FLC) is a rare liver cancer affecting young adults without underlying cirrhosis. Although almost all FLC patients share an immunogenic DNAJB1-PRKACA fusion oncogene, endogenous antitumor immunity and clinical response to immunotherapy are limited. We hypothesized that the lack of response to immunotherapy is mediated by both T-cell exclusion and intratumoral immunosuppression.<br><br>METHODS: We used high-throughput single-nucleus RNA sequencing to explore the tumor immune microenvironment (TIME) of FLC. We then used multiplex immunohistochemistry, live imaging, single-cell sequencing, and spatial proteomics in a human tumor slice culture (TSC) system to dissect and experimentally modulate the FLC TIME.<br><br>RESULTS: We identified significant dysregulation of stromal-immune signaling pathways within the FLC TIME relative to adjacent nontumor liver, notably including interactions between CXCL12[+] myofibroblasts and CXCR4[+] lymphocytes. CXCR4 inhibition was sufficient to mobilize stromal T cells into the carcinoma compartment, with the addition of PD-1 blockade independently activating T-cell antitumor effector function. Combination CXCR4 and PD-1 blockade resulted in a significant increase in tumor cell death relative to either treatment alone in a human TSC model.<br><br>CONCLUSIONS: Our findings demonstrate that immune resistance in FLC is mediated by both local T-cell exclusion and exhaustion, with combination CXCR4 and PD-1 blockade acting cooperatively to overcome these independent mechanisms. These results highlight the versatility of the human TSC system to aid in the study of rare cancer types and provide important preclinical evidence for the rational design of combination immunotherapy in FLC, which currently lacks any effective systemic therapy.}, }
@article {pmid41701629, year = {2026}, author = {Emamekhoo, H and Riaz, IB and Martin, DB and Gabriel, PE and Shah, NJ and Bruckner, L and Arafat, W and Fu, P and Freimuth, RR and Liebovitz, DM and Stillman, RC and Stapp, RT and Perkins, RM and Sugalski, J and Heinrichs, T and Tevaarwerk, AJ}, title = {Deriving wisdom from data: The value and continued rationale for structured data in the era of artificial intelligence-driven oncology care.}, journal = {Cancer}, volume = {132}, number = {4}, pages = {e70307}, doi = {10.1002/cncr.70307}, pmid = {41701629}, issn = {1097-0142}, mesh = {Humans ; *Artificial Intelligence ; *Electronic Health Records ; *Medical Oncology/methods ; *Neoplasms/therapy ; Decision Support Systems, Clinical ; }, abstract = {The adoption of electronic health records (EHRs) has transformed health care, improving efficiency and chart accessibility. However, the widespread reliance on unstructured data entry and the lack of standardized documentation frameworks have resulted in significant data fragmentation across health care systems. The prevalence of unstructured data in EHRs limits their potential for clinical decision support, trial matching, real-world evidence (RWE) generation, and quality measurement. Data fragmentation in health care triggers a cascade of challenges that ultimately compromise patient care. Clinicians face an excessive documentation burden and struggle to locate critical information buried in unstructured notes. Researchers encounter difficulties in extracting reliable clinical data. EHR vendors grapple with standardizing unstructured information for interoperability, and payers are unable to process unstructured clinical data efficiently to support value-based care models. These challenges are particularly acute in oncology, where complex clinical elements like cancer staging, disease status, and treatment changes require precise, structured documentation. Emerging artificial intelligence (AI) technologies, such as large language models (LLMs) and ambient listening, offer a path to automate structured data generation while reducing the workload on providers. Here, the authors propose LLM-based workflows that balance automation with clinician verification, streamlining data entry without compromising accuracy. Realizing these benefits requires coordinated efforts among clinicians, researchers, EHR vendors, payers, and policymakers to align regulatory frameworks with AI-driven innovations. This article outlines a strategy to enhance structured data capture within EHRs, ultimately improving patient care, research, and health care efficiency.}, }
@article {pmid41701631, year = {2026}, author = {Osmancevic, A and Daka, B and Larson, JC and Allison, M and Burney, RO and Shadyab, AH and Cauley, JA and Crandall, CJ}, title = {Endogenous sex hormones, sex hormone-binding globulin, and muscle health: insights into sarcopenia and sarcopenic obesity from the Women's Health Initiative.}, journal = {Menopause (New York, N.Y.)}, volume = {}, number = {}, pages = {}, pmid = {41701631}, issn = {1530-0374}, support = {ALFGBG-966255//ALF-agreement/ ; }, abstract = {OBJECTIVE: The relationship between sex hormones and lean body mass in postmenopausal women is unclear. To address this, we conducted a longitudinal observational study using data from the Women's Health Initiative study.<br><br>METHODS: We analyzed endogenous serum sex hormones and sex hormone-binding globulin (SHBG) at baseline in 1,565 postmenopausal women not using hormone therapy, who underwent 3 lean body mass measurements over 6 years. Sex hormone concentrations were assessed at baseline using radioimmunoassay. Lean body mass was assessed by dual-energy x-ray absorptiometry at baseline, year 3 and 6. Free estradiol and free testosterone concentrations were calculated. Each sex hormone was analyzed independently of the other hormones. Associations between sex hormones or SHBG were examined using repeated-measures linear regression for lean mass and repeated-measures logistic regression for sarcopenia/sarcopenic obesity. Regression models were adjusted for age, race/ethnicity, lifestyle, and metabolic confounders.<br><br>RESULTS: Concentration of free testosterone in the highest quartile was associated with a 55% lower odds for sarcopenia compared with the lowest quartile (OR: 0.45; 95% CI: 0.25-0.81). Similarly, individuals with the highest concentration of free estradiol had a 54% reduced odds of sarcopenia (OR: 0.46, 95% CI: 0.28-0.76). Conversely, a higher concentration of SHBG at baseline was significantly associated with reduced total lean mass and a higher odds of sarcopenia.<br><br>CONCLUSION: Among postmenopausal women, higher SHBG concentrations at baseline were associated with lower lean body mass and a higher odds of sarcopenia, while higher free estradiol and free testosterone concentrations were associated with a lower odds of sarcopenia.}, }
@article {pmid41703241, year = {2026}, author = {Topalidou, I and Lehrbach, N}, title = {Coordinated control of proteasome subunit gene expression promotes stress resistance, proteostasis, and longevity.}, journal = {GeroScience}, volume = {}, number = {}, pages = {}, pmid = {41703241}, issn = {2509-2723}, support = {R35GM142728/GM/NIGMS NIH HHS/United States ; P30AG013280/AG/NIA NIH HHS/United States ; }, abstract = {The proteasome is essential for cellular protein homeostasis through selective destruction of damaged and misfolded proteins. Failure of proteasome-dependent turnover accompanied by accumulation and aggregation of aberrant proteins is a hallmark of aging and late-onset neurodegenerative diseases. SKN-1A/Nrf1, a member of the NFE2L/Nrf family of transcription factors, is a master regulator of proteasome biogenesis. Through transcriptional control of proteasome subunit gene expression, SKN-1A/Nrf1 controls homoeostatic and stress-responsive upregulation of proteasome levels in adaptation to proteasome dysfunction or protein misfolding. SKN-1A/Nrf1 acts in concert with another Nrf family transcription factor, SKN-1C/Nrf2, to regulate many aspects of physiology including stress responses, redox balance, immunity, and metabolism. Here, we demonstrate that a small deletion in the promoter of the pbs-5 gene, which encodes an essential proteasome subunit, uncouples its expression from transcriptional regulation by SKN-1A/Nrf1. This disruption leads to compensatory SKN-1A/Nrf1-dependent upregulation of other proteasome subunit genes, resulting in a homeostatic imbalance in proteasomal gene expression. This pbs-5 regulatory mutation phenocopies some, but not all, aspects of SKN-1A/Nrf1 inactivation, providing evidence that coordinated regulation of proteasomal subunit gene expression underlies a subset of SKN-1A/Nrf1's physiological roles. In comparing the effects of the pbs-5 promoter deletion with isoform-specific inactivation of SKN-1A or SKN-1C, we show that the pbs-5 promoter mutation completely abrogates multiple lifespan extension paradigms. These results reveal that coordinated homeostatic regulation of proteasome subunit gene expression is critical for longevity and healthy aging.}, }
@article {pmid41703731, year = {2026}, author = {Pitcher, TJ and Long, KJ and Kammer, MN and Schuldheisz, S and Bajantri, B and Gleeson, T and Zanchi, D and Bansal, S and Yuhico, L and Peek, LJ and Jett, JR and Nair, VS and Silvestri, GA}, title = {Validation of a blood-based autoantibody test to assess lung cancer risk in 4-30 mm pulmonary nodules: a retrospective pooled analysis of four cohort studies.}, journal = {Future oncology (London, England)}, volume = {22}, number = {7}, pages = {831-842}, pmid = {41703731}, issn = {1744-8301}, mesh = {Humans ; Retrospective Studies ; *Lung Neoplasms/blood/diagnosis/immunology/pathology/epidemiology ; *Autoantibodies/blood/immunology ; Female ; Middle Aged ; Male ; Aged ; *Biomarkers, Tumor/blood ; *Multiple Pulmonary Nodules/blood/diagnosis/immunology/pathology ; Adult ; Sensitivity and Specificity ; *Solitary Pulmonary Nodule/blood/diagnosis/pathology/immunology ; Risk Assessment ; Aged, 80 and over ; }, abstract = {AIM: To validate a blood-based autoantibody test (AAT) as a high specificity, rule-in biomarker for 4-30 mm indeterminate pulmonary nodules (IPN) across malignancy risk.<br><br>METHODS: Retrospective pooled analysis of four cohorts including adults with a 4-30&#x2009;mm IPN, AAT result, and benign or malignant diagnosis. AAT results were classified as Moderate Level (all patients with elevated autoantibodies), High Level (stricter subset within Moderate Level), or No Significant Level of Autoantibodies Detected (NSLAD). Post-test probability of cancer (pCA) was calculated by applying AAT likelihood ratios to pretest pCA. Performance was assessed overall, by nodule size, and risk strata.<br><br>RESULTS: Among 1164 patients (35% cancer prevalence), Moderate Level results showed sensitivity 16%, specificity 91%, and PPV 50%. A stricter subset of positives at the High Level, specificity 96%, and PPV 57%, with sensitivity 9%. When post-test pCA exceeded 65%, specificity was 97% and PPV 69%, while sensitivity was 12%. Performance was consistent across cohorts, nodule sizes, and risk strata, indicating size- and risk-independent discrimination. ~10% of intermediate-risk cancers (pretest 5-65%) were reclassified above the 65% threshold, creating a group with enriched malignancy risk.<br><br>CONCLUSIONS: AAT provides size- and risk-independent, high-specificity rule-in performance, identifying subsets of patients whose malignancy risk may justify expedited evaluation.}, }
@article {pmid41705193, year = {2026}, author = {Boppana, S and Blosser, CD and Webber, AB and Gupta, G and Singh, N and Master, S and Parasuraman, R and Campagnaro, EL and Java, A and Sprangers, B and Bhasin-Chhabra, B and Lum, EL and Khirfan, D and Alexander, M and Leung, N and Landau, H and Murakami, N}, title = {Clinical practice pattern of management of plasma cell dyscrasia for kidney transplant candidates and recipients in the United States.}, journal = {Journal of onco-nephrology}, volume = {}, number = {}, pages = {}, pmid = {41705193}, issn = {2399-3707}, support = {K08 DK120868/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Plasma cell dyscrasia (PCD) is a rare but important cause of end stage kidney disease (ESKD). Kidney transplant is the treatment of choice in patients with ESKD. However, the complexity of PCD care and risk of disease recurrence poses challenges to kidney transplant candidacy and outcomes. We examined the current clinical practice patterns of clinicians who care for patients with PCD and identified barriers to kidney transplantation for patients with PCD.<br><br>METHODS: A web-based survey was developed and distributed from January to July 2024 to kidney transplant clinicians (American Society of Transplant (AST) members), hematologists (PCD experts), and onco-nephrologists.<br><br>RESULTS: Seventy clinicians (50 transplant nephrologists, 18 hematologists, and two surgeons) from 42 transplant centers in the US participated in the survey. Clinical practice patterns pre and post kidney transplant for patients with PCD are highly variable among institutions, and only 36% reported having a protocol for pre- and post-transplant management for patients with PCD. Particularly, the requirement for pre-transplant hematologic remission criteria, induction and maintenance immunosuppression regimens and protocols for prophylaxis and screening for opportunistic infection are areas of future study. Clinicians listed lack of data and practice guidance as well as communication challenges among multiple specialties especially hematology and kidney transplant clinicians as notable barriers.<br><br>CONCLUSIONS: Our study identified the highly variable current practice patterns when evaluating and managing patients with PCD for kidney transplant. Our findings emphasize the need for collecting and sharing clinical data to support standardized practices and serve as a basis for the upcoming multi-societal management recommendation for kidney transplant for patients with PCD.}, }
@article {pmid41705755, year = {2026}, author = {Fiorica, PN and Zimbalist, A and Sheng, H and Laurent, CA and Roh, JM and Lee, VS and Ergas, IJ and Delmerico, J and Zhu, Q and Cheng, RK and Rillamas-Sun, E and Iribarren, C and Rana, JS and Nguyen-Huynh, M and Hershman, DL and Ambrosone, CB and Kushi, LH and Greenlee, H and Kwan, ML and Yao, S}, title = {Polygenic Risk for Cardiometabolic and Cardiovascular Disease in a Multiethnic Cohort of Breast Cancer Survivors.}, journal = {JACC. CardioOncology}, volume = {8}, number = {1}, pages = {65-76}, pmid = {41705755}, issn = {2666-0873}, abstract = {BACKGROUND: Because of cancer treatment-related cardiotoxicities, women with histories of breast cancer are at increased risk for cardiovascular disease (CVD). Many polygenic scores (PGS) have been developed for predicting risk for CVD-related conditions in the general population, but their performance in breast cancer patients remains largely unexplored.<br><br>OBJECTIVES: The aim of this study was to examine the performance of PGS for CVD-related traits to predict incident cardiometabolic disorder (CMD) and CVD in women with histories of breast cancer.<br><br>METHODS: In a prospective multiethnic cohort of 3,620 breast cancer survivors, 27 PGS for CVD-related traits were we computed, and their associations with 12 incident CMD and CVD events were examined. The performance of these PGS was compared relative to clinical covariates-only models and by cardiotoxic cancer treatment.<br><br>RESULTS: Twenty-three significant associations were identified after Bonferroni correction between PGS and CMD or CVD events in breast cancer patients. Although the model performance of PGS and multi-PGS added to or combined with clinical models for CMD and CVD risk prediction was numerically greater, these were not statistically significant. For some outcomes, PGS performed worse among patients who received cardiotoxic cancer treatments.<br><br>CONCLUSIONS: Although there may be potential value of PGS in predicting the risk for CMD and CVD events in women with histories of breast cancer, current PGS performance is limited. This work highlights the need to develop de novo PGS in breast cancer patients and to include ancestrally diverse patient populations.}, }
@article {pmid41705757, year = {2026}, author = {Onerup, A and Liu, Q and Izumi, S and Martínez-Martínez, JM and Dixon, SB and Chow, EJ and Hudson, MM and Snyder, C and Nathan, PC and Armstrong, GT and Ness, KK and Yasui, Y}, title = {Potential of Exercise for Prevention of Cardiovascular Disease in Survivors of Childhood Hodgkin Lymphoma.}, journal = {JACC. CardioOncology}, volume = {8}, number = {1}, pages = {87-89}, pmid = {41705757}, issn = {2666-0873}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, }
@article {pmid41706088, year = {2026}, author = {Pidala, J and Onstad, L and Carpenter, P and Hamilton, BK and Kitko, CL and Juckett, M and Cutler, C and Lee, SJ}, title = {Longitudinal Study of Late Acute and Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation: A Long-Term Follow-up Study from the Chronic Graft-Versus-Host Disease Consortium.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {2}, pages = {205.e1-205.e12}, pmid = {41706088}, issn = {2666-6367}, support = {R01 CA118953/CA/NCI NIH HHS/United States ; U54 CA163438/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology/mortality/pathology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Male ; Middle Aged ; Adult ; Longitudinal Studies ; Chronic Disease ; Follow-Up Studies ; Transplantation, Homologous ; Acute Disease ; Adolescent ; Young Adult ; Aged ; Bronchiolitis Obliterans/etiology ; Child ; }, abstract = {Late acute and chronic graft-versus-host disease (GVHD) contribute to morbidity and death after allogeneic hematopoietic cell transplantation (HCT). A prior national Chronic GVHD Consortium longitudinal study enrolled patients pre- or early post-HCT and identified the incidence of late acute GVHD, chronic GVHD, and chronic GVHD subtypes of bronchiolitis obliterans syndrome (BOS) and cutaneous sclerosis. We now report 10-yr follow-up from that study in a long-term follow-up analysis (N = 911 subjects). Late acute GVHD occurred in 11% at a median of 5.5 mo. Chronic GVHD in total occurred in 54% with median onset of 7.4 mo. BOS (4% of subjects, median onset 12.6 mo) and cutaneous sclerosis (10% of subjects, median onset of 17.2 mo) were less frequent and had later-onset. The long-term analysis demonstrated additional GVHD events occurring beyond 1 to 2 yr post-HCT. Inter-conversion between GVHD types was common, and notably included new development of BOS and cutaneous sclerosis after initial chronic GVHD presentation without these manifestations. GVHD-free, relapse-free survival (GVHD-DFS, survival without relapse or development of late acute or chronic GVHD) was 22% at 2 yr, 18% at 5 yr, and 15% at 10 yr post-HCT. Non-relapse mortality continued to increase beyond 2 yr, with 10-yr estimates up to 35% (late acute), 31% (chronic GVHD), 62% (BOS), and 36% (cutaneous sclerosis). Durable complete discontinuation of immune suppression was uncommon for all GVHD types. These data suggest that extended surveillance for late acute and chronic GVHD is needed post-HCT due to late occurrences, and that associated mortality is high through 10 yr post-GVHD onset.}, }
@article {pmid41706623, year = {2026}, author = {Dontchos, BN and Narayan, AK and Grimm, LJ and Edmonds, CE and Lam, DL and Lawson, MB and Miles, RC}, title = {The Advantages and Disadvantages of Same-Day Breast Imaging Services: Clinical Review, Implications, and Future Directions.}, journal = {Journal of breast imaging}, volume = {}, number = {}, pages = {}, doi = {10.1093/jbi/wbaf061}, pmid = {41706623}, issn = {2631-6129}, abstract = {Combining patient services into fewer clinical visits has been increasingly explored across medical specialties as more attention is given to patient-centered care, patient access, and care delivery efficiency from health enterprises. The typical breast imaging care model requires multiple clinical visits to achieve a final diagnosis and, therefore, might be optimized to perform 2 or more steps in the process in 1 patient clinical visit. Recent studies suggest that this model can mitigate patient disparities in timeliness of care, improve patient satisfaction, and even improve patient adherence. Despite the potential benefits, there is variability in the use of same-day services across breast imaging facilities because of various local/institutional level barriers, staffing limitations, and concerns about interpreting examinations in real time. In this review, we describe the various same-day models that have been reported in the breast imaging literature, discuss their impact, and present evidence that may support further adoption of these care models. We also explore the barriers and limitations to this model and future directions of same-day services.}, }
@article {pmid41707096, year = {2026}, author = {Mulenga, H and Mendelsohn, SC and Fiore-Gartland, A and Penn-Nicholson, A and Musvosvi, M and Tameris, M and Walzl, G and Naidoo, K and Churchyard, G and Scriba, TJ and Hatherill, M}, title = {Risk factors for immunological sensitization to Mycobacterium tuberculosis and progression to incident TB disease among HIV-uninfected adults in a high burden setting.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiag100}, pmid = {41707096}, issn = {1537-6613}, abstract = {BACKGROUND: Identifying risk factors for Mtb sensitization (defined as IGRA-positive) and progression to TB disease is critical to guide targeted prevention strategies.<br><br>METHODS: We analyzed data from a prospective cohort of adults (18-60 years) without HIV, enrolled at five high-incidence South African sites. Participants underwent testing for Mtb sensitization and microbiologically-confirmed TB at baseline, and during 15 months follow-up. Multivariable logistic and Cox regression models were used to assess factors associated with Mtb sensitization and TB progression. Sampling weights were applied to reflect the screened population.<br><br>RESULTS: Among 2,912 participants with valid IGRA results, 63.4% (n=1895) were Mtb-sensitized. Prevalent TB was detected in 1.81% (62/1895) of Mtb-sensitized versus 0.62% (12/1017) of Mtb-unsensitized individuals (p=0.01). During follow-up of participants without prevalent TB, 2.01% (48/1833) Mtb-sensitized and 0.53% (8/1005) Mtb-unsensitized individuals developed TB (p=0.01). Factors associated with Mtb sensitization included increasing age (adjusted-odds-ratio; aOR=1.02 , 95%CI 1.01-1.03), male sex (aOR=1.34, 95%CI 1.08-1.67), smoking (aOR=1.31, 95%CI 1.05-1.64), prior TB (aOR=2.20, 95%CI 1.40-3.47), and TB contact history (aOR=1.40, 95%CI 1.08-1.83). Risk factors for progression to TB were Mtb sensitization (adjusted-hazard-ratio; aHR=3.05, 95%CI 1.14-8.18), smoking history (aHR=2.34, 95%CI 1.03-5.31), and lower body-mass index (aHR=0.89, 95%CI 0.82-0.97).<br><br>CONCLUSION: Mtb-sensitized individuals had a three-fold higher risk of prevalent TB and progressing to TB compared to Mtb-unsensitized individuals. In high-prevalence settings, identifying individuals at greatest risk-such as those recently infected, with a history of smoking, or low BMI-could help refine TB prevention efforts and reduce community-level transmission.}, }
@article {pmid41707657, year = {2026}, author = {Chhan, CB and Lang, K and Davis, AR and Wan, YH and Aldridge, NT and Kher, G and Scharffenberger, SC and Hardy, SR and Iureniev, R and Giltiay, NV and Edwards, KR and Radtke, S and Kiem, HP and Pancera, M and McGuire, AT}, title = {Transgenic mouse-derived human monoclonal antibodies targeting EBV gp350 and gp42 provide basis for therapeutic development.}, journal = {Cell reports. Medicine}, volume = {7}, number = {2}, pages = {102618}, pmid = {41707657}, issn = {2666-3791}, mesh = {Animals ; Mice, Transgenic ; Humans ; *Herpesvirus 4, Human/immunology ; *Antibodies, Monoclonal/immunology ; Mice ; Epstein-Barr Virus Infections/immunology ; Antibodies, Neutralizing/immunology ; B-Lymphocytes/immunology ; *Antibodies, Viral/immunology ; }, abstract = {Epstein-Barr virus (EBV) causes infectious mononucleosis and contributes to neurodegenerative disorders and malignancies, particularly in immune-compromised hosts. Transplant patients face high risk of post-transplant lymphoproliferative disease, a life-threatening EBV-driven lymphoma. There are no EBV-specific vaccines or treatments; however, neutralizing antibodies against EBV glycoproteins may offer utility as therapeutic agents. EBV entry into B cells involves gp350, which binds complement receptors, and gp42, which engages HLA class II to trigger fusion. Most existing monoclonal antibodies (mAbs) against these antigens are non-human, limiting clinical use. Using a transgenic mouse model, we generate two gp350 and eight gp42 genetically human neutralizing mAbs that block receptor binding. Structural analyses reveal extended sites of vulnerability relevant to vaccine development. Delivery of a gp42 mAb protects humanized mice from EBV challenge, while a gp350 mAb provides partial protection. These mAbs highlight the utility of transgenic mice to produce therapeutic mAbs for preventing EBV-driven disease.}, }
@article {pmid41708595, year = {2026}, author = {Moses, AB and Yeh, AC}, title = {The gut microbiome in graft-versus-host disease: mechanisms of immune modulation and therapeutic approaches.}, journal = {Gut microbes}, volume = {18}, number = {1}, pages = {2631224}, pmid = {41708595}, issn = {1949-0984}, mesh = {*Graft vs Host Disease/immunology/therapy/microbiology ; Humans ; *Gastrointestinal Microbiome/immunology ; Animals ; Hematopoietic Stem Cell Transplantation/adverse effects ; Immunity, Innate ; T-Lymphocytes/immunology ; Gastrointestinal Tract/microbiology/immunology ; Adaptive Immunity ; Probiotics/administration &amp; dosage ; }, abstract = {Graft-versus-host disease (GvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation and occurs when T cells from the donor graft target recipient-derived antigen on host tissue. The involvement of the gastrointestinal (GI) tract drives morbidity and mortality-not coincidentally, the GI tract also harbors the most complex and abundant human microbial reservoir. In this review, we first revisit how the microbiota initiates, propagates, and protects against GvHD in the context of both innate and adaptive immunity. Historically, the impact of the microbiota on GvHD has been ascribed primarily to the activation of innate immunity, setting the stage for donor alloreactivity. Although established models of GvHD focus on donor-host genetic disparity as the principal driver of donor T-cell activation, commensal microbes in the GI tract, whose collective gene content exceeds that of the human genome by more than two orders of magnitude, constitutes an immense and poorly understood source of potential T-cell antigens. We next discuss the evolution of therapeutic approaches aimed at modifying the microbiota to improve GvHD outcomes, incorporating over 40 clinical studies spanning the last 40 years, from broad decontamination strategies to pre/probiotic approaches and targeted ecosystem replacement, including fecal microbiota transplantation.}, }
@article {pmid41709952, year = {2026}, author = {Eyrich, NW and Huang, Y and Zheng, Y and Wei, J and Sokoll, L and Chan, DW and Patil, D and Chinnaiyan, A and Tomlins, SA and Lotan, Y and Lin, D and Scherr, D and Wang, Y and Kibel, A and Taneja, SS and Bidair, M and Thompson, IM and Sanda, MG and Narayan, VM}, title = {Combining Serum Prostate Health Index With Urinary PCA3 and TMPRSS2:ERG RNA Testing Improves Detection of Clinically Significant Prostate Cancer.}, journal = {JU open plus}, volume = {4}, number = {2}, pages = {e00019}, pmid = {41709952}, issn = {2771-554X}, abstract = {PURPOSE: We sought to determine whether combining prostate health index (Phi) with urinary prostate cancer antigen 3 (PCA3) and TMPRSS2:ERG (T2:ERG) could improve selection of men for prostate biopsy. These biomarkers have been validated in prostate cancer (PCa) detection separately, but their combination has not previously been developed.<br><br>MATERIALS AND METHODS: Prebiopsy blood and post-digital rectal examination urine specimens were assayed to predict subsequent biopsy outcomes from training and validation cohorts (1073 participants across 11 academic centers). Clinical algorithms for combining Phi and PCA3-T2:ERG to predict Grade Group &#x2265; 2 (GG &#x2265; 2) PCa were formulated using the training cohort (N = 512). Prediction rules and hypotheses were locked before validation using biopsy-na&#xef;ve men from the NCI Early Detection Research Network urinary PCA3 trial (N = 561). Rules were compared in weighted sum of specificity and sensitivity with weights specified a priori, and P values were obtained through bootstrap in the validation study.<br><br>RESULTS: Primary validation analysis showed that Phi combined with urinary PCA3 outperformed Phi alone (P = .002). Furthermore, serum Phi combined with urinary PCA3-T2:ERG outperformed urinary PCA3-T2:ERG in each of the 3 algorithms reflecting different potential clinical workflows: (1) serum Phi and urine PCA3-T2:ERG tested simultaneously, either exceeding its own threshold (P = .04); (2) urine PCA3-T2:ERG first and those in the grey zone resolved by subsequent serum Phi (P = .03); and (3) serum Phi first and those in the grey zone resolved by subsequent urine PCA3-T2:ERG (P = .002).<br><br>CONCLUSIONS: Combining serum Phi with urinary PCA3 RNA alone or together with urinary T2:ERG RNA, simultaneously or sequentially, improves selection of men for initial prostate biopsy and represents an avenue to improve early detection of aggressive PCa.}, }
@article {pmid41713588, year = {2026}, author = {Akaike, T and Thakuria, M and Silk, AW and Hippe, DS and Ch'en, PY and Guja, KE and Youn Park, S and Tsai, K and Yom, SS and Yu, SS and Choi, J and Chandra, S and Nghiem, PT and Zaba, LC}, title = {Response to Gao and Chen, "Comments on Akaike et al's 'Circulating tumor DNA level is associated with time to clinical recurrence in Merkel cell carcinoma: Implications for patient management'".}, journal = {Journal of the American Academy of Dermatology}, volume = {}, number = {}, pages = {}, pmid = {41713588}, issn = {1097-6787}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, }
@article {pmid41713639, year = {2026}, author = {Jenkins, MT and Dubin, R and Dickerson, KM and Nguyen, P and Wang, J and Lee, SC and Lu, R and Welner, RS and Ferrell, PB}, title = {TET2 loss enhances early response to inflammation in primitive and committed myeloid cells.}, journal = {Experimental hematology}, volume = {157}, number = {}, pages = {105383}, doi = {10.1016/j.exphem.2026.105383}, pmid = {41713639}, issn = {1873-2399}, support = {I01 BX005991/BX/BLRD VA/United States ; R56 DK138826/DK/NIDDK NIH HHS/United States ; }, abstract = {In vivo IL-1β exposure elicits enhanced hematopoietic stem cell (HSC) self-renewal and myeloid priming in Tet2[KO] mice, but information on how Tet2[KO] affects the early transcriptional response to IL-1β is lacking. To address this, we used an inducible, in vitro model of myeloid differentiation coupled with RNA-sequencing (RNA-seq) to study the effects of Tet2[KO] on short-term IL-1β stimulation. In both Tet2[KO] progenitor and differentiated states, we identified baseline increases in the expression of several cytokine signaling receptors, including Il1r1, as well as increases in inflammasome components. Interaction effect modeling revealed that loss of TET2 and IL-1β stimulation collaborate, leading to significant increases in both inflammatory cytokine expression and regulators of proliferation and differentiation in the progenitor state, and elevated cytokine production in differentiated cells. We then show that IKK-complex inhibition prevents both the IL-1β induced proliferation of Tet2[KO] progenitors and TNFα production in differentiated myeloid cells, highlighting a potential therapeutic target in TET2-deficient cells.<END ABSTRACT>.}, }
@article {pmid41714624, year = {2026}, author = {Paila, YD and Pajon, R and Banbury, B and Fields, P and Maglinao, M and De Rosa, SC and Morris, D and McElrath, MJ and Siangphoe, U and Cohen, KW and Paris, R}, title = {Potent and dose-sparing next-generation SARS-CoV-2 vaccine, mRNA-1283, induces polyfunctional and durable T cell immunity.}, journal = {NPJ vaccines}, volume = {11}, number = {1}, pages = {}, pmid = {41714624}, issn = {2059-0105}, support = {N/A//Moderna, Inc./ ; }, abstract = {Cell-mediated immunity contributes to durable protection against severe COVID-19, particularly as antibody responses wane or viral variants partially evade neutralization. Here, we characterize SARS-CoV-2-specific T cell responses elicited by a next-generation COVID-19 vaccine, mRNA-1283, which encodes the receptor-binding and N-terminal domains of the spike protein, in a phase 1 randomized clinical trial (NCT04813796). COVID-19-naïve, healthy adults (18-55 years) received two doses of mRNA-1283 (10 µg, 30 µg, or 100 µg), two doses of mRNA-1273 (100 µg; full-length spike comparator), or a single-dose regimen of mRNA-1283. Using intracellular cytokine staining, we show that two-dose regimens of mRNA-1283 or mRNA-1273 induce Th1-biased, polyfunctional spike-specific CD4+ and CD8+ T cell responses that were maintained through Day 209. TCRβ sequencing demonstrated significant increases in the breadth and frequency of SARS-CoV-2-associated TCRs, which correlated with functional spike-specific T cell responses. Therefore, the low-dose (10 µg) regimen of the next-generation COVID-19 vaccine, mRNA-1283, induces polyfunctional and durable CD4+ and CD8+ T cell immunity comparable to the standard 100 µg mRNA-1273 vaccine, supporting a dose-sparing strategy without compromising long-term cellular protection against severe COVID-19.}, }
@article {pmid41716469, year = {2026}, author = {Rankin, AW and Keating, AK and Abu-Arja, RF and Thakar, MS and Rangarajan, HG}, title = {Current and emerging maintenance strategies after stem cell transplantation in children and adolescents with acute leukemias.}, journal = {Molecular therapy. Oncology}, volume = {34}, number = {1}, pages = {201141}, pmid = {41716469}, issn = {2950-3299}, abstract = {Hematopoietic stem cell transplantation (HSCT) can promote durable long-term remissions for children and adolescents with high-risk acute leukemias. While many patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) can achieve a cure, post-HSCT relapse remains a possibility for many. Recent therapeutic advances, particularly in the realm of targeted therapeutics, have revolutionized both first-line and relapsed/refractory management strategies, opening the door to more personalized and potentially less toxic approaches to treatment. Many of these agents have also either been proposed or have been actively investigated as having a role in the post-HSCT setting. Post-HSCT relapse often carries a dismal prognosis, and early prophylactic intervention has in many cases been shown to improve outcomes. Herein, we comprehensively review maintenance strategies for prevention of post-HSCT relapse of ALL and AML, with a specific focus on pediatric and adolescent populations. While drawing on experience in adult patients, we highlight data specific to pediatrics where available and draw attention to areas where further research in children and adolescents is needed. Future efforts aimed at determining who will benefit from, when to initiate and discontinue, and what agent(s) to employ as maintenance will be crucial to optimizing post-HSCT outcomes.}, }
@article {pmid41716520, year = {2025}, author = {Friedman, EM and Wang, J and Weden, MM and Slaughter, ME and Shih, RA and Rutter, CM}, title = {Projected Demographic Trends in the Likelihood of Having or Becoming a Dementia Family Caregiver in the U.S. Through 2060.}, journal = {Populations}, volume = {1}, number = {2}, pages = {}, pmid = {41716520}, issn = {3042-4372}, support = {R21 AG055815/AG/NIA NIH HHS/United States ; }, abstract = {This study predicts how sociodemographic trends-smaller family sizes, increased longevity, and marital patterns-could affect family care for people with dementia through 2060. By coupling dementia information from the Health and Retirement Study with a well-established kinship microsimulation model, we analyze the impact of demographic changes on the future care landscape, focusing on changes in race and gender differences in two key areas: (1) the availability of family caregivers for people with dementia, and (2) the likelihood of having a family member with dementia, among those without dementia. Our model projections suggest that future dementia cohorts will be more likely to have a living spouse than the current ones, with diminishing gender disparities due to increased male longevity. However, racial disparities will persist, particularly for Black women. The likelihood of older adults lacking spouses, children, and siblings will increase, but remain low. For potential caregivers, we predict an increased likelihood and longer duration of exposure to family members with dementia in future birth cohorts, particularly for Black individuals, potentially placing more people at risk of the adverse health and well-being outcomes associated with caregiving.}, }
@article {pmid41718400, year = {2026}, author = {Kuhlmann, AS and Peters, T and Hamlin, DK and Li, Y and Wang, X and Stackhouse, M and Cole, FM and Martinez-Reyes, J and Sandmaier, BM and Kiem, HP and Wilbur, DS and Harrington, RD and Pincus, SH}, title = {Comparative In Vitro Evaluation of Anti-HIV Immunotoxin, Antibody-Drug Conjugate, and Radioimmunoconjugate Targeted by the Same Antibody.}, journal = {Antibodies (Basel, Switzerland)}, volume = {15}, number = {1}, pages = {}, pmid = {41718400}, issn = {2073-4468}, support = {R01AI136758//National Institute of Allergy and Infectious Diseases/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: We are developing cytotoxic immunoconjugates (CICs) to eliminate HIV-infected cells. We investigated the efficacy and kinetics of killing by different forms of CICs targeted by the same monoclonal antibody (mAb), an immunotoxin (IT), antibody-drug conjugate (ADC), and radioimmunoconjugate (RIC).<br><br>METHODS: We compared in vitro effects of CICs made by conjugating anti-gp41 mAb 7B2 to deglycosylated ricin A chain (7B2-dgA), the anthracycline derivative PNU-159682 (7B2-PNU), or the &#x3b1;-emitting isotope actinium-225 (7B2-[225]Ac). Kinetic analyses of cell growth were performed measuring electrical impedance every 15 min over a 7-day period using cells stably expressing the HIV envelope and Env-negative parent cells.<br><br>RESULTS: 7B2-dgA and 7B2-[225]Ac were more potent and acted more rapidly to kill cells than 7B2-PNU. Both the 7B2-PNU and 7B2-[225]Ac induced bystander-cell killing, whereas the IT did not and consequently allowed the outgrowth of Env-negative cells. Low dose or brief exposure to 7B2-PNU resulted in an increased rate of cell growth.<br><br>CONCLUSIONS: An IT, ADC, and RIC showed substantial differences in the degree of specific toxicity, kinetics, and mechanisms of killing. The results of this side-by-side comparison have implications for the development of CICs to treat HIV, as well as other conditions.}, }
@article {pmid41719110, year = {2026}, author = {Beyrer, C and Ratevosian, J and Carpino, T and Rosenberg, NE and Gelderblom, HC and Sullivan, PS and Deeks, SG and Gray, G}, title = {The HIV/AIDS response as we knew it is over: Where do we go from here?.}, journal = {Journal of the International AIDS Society}, volume = {29}, number = {2}, pages = {e70077}, pmid = {41719110}, issn = {1758-2652}, mesh = {Humans ; *HIV Infections/prevention &amp; control/drug therapy/epidemiology ; Global Health ; Pre-Exposure Prophylaxis ; *Acquired Immunodeficiency Syndrome/prevention &amp; control/epidemiology/drug therapy ; Public Health ; }, abstract = {INTRODUCTION: The global HIV response, once a model of progress and innovation, faces a profound moment. Despite four decades of pivotal scientific and programmatic advances-most notably in antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP)-the world remains off track to meet the 2025 and 2030 targets for ending AIDS as a public health threat. New acquisitions and AIDS-related deaths remain unacceptably high, particularly among key populations and in low- and middle-income countries. The abrupt U.S. funding reversals in 2025 have severely disrupted support for HIV efforts. Cuts to U.S. and international institutions have compromised HIV prevention, treatment and surveillance systems worldwide, and may already have begun reversing two decades of progress.<br><br>DISCUSSION: To avert this crisis, the HIV and public health community, together with governments and global funders, must urgently invest in scaling long-acting treatment and prevention tools, rebuild disaggregated data systems and strengthen implementation science rooted in community-led approaches. Digital health technologies offer promise to enhance service delivery, surveillance, monitoring and evaluation, especially in resource-constrained settings, but demand ethical governance and infrastructure investment. The global research ecosystem must become more evenly distributed and inclusive, with a shift towards country-led partnerships, national data sovereignty and regional co-operation.<br><br>CONCLUSIONS: Looking to 2030 and beyond, the strategy to end HIV should include expanded access to long-acting ART and PrEP, sustained investments in HIV vaccine and cure research, and robust monitoring and evaluation systems. Achieving epidemic control-and ultimately ending the HIV pandemic-will require not only biomedical tools but also political will, community leadership and equitable financing. The lessons of the past underscore that sustained progress is possible, but only if we meet this moment with urgency, imagination and solidarity.}, }
@article {pmid41720346, year = {2026}, author = {Xiao, J and Guo, D and Xing, X and Jiang, L and Qi, S and Wang, J and Bai, W and Yu, S and Shen, F and Guo, X and Wang, X and Zhou, W and Li, H and Zhao, F and Feng, L and Zhang, J and Xu, Y and Yang, D and Liu, H and Sun, D}, title = {Phloretin targeting the 3CLpro Cys144 exhibits broad-spectrum antiviral activity against swine enteric coronavirus.}, journal = {Virologica Sinica}, volume = {41}, number = {1}, pages = {208-226}, pmid = {41720346}, issn = {1995-820X}, mesh = {Animals ; *Antiviral Agents/pharmacology/chemistry/therapeutic use ; Swine ; Molecular Docking Simulation ; *Coronavirus Infections/drug therapy/veterinary/virology ; *Phloretin/pharmacology/chemistry/therapeutic use ; Porcine epidemic diarrhea virus/drug effects ; *Swine Diseases/drug therapy/virology ; Molecular Dynamics Simulation ; Deltacoronavirus/drug effects ; Transmissible gastroenteritis virus/drug effects ; Structure-Activity Relationship ; *Viral Proteins/chemistry/antagonists &amp; inhibitors/genetics ; Coronavirus 3C Proteases ; *Coronavirus/drug effects ; }, abstract = {Swine enteric coronaviruses (SECoVs) cause severe watery diarrhea and high mortality in piglets, resulting in significant economic losses to the global pig industry. However, frequent mutations in SECoVs significantly compromise vaccine-induced immunity and limit cross-protection against emerging variants. Therefore, there is an urgent need to develop new broad-spectrum antiviral drugs to be the last line of defense to supplement vaccine immunity. In this study, we utilized molecular docking and molecular dynamics simulations to identify phloretin as a broad-spectrum SECoV inhibitor. Phloretin has demonstrated prophylactic and therapeutic efficacy in vitro and in vivo, improving the survival of SECoV-infected piglets. It was further found that phloretin exerts a broad-spectrum antiviral effect by acting on the conserved 3CLpro Cys144 site of three SECoVs. It is worth noting that derivative A12, designed on the basis of the structure-activity relationship (SAR) between phloretin and 3CLpro, showed a 15.7, 2.6, and 8.4-fold increase in antiviral effect against porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), and porcine delta coronavirus (PDCoV), respectively. This study reveals a 3CLpro Cys144 targeting broad-spectrum strategy for use against SECoVs, providing a candidate drug to bridge the vaccine immunity gap.}, }
@article {pmid41720427, year = {2026}, author = {Motzer, RJ and Albiges, L and Treviño Aguirre, SA and Kanesvaran, R and Centkowski, P and Reimers, MA and Sade, JP and Pouessel, D and Biscaldi, E and Esteban, E and Arranz Arija, J&#xc1; and Tykodi, SS and van Kooten Losio, M and Dighe, A and Ma, H and Valmeekam, V and Simmons, A and Scheffold, C and Andrianova, S and Braun, DA and Powles, T and Choueiri, TK}, title = {Cabozantinib plus nivolumab and ipilimumab in previously untreated, advanced renal cell carcinoma: final results and biomarker analyses from the phase III COSMIC-313 study.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2026.02.011}, pmid = {41720427}, issn = {1569-8041}, abstract = {BACKGROUND: Primary results from COSMIC-313 demonstrated significantly longer progression-free survival (PFS) with first-line cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in patients with advanced renal cell carcinoma. Final efficacy and safety results, as well as data from exploratory biomarker analyses, are reported here.<br><br>PATIENTS AND METHODS: The design, participants, and primary-endpoint PFS outcomes have been reported previously for this phase III, double-blind, randomized (1 : 1) study of cabozantinib or placebo plus nivolumab and ipilimumab in adults with previously untreated, advanced clear cell renal cell carcinoma. The secondary endpoint was overall survival (OS) in the intention-to-treat population. Exploratory biomarker analyses investigated the potential association between immune cell types and gene signatures with clinical outcomes.<br><br>RESULTS: After a median follow-up of 45.0 months, the updated median PFS in the cabozantinib (triplet) arm was longer than in the placebo (doublet) arm (16.6 versus 11.2 months; hazard ratio 0.82, 95% confidence interval 0.69-0.98). There was no significant difference in median OS (hazard ratio 1.02, 95% confidence interval 0.85-1.23, P = 0.84), and the safety profile was consistent with the earlier analysis (grade 3/4 treatment-related adverse events occurred in 75% and 43% of patients in the triplet and doublet arms, respectively). In patients with higher levels of M2-like macrophages, the triplet regimen was associated with significantly improved PFS and OS compared with the doublet regimen. Responders in the triplet arm exhibited elevated angiogenic signatures and reduced immune-related pathways, while responders in the doublet arm had robust immune activation.<br><br>CONCLUSIONS: Long-term results from COSMIC-313 continue to demonstrate a PFS benefit with the addition of cabozantinib to nivolumab and ipilimumab. There was no OS benefit and no new safety signals were observed. Exploratory biomarker analyses suggest adding cabozantinib to nivolumab and ipilimumab improves survival in patients with high levels of M2-like macrophages.}, }
@article {pmid41720768, year = {2026}, author = {Singh, R and Venkadakrishnan, VB and Imada, E and Yamada, Y and Brady, NJ and Dunmore, KE and Garner, R and Booker, MA and Hanratty, B and Haffner, MC and Tolstorukov, MY and Marchionni, L and Robinson, BD and Rickman, DS and Beltran, H}, title = {Crosstalk between EZH2 and DNA methylation mediates neuroendocrine prostate cancer lineage plasticity.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41720768}, issn = {2041-1723}, support = {R37CA241486-01A1//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 CA274963/CA/NCI NIH HHS/United States ; K22 CA269707/CA/NCI NIH HHS/United States ; 23YOUNG15//Prostate Cancer Foundation (PCF)/ ; R01 CA301637/CA/NCI NIH HHS/United States ; W81XWH2210197//U.S. Department of Defense (United States Department of Defense)/ ; P50 CA211024/CA/NCI NIH HHS/United States ; }, mesh = {Male ; *Enhancer of Zeste Homolog 2 Protein/metabolism/genetics ; Animals ; *DNA Methylation ; *Prostatic Neoplasms/genetics/metabolism/pathology ; Humans ; Mice ; DNA (Cytosine-5-)-Methyltransferase 1/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Histones/metabolism ; PTEN Phosphohydrolase/genetics/metabolism ; *Neuroendocrine Tumors/genetics/metabolism/pathology ; *Carcinoma, Neuroendocrine/genetics/metabolism/pathology ; Retinoblastoma Binding Proteins/genetics/metabolism ; Epigenesis, Genetic ; Ubiquitin-Protein Ligases/genetics/metabolism ; N-Myc Proto-Oncogene Protein/genetics/metabolism ; Cell Line, Tumor ; Cell Lineage/genetics ; Promoter Regions, Genetic ; }, abstract = {Prostate cancer lineage plasticity is associated with changes in DNA methylation and enhancer of zeste homolog 2 (EZH2) activity. How these epigenetic programs functionally interact to modulate transcriptional reprogramming in neuroendocrine prostate cancer (NEPC) is not well understood. In this study, we demonstrate that hypomethylated regions of DNA preferentially accumulate the repressive mark, H3K27me3. We established an NEPC mouse model with deletion of Ezh2 in the background of Pten and Rb1 loss plus human MYCN overexpression. Deletion or pharmacological inhibition of EZH2 in NEPC murine or patient-derived models leads to a genome-wide rewiring of DNA methylation, characterized by hypomethylation and upregulation of neuroendocrine-lineage genes along with hypermethylation and repression of polycomb repressive complex 2 (PRC2) targets. On the other hand, deletion of DNA methyltransferase 1 (DNMT1) results in significant changes in H3K27me3 distribution, particularly affecting bivalent promoters bearing both H3K27me3 and active H3K4me3 marks. In NEPC models, neuroendocrine-lineage genes are repressed upon DNMT1 deletion associated with increased H3K27me3. Conversely, in prostate adenocarcinoma models, DNMT1 deletion leads to de-repression of neuroendocrine lineage genes with a loss of H3K27me3 marks. Our findings reveal a functional interplay between two repressive epigenetic machineries that mediates lineage plasticity in prostate cancer.}, }
@article {pmid41720775, year = {2026}, author = {Scheck, R and Melzer, M and Gladkov, G and Leyre, L and Ward, AR and Reeves, DB and Perkins, N and Huynh, TT and McMahon, DK and Bosch, RJ and Macatangay, BJ and Cyktor, JC and Eron, JJ and Mellors, JW and Gandhi, RT and Buchauer, L and Jones, RB and Gaebler, C}, title = {Q4ddPCR: a flexible, 4-target assay for high-resolution HIV reservoir profiling.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41720775}, issn = {2041-1723}, support = {UM1 AI068634, UM1 AI068636, UM1 AI106701//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; UM1 AI068634/AI/NIAID NIH HHS/United States ; 101162138//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Excellent Science (H2020 Priority Excellent Science)/ ; Walter-Benjamin Stipendium, 549131684//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; R01 AI186721-01//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UM1 AI191237/AI/NIAID NIH HHS/United States ; R37 AI181626/AI/NIAID NIH HHS/United States ; UM1 AI164565/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/virology/drug therapy ; *Proviruses/genetics/isolation &amp; purification ; *HIV-1/genetics/isolation &amp; purification ; *DNA, Viral/genetics ; Viral Load ; *Polymerase Chain Reaction/methods ; Genome, Viral ; }, abstract = {Precise and scalable quantification of the intact HIV reservoir is critical for advancing curative strategies. Current reservoir assays, such as the intact proviral DNA assay (IPDA), are limited by quantification failures or misclassification of defective proviruses due to HIV sequence heterogeneity. Q4ddPCR is a modular, droplet digital PCR simultaneously targeting four conserved regions in the HIV genome to improve specificity, reduce quantification gaps, and provide multi-layered readouts. It comprises two configurations: one fully based on Q4PCR primer/probes and one combining IPDA with gag and pol primer/probes from Q4PCR. We benchmark Q4ddPCR against 3650 near full-length proviral sequences from 13 virally suppressed people with HIV (PWH) generated by Q4PCR. Q4ddPCR closely matches sequence-confirmed reservoir measurements, and multi-probe readouts reveal clonal reservoir dynamics not detectable by IPDA. Q4ddPCR enables intact reservoir quantification in 95% of samples across four independent cohorts and in 16 PWH, strongly correlates with viral outgrowth. In longitudinal samples from 42 participants over the first 4.5 years on antiretroviral therapy (ART), Q4ddPCR reports lower proviral frequencies and a steeper decline in intact proviral DNA compared to IPDA. Collectively, our findings confirm key predictions from mathematical modeling, demonstrating that multi-target assays improve specificity and more accurately capture intact reservoir dynamics.}, }
@article {pmid41720947, year = {2026}, author = {Hart, SFM and Alcala, N and Feder, AF and Harris, K}, title = {A signature-agnostic test for differences between tumor mutation spectra reveals carcinogen and ancestry effects.}, journal = {Communications biology}, volume = {9}, number = {1}, pages = {}, pmid = {41720947}, issn = {2399-3642}, support = {1DP2CA280623//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 2R35GM133428//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32-HG000035//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; R35 GM133428/GM/NIGMS NIH HHS/United States ; T32 HG000035/HG/NHGRI NIH HHS/United States ; DP2 CA280623/CA/NCI NIH HHS/United States ; 24-0106/AICR_/Worldwide Cancer Research/United Kingdom ; }, mesh = {Humans ; *Carcinogens/toxicity ; Animals ; *Mutation ; Mice ; *Neoplasms/genetics/chemically induced ; }, abstract = {Despite dozens of tools to identify mutational signatures in cancer samples, there is not an established metric for quantifying whether signature exposures differ significantly between two heterogeneous groups of samples. We demonstrate that a signature-agnostic metric - the aggregate mutation spectrum distance permutation method (AMSD) - can rigorously determine whether mutational exposures differ between groups, a hypothesis that is not directly addressed by signature analysis. First, we reanalyze a study of carcinogen exposure in mice, determining that eleven of twenty tested carcinogens produce significant mutation spectrum shifts. Only three of these carcinogens were previously reported to induce distinct mutational signatures, suggesting that many carcinogens perturb mutagenesis by altering the composition of endogenous signatures. Next, we interrogate whether patient ancestry has a measurable impact on human tumor mutation spectra, finding significant ancestry-associated differences across ten cancer types. Some have been previously reported, such as elevated SBS4 in African lung adenocarcinomas, while some have not to our knowledge been reported, such as elevated SBS17a/b in European esophageal carcinomas. These examples suggest that AMSD is a robust tool for detecting differences among groups of tumors or other mutated samples, complementing descriptive signature deconvolution and enabling the discovery of environmental and genetic influences on mutagenesis.}, }
@article {pmid41721421, year = {2026}, author = {Kenny, A and Voldal, EC and Xia, F and Chan, KCG and Heagerty, PJ and Hughes, JP}, title = {Factors affecting power in stepped wedge trials when the treatment effect varies with time.}, journal = {Trials}, volume = {27}, number = {1}, pages = {}, pmid = {41721421}, issn = {1745-6215}, support = {R37AI029168//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; Time Factors ; *Randomized Controlled Trials as Topic/methods/statistics &amp; numerical data ; *Research Design/statistics &amp; numerical data ; Sample Size ; Computer Simulation ; Models, Statistical ; Treatment Outcome ; Data Interpretation, Statistical ; Software ; Cluster Analysis ; }, abstract = {BACKGROUND: Stepped wedge cluster randomized trials (SW-CRTs) have historically been analyzed using immediate treatment (IT) models, which assume the effect of the treatment is immediate after treatment initiation and subsequently remains constant over time. However, recent research has shown that this assumption can lead to severely misleading results if treatment effects vary with exposure time, i.e., time since the intervention started. Models that account for time-varying treatment effects, such as the exposure time indicator (ETI) model, allow researchers to target estimands such as the time-averaged treatment effect (TATE) over an interval of exposure time, or the point treatment effect (PTE) representing a treatment contrast at one time point. However, this increased flexibility results in reduced power.<br><br>METHODS: In this paper, we use public power calculation software and simulation to characterize factors affecting SW-CRT power. Key elements include choice of estimand, study design considerations, and analysis model selection.<br><br>RESULTS: For common SW-CRT designs, the sample size (clusters per sequence or individuals per cluster-period) must be increased substantially, commonly by a factor of 1.5 to 3, but often by much more, to maintain 90% power when switching from an IT model to an ETI model (targeting the TATE over the study). However, the inflation factor is lower for TATE estimands over shorter periods that exclude longer exposure times. In general, SW-CRT designs (including the "staircase" variant) have much greater power for estimating "short-term effects" relative to "long-term effects." For an ETI model targeting a TATE estimand, substantial power can be gained by adding time points to the start of the study or increasing baseline sample size, but surprisingly, little power is gained from adding time points to the end of the study. More restrictive choices for modeling the exposure time or calendar time trends (e.g., splines or linear terms) have little effect on power for TATE estimands but increases power for PTE estimands. If the effect curve is constant after a washout period, a "delayed constant treatment" model that uses exposure time indicators during the washout period but assumes a constant effect thereafter can slightly increase power relative to an IT model that discards washout period data.}, }
@article {pmid41722572, year = {2026}, author = {Abadie, FMC and Suiter, CC and Smith, NT and Daza, RM and Rominger, MC and Parrish, P and McDiarmid, TA and Lalanne, JB and Martin, B and Calderon, D and Ellison, A and Berger, AH and Shendure, J and Starita, LM}, title = {A multiplex, prime editing framework for identifying drug resistance variants at scale.}, journal = {Cell genomics}, volume = {}, number = {}, pages = {101167}, doi = {10.1016/j.xgen.2026.101167}, pmid = {41722572}, issn = {2666-979X}, abstract = {CRISPR-based genome editing has revolutionized functional genomics, enabling thousands of perturbations to be concurrently assayed in single experiments. However, for methods such as saturation genome editing (SGE), which aims to generate and assay libraries of point mutations, a challenge is that only one region (e.g., one exon) is studied per experiment. Here, we describe prime-SGE, a prime editing-based framework in which libraries of specific point mutations are installed into genes throughout the genome and then functionally assessed by sequencing of prime editing guide RNAs (pegRNAs) rather than the mutations themselves. We apply prime-SGE in two cell lines to assay thousands of point mutations in eight oncogenes for their ability to confer drug resistance to four tyrosine kinase inhibitors. Our prime-SGE strategy, combined with ongoing improvements in prime editing efficiency, opens the door to efficient positive selection screens of large numbers of point mutations at locations throughout the genome.}, }
@article {pmid41722658, year = {2026}, author = {Al-Hallaq, HA and Zoberi, JE and Tran, A and Kim, H and Lowenstein, JR and Meyer, J}, title = {A National Survey of Medical Physicists: Part 2-Assessing Work Effort and Perceived Challenges and Satisfaction in HDR Brachytherapy.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2026.02.229}, pmid = {41722658}, issn = {1879-355X}, abstract = {PURPOSE: To collect national data from medical physicists on work effort, challenges, and job satisfaction in high-dose rate (HDR) brachytherapy (BT) as a function of procedure complexity.<br><br>METHODS AND MATERIALS: A survey was administered in cooperation with IROC-Houston. Question topics included demographics, practice patterns, caseload, procedure complexity, relative time and effort required for simple and complex cases, and challenges/satisfaction associated with HDR BT.<br><br>RESULTS: Of 429 completed responses, 365 performed HDR BT. The most commonly treated anatomic sites were gynecologic, prostate, and skin, with 56% of respondents' clinics performing interstitial procedures. Respondents indicated that the median time and intensity ratios of a single-channel HDR BT, relative to a weekly chart check (CPT77336), were 5 and 3, respectively, implying a work ratio of 15. When comparing the most complex procedure with a single-channel treatment, the median time and intensity ratios reported were both 5, implying a work ratio of 25. The time and intensity ratios scaled with increasing complexity for gyne procedures (ie, 1, 2-3, and &#x2265;4 channels). Most respondents reported that it was more stressful to cover HDR BT versus external beam radiation therapy (EBRT) (82%) and to switch between services (73%). Job satisfaction was impacted most positively by direct patient contact and the experience level of authorized users, but most negatively by increased stress compared with other services and maintaining skill levels due to infrequent cases. Only the subset of respondents at clinics treating complex gyne with a high caseload (&#x2265;25 patients/y) indicated that staff allocation was inadequate or that a colleague had left their position due to HDR BT.<br><br>CONCLUSIONS: The results show a relationship between work effort and procedure complexity, which is currently not addressed in national staffing recommendations. To sustain a workforce capable of supporting HDR brachytherapy into the future, professional societies/leaders must recognize the stress and intensity of complex cases and adjust staffing recommendations accordingly.}, }
@article {pmid41724531, year = {2026}, author = {Brück, CC and Mwangi, LW and van Wifferen, F and Hsu, L and Thomas, M and Peters, U}, title = {Risk-based screening for early detection of colorectal cancer: an overview.}, journal = {Best practice &amp; research. Clinical gastroenterology}, volume = {80}, number = {}, pages = {102014}, doi = {10.1016/j.bpg.2025.102014}, pmid = {41724531}, issn = {1532-1916}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/epidemiology/genetics ; *Early Detection of Cancer/methods/economics ; Risk Assessment ; Risk Factors ; Cost-Benefit Analysis ; *Mass Screening/methods/economics ; }, abstract = {Screening programs for colorectal cancer (CRC) reduce CRC incidence and mortality, while balancing benefits and harms of the population. However, benefits vary widely among individuals. Low-risk individuals may face unnecessary burdens, while high-risk individuals could benefit from more intensive screening. Risk-based screening addresses these issues by tailoring screening strategies using risk factors such as age, sex, race, ethnicity, lifestyle factors, genetic predisposition, and previous screening results. Potential benefits of risk-based screening include improved cost-effectiveness, efficient resource use and reduced unnecessary procedures. Challenges include a lack of validated risk stratification tools, data availability, healthcare capacity, and ethical considerations. Several countries started to evaluate risk-based screening programs with optimistic results. While promising, further research is necessary to address the remaining challenges. Nevertheless, risk-based screening has the potential to enhance patient experiences, optimize the balance of individual-level benefits and harms, and positively impact the overall burden and costs associated with CRC screening.}, }
@article {pmid41724648, year = {2026}, author = {Gupta, S and Li, R and Hensley, PJ and Daneshmand, S and Faltas, BM and Grivas, P and Lobo, N and Mir, MC and Meeks, JJ and Mouw, KW and Moschini, M and Necchi, A and Oualla, K and Pohar, KS and Rosenberg, JE and Schmidt, B and Siefker-Radtke, AO and Steinberg, GD and Stenzl, A and Buckley, RJ and Kamat, AM}, title = {Optimal Management of Muscle-invasive Bladder Cancer: Recommendations from the International Bladder Cancer Group.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2026.01.029}, pmid = {41724648}, issn = {1873-7560}, abstract = {BACKGROUND AND OBJECTIVE: The management of muscle-invasive bladder cancer (MIBC) is evolving rapidly with the emergence of new perioperative treatments and approaches for bladder preservation. We provide guidance on clinical staging and optimal therapeutic sequencing for patients with MIBC in clinical practice and within the context of clinical trial design.<br><br>METHODS: The International Bladder Cancer Group (IBCG) convened global experts in bladder cancer to develop recommendations for the management of MIBC and to guide clinical trial design. Working groups reviewed the literature and developed draft recommendations. This was followed by voting by the IBCG members during a live meeting in August 2024 using a modified Delphi process. Recommendations achieving &#x2265;75% agreement during the meeting were further refined and presented.<br><br>KEY FINDINGS AND LIMITATIONS: The IBCG recommends thorough clinical staging and multidisciplinary care for patients with MIBC. Contemporary retrospective comparisons suggest that radical cystectomy (RC) and trimodal therapy have similar oncologic efficacy. Patients with pure squamous-cell carcinoma or adenocarcinoma are best managed with upfront RC, while cisplatin-based neoadjuvant therapy before RC is recommended for other histologic subtypes. Risk-stratified adjuvant therapy approaches should be used after RC. There are no currently validated predictive biomarkers to guide clinical decision-making in MIBC outside the context of a clinical trial. The IBCG recommends the use of time-to-event endpoints for perioperative therapy trials, and bladder-intact event-free survival for bladder preservation trials, with an emphasis on incorporating patient-reported quality-of-life endpoints.<br><br>The IBCG consensus recommendations provide practical guidance on optimal treatment sequencing strategies in the management of MIBC.}, }
@article {pmid41725518, year = {2026}, author = {Kikawa, C and Loes, AN and Huddleston, J and Figgins, MD and Steinberg, P and Griffiths, T and Drapeau, EM and Peck, H and Barr, I and Englund, JA and Hensley, SE and Bedford, T and Bloom, JD}, title = {High-throughput neutralization measurements correlate strongly with evolutionary success of human influenza strains.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {41725518}, issn = {2050-084X}, support = {R01 AI127893/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; R01AI165821//National Institute of Allergy and Infectious Diseases/ ; T32AI083203//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *Influenza, Human/virology/immunology ; *Influenza A Virus, H3N2 Subtype/immunology/genetics/growth &amp; development ; *Neutralization Tests/methods ; *Antibodies, Neutralizing/blood/immunology ; *Antibodies, Viral/blood/immunology ; Child ; Hemagglutinin Glycoproteins, Influenza Virus/genetics/immunology ; Adult ; *Evolution, Molecular ; Child, Preschool ; Adolescent ; Young Adult ; High-Throughput Screening Assays ; }, abstract = {Human influenza viruses rapidly acquire mutations in their hemagglutinin (HA) protein that erode neutralization by antibodies from prior exposures. Here, we use a sequencing-based assay to measure neutralization titers for 78 recent H3N2 HA strains against a large set of children and adult sera, measuring ~10,000 total titers. There is substantial person-to-person heterogeneity in the titers against different viral strains, both within and across age cohorts. The growth rates of H3N2 strains in the human population in 2023 are highly correlated with the fraction of sera with low titers against each strain. Notably, strain growth rates are less correlated with neutralization titers against pools of human sera, demonstrating the importance of population heterogeneity in shaping viral evolution. Overall, these results suggest that high-throughput neutralization measurements of human sera against many different viral strains can help explain the evolution of human influenza.}, }
@article {pmid41726464, year = {2024}, author = {Yaseen, F and ,  and Hippe, DS and Soni, PV and Wang, S and Duan, C and Gennari, JH and Bowen, SR}, title = {Variogram Modeling of Spatially Variant Early Response to Therapy in Advanced Non-Small Cell Lung Cancer.}, journal = {AMIA ... Annual Symposium proceedings. AMIA Symposium}, volume = {2024}, number = {}, pages = {1454-1463}, pmid = {41726464}, issn = {1942-597X}, mesh = {*Carcinoma, Non-Small-Cell Lung/therapy/pathology/diagnostic imaging ; Humans ; *Lung Neoplasms/therapy/pathology/diagnostic imaging ; }, abstract = {Predicting heterogeneity in treatment response for non-small cell lung cancer (NSCLC) at multiple scales, both between patients and spatially within each patient, can support clinical decisions that personalize oncologic management. In this study, we evaluated different variogram models of voxel-level spatial correlation in tumor response in locally advanced NSCLC and metastatic NSCLC from two different clinical trials. The Stable model achieved the lowest root mean squared error (RMSE) on average (mean: 5.2-5.5%), followed by the Matérn model (mean: 5.8-7.4%), both of which performed better than most other models. In contrast, the Exponential model had the highest RMSE (mean: 9.4-15.6%). These results remained consistent across two different cohorts of NSCLC. Given the robust performance of the Stable model, it may generalize for modeling spatial response in other clinical settings beyond NSCLC and should be further studied.}, }
@article {pmid41726900, year = {2026}, author = {Baraznenok, E and Hsieh, HC and Lan, L and Konnick, EQ and Figiel, S and Rao, SR and Woodcock, DJ and Mills, IG and Hamdy, F and Valk, JE and Carter, KT and Yu, M and Paulson, TG and Dintzis, S and Grady, WM and Liu, JTC}, title = {Assessing the effects of a 3D pathology tissue-processing workflow on downstream molecular analyses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41726900}, issn = {2692-8205}, abstract = {Non-destructive 3D pathology methods have emerged in recent years with the potential to enhance standard 2D histopathology by greatly increasing the amount of tissue sampled by imaging and by providing volumetric morphological context. Another key advantage is that tissues remain intact, allowing re-embedding after imaging for potential long-term storage and future histological or molecular analyses. However, the impact of 3D pathology protocols on biomolecules - including DNA, RNA, and proteins - and their compatibility with downstream assays, has not been systematically evaluated. Here, we applied a previously optimized 3D pathology protocol - involving deparaffinization, fluorescent H&amp;E-analog staining, optical clearing, and open-top light-sheet microscopy - to formalin-fixed paraffin-embedded (FFPE) specimens of breast, prostate, and head and neck cancer. Following the protocol, tissues were re-embedded in paraffin and compared with paired FFPE controls that did not undergo 3D pathology processing. DNA and RNA were extracted and subjected to quality assessments. Amplifiability was tested by PCR and reverse transcription quantitative PCR (RT-qPCR) of housekeeping genes. Although the results showed a slight decrease in the average yield and increased fragmentation of both DNA and RNA, amplifiability was largely preserved. Sanger sequencing of the PCR products confirmed accurate sequence determinations, while total RNA sequencing indicated that the global transcriptomic profile was largely unchanged. IHC staining of common biomarkers produced comparable signals, suggesting those proteins are well preserved after the 3D pathology workflow. These results demonstrate the feasibility of combining 3D pathology with downstream molecular applications.}, }
@article {pmid41726945, year = {2026}, author = {Patton, RD and Netzley, A and Persse, TW and Nair, A and Galipeau, PC and Coleman, IM and Itagi, P and Chandra, P and Adil, M and Vashisth, M and Sayar, E and Hiatt, JB and Dumpit, R and Kollath, L and Demirci, RA and Ghodsi, A and Lam, HM and Morrissey, C and Iravani, A and Chen, DL and Hsieh, AC and MacPherson, D and Haffner, MC and Nelson, PS and Ha, G}, title = {Deep learning-based non-invasive profiling of tumor transcriptomes from cell-free DNA for precision oncology.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41726945}, issn = {2692-8205}, abstract = {Circulating tumor DNA (ctDNA) profiling from liquid biopsies is increasingly adopted as a minimally invasive solution for clinical cancer diagnostic applications. Current methods for inferring gene expression from ctDNA require specialized assays or ultra-deep, targeted sequencing, which preclude transcriptome-wide profiling at single-gene resolution. Herein we jointly introduce Triton, a tool for comprehensive fragmentomic and nucleosome profiling of cell-free DNA (cfDNA), and Proteus, a multi-modal deep learning framework for predicting single gene expression, using standard depth (~30-120x) whole genome sequencing of cfDNA. By synthesizing fragmentation and inferred nucleosome positioning patterns in the promoter and gene body from Triton, Proteus reproduced expression profiles using pure ctDNA from patient-derived xenografts (PDX) with an accuracy similar to RNA-Seq technical replicates. Applying Proteus to cfDNA from four patient cohorts with matched tumor RNA-Seq, we show that the model accurately predicted the expression of specific prognostic and phenotype markers and therapeutic targets. As an analog to RNA-Seq, we further confirmed the immediate applicability of Proteus to existing tools through accurate prediction of gene pathway enrichment scores. Our results demonstrate the potential clinical utility of Triton and Proteus as non-invasive tools for precision oncology applications such as cancer monitoring and therapeutic guidance.}, }
@article {pmid41727151, year = {2026}, author = {Simonich, CAL and McMahon, TE and Kampman, L and Chu, HY and Bloom, JD}, title = {Complete definition of how mutations affect antibodies used to prevent RSV.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41727151}, issn = {2692-8205}, abstract = {New antibodies targeting the F protein of respiratory syncytial virus (RSV) have substantially reduced infant hospitalizations. However, viral resistance is a concern: one antibody failed clinical trials due to emergence of a resistant strain, and sporadic resistance mutations to the most widely used antibody (nirsevimab) have been identified in breakthrough infections. Here we define how RSV F mutations affect antibody neutralization. We first provide a biophysical model of how the buffering effect of bivalent IgG binding combines with differences in monovalent Fab potency to explain why nirsevimab resistance mutations are more common in subtype B than subtype A RSV strains. We then perform pseudovirus deep mutational scanning to safely measure how nearly all mutations to F affect its cell entry function and neutralization by the IgG and Fab forms of nirsevimab, clesrovimab, and several other key antibodies. We use these measurements to enable real-time surveillance of RSV sequences for antibody resistance, and identify rare strains with sporadic resistance mutations. Overall, our work improves understanding of the mechanisms by which viral mutations impact antibody neutralization, enables monitoring for natural RSV strains resistant to antibodies of public-health importance, and can help guide development of future antibodies with resilience to viral escape.}, }
@article {pmid41727567, year = {2026}, author = {Termini, C and Woodruff, K and Patel, D and Peplinski, J and Setiawan, N and Hagen, M and Meshinchi, S}, title = {HS6ST1 regulates acute myeloid leukemia chemotherapy resistance via TGF-β1 signaling.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {41727567}, issn = {2693-5015}, abstract = {Despite therapeutic advances, relapse remains the leading cause of death in patients with acute myeloid leukemia (AML). Growth factor signaling controls AML survival, proliferation, relapse, and chemotherapy resistance. Here, we studied heparan sulfate proteoglycans, a class of molecules that bind growth factors via their heparan sulfate chains to change their signaling ability. Heparan sulfate-growth factor interactions are controlled by the addition of sulfate groups catalyzed by heparan sulfotransferases, such as those encoded by HS2ST1 and HS6ST1. Using AML patient cohort analyses, we demonstrate that increased HS6ST1 expression is associated with worse survival and increased relapse risk for AML patients harboring KMT2A-rearrangements. Using cell line derived xenografts, we show that AML cells depleted of HS2ST1, but not HS6ST1, have increased bone marrow leukemic burden. Further, AML cells depleted of HS6ST1 are more sensitive to cytarabine than Control cells, suggesting that HS6ST1 regulates AML chemotherapy resistance. Heparan sulfate antagonism with surfen synergized with cytarabine to further support AML cell death compared to cytarabine alone. Mechanistically, we demonstrate that HS6ST1 depletion in AML cells reduces TGF-β1-mediated signaling, which diminishes cell survival upon cytarabine treatment. Together, our data show that HS6ST1 promotes AML cell chemotherapy resistance by supporting TGF-β1 signaling.}, }
@article {pmid41728343, year = {2026}, author = {Burugupally, G and Nakamura, M and Aarrestad, C and Parkhurst, SM}, title = {The LDL pathway regulates actomyosin ring dynamics necessary for optimal cell wound repair.}, journal = {microPublication biology}, volume = {2026}, number = {}, pages = {}, pmid = {41728343}, issn = {2578-9430}, abstract = {Individual cells must rapidly repair any cortical damage from environmental or physiological stresses, to survive and to contribute to maintaining the proper function of tissues and organs. The formation of an actomyosin ring around the wound periphery is an important step in physically closing the cell wound. Here, we find that the Low-Density Lipoprotein (LDL) pathway, which is usually associated with plasma membrane homeostasis, is needed for optimal cell wound repair. In this context, the LDL pathway is required for robust actomyosin ring formation, revealing an unexpected role in regulating actin dynamics during cell wound repair.}, }
@article {pmid41728684, year = {2026}, author = {Chiusolo, P and Bacigalupo, A and Salit, R and Schroeder, T and Finazzi, MC and Gurnari, C and Pagliuca, S and Metzdorf, J and Rautenberg, C and Robin, M and Rubio, MT and Maciejewski, J and Popat, U and Rambaldi, A and Reinhardt, HC and Scott, B and Kröger, N and Gagelmann, N}, title = {PTCy or ATG for Matched Transplantation in Myelofibrosis.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70244}, pmid = {41728684}, issn = {1096-8652}, }
@article {pmid41730188, year = {2026}, author = {Hong, SJH and Patton, M and Barton, KS and Palermo, TM and Mulholland, K and Chow, EJ and Lau, N}, title = {Facilitators and Barriers to Implementing Mobile Mental Health Interventions: Qualitative Study of the Consolidated Framework for Implementation Research in Pediatric Oncology Providers.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e87533}, pmid = {41730188}, issn = {1438-8871}, mesh = {Humans ; *Telemedicine ; Female ; Qualitative Research ; Adult ; Male ; Adolescent ; *Mobile Applications ; *Medical Oncology ; *Neoplasms/psychology/therapy ; *Mental Health ; Young Adult ; *Health Personnel ; Pediatrics ; Middle Aged ; }, abstract = {BACKGROUND: Adolescent and young adult (AYA) cancer survivors experience unique psychosocial needs during and after treatment. Mobile health (mHealth) interventions are an emerging area of research to help address unmet psychosocial needs. However, few studies have examined provider perspectives on the design-to-implementation pipeline.<br><br>OBJECTIVE: Guided by the Consolidated Framework for Implementation Research (CFIR), our study aimed to examine provider perspectives on facilitators and barriers to implementing mHealth apps in routine clinical care.<br><br>METHODS: AYA oncology providers participated in a semistructured 1:1 interview on facilitators and barriers to incorporating mHealth apps as psychosocial standard of care. We conducted a directed content analysis of the interviews using a standardized CFIR codebook and construct definitions, with codebook adaptations for mHealth innovations and the population of AYAs with cancer.<br><br>RESULTS: A total of 20 providers (mean 39, SD 7.0 years; 80% female and 70% non-Hispanic White) representing various medical and psychosocial roles participated in the interviews. The data were analyzed with 16 CFIR constructs. We identified the following facilitators to mHealth implementation across four CFIR domains: (1) Innovation: alignment with patient needs, patient-centered co-design, strong research evidence, and user-friendly design; (2) Outer Setting: shared commitment to addressing mental health needs and openness to mHealth use; (3) Inner Setting: openness to training on mHealth use; and (4) Individuals: engaging key implementation partners such as bedside nurses and social workers and strong clinical team buy-in. We identified the following barriers to mHealth implementation across three CFIR domains: (1) Innovation: associated costs, (2) Outer Setting: heavy clinical workloads, and (3) Inner Setting: lack of cross-team collaboration and communication and clinical workflow integration.<br><br>CONCLUSIONS: Our findings highlight key considerations for mHealth co-design, the adoption of mHealth apps into routine care, implementation strategies, and provider training opportunities in the context of AYA cancer care. Partnering with AYA cancer survivors, families, and providers will be crucial for developing and implementing mHealth apps with the ultimate goal of advancing universally accessible evidence-based digital health care.}, }
@article {pmid41730232, year = {2026}, author = {Singal, AG and Jin, Q and Marrero, J and Parikh, ND and Lok, AS and Lopez, C and Page-Lester, S and Roberts, LR and Reddy, R and Luster, M and Khaderi, S and Asrani, SK and El-Serag, HB and Kanwal, F and Feng, Z and Tayob, N}, title = {Validation of longitudinal biomarker screening algorithms for HCC detection in patients with cirrhosis.}, journal = {Hepatology communications}, volume = {10}, number = {3}, pages = {}, pmid = {41730232}, issn = {2471-254X}, mesh = {Humans ; *Carcinoma, Hepatocellular/diagnosis/blood/etiology ; *Liver Neoplasms/diagnosis/blood/etiology ; Male ; Female ; Middle Aged ; *Liver Cirrhosis/complications/blood ; *Algorithms ; *Early Detection of Cancer/methods ; Aged ; *Biomarkers, Tumor/blood ; Longitudinal Studies ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: Blood-based biomarker panels, including GALAD, have been proposed as an alternative to abdominal ultrasound for hepatocellular carcinoma (HCC) surveillance. Studies suggest longitudinal evaluation of biomarkers can improve test performance; however, no large studies have validated these findings.<br><br>METHODS: We leveraged the HCC Early Detection Strategy (HEDS) study (n=1019 patients with cirrhosis; 99 incident HCC) and Texas HCC Consortium (THCCC) (n=2345 patients with cirrhosis; 126 incident HCC) to compare the performance of fixed-threshold GALAD (cutoff of -1.36), and 4 longitudinal algorithms: longitudinal GALAD, PALAD, mFB-ALAD, and mPEB-ALAD. The HEDS cohort was used to derive longitudinal algorithms, and external validation was performed in THCCC. Patient-level sensitivity and test-level false-positive rate (FPR) were examined overall and across subgroups by age, sex, and cirrhosis etiology.<br><br>RESULTS: In THCCC, fixed-threshold GALAD had higher sensitivity in the 6 months before HCC diagnosis (71.4%, 95% CI: 62.9%-81.7%) than longitudinal GALAD (55.1%, 95% CI: 49.3-66.4), PALAD (55.1%, 95% CI: 50.0%-70.5%), mPEB-ALAD (53.1%, 95% CI: 43.6%-62.0%), and mFB-ALAD (42.9%, 95% CI: 32.3-48.5). However, fixed-threshold GALAD had a higher FPR (25.4%, 95% CI: 23.7%-26.9%) compared with longitudinal GALAD (15.0%, 95% CI: 12.8%-15.8%), PALAD (13.0%, 95% CI: 10.2%-14.6%), and mFB-ALAD (11.2%, 95% CI: 9.6%-12.1%) but comparable to mPEB-ALAD (22.9%, 95% CI: 21.2%-23.8%). In subgroup analyses, fixed-threshold GALAD had the highest FPR in males (35.6%) and those aged &#x2265;65 (43.5%); longitudinal algorithms had significantly lower FPRs in subgroups but with lower sensitivity for HCC.<br><br>CONCLUSIONS: Improvements in FPRs with longitudinal GALAD algorithms, as compared with fixed-threshold GALAD, are offset by significantly decreased sensitivity for HCC detection.}, }
@article {pmid41730389, year = {2026}, author = {Chari, ST and Feng, Z}, title = {Reply.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2026.02.019}, pmid = {41730389}, issn = {1528-0012}, }
@article {pmid41730823, year = {2026}, author = {Hudson, A and Borgetti, S and Rick, AM and Laurens, MB and Robinson, ST and Gay, CL and Baden, LR and Goepfert, PA and Rouphael, N and El Sahly, HM and Gray, GE and Grinsztejn, B and Sobieszczyk, ME and Falsey, AR and Huang, Y and Janes, H and Follmann, D and Koup, RA and Priddy, F and Hendriks, J and Shoemaker, K and Dunkle, LM and de Bruyn, G and Devlin, L and Neuzil, KM and Kublin, JG and Corey, L and Walsh, SR and Kotloff, KL and Gilbert, PB}, title = {Impact of prior SARS-CoV-2 acquisition on binding and neutralizing antibody responses following COVID-19 vaccination: A cross-protocol analysis of individual-level data from six phase 3 clinical trials.}, journal = {Vaccine}, volume = {77}, number = {}, pages = {128380}, pmid = {41730823}, issn = {1873-2518}, support = {UM1 AI069423/AI/NIAID NIH HHS/United States ; UM1 AI148450/AI/NIAID NIH HHS/United States ; UM1 AI148576/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UL1 RR025758/RR/NCRR NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/blood/immunology ; *COVID-19/prevention &amp; control/immunology ; *Antibodies, Viral/blood/immunology ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; *SARS-CoV-2/immunology ; Female ; Male ; Middle Aged ; Adult ; Immunogenicity, Vaccine ; Clinical Trials, Phase III as Topic ; Vaccination ; Vaccine Efficacy ; Aged ; }, abstract = {BACKGROUND: The COVID-19 Prevention Network (CoVPN) co-conducted six COVID-19 phase 3 vaccine efficacy (VE) trials that featured harmonized immunogenicity analyses using validated antibody assays. These trials enabled a uniquely comprehensive characterization of immunogenicity produced by different vaccine platforms and regimens in individuals with and without prior SARS-CoV-2 acquisition.<br><br>METHODS: Comparisons of serum binding antibody concentration and serum neutralization antibody ID50 titers were performed across three strata: vaccine immunity (vaccination in SARS-CoV-2-na&#xef;ve individuals), natural immunity (placebo with prior SARS-CoV-2 acquisition), and hybrid immunity (vaccination after prior SARS-CoV-2 acquisition). We compared immunogenicity across immunity strata for each trial and each dose, adjusting for age, sex assigned at birth, and body mass index. Antibody levels were also examined in relation to VE.<br><br>RESULTS: Antibody levels in response to a single vaccine dose varied across trials and generally increased most substantially after a second dose in na&#xef;ve participants. Fold rise in antibody levels after a single dose were more pronounced in participants with hybrid immunity: a single dose of any of the tested vaccine yielded responses comparable to or exceeding the post-dose-two (peak) response of any two-dose vaccine in na&#xef;ve participants. Population-level antibody levels demonstrated high concordance with VE across trials and immunity strata.<br><br>CONCLUSIONS: In SARS-CoV-2-na&#xef;ve individuals, a two-dose vaccine regimen is needed to provide antibody levels correlated with protection against disease caused by the cognate virus strain. In contrast, in individuals with prior SARS-CoV-2 acquisition, a single dose of any of the tested vaccines/platforms (mRNA/protein/vector) provides comparably high antibody levels.}, }
@article {pmid41732008, year = {2026}, author = {Yu, EY and Gratzke, C and Burotto, M and Zhang, AY and Lévesque, E and Ortega, F and Peer, A and Vile, D and Chen, ZH and Song, Y and Schloss, C and Todoric, J and Garratt, C and Poehlein, C and Antonarakis, ES and Fizazi, K}, title = {Steroidogenesis inhibitor opevesostat (MK-5684) for metastatic castration-resistant prostate cancer: OMAHA-003 and OMAHA-004 trial designs.}, journal = {Future oncology (London, England)}, volume = {22}, number = {7}, pages = {765-772}, pmid = {41732008}, issn = {1744-8301}, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology/mortality ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic ; Receptors, Androgen/metabolism/genetics ; *Thiohydantoins/therapeutic use/adverse effects/administration &amp; dosage ; Neoplasm Metastasis ; Treatment Outcome ; Androstadienes ; Benzimidazoles ; }, abstract = {Treatment options for metastatic castration-resistant prostate cancer (mCRPC) include androgen receptor pathway inhibitors (ARPIs), taxanes, radium-223, Lu-PSMA, poly (ADP-ribose) polymerase inhibitors, and immunotherapy in select patients. Resistance to ARPIs and hormone-based therapies has been associated with AR-ligand-binding domain mutations that can lead to promiscuous stimulation by other steroid hormones. There is a need to explore alternative targets and develop next-generation ARPIs or combination therapies that overcome this resistance. We describe the rationale and design of the randomized phase III trials OMAHA-003 (NCT06136624) and OMAHA-004 (NCT06136650), which will evaluate the efficacy and safety of opevesostat, a steroidogenesis inhibitor, versus ARPI switch in previously treated mCRPC. Results may support opevesostat as a potential new treatment option for mCRPC.Clinical trial registration: www.clinicaltrials.gov identifiers are NCT06136624 and NCT06136650.}, }
@article {pmid41733330, year = {2026}, author = {Su, M and Khan, AM and Cowan, AJ and Anderson, LD and Kaur, G and Banerjee, R}, title = {Resumption of bone-modifying agents in relapsed multiple myeloma does not improve outcomes: A real-world analysis.}, journal = {British journal of haematology}, volume = {208}, number = {4}, pages = {1324-1330}, doi = {10.1111/bjh.70395}, pmid = {41733330}, issn = {1365-2141}, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; Recurrence ; *Bone Density Conservation Agents/therapeutic use/administration &amp; dosage/adverse effects ; Aged, 80 and over ; Adult ; Treatment Outcome ; }, abstract = {While bone-modifying agents (BMAs) are well-established components of frontline therapy in multiple myeloma, there are no data in the modern era to support their use in the relapsed setting. We conducted a retrospective analysis of US patients with relapsed/refractory multiple myeloma (RRMM) diagnosed between 2014 and 2023. Progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models adjusting for covariates including BMA receipt (BMA-received) versus not (BMA-deferred) at relapse. Of 1112 RRMM patients, 633 (56.9%) patients received BMAs following relapse. Compared to BMA-received patients, BMA-deferred patients had slightly worsened renal function and were less likely to have received BMAs during frontline therapy. There were no differences in PFS between groups: median PFS 10.1 months (95% confidence interval [CI] 8.9-11.8 months) for BMA-deferred patients versus 9.2 months (95% CI 7.7-11.3 months; p = 0.08) for BMA-received patients. There were no differences in OS: median OS 39.6 months (95% CI 33.9-58.1 months) for BMA-deferred patients versus 51.5 months (95% CI 41.8-60.1 months; p = 0.10) for BMA-received patients. Given the lack of clear benefit to BMA in the modern era, our data support future investigations to better personalize decision-making around BMA resumption in RRMM.}, }
@article {pmid41733389, year = {2026}, author = {DeMeules, MM and Proll, SC and Hua, X and Srinivasan, S and Loeffelholz, T and Liu, C and Wu, MC and Fiedler, TL and Hoffman, NG and Bourassa, LA and Pergam, SA and Fredricks, DN}, title = {Gut Microbiota and Intestinal Monodomination as a Predictor for Bacteremia in Allogeneic Hematopoietic Cell Transplant Recipients.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiag005}, pmid = {41733389}, issn = {1537-6613}, support = {R01 AI134808/AI/NIAID NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; R01 AI134808/NH/NIH HHS/United States ; P30CA015704//Fred Hutch Cancer Center/ ; }, abstract = {BACKGROUND: Bacteremia is a frequent complication in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Alterations to the gut microbiota after HCT have been associated with adverse outcomes including bacteremia and reduced overall survival. Previous studies suggest that loss of gut bacterial diversity and domination by a single species may predict bloodstream infections, but the degree of domination leading to the optimal positive predictive value (PPV) has not been defined.<br><br>METHODS: Stool samples were collected weekly from allogeneic HCT recipients and were analyzed by 16S rRNA gene PCR with sequencing to determine gut microbiota composition and document domination events. Bacteremia events were captured by review of medical records. The PPV for bacteremia of any detection of that species in stool and for domination events at 10%, 30%, and 50% abundance were calculated.<br><br>RESULTS: Of 277 HCT recipients, 95 experienced bacteremia, with 130 bacteremia events. Intestinal domination was associated with but not highly predictive for bacteremia, reflected by low PPV. Presence of coagulase-negative Staphylococcus in the gut at >30% relative abundance was associated with increased risk of coagulase-negative Staphylococcus bloodstream infections with PPV of 38%.<br><br>CONCLUSIONS: Hematopoietic cell transplantation is associated with significant disruption to the gut microbiota, particularly in patients who subsequently develop bacteremia. Intestinal domination may not be as useful as previously thought given its low PPV for most species implicated in bloodstream infections. The association between gut colonization with Staphylococcus and bacteremia events suggests that the gut may be an under-recognized portal of entry for these organisms in patients after HCT.}, }
@article {pmid41734278, year = {2026}, author = {Piliper, E and Goya, S and Greninger, AL}, title = {RUMINA: high-throughput deduplication of unique molecular identifiers for amplicon and whole-genome sequencing with enhanced error correction.}, journal = {Bioinformatics (Oxford, England)}, volume = {42}, number = {3}, pages = {}, pmid = {41734278}, issn = {1367-4811}, support = {64903//NIH ACDC/AViDD/ ; //Department of Laboratory Medicine and Pathology at the University of Washington Medical Center/ ; }, mesh = {*High-Throughput Nucleotide Sequencing/methods ; *Software ; *Whole Genome Sequencing/methods ; Humans ; *Sequence Analysis, DNA/methods ; }, abstract = {MOTIVATION: Unique molecular identifiers (UMIs) are widely used in next-generation sequencing to enable accurate molecular counting and error correction. However, challenges remain in accurately collapsing UMI clusters, especially when read counts are low or sparse read clusters arise from barcode sequencing errors.<br><br>RESULTS: We present RUMINA, a Rust-based pipeline for UMI-aware deduplication and error correction, optimized for both amplicon and shotgun sequencing. RUMINA supports multiple UMI cluster strategies, alongside majority-rule read selection independent of mapping quality, as well as discrete handling of 1-2 read clusters, paired-end merging, and read-length stratification. Benchmarking using simulated HIV population sequencing data and real-world iCLIP and TCR datasets showed that RUMINA improves ultra-low frequency SNV detection (0.01%-1%), reduces false positives, enhances reproducibility, and processes sequencing data up to 10-fold faster than existing tools. By integrating UMI- and sequence-level correction in a high-performance framework, RUMINA offers a fast, scalable, and robust solution for UMI-enabled sequencing workflows.<br><br>RUMINA is implemented in Rust and distributed as open-source code and precompiled binaries. Source code and installation instructions are available at https://github.com/greninger-lab/rumina. Documentation associated with this manuscript is available at https://github.com/greninger-lab/rumina_paper.}, }
@article {pmid41734346, year = {2026}, author = {Maynard, L and Starke, CE and Poole, NH and Rust, BJ and Zhu, H and Stensland, L and Huang, ML and Pérez-Osorio, AC and Atherley, JI and Einhaus, TK and Murray, JD and Pampena, MB and Betts, MR and Jerome, KR and Riley, JL and Kiem, HP and Peterson, CW}, title = {Antigen-boosted CD4 CAR-T cells fail to expand or control viremia in multiple nonhuman primate models of HIV.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025032142}, pmid = {41734346}, issn = {1528-0020}, abstract = {Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated curative potential in B cell malignancies, yet translating this success to chronic infections like human immunodeficiency virus (HIV) remains a major challenge. In people living with HIV (PLWH) on suppressive antiretroviral therapy (ART), low antigen levels limit CAR-T cell expansion and persistence. We previously reported data from a pilot study which suggested that HIV-targeted CD4CAR-T cells could overcome this barrier through exogenous antigen supplementation, leading to robust in vivo expansion. Here, we sought to comprehensively confirm and expand on those findings. We tested a broad array of strategies to enhance CD4CAR-T cell efficacy, including CRISPR-Cas9-mediated gene editing of immune checkpoint and HIV-associated genes, single and pooled competitive infusions of engineered CAR-T cells, distinct CAR constructs incorporating either CD28 or 4-1BB costimulatory domains, and exogenous antigen boosting. We also developed highly sensitive droplet digital PCR (ddPCR) assays both to quantify CAR-T cell frequency and corroborate flow cytometry-based quantification of CD4CAR T-cell expansion. We evaluated these new approaches across multiple NHP models of HIV, including both simian immunodeficiency virus (SIV)- and simian-human immunodeficiency virus (SHIV)-infected, ART-suppressed NHPs. Although CD4CAR-T cell products exhibited antigen-specific proliferation and cytotoxicity ex vivo, they failed to expand, persist, or control viremia in vivo. We were also unable to confirm previously observed CD4CAR T cell expansions from our earlier studies, which will be retracted. Together these data highlight the need for alternative strategies to potentiate anti-HIV CD4CAR-T cells in the immunocompetent setting.}, }
@article {pmid41734378, year = {2026}, author = {Tan, CR and Usmani, SZ and Derkach, A and De Menezes Silva Corraes, A and Parrondo, RD and Ailawadhi, S and Asoori, S and Dave, M and Popat, R and Morjaria, O and Hajek, R and Mihalyova, J and Htut, M and Janakiram, M and Visram, A and Kastritis, E and Dimopoulos, MA and Martínez-López, J and Nagarajan, C and Bal, S and Costa, LJ and Einsele, H and Steinbrunn, T and Waldschmidt, JM and Riedhammer, C and Banerjee, R and Chng, WJ and Tso, AC and Lin, Y and Martin, TG and Mian, H}, title = {Early Mortality with Bispecific Antibody Therapy in RRMM: An IMWG Immunotherapy Database Real-World Analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025019231}, pmid = {41734378}, issn = {2473-9537}, abstract = {Recent therapeutic advances, including bispecific antibody therapies (bsAbs) have improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM). However, early mortality (EM) remains a significant challenge, even in the era of novel immunotherapies. We conducted a multicenter, retrospective analysis of real-world patients with RRMM treated with commercial bsAbs to evaluate the incidence and causes of EM. Between May 2022 and June 2025, 441 patients were treated across seven countries. EM, defined as death within 12 months of therapy initiation, occurred in 148 patients (34%) with median time from bsAb initiation to death of 2.87 months (IQR 1.38-6.85). The leading cause of EM was progressive disease (72%), followed by infection (13%); regardless of cause of death 82% had active disease at the time of death. Our findings highlight that despite encouraging efficacy, EM remains high among real-world bsAb recipients, emphasizing the need for improved disease control strategies and supportive care interventions.}, }
@article {pmid41734386, year = {2026}, author = {Sekeres, MA and DeZern, AE and Otterstatter, M and Padron, E and Al Baghdadi, T and Foran, JM and Komrokji, RS and Abel, GA and Saber, W and Gore, SD and Lee, C and Bejar, R and Liu, JJ and Deeg, HJ and Sherman, S and Lindsley, RC and Walter, MJ and Gillis, N}, title = {Exposure to Agent Orange and Association with Myelodysplastic Syndromes.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025019262}, pmid = {41734386}, issn = {2473-9537}, }
@article {pmid41735346, year = {2026}, author = {Kong, X and Wang, B and Wu, X and Cho, H and Fu, W and Li, Q and Zhang, R and Nasri, U and Zheng, M and Wu, A and Qin, H and Li, JH and Pillai, R and O'Sullivan, TE and Nakamura, R and Martin, PJ and Chen, Y and Zeng, D}, title = {Stem-like memory-T maintenance and differentiation into tissue-resident T cells sustain chronic graft-versus-host disease in mice.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41735346}, issn = {2041-1723}, support = {R01HL170099//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01HL162847//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {Animals ; *Graft vs Host Disease/immunology/pathology ; *Cell Differentiation/immunology ; *Memory T Cells/immunology ; Mice ; *Immunologic Memory ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-bcl-6/metabolism/genetics/immunology ; *CD4-Positive T-Lymphocytes/immunology ; Hepatocyte Nuclear Factor 1-alpha/metabolism/genetics/immunology ; Basic Helix-Loop-Helix Proteins/metabolism/immunology/genetics ; Chronic Disease ; Lectins, C-Type/metabolism ; Antigens, Differentiation, T-Lymphocyte/metabolism ; Antigens, CD/metabolism ; Female ; Receptors, Antigen, T-Cell/metabolism/immunology ; }, abstract = {Pathogenic CD4[+] memory T cells (Tm) sustain chronic inflammation, but mechanisms remain undefined. Here, we identify four donor-type CD4[+] Tm subsets in the target tissues of autoimmune-like chronic graft-versus-host disease in mice: Ly108[+]CD69[-] stem-like memory T cells (Tsm), Ly108[+]CD69[+] resident memory progenitor T cells (Trmp), Ly108[-]CD69[+] terminally differentiated tissue-resident T cells (Trm), and Ly108[-]CD69[-] intermediate T cells (Tint). Trm are terminally differentiated but not exhausted and show highly biased clonotypes with high proinflammatory cytokine expression. Tsm cells require TCR-MHCII interactions for their maintenance and expansion and show greater capacity than Trmp cells in self-renewal/expansion, generation of Trm, and pathogenicity in adoptive recipients. The transcription factors TCF1/BCL6 and BHLHE40 differentially regulate the stemness and differentiation of Tsm into Trm, respectively, and their selective targeting reduces the number of Trm in tissues and ameliorates inflammation. Thus, our findings indicate that targeting the Tsm subset, involved in the maintenance of the pathogenic Tm pool, offers an attractive approach to treat T cell-mediated chronic inflammation.}, }
@article {pmid41735628, year = {2026}, author = {Ogunjimi, B and Warren-Gash, C and Ouwendijk, WJD and Breuer, J and Mogensen, TH and Koelle, DM}, title = {Varicella zoster virus and the central nervous system.}, journal = {Nature reviews. Microbiology}, volume = {}, number = {}, pages = {}, pmid = {41735628}, issn = {1740-1534}, support = {R01 AG064800/AG/NIA NIH HHS/United States ; }, abstract = {Varicella zoster virus (VZV) causes varicella, also known as chickenpox, after which VZV remains latent in neural ganglia. VZV reactivation can result in herpes zoster, also known as shingles. In addition to its well-known effects on the peripheral nervous system, reports increasingly suggest that VZV can have potentially devastating effects on the central nervous system (CNS). Several epidemiological studies indicate that VZV reactivation is associated with stroke and interest is growing in potential associations of VZV with dementia. In the past 5-6 years, vaccination against herpes zoster has been reported to reduce the risk of developing cardiovascular events (including stroke) and dementia in observational studies, although interpretation of their findings is hindered by complex methodological challenges. This Review considers the relationship between VZV and the CNS from a multidisciplinary perspective that focuses on VZV physiology and immunity. The strengths and weaknesses of published studies are discussed, and areas for future investigation that remain to be addressed before the links between VZV and CNS conditions can be considered definitive and medically actionable are highlighted. Finally, these insights are integrated into an overarching conclusion that addresses potential consequences of the connection between VZV and the CNS for both public health and healthy ageing.}, }
@article {pmid41736871, year = {2026}, author = {Begnel, ER and Maqsood, R and Holland, LA and Ojee, E and Owiti, P and Adhiambo, J and Mabele, E and Gantt, S and Chohan, BH and Kinuthia, J and Wamalwa, D and Lim, ES and Lehman, DA and Slyker, J}, title = {Comparison of gut virome in Kenyan infants born to women with and without HIV.}, journal = {iScience}, volume = {29}, number = {3}, pages = {114900}, pmid = {41736871}, issn = {2589-0042}, support = {P01 HD107669/HD/NICHD NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 HD092311/HD/NICHD NIH HHS/United States ; }, abstract = {The gut virome develops in infancy, seeded from numerous sources including the maternal virome. Altered infant virome development from exposure to maternal HIV infection could contribute to the higher observed morbidity among children who are HIV-exposed, uninfected (CHEU) versus HIV-unexposed (CHUU). To assess whether infant HIV exposure affects gut virome development, we sequenced the DNA virome in stool samples collected between birth-2 years from 37 CHUU and 32 CHEU whose mothers received optimized antiretroviral therapy (ART). Richness and Shannon diversity increased with age and introduction of foods other than breastmilk, and Bray-Curtis distances varied by age. Virome richness was lower among CHEU than CHUU, but Shannon diversity and Bray-Curtis distances did not differ by HIV exposure. These findings suggest that HIV exposure is not a major determinant of the infant virome when mothers receive optimized ART.}, }
@article {pmid41737546, year = {2024}, author = {Shao, Y and Gao, F}, title = {Likelihood-based inferences for active-arm trial with counterfactual incidence based on recency assay.}, journal = {Statistical communications in infectious diseases}, volume = {16}, number = {1}, pages = {}, pmid = {41737546}, issn = {2194-6310}, support = {R01 AI029168/AI/NIAID NIH HHS/United States ; R01 AI177078/AI/NIAID NIH HHS/United States ; }, abstract = {OBJECTIVES: The approach of using HIV recency assay to estimate the counterfactual incidence rate is being used as the primary efficacy method in a few ongoing large-scale HIV pre-exposure prophylaxis (PrEP) trials, and the current available approach for the inference is based on the Wald method that leverages the asymptotic distribution of the estimators. One issue with the Wald test is that it does not work well when the number of HIV infections are small in the active arm, and it fails to work when there are zero HIV infections. As future long-acting PrEP products are becoming more efficacious, it is very likely that a small or zero number of infections will be observed in HIV prevention trials, especially for subgroup analyses or interim analyses, hence there is a pressing need to develop inference methods that work under such scenarios.<br><br>METHODS: It is well known that when the sample size is small to moderate, likelihood ratio tests are more reliable than Wald tests in terms of actual error probabilities coming close to matching nominal levels. In this manuscript we derive the likelihood ratio test and the likelihood-based confidence intervals for HIV prevention trials based on recency assays.<br><br>RESULTS: Compared with the Wald test, the proposed method works when there are zero infections. Additionally, unlike the Wald test, the p-value from the likelihood ratio test is an increasing function with respect to the number of infections, which is a desirable property as otherwise it will cause confusions.<br><br>CONCLUSIONS: For HIV PrEP trials based on recency assay, the likelihood-based p-value and confidence interval can be preferable to the Wald based inference methods when the number of HIV infections is expected to be small.}, }
@article {pmid41738780, year = {2026}, author = {Lilly, M and Ruiz, F and Foreman, WB and Chohan, V and Guenthoer, J and Depierreux, D and Baharani, VA and Ralph, D and Harteloo, A and Chu, HY and Bieniasz, PD and Starr, TN and Overbaugh, J}, title = {Re-infection with SARS-CoV-2 is associated with increased antibody breadth and potency against diverse sarbecovirus strains.}, journal = {mBio}, volume = {17}, number = {4}, pages = {e0361225}, pmid = {41738780}, issn = {2150-7511}, support = {AI138709/NH/NIH HHS/United States ; DP2 AI177890/NH/NIH HHS/United States ; //Searle Scholars Program/ ; U01 AI150747/NH/NIH HHS/United States ; DGE-2140004//NSF | National Science Foundation Graduate Research Fellowship Program (GRFP)/ ; //Washington Research Foundation/ ; P01 AI165075/NH/NIH HHS/United States ; //Boehringer Ingelheim/ ; }, mesh = {*SARS-CoV-2/immunology ; Humans ; *COVID-19/immunology/virology ; *Antibodies, Viral/immunology/blood ; Antibodies, Monoclonal/immunology ; *Reinfection/immunology/virology ; Antibodies, Neutralizing/immunology ; Spike Glycoprotein, Coronavirus/immunology ; *Broadly Neutralizing Antibodies/immunology ; Animals ; Neutralization Tests ; }, abstract = {The ease with which emerging SARS-CoV-2 variants escape neutralizing antibodies limits the protection afforded by a prior exposure, be it infection or vaccination. While rare, broadly neutralizing antibodies with activity toward diverse sarbecoviruses have been detected in convalescent serum. Motivated by findings that plasma responses show increased neutralization breadth and potency with continued antigen exposure, we isolated monoclonal antibodies (mAbs) after a SARS-CoV-2 re-infection and compared them to those isolated 1 year prior, after the first breakthrough infection. Among clonal lineage members identified at both time points, mAbs from the later time point showed improved neutralization potency and breadth. One mAb isolated after re-infection, C68.490, targets a conserved region in the receptor binding domain and shows remarkable activity not only against SARS-CoV-2 variants, but also diverse sarbecoviruses from more distant clades present in animal reservoirs. These findings suggest that a focus on individuals with diverse and repeated antigen exposure could lead to the identification of antibodies with therapeutic utility not just toward current and future SARS-CoV-2 variants, but also distant sarbecoviruses in the event of a future spillover.IMPORTANCESpillover of SARS-related viruses (sarbecoviruses) from animal reservoirs into humans has occurred multiple times in the past few decades. The most recent spillover due to SARS-CoV-2 continues to cause significant disease burden, and treatment options are few, in part because of selection for new variants due to immune escape. Thus, discovering antibodies that can block infection with sarbecoviruses, including SARS-CoV-2 variants, remains critical for both the current pandemic as well as those to come. Our study shows that an individual who was vaccinated and then had repeated breakthrough infections with distinct SARS-CoV-2 variants generated more potent antibodies after the second infection compared to the first infection. Notably, we discovered an antibody in this individual that not only neutralized the dominant SARS-CoV-2 variants but also a range of diverse sarbecoviruses present in animal reservoirs. This antibody thus holds promise as a therapeutic for both the current pandemic and future spillover events.}, }
@article {pmid41739467, year = {2026}, author = {Childers, CP and Tracy, BM and Senkowski, CK}, title = {Beyond Modifier 22-A Path to Recognizing Surgical Complexity.}, journal = {JAMA surgery}, volume = {161}, number = {4}, pages = {317-318}, doi = {10.1001/jamasurg.2025.6831}, pmid = {41739467}, issn = {2168-6262}, }
@article {pmid41739906, year = {2026}, author = {Lima, NS and McCormick, L and Li, S and Wake, CG and Subramanian, R and Spangler, A and Pinto, Y and Catalano, W and Henry, AR and Laboune, F and Teng, IT and Lyke, KE and Atmar, RL and Deming, ME and Jackson, LA and Branche, AR and Rostad, CA and Martin, JM and Johnston, CM and Rupp, RE and Kottkamp, AC and Brady, RC and Backer, M and Edupuganti, S and ,  and Posavad, CM and Roberts, PC and Kwong, PD and Andrews, S and Schramm, CA and Douek, DC and , }, title = {The vaccine platform used for COVID-19 primary immunization shapes the quality of the human B cell response to a vaccine boost.}, journal = {Science translational medicine}, volume = {18}, number = {838}, pages = {eaeb9837}, doi = {10.1126/scitranslmed.aeb9837}, pmid = {41739906}, issn = {1946-6242}, mesh = {Humans ; *COVID-19/immunology/prevention &amp; control ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; *B-Lymphocytes/immunology ; *SARS-CoV-2/immunology ; Antibodies, Viral/immunology ; Spike Glycoprotein, Coronavirus/immunology ; *Immunization, Secondary ; Immunoglobulin G/immunology ; Adenoviridae/genetics ; Vaccination ; Memory B Cells/immunology ; Immunoglobulin A/immunology ; Immunologic Memory ; }, abstract = {Improving long-term protective immunity elicited by prime-boost vaccinations requires a deeper understanding of the immunologic outcomes of different vaccine platforms. Given the variety of platforms used to develop vaccines against SARS-CoV-2, we reasoned that SARS-CoV-2 offered an opportunity to compare vaccine platforms in humans. We used flow cytometry and single-cell transcriptomics to explore the B cell response to different homologous and heterologous vaccine regimens. We found that an adenovirus vector prime followed by a messenger RNA (mRNA) vaccine boost showed the greatest short-term B cell expansion and preferentially elicited an activated atypical B cell subset that was associated with antibody binding titers against spike protein. In contrast, an mRNA primary series followed by homologous boost induced a different activated B cell subset with more proliferative potential and high frequencies of a long-lived resting memory subset. Moreover, immunoglobulin A (IgA)-expressing memory B cells had more somatic hypermutations than the predominant IgG-expressing B cell population. This heterogeneity in vaccine-elicited B cell responses underscores the potential of tailoring vaccine regimens that combine different platforms to achieve potent and durable protection against infectious diseases.}, }
@article {pmid41740031, year = {2026}, author = {Dumbrava, EE and Shapiro, GI and Parikh, AR and Johnson, ML and Tolcher, AW and Thompson, JA and El-Khoueiry, AB and Vandross, AL and Kummar, S and Shepard, DR and LeDuke, K and Sheehan, L and Alland, L and Haque, A and Jalota, D and Fellous, M and Schram, AM}, title = {Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors.}, journal = {The New England journal of medicine}, volume = {394}, number = {9}, pages = {872-883}, doi = {10.1056/NEJMoa2508820}, pmid = {41740031}, issn = {1533-4406}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Antineoplastic Agents/adverse effects/administration &amp; dosage/pharmacokinetics ; Dose-Response Relationship, Drug ; Maximum Tolerated Dose ; Mutation ; *Neoplasms/blood/drug therapy/genetics ; *Tumor Suppressor Protein p53/genetics/metabolism ; *Drugs, Investigational/administration &amp; dosage/adverse effects/pharmacokinetics ; Protein Stability/drug effects ; Administration, Oral ; Nausea/chemically induced/epidemiology ; Vomiting/chemically induced/epidemiology ; Anemia/chemically induced/epidemiology ; Creatinine/blood ; Fatigue/chemically induced/epidemiology ; Proof of Concept Study ; Treatment Outcome ; }, abstract = {BACKGROUND: Rezatapopt is an investigational, first-in-class, oral, selective p53 reactivator that specifically binds to Y220C-mutated p53, which stabilizes p53 in its wild-type conformation and restores its functionality.<br><br>METHODS: In this phase 1, single-group, dose-escalation and dose-optimization study, we assigned heavily pretreated patients with locally advanced or metastatic solid tumors harboring a TP53 Y220C mutation to receive rezatapopt during continuous 21-day treatment cycles. The primary objectives were to determine the maximum tolerated dose and recommended phase 2 dose. Primary end points included dose-limiting toxic effects and adverse events. Secondary end points included preliminary efficacy and pharmacokinetic features.<br><br>RESULTS: A total of 77 patients received rezatapopt at one of eight escalating doses: 150 mg, 300 mg, 600 mg, 1150 mg, 1500 mg, 2000 mg, or 2500 mg once daily or 1500 mg twice daily. The maximum tolerated dose was 1500 mg twice daily. On the basis of safety, efficacy, and pharmacokinetic data, 2000 mg once daily with food was selected as the recommended phase 2 dose. During the treatment period, 76 patients (99%) had at least one adverse event and 29 (38%) had an adverse event of grade 1 or 2. The most common adverse events were nausea (in 58% of patients), vomiting (in 44%), an increased blood creatinine level (in 39%), fatigue (in 39%), and anemia (in 36%). Treatment-related adverse events occurred in 67 patients (87%) and those of grade 1 or 2 in 48 (62%); 2 patients (3%) discontinued rezatapopt because of a treatment-related adverse event. Most gastrointestinal adverse events resolved with the treatment of symptoms and were less frequent when rezatapopt was given with food. Anemia was the most common adverse event of grade 3 or higher during the treatment period, occurring in 16% of patients. The overall response (complete or partial response) was 20% among all patients and 30% among those who had a KRAS wild-type tumor and received a dose of at least 1150 mg once daily. Confirmed responses were seen across multiple tumor types, including ovarian and breast cancers. All patients with a response had a solid tumor that harbored TP53 Y220C and wild-type KRAS.<br><br>CONCLUSIONS: In this phase 1 study involving heavily pretreated patients, the most common adverse events associated with rezatapopt were nausea and vomiting. Antitumor activity occurred across multiple tumor types, providing proof of concept for p53 reactivation. (Funded by PMV Pharmaceuticals; PYNNACLE ClinicalTrials.gov number, NCT04585750.).}, }
@article {pmid41740062, year = {2026}, author = {Hurwitz, LM and O'Brien, KM and Townsend, MK and Reid, BM and Fridley, BL and Fan, W and Schabath, MB and Bodelon, C and Chan, AT and Fortner, RT and Håkansson, N and Harris, HR and Lacey, JV and Liao, LM and Merritt, MA and Patel, AV and Poynter, JN and Robien, K and Sandler, DP and Wentzensen, N and Wolk, A and Zheng, W and Tworoger, SS and Trabert, B}, title = {Longer-term aspirin use and subsequent ovarian cancer risk in the Ovarian Cancer Cohort Consortium.}, journal = {International journal of epidemiology}, volume = {55}, number = {2}, pages = {}, pmid = {41740062}, issn = {1464-3685}, support = {P01 CA87969//National Cancer Institute at the National Institutes of Health/ ; //NIH-AARP Diet and Health Study was funded by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health/ ; 5NU58DP006344//Centers for Disease Control and Prevention's National Program of Cancer Registries/ ; R01 CA039742/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; //National Cancer Institute's Surveillance/ ; U01 CA202979/CA/NCI NIH HHS/United States ; //American Cancer Society/ ; U01 CA199277/CA/NCI NIH HHS/United States ; UM1 CA164917/CA/NCI NIH HHS/United States ; HHSN261201800015I/CA/NCI NIH HHS/United States ; W81XWH-19-1-0346//US Department of Defense Ovarian Cancer Research/ ; Z01 ES044005/ImNIH/Intramural NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; //Division of Cancer Prevention at the National Cancer Institute/ ; R01 CA39742//National Cancer Institute at the National Institutes of Health/ ; U01CA202979//National Cancer Institute Intramural Research Program. The Southern Community Cohort Study was supported by National Cancer Institute at the National Institutes of Health/ ; U01 CA176726/CA/NCI NIH HHS/United States ; 103885//California Health and Safety Code Section/ ; HHSN261201800009I/CA/NCI NIH HHS/United States ; //H. Lee Moffitt Cancer Center &amp; Research Institute/ ; //Intramural Research Program of the National Cancer Institute at the National Institutes of Health/ ; UM1 CA186107/CA/NCI NIH HHS/United States ; HHSN261201800032I/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; R01 CA077398/CA/NCI NIH HHS/United States ; P30-CA076292//NCI-designated Comprehensive Cancer Center/ ; W81XWH-12-1-0561//US Department of Defense Ovarian Cancer Research Program/ ; //Biostatistics and Bioinformatics Shared Resource/ ; }, mesh = {Humans ; Female ; *Aspirin/administration &amp; dosage/therapeutic use ; *Ovarian Neoplasms/epidemiology/prevention &amp; control ; Middle Aged ; Prospective Studies ; Aged ; Risk Factors ; Logistic Models ; *Anti-Inflammatory Agents, Non-Steroidal/administration &amp; dosage ; Adult ; }, abstract = {BACKGROUND: Observational studies have reported lower ovarian cancer risk among individuals taking aspirin frequently (i.e. daily/near daily). However, most studies relied on a single assessment of aspirin use, which may have led to misclassification and precluded the examination of patterns of use over time. We examined the association between aspirin use, assessed at multiple time points, and ovarian cancer risk.<br><br>METHODS: Data were pooled from 10 prospective cohort studies from the Ovarian Cancer Cohort Consortium (n&#x2009;=&#x2009;675&#x200a;901 participants; 5528 cases; median follow-up&#x2009;=&#x2009;13&#x2009;years). Frequent aspirin use was self-reported via repeat questionnaires. We examined multiple time-updated, lagged aspirin-exposure metrics and risk of ovarian cancer by using pooled logistic regression adjusted for time-updated confounders.<br><br>RESULTS: While ever frequent aspirin use was not associated with ovarian cancer [odds ratio (OR) 0.97; 95% confidence interval (CI): 0.91-1.03], individuals who reported long-term use experienced a 14% reduction in ovarian cancer risk (>6&#x2009;years; OR 0.86; 95% CI: 0.77-0.97). This risk reduction was evident among individuals with at least three ovarian cancer risk factors (OR 0.65; 95% CI: 0.50-0.85) but not among individuals with fewer than three ovarian cancer risk factors (OR 0.94; 95% CI: 0.82-1.08), P-interaction&#x2009;=&#x2009;.02). Reduced ovarian cancer risks were also observed for low-dose aspirin use (OR 0.90; 95% CI: 0.80-1.01 for ever low-dose use; OR 0.75; 95% CI: 0.56-0.99 for long-term low-dose use) but not ever regular-dose use (OR 1.09; 95% CI: 0.94-1.27).<br><br>CONCLUSION: Long-term use of aspirin, and particularly low-dose aspirin, is associated with lower ovarian cancer risk, especially among individuals with other established risk factors for ovarian cancer. Research should continue to explore the potential role of long-term, low-dose aspirin use for ovarian cancer primary prevention.}, }
@article {pmid41740148, year = {2026}, author = {Lau, N and Zhou, C and Hong, SJ and Aalfs, H and Higgins, S and Badillo, I and McCauley, E and Ketterl, T and Chow, EJ and Fann, JR and Heathcote, LC and Palermo, TM}, title = {Digital Attention Bias in Cancer Survivors Intervention for Adolescent and Young Adult Cancer Survivors: Protocol for a Pilot Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e82665}, pmid = {41740148}, issn = {1929-0748}, mesh = {Humans ; *Cancer Survivors/psychology ; Adolescent ; Pilot Projects ; Young Adult ; Adult ; *Attentional Bias ; Male ; Female ; Anxiety/therapy/psychology ; Randomized Controlled Trials as Topic ; Text Messaging ; *Neoplasms/psychology ; }, abstract = {BACKGROUND: Adolescent and young adult cancer survivors face a high burden of psychological late effects, with cancer-related anxiety being a prevalent mental health concern. Despite the significant need for care, more than half of adolescent and young adult cancer survivors, who require psychosocial services, remain untreated. Digital health interventions offer a promising solution to bridge this care gap. Attention bias modification (ABM) is an evidence-based digital intervention for anxiety disorders. This intervention targets automatic and unconscious negative attention biases and retrains attention away from threat and toward neutral or positive stimuli. Recent research has successfully adapted ABM interventions for cancer survivors. However, ABM has not yet been adapted or tested for adolescent and young adult cancer survivors.<br><br>OBJECTIVE: This protocol describes a pilot randomized controlled trial designed to evaluate a novel digital anxiety intervention, the Attention Bias in Cancer survivors (ABCs) intervention, for adolescent and young adult cancer survivors.<br><br>METHODS: This is a single-site, 2-arm, pilot randomized controlled trial enrolling 60 cancer survivors aged 15 to 29 years. Participants will be randomized 1:1 to the ABCs intervention or a sham control condition. The ABCs intervention combines an ABM mobile intervention with daily gratitude and savoring SMS text messages (positive psychology prompts to savor positive emotions) over a 4-week period. The sham condition consists of sham ABM (showing the same cancer-related word stimuli as the active intervention condition but without attention retraining) and daily mood monitoring SMS text messages (prompts to report on current mood and stress levels). The primary objectives are to evaluate intervention feasibility (defined as &#x2265;50% enrollment and &#x2265;70% retention) and acceptability (defined by cutoff scores on the Client Satisfaction Questionnaire and System Usability Scale). Secondary exploratory outcomes include patient-reported measures of attention bias, anxiety, fear of recurrence, pain, resilience, and other psychosocial outcomes.<br><br>RESULTS: This study was funded in August 2023, and study recruitment began in November 2024. We have completed data collection as of February 2026. We anticipate that data analyses will be completed by September 2026. Manuscript preparation and submission are anticipated for December 2026.<br><br>CONCLUSIONS: This pilot trial examines the feasibility and acceptability of a digital positive psychological intervention targeting anxiety in adolescent and young adult cancer survivors. Exploratory outcomes will inform sample size calculations for a future-powered multisite clinical trial. The ABCs intervention may provide scalable and accessible evidence-based psychosocial care and improve health outcomes.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT06682039; https://clinicaltrials.gov/study/NCT06682039.<br><br>DERR1-10.2196/82665.}, }
@article {pmid41740461, year = {2026}, author = {Whitaker, JA and Rebolledo, PA and Abate, G and Babu, TM and Rouphael, NG and Wald, A and El Sahly, HM and Jooss, K and Hart, MG and Makowski, M and Mu, J and Carmack, A and Archer, JI and Roberts, PC and Makhene, M and Posavad, CM and McElrath, MJ and De Rosa, SC and Coler, R and Montefiori, D and Eaton, A and Suthar, MS and Atmar, RL and Hoft, DF and , }, title = {The safety, reactogenicity, and immunogenicity of the self-amplifying mRNA COVID-19 vaccine GRT-R910 as a booster in healthy adults.}, journal = {Vaccine}, volume = {77}, number = {}, pages = {128358}, doi = {10.1016/j.vaccine.2026.128358}, pmid = {41740461}, issn = {1873-2518}, mesh = {Humans ; Adult ; Middle Aged ; Female ; Male ; *COVID-19 Vaccines/immunology/adverse effects/administration &amp; dosage ; *Immunization, Secondary/methods ; *COVID-19/prevention &amp; control/immunology ; Antibodies, Viral/blood/immunology ; *SARS-CoV-2/immunology ; Antibodies, Neutralizing/blood/immunology ; *Immunogenicity, Vaccine ; Young Adult ; Adolescent ; Spike Glycoprotein, Coronavirus/immunology ; Healthy Volunteers ; Aged ; Vaccines, Synthetic/immunology/administration &amp; dosage/adverse effects ; mRNA Vaccines ; }, abstract = {BACKGROUND: GRT-R910 (Gritstone bio, Inc), a self-amplifying mRNA vaccine expressing SARS CoV-2 (D614G) spike protein and T-cell epitopes, was evaluated as a booster vaccine in a phase 1 study in 2021-2022.<br><br>METHODS: This open-label, dose escalation study enrolled healthy adults &#x2265;112&#xa0;days after completion of primary COVID-19 vaccination, booster of approved mRNA COVID-19 vaccine, or known SARS-CoV-2 infection. Persons aged 18-60&#xa0;years received single doses of 3 or 6&#xa0;&#x3bc;g GRT-R910 (n&#xa0;=&#xa0;10/group). Persons >60&#xa0;years of age received GRT-R910 at 3, 6, or 10&#xa0;&#x3bc;g (n&#xa0;=&#xa0;8-10/group). Safety and immunogenicity responses were assessed for 1&#xa0;year after vaccination.<br><br>RESULTS: We enrolled 48 participants. Most participants developed mild-to-moderate systemic reactions and/or injection site tenderness. Eight of 48 (17%) had severe systemic reactions. Pseudovirus neutralizing antibody geometric mean fold rise (GMFR) responses against SARS-CoV-2 (D614G) at Day 29 and Day 181, respectively, among those &#x2264;60&#xa0;years were 5.2 (95% CI 2.1, 13.3) and 6.1 (2.8, 13.2) after 3&#xa0;&#x3bc;g, and 3.6 (1.3, 10.4) and 2.4 (0.2, 33.0) after 6&#xa0;&#x3bc;g. The GMFR responses among those aged >60&#xa0;years were 8.1 (2.1, 31.4) and 8.2 (1.2, 57.5) after 3&#xa0;&#x3bc;g, 2.7 (1.1, 6.7) and 1.8 (0.5, 6.7) after 6&#xa0;&#x3bc;g, 3.3 (1.5, 7.4) and 3.3 (1.3, 8.0) after 10&#xa0;&#x3bc;g. The 6&#xa0;&#x3bc;g dose group in those &#x2264;60&#xa0;years, 6&#xa0;&#x3bc;g and 10&#xa0;&#x3bc;g dose groups in those aged >60&#xa0;years had higher baseline geometric mean titers (GMTs), which, in turn may have lowered the GMFR for those groups. GMFR persistence until Day 181 in most groups indicated these boosts were associated with durable increases in GMFR. Neutralizing antibody titers assessed via focus reduction neutralization test against SARS-CoV-2 D614G largely mirrored the PsVNA findings.<br><br>CONCLUSIONS: GRT-R910 was safe but reactogenic when administered to previously vaccinated or infected adults and boosted anti-SARS-CoV-2 neutralizing antibody responses in most participants with responses that appeared durable for up to 6&#xa0;months.<br><br>CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04776317.<br><br>CLINICALTRIALS: gov ID NCT04776317.}, }
@article {pmid41740864, year = {2026}, author = {Berg, DMNVD and Brück, CC and Lima, PN and Alarid-Escudero, F and Hahn, AI and Lansdorp-Vogelaar, I and , }, title = {The Best Screening Test is the One That Gets Followed-up on.}, journal = {Gastroenterology}, volume = {}, number = {}, pages = {}, doi = {10.1053/j.gastro.2026.02.013}, pmid = {41740864}, issn = {1528-0012}, }
@article {pmid41742599, year = {2026}, author = {Marsh, SGE and Osoegawa, K and Bodmer, WF and Bontrop, RE and Carrington, MN and Erlich, HA and Heidt, S and Holdsworth, R and Mayr, WR and Maiers, M and Parham, P and Petersdorf, EW and Robinson, J and Trowsdale, J and Fernández-Viña, M}, title = {Nomenclature for Factors of the HLA System, 2026.}, journal = {HLA}, volume = {107}, number = {3}, pages = {e70595}, pmid = {41742599}, issn = {2059-2310}, }
@article {pmid41744290, year = {2026}, author = {Armstrong, AJ and Morris, MJ and Abida, W and Aggarwal, RR and Antonarakis, ES and Attard, G and Beltran, H and Bryce, A and Carducci, MA and Cheng, HH and Chen, DL and Chi, KN and Childs, DS and Dahut, W and Emmett, L and Fizazi, K and Gafita, A and George, DJ and Hermann, K and Hofman, MS and Hope, T and Hussain, M and Kelly, WK and Kessler, E and Kuo, PH and Lang, J and Liu, G and Marshall, CH and Morgans, AK and McKay, RR and Nanus, D and Nelson, P and Paller, C and Reichert, ZR and Ryan, CJ and Sartor, AO and Schöder, H and Schwartz, LH and Sharifi, N and Stadler, WM and Stein, M and Sternberg, CN and Szmulewitz, RZ and Tagawa, ST and Sokolova, AO and Wyatt, AW and Yamoah, K and Yu, EY and Halabi, S and Scher, HI and , }, title = {Trial Design and Objectives for Patients With Prostate Cancer: Recommendations From the Prostate Cancer Working Group 4.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2502834}, doi = {10.1200/JCO-25-02834}, pmid = {41744290}, issn = {1527-7755}, abstract = {PURPOSE: The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer.<br><br>METHODS: We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer.<br><br>RESULTS: PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework.<br><br>CONCLUSION: PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator-na&#xef;ve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.}, }
@article {pmid41744883, year = {2026}, author = {Bea, JW and Ziller, SG and Decker, D and Roe, DJ and Odegaard, AO and Ochs-Balcom, HM and Lima, SM and Caan, B and Wactawski-Wende, J and Pichardo, MS and Harris, H and Chen, Z}, title = {DXA-Derived Visceral and Subcutaneous Adipose Tissue and Postmenopausal Breast Cancer Mortality.}, journal = {Current oncology (Toronto, Ont.)}, volume = {33}, number = {2}, pages = {}, pmid = {41744883}, issn = {1718-7729}, support = {R01CA253302//National Cancer Institute at the National Institutes of Health/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/mortality/pathology ; *Postmenopause ; Middle Aged ; *Intra-Abdominal Fat/diagnostic imaging ; *Absorptiometry, Photon/methods ; *Subcutaneous Fat/diagnostic imaging ; Aged ; }, abstract = {BACKGROUND: Elevated abdominal adipose tissue at time of diagnosis is associated with breast cancer mortality. We sought to understand the association between abdominal adipose tissue (subcutaneous, SAT and visceral, VAT) assessed via dual-energy X-ray absorptiometry (DXA) and breast cancer mortality in the prevention setting.<br><br>METHODS: Women enrolled in the Women's Health Initiative study with baseline whole-body DXA scans were included in the study (n = 9767). Causes of death were adjudicated up to 27 years of follow-up. Competing risk models were used to examine independent associations between baseline VAT, SAT, per 100 cm[2], and breast cancer-specific deaths; findings were reported as sub-hazard ratios (SHR) and confidence intervals (CI). Time-varying analyses additionally included DXA at years 3 and 6. Covariates included demographic, lifestyle, and tumor factors.<br><br>RESULTS: Baseline VAT and SAT ranged from undetectable to 616.25 cm[2] and 55.26-952.46 cm[2], respectively. There were 738 incident breast cancer cases post-enrollment, and 87 breast cancer-related deaths. Median age at diagnosis was 62 years. In adjusted models, higher baseline VAT and SAT were significantly associated with higher risk breast cancer mortality (49% and 40%, respectively); time-varying models were similar.<br><br>CONCLUSIONS: Higher VAT and SAT were similarly associated with breast cancer mortality in this group of postmenopausal women.}, }
@article {pmid41746611, year = {2026}, author = {Andrasik, M and Broder, G and Louis, K and Baepanye, K and Kamel, L and Davis, A and Segura, P and Makhubalo, B and Leon Rhandomy, MR and Soler, J and Certo, SK and Gonzalez, R and Dawit, W and Reinstein, S and Shipman, CE and Seyama, L and Sanchez Sarmiento, H and Mpongo, NC and Swann, E and Morar, NS}, title = {Building Trust and Engaging Communities for HIV Prevention Research Globally.}, journal = {AIDS education and prevention : official publication of the International Society for AIDS Education}, volume = {38}, number = {1}, pages = {1-17}, doi = {10.1521/aeap.2026.38.1.1}, pmid = {41746611}, issn = {1943-2755}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control ; *Community Participation ; *Trust ; *AIDS Vaccines ; International Cooperation ; Global Health ; Community-Based Participatory Research ; *Biomedical Research ; }, abstract = {The HIV Vaccine Trials Network (HVTN) is the largest publicly funded international collaboration facilitating the evaluation of vaccines to prevent HIV and TB. Central to the HVTN's success is the reliance on robust community engagement methods, ensuring community participation and facilitating community awareness and knowledge of research. Community engagement is a dynamic process that requires active participation from all stakeholders to ensure success. The HVTN and its global Clinical Research Sites (CRSs) located in Africa, Latin America, and North America are known as the Network. We describe relationships across the Network, specific staff roles and responsibilities, and the myriad activities undertaken to ensure optimal community engagement. Key activities include involving active Community Advisory Boards (CABs), using community consultations, and having trained Community Engagement staff at each CRS. Operating with robust community engagement has resulted in rapid enrollment and high retention of diverse participant populations across Network studies.}, }
@article {pmid41746629, year = {2026}, author = {Shadman, M and LeBlanc, M and Rimsza, L and Leonard, JP and Smith, SM and Li, H and Friedberg, JW}, title = {Treatment of Follicular Lymphoma With CHOP and Anti-CD20 Therapy: 15-Year Follow-Up of the SWOG S0016 Trial.}, journal = {JAMA oncology}, volume = {12}, number = {4}, pages = {394-401}, pmid = {41746629}, issn = {2374-2445}, mesh = {Humans ; *Lymphoma, Follicular/drug therapy/mortality/pathology ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; Female ; Cyclophosphamide/therapeutic use/adverse effects/administration &amp; dosage ; Male ; Vincristine/therapeutic use/adverse effects/administration &amp; dosage ; Doxorubicin/administration &amp; dosage/adverse effects/therapeutic use ; Middle Aged ; Prednisone/therapeutic use/adverse effects/administration &amp; dosage ; *Rituximab/administration &amp; dosage/therapeutic use/adverse effects ; Follow-Up Studies ; Aged ; Adult ; Treatment Outcome ; Radioimmunotherapy ; }, abstract = {IMPORTANCE: Follicular lymphoma (FL) has historically been regarded as incurable, with patients experiencing late relapses after initial chemoimmunotherapy treatment.<br><br>OBJECTIVE: To provide 15-year follow-up data from the SWOG S0016 trial that evaluated the potential for long-term remission and cure following chemoimmunotherapy with cyclophosphamide, hydroxydaunorubicin/doxorubicin, oncovin, and prednisone/prednisolone (CHOP)-based regimens.<br><br>This multicenter, intergroup study was conducted at academic and community practice locations throughout the US and enrolled patients with untreated, advanced-stage FL. Cure modeling, which involves estimating the proportion of patients cured of the disease, was conducted by incorporating background mortality rates to estimate the proportion of patients cured of FL during the S0016 trial. Patients were enrolled between May 2001 and October 2008 and followed up for a median (IQR) of 15.5 (13.6-16.9) years. The 15-year analysis was conducted in June 2025.<br><br>INTERVENTIONS: Patients were randomized to receive either rituximab plus CHOP (R-CHOP) or CHOP followed by radioimmunotherapy (CHOP-RIT).<br><br>MAIN OUTCOMES: The main outcomes were 15-year progression free survival (PFS) and overall survival (OS). Secondary outcomes included cure modeling.<br><br>RESULTS: A total of 531 eligible patients (242 female patients [46%]; median [IQR] age, 53 [45-61] years) were included in the final analysis (267 [50%] received R-CHOP and 264 [50%] CHOP-RIT). The overall 15-year OS was 70%, with no significant difference between treatment arms, and the 15-year PFS was 40% (95% CI, 36.0%-44.7%). CHOP-RIT demonstrated superior 15-year PFS (47% vs 34%; P&#x2009;=&#x2009;.004) compared with R-CHOP. Cure modeling estimated an overall cure rate of 42%, with the highest cure rates observed in patients with low Follicular Lymphoma International Prognostic Index scores and normal &#x3b2;2 microglobulin levels. The rate of relapse declined substantially over time, from 6.8% during the first 5 years to 0.6% between 15 to 20 years.<br><br>CONCLUSIONS AND RELEVANCE: The results of this secondary analysis suggest that a subset of patients with advanced-stage FL can achieve cure with CHOP-based chemoimmunotherapy, as relapse rates decline over time. This finding represents a paradigm shift in the understanding of and approach to FL, with implications for initial patient discussions and future research strategies.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00006721.}, }
@article {pmid41746780, year = {2026}, author = {Shaffer, BC and Lee, SJ and Perales, MA}, title = {How I Treat: Selection of Hematopoietic Cell Donors in the Era of Post-Transplant Cyclophosphamide.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025030823}, pmid = {41746780}, issn = {1528-0020}, abstract = {Selection of a hematopoietic progenitor cell donor for allogeneic hematopoietic cell transplantation (allo HCT) is essential for treatment planning; however, the parameters that define an "optimal" donor in the modern era are not well defined. Historically, donor-recipient human leukocyte antigen (HLA) mismatching correlated strongly with risk for graft versus host disease (GVHD) and reduced survival. For this reason, donor selection was typically hierarchical: HLA matched related and unrelated donors were evaluated first, followed by HLA mismatched donors (or deferral of HCT altogether) in patients lacking an HLA matched donor. The advent of post-transplant cyclophosphamide (PTCy)-based GVHD prevention has changed this paradigm. Survival outcomes following HLA-mismatched donor HCT with PTCy, including from related haploidentical or HLA-mismatched unrelated donors, are not different than HLA matched donor recipients in recent clinical trials and retrospective studies. These encouraging results present a new challenge: In the PTCy era, how should donors be prioritized among the many potential sources available? Herein we review HLA and non-HLA parameters that inform donor selection and discuss approaches to increase donor availability. Case vignettes focusing on concepts that may be adapted to heterogenous clinical scenarios are presented.}, }
@article {pmid41747197, year = {2026}, author = {Sharp, J and Strati, P and Bhatta, S and Huang, JJ and Thomas, CJ and Elghawy, O and Reef, D and Gorzewski, AM and Wang, JS and Shouse, G and Reinert, C and Teferra, A and Toro Velez, E and Pelcovits, A and Ollila, TA and Clark, WB and Yazbeck, V and Maakaron, JE and Kamdar, M and Fitzgerald, LA and Danilov, AV and Karmali, R and Grover, NS and Barta, SK and Voorhees, TJ and Chen, AI and Shadman, M and Ahmed, S and Epperla, N}, title = {Real-World Outcomes and Toxicities of CAR-T in Relapsed/Refractory Follicular Lymphoma: A Multicenter Cohort Study.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025019115}, pmid = {41747197}, issn = {2473-9537}, abstract = {Chimeric antigen receptor T-cell (CAR-T) therapy revolutionized treatment of relapsed/refractory (R/R) follicular lymphoma (FL). Real-world efficacy and toxicity data are needed as clinical trial populations are often not representative. Hence, we conducted a multi-center retrospective study of patients with R/R FL undergoing commercial CAR-T with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between 2021 and 2024. Endpoints included measures of efficacy (overall response rate [ORR], complete response rate [CRR], progression-free survival [PFS], and overall survival [OS]) and toxicity (rates of cytokine release syndrome [CRS] and immune effector cell-associated neurotoxicity syndrome [ICANS]). Among 136 patients, 100 (74%) received axi-cel and 36 (26%) received tisa-cel. Axi-cel patients were younger (median age 60 vs 68 years, p=0.001) and received bendamustine lymphodepletion less often (9% vs 33%, p<0.001). Median follow up was 14.4 months (range 0.8 - 72.0 months). In the unweighted analysis, axi-cel was associated with higher ORR (96% vs 80%, p=0.007), CRR (88% vs 71%, p=0.024), and longer median PFS (30.5 months vs 11.9 months, p=0.021) compared with tisa-cel. Median OS did not differ significantly between the two products (not reached vs 23.6 months, p=0.061). Rates of CRS were comparable (75% vs 75%, p=0.99), whereas ICANS occurred more frequently with axi-cel (42% vs 17%, p=0.008). After inverse probability of treatment weighting, efficacy outcomes were largely similar between axi-cel and tisa-cel, however, axi-cel remained associated with significantly higher toxicity. In real-world settings, both axi-cel and tisa-cel demonstrated efficacy in patients with R/R FL, although PFS was inferior to that reported in clinical trials.}, }
@article {pmid41747248, year = {2026}, author = {Kelly, MM and Dempsey, A and Ameral, V and Petrakis, BA and Reilly, ED and Quigley, K and Bricker, JB and Heffner, JL}, title = {Web-Based Acceptance and Commitment Therapy Tobacco Cessation Program for Veterans With Mental Health Disorders: Adaptation and Usability Testing.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e75394}, pmid = {41747248}, issn = {2561-326X}, mesh = {Humans ; *Veterans/psychology/statistics &amp; numerical data ; Male ; Female ; *Mental Disorders/psychology/complications ; Middle Aged ; *Acceptance and Commitment Therapy/methods ; Qualitative Research ; Adult ; *Tobacco Use Cessation/methods/psychology ; *Smoking Cessation/methods/psychology ; Aged ; Internet ; }, abstract = {BACKGROUND: US veterans with mental health disorders have high rates of smoking and low rates of smoking cessation.<br><br>OBJECTIVE: This study aims to focus on an adaptation of a web-based acceptance and commitment therapy (ACT) tobacco cessation intervention (Vet WebQuit) for veterans with mental health disorders who use tobacco and used a qualitative approach to test its usability (n=16).<br><br>METHODS: Participants were asked to walk through the site during laboratory-based usability testing and "think aloud" about the features of the intervention. A trained facilitator used semistructured interview questions to assess participants' experiences with Vet WebQuit and obtain feedback on their impressions of the site. Qualitative analyses identified themes regarding participants' experiences with the intervention, usability concerns, and recommendations for improving Vet WebQuit.<br><br>RESULTS: Overall, veterans found that the Vet WebQuit layout was simple and easy to navigate and use. Veterans reported that several features of the program were useful, including the quit plan, identification of triggers, content that targets mental health concerns (eg, dealing with anger), information on the health effects of smoking, tools for managing triggers (eg, urge surfing), and involving others in their quit plan. Veterans reported that particular features of the ACT approach for tobacco cessation were appealing to them, including the distinction between internal and external smoking triggers, the inclusion of the serenity prayer, and mindfulness exercises, which they could use as a tool reduce the intensity of cravings. Veterans reported wanting more information on the health aspects of smoking (ie, effects on breathing and lung capacity) as a way to motivate them to quit smoking. In addition, they suggested targeting specific mental health concerns that serve as triggers for smoking, including nightmares, boredom, and social isolation.<br><br>CONCLUSIONS: Overall, results from this project identified important elements of ACT digital tobacco cessation interventions for veterans with mental health disorders.}, }
@article {pmid41747891, year = {2026}, author = {Booth, A and Hillman, S and Laumann, K and Zhao, YQ and LeBlanc, M and Chansky, K and Giri, S and Dill, J and Johnson, J and Kelley, K and Martin, L and Osarogiagbon, RU and Morris, MJ and Chiang, AC and Kozono, DE and Blanke, CD and Galanis, E and Gray, JE and Stinchcombe, TE and Aljumaily, R and Morgensztern, D and Mandrekar, SJ}, title = {PROSPECT-LUNG: A National Clinical Trials Network Trial Advancing Pragmatic Innovation in Cancer Clinical Trials.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {}, number = {}, pages = {103650}, doi = {10.1016/j.jtho.2026.103650}, pmid = {41747891}, issn = {1556-1380}, support = {UG1 CA233290/CA/NCI NIH HHS/United States ; UG1 CA189873/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; UG1 CA189830/CA/NCI NIH HHS/United States ; U10 CA180882/CA/NCI NIH HHS/United States ; UG1 CA233253/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Clinical trial designs marked by extensive data collection, restrictive eligibility, and lengthy protocols create inefficiencies, increase costs, and hinder accrual. These are further compounded by staffing shortages and operational burdens. By incorporating pragmatic features, including simplified eligibility criteria, streamlined protocol, and data collection, the PROSPECT-Lung trial, CTIU2317-A082304-S2402 Perioperative versus Adjuvant Systemic Therapy in Patients with Resectable NSCLC, paves the way forward as a model for enhancing clinical trial efficiency and feasibility, while maintaining scientific rigor.<br><br>METHODS: PROSPECT-Lung (CTIU2317-A082304-S2402) is a pragmatic, phase III, open-label, randomized trial comparing 3-year real-world event-free survival and overall survival using approved perioperative and adjuvant immunotherapy-based treatment strategies in patients with resectable NSCLC. Protocol length and data collection elements were compared with Alliance A081801, Integration of Immunotherapy into Adjuvant Therapy for Resected NSCLC: ALCHEMIST CHEMO-IO (ClinicalTrials.gov Identifier: NCT04267848), a phase III trial in the same disease setting, to quantify streamlining efforts.<br><br>RESULTS: Relative to A081801, PROSPECT-Lung achieved major reductions in trial complexity. Protocol length decreased from 88 to 30 pages (65%), and data fields per patient were reduced from 2523 to 438 (82.6%), driven by streamlined summary versus cycle-by-cycle data collection. These efficiencies translate to estimated site workload reductions from 210 hours per patient in A081801 to 36.5 hours in PROSPECT-Lung. At full accrual, this equates to more than 190,000 hours saved in chart review, data entry, documentation, and quality control.<br><br>CONCLUSION: By broadening eligibility and streamlining logistics, PROSPECT-Lung reduces burden for patients, investigators, and sites while preserving scientific integrity. This pragmatic approach, when appropriate and possible, provides a replicable model for future cancer trials, promoting efficiency, accessibility, and real-world relevance.<br><br>GOV IDENTIFIER: NCT06632327 (CTIU2317-A082304-S2402).}, }
@article {pmid41748695, year = {2026}, author = {Jutzi, JS and Crosse, E and Kim, CJ and van Gasteren, B and Laurore, C and Rolles, B and Kramer, F and Tishena, A and Rocha, AV and Wazir, M and Weeks, LD and How, J and Stahl, M and Luskin, MR and Lindsley, RC and Pozdnyakova, O and Rai, S and Graubert, TA and Bradley, RK and Mullally, A and Marneth, AE}, title = {Mutant SRSF2-associated impaired erythropoiesis is defined by increased mTORC1 signaling due to FYN missplicing.}, journal = {Leukemia}, volume = {40}, number = {4}, pages = {783-793}, pmid = {41748695}, issn = {1476-5551}, support = {W81XWH-20-1-0904//U.S. Department of Defense (United States Department of Defense)/ ; W81XWH2110909//U.S. Department of Defense (United States Department of Defense)/ ; Hypatia//Radboud Universitair Medisch Centrum (Radboudumc)/ ; 70114570//Deutsche Krebshilfe (German Cancer Aid)/ ; R01HL131835//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; I15-0026//Starr Foundation/ ; }, mesh = {*Serine-Arginine Splicing Factors/genetics ; *Erythropoiesis/genetics ; Animals ; Mice ; Humans ; *Mechanistic Target of Rapamycin Complex 1/metabolism/genetics ; Signal Transduction ; *RNA Splicing ; *Mutation ; *Proto-Oncogene Proteins c-fyn/genetics/metabolism ; *Myeloproliferative Disorders/genetics/pathology/metabolism ; Janus Kinase 2/genetics ; }, abstract = {Somatic mutations in RNA splicing regulators, including the serine/arginine-rich protein SRSF2, are frequently observed in myeloid malignancies. Using mouse models and primary human samples, we investigated the impact of SRSF2 mutations on erythropoiesis. We found reduced erythropoiesis in Srsf2[P95H] versus wild-type mice upon stress-induced erythropoiesis and identified that SRSF2 mutations correlate with reduced hemoglobin in JAK2-mutant patients with myeloproliferative neoplasms (MPN). Consistent with this, Jak2[V617F]-Srsf2[P95H] versus Jak2[V617F] mice displayed reduced red blood cell counts and erythroid precursor frequencies. RNA-sequencing on erythroid precursors showed reduced expression of heme metabolism and mitotic spindle-related genes, and increased expression of mTORC1 signaling in Srsf2[P95H] versus wild-type cells. RNA splicing analyses on the same cells and on human patient samples identified aberrant FYN splicing in SRSF2[mut] cells, with increased aberrant FYNB over normal FYNT transcripts. FYNB, but not FYNT, expression resulted in reduced erythroid differentiation and increased phosphorylation of mTORC1 downstream target S6. Additionally, increased S6 phosphorylation was confirmed in primary Srsf2[P95H] erythroid cells. mTORC1 pathway inhibition using rapamycin normalized FYNB- and Srsf2[P95H]-induced impaired erythropoiesis and significantly increased erythroid colony formation of SRSF2-mutant myelodysplastic neoplasm (MDS) bone marrow cells. Our data reveal targetable molecular mechanisms of impaired erythropoiesis in SRSF2-mutant cells.}, }
@article {pmid41748788, year = {2026}, author = {Montano-Campos, JF and Adair, JE and Basu, A and Kyeyune, RB and Bayigga, L and Kityo-Mutuluuza, C and Hansen, R}, title = {Cost-effectiveness of gene therapy for sickle cell disease in Uganda: tailoring high-income evidence to Uganda's context.}, journal = {Gene therapy}, volume = {33}, number = {2}, pages = {109-117}, pmid = {41748788}, issn = {1476-5462}, support = {U42OD011123//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01AI167009//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; INV002613//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; R01AI158728//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P51OD010425//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; INV03398//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; }, mesh = {*Anemia, Sickle Cell/therapy/economics/genetics ; Uganda ; Humans ; *Cost-Benefit Analysis ; *Genetic Therapy/economics/methods ; Adult ; Adolescent ; Male ; Female ; Markov Chains ; }, abstract = {Blood stem cell gene therapy to treat hemoglobinopathies is beginning to transform health for small numbers of patients in the U.S. and Europe, where these conditions qualify as rare diseases. Yet hemoglobinopathies are common globally, disproportionately affecting low- and middle-income countries (LMICs), creating an ethical imperative to ensure access where disease burden is greatest. Gene therapy could have blockbuster drug potential if distributable to these regions, but cost is a major barrier. Cost-effectiveness analysis (CEA) models are seldom adapted to low-income settings, where limited data and resources constrain efforts to contextualize high-income evidence. Here, we present a novel framework to evaluate high-income country authorized gene therapies in LMIC contexts. Uganda, where sickle cell disease (SCD) imposes a major burden and no curative therapies are available, is the test case. We evaluate cost-effectiveness of gene therapy for adolescents and adults with SCD in Uganda, adapting U.S. evidence to local economic conditions. Using a three-state Markov model to estimate lifetime costs of standard-of-care in Uganda, two U.S.-based CEA models were adapted using scaling factors and applied to two authorized gene therapies for SCD, Lyfgenia™ (lovo-cel) and Casgevy® (exa-cel), assuming biologically consistent efficacy across populations. Incremental cost-effectiveness ratios (ICERs) were calculated from healthcare and societal perspectives, with internationally accepted gross domestic product-based thresholds. This study demonstrates that Casgevy could be cost-effective in Uganda at a scaled cost when societal benefits are considered. This framework enables CEAs for emerging therapies where local clinical trial data are limited, supporting local decision-makers, global funders, and manufacturers in advancing equitable access to transformative therapies in LMICs.}, }
@article {pmid41749842, year = {2026}, author = {Chakrabarti, S and Cohen, SA and Tin, A and Dangl, A and Chung, KY and Tejani, MA and Fakih, MG and Chandana, SR and Donahue, CA and George, V and Malla, M and Aushev, VN and George, GV and Ortiz, JB and Herter, WK and Nagarajan, A and Weinberg, BA and Sharma, VR and Botta, GP and Cho, M and Azzi, G and Kasi, A and Dayyani, F and Hanna, DL and Somer, BG and Malhotra, M and Sharma, S and Jurdi, A and Liu, MC and Landmann, RG and Dasari, A}, title = {Utility of Circulating Tumor DNA to Assess Tumor Response in Patients with Locally Advanced Rectal Cancer Undergoing Neoadjuvant Therapy.}, journal = {Cancers}, volume = {18}, number = {4}, pages = {}, pmid = {41749842}, issn = {2072-6694}, abstract = {BACKGROUND: Circulating tumor (ct)DNA is a prognostic biomarker in gastrointestinal malignancies. In rectal cancer, its utility to inform perioperative management and predict recurrence, particularly in patients undergoing non-operative management (NOM), remains unclear. Studies are needed to clarify how post-neoadjuvant therapy (NAT) and post-surgical ctDNA status correlate with clinical outcomes in localized rectal cancer.<br><br>METHODS: We retrospectively analyzed ctDNA data from 220 patients with rectal cancer using a personalized tumor-informed assay (Signatera&#x2122;, Natera, Inc., Austin, TX, USA). Of these, 148 (67.3%) underwent NAT followed by surgery, and 72 (32.7%) underwent NAT followed by NOM. We assessed associations between post-NAT ctDNA status and survival outcomes. In the surgical cohort, we examined associations between post-operative ctDNA status and clinical response, pathological response, survival outcomes, and NAR scores.<br><br>RESULTS: In the surgical cohort, ctDNA positivity at the post-operative MRD timepoint was a strong predictor of recurrence, with an 88.3% relapse rate compared to 11.5% in ctDNA-negative patients (p < 0.001). Among the 64 NOM patients with post-NAT ctDNA, 21.9% (14/64) were ctDNA-positive, of whom 100% (14/14) relapsed (92.9% local-only), 13 relapsed by the time of data cut-off, and one relapsed 8 months after the cut-off. Only 10% (5/50) of the ctDNA-negative NOM patients experienced local recurrence (p < 0.0001). ctDNA positivity post-NAT was associated with inferior DFS (p = 0.003).<br><br>CONCLUSION: ctDNA was a strong predictor of recurrence in rectal cancer, including in NOM settings. In NOM patients, ctDNA detected local recurrences, highlighting its potential to guide post-NAT surveillance and treatment.}, }
@article {pmid41752282, year = {2026}, author = {Amissah, CM and Crump, AA and Fu, YH and Khadka, S and Contreras, J and Jones, SMW and Reeve, BB and Villalonga-Olives, E}, title = {Developing an Index to Measure Structural Racism: Methodological Process, Challenges, and Considerations.}, journal = {International journal of environmental research and public health}, volume = {23}, number = {2}, pages = {}, pmid = {41752282}, issn = {1660-4601}, support = {R01MD019029//National Institute of Health/ ; }, mesh = {Humans ; United States ; *Racism ; Hispanic or Latino ; *Health Status Disparities ; Delphi Technique ; Black or African American ; White ; }, abstract = {Access to valid and reliable measures of structural racism is essential for addressing health inequities, yet few validated ecological-level indices exist for assessing structural racism affecting Black and Hispanic populations in the United States. Guided by the National Institute on Minority Health and Health Disparities framework, our interdisciplinary team undertook the development of an ecological-level structural racism index. In the process, we encountered substantive methodological and data-related challenges that warrant explicit documentation. This paper describes the methodological process used to identify and select indicators of structural racism, including a modified Delphi consensus process involving social epidemiologists, health inequality researchers, community members, economic inequality specialists, and psychometricians. We outline a five-step approach for extracting and harmonizing geographic-level data from publicly available sources and discuss key challenges encountered, including limited availability of granular geographic data, insufficient data documentation guidelines, inconsistent reporting frequencies, and difficulties in adapting publicly available datasets for structural racism measurement. Rather than presenting a finalized index, this paper serves as a methodological guide and cautionary account for researchers seeking to develop ecological measures of structural racism, emphasizing the importance of transparency, adaptability, and rigorous data selection in advancing public health equity research.}, }
@article {pmid41756882, year = {2026}, author = {Zambidis, AE and Siddaramaiah, LK and Konecny, AJ and Gray, M and Prlic, M}, title = {CaptureBody - an anti-CD45 × anti-IgG bispecific antibody enables accurate unmixing for spectral flow cytometry.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41756882}, issn = {2692-8205}, abstract = {Accurate spectral unmixing is a critical step for flow cytometry data analysis and requires a single stain control for every fluorescent parameter used in an experiment. Currently, compensation particles are often used for making single stain controls when a target protein is of low abundance or a cell type is of low frequency. However, compensation particles introduce incongruencies in emission spectra compared to cells resulting in spectral unmixing or compensation errors. To enable the use of cells regardless of the abundance of target proteins or immune cell type, we generated a bispecific antibody that links a human anti-CD45 and mouse anti-IgG variable region. We refer to this new bispecific tool as CaptureBody (CB) and highlight the benefits of its final nanobody-based design. We provide all sequences and methods necessary for the in-house expression of a CaptureBody to disseminate their use for spectral flow cytometry experiments.}, }
@article {pmid41756883, year = {2026}, author = {Wirbel, J and Saber, W and Martens, MJ and Peled, JU and Andermann, TM and Fei, T and Brooks, EF and Doyle, B and Pincus, NB and Jenq, RR and Bar, M and Bolaños-Meade, J and Bratrude, B and Chhabra, S and Choi, SW and Clark, W and Das, S and Elmariah, H and Gooptu, M and Holtan, SG and Jones, RJ and Levine, JE and Logan, BR and Al Malki, MM and Murthy, HS and Rashidi, A and Rezvani, AR and Riches, ML and Runaas, L and Sandhu, K and Spahn, A and Sung, AD and van den Brink, MRM and Horowitz, MM and Hamadani, M and Kean, LS and Perales, MA and Bhatt, AS}, title = {Differential effects of two common GVHD prophylaxis regimens on the gut microbiome: Results from the BMT CTN 1801 study.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41756883}, issn = {2692-8205}, support = {UG1 HL069249/HL/NHLBI NIH HHS/United States ; }, abstract = {Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for many hematological malignancies, but graft-versus-host disease (GVHD) is a common complication. Low gut microbiome diversity is associated with higher GVHD risk and shorter survival in multiple studies. Recently, the BMT CTN 1703 clinical trial demonstrated superiority of a GVHD-prophylaxis regimen including post-transplant cyclophosphamide (PTCy) compared to the standard prophylaxis (tacrolimus and methotrexate, Tac/MTX) in terms of GVHD-free, relapse-free survival at one year among reduced intensity conditioning allo-HCT recipients. However, the effect of PTCy on the gut microbiome and its association with clinical outcome have not been described. Here, we report on a companion randomized clinical controlled trial (BMT CTN 1801), which collected 2575 longitudinal stool samples from 304 study participants. Samples were obtained up to weekly up to day 84 post allo-HCT and at less frequent intervals thereafter, up to 2 years. Microbiome diversity and absolute microbial load were lower in the PTCy group compared to the Tac/MTX group on days 14-28 post-HCT. However, diversity at the timepoint closest to neutrophil engraftment was not significantly associated with non-relapse mortality after one year or other clinical outcomes, contrary to expectations from previous studies. Microbial domination events, when a single species exceeds 30% relative abundance, were comparable across treatment arms and reflected both pathogen blooms as well as less severe disruptions of the microbial community. Clostridium scindens and secondary bile acid metabolism pathways were less prevalent in the PTCy arm than in the Tac/MTX arm post-HCT, yet presence of secondary bile acid metabolism pathways was associated with a lower risk of chronic GVHD. Given that PTCy was associated with a greater disruption of the microbiome as measured by diversity, absolute microbial abundance, and bile acid metabolism capability, but better clinical outcomes overall, these data suggest that the importance of the microbiome in modulating the host immune systems after allo-HCT is specific to different types of GVHD prophylaxis.}, }
@article {pmid41757067, year = {2026}, author = {Kikawa, C and Huddleston, J and Turner, SA and Loes, AN and Liu, J and Gang, S and Griffiths, T and Drapeau, EM and Cowling, BJ and Ho, F and Leung, NHL and Englund, JA and Lacombe, K and Watanabe, S and Hasegawa, H and Busch, M and Lanteri, M and Stone, M and Spencer, B and Neher, RA and Smith, DJ and Bedford, T and Hensley, SE and Bloom, JD}, title = {Near real-time data on the human neutralizing antibody landscape to influenza virus as of early 2026 to inform vaccine-strain selection.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41757067}, issn = {2692-8205}, abstract = {Twice each year, a decision is made on whether to update the strains included in the seasonal influenza vaccine to better match the most recent circulating viral strains. To characterize the antigenic properties of current seasonal influenza A strains to inform the upcoming decision about which strains to include in the 2026-2027 Northern Hemisphere vaccine, here we perform high-throughput sequencing-based neutralization assays using a library of 57 H3N2 and 34 H1N1 influenza hemagglutinins reflecting the circulating diversity of strains in late 2025 to early 2026. We assay this library against 302 human sera collected in late 2025. The resulting data set encompasses 27,409 titers, and provides a near real-time portrait of the human neutralizing antibody landscape against influenza virus. We find that many human sera have lower titers against the K subclade of H3N2 and the D.3.1.1 subclade of H1N1; these subclades have recently become dominant among their respective subtypes. Our measurements also reveal variability in titers to different subvariants within the K subclade of H3N2, with titers especially low to subclade K strains with additional mutations in antigenic regions D and E. We make all our data and accompanying visualizations publicly available to enable their use in vaccine-strain selection and analyses of influenza evolution and immunity.}, }
@article {pmid41757210, year = {2026}, author = {Liu, J and Gang, S and Kikawa, C and Rodriguez, AJ and Li, SH and Ye, N and Griffiths, T and Drapeau, EM and Atkinson, RK and Loes, AN and Collman, RG and Ferguson, JA and Han, J and Ward, AB and Bloom, JD and Hensley, SE}, title = {Mapping the specificity of H3N2 strain-specific and cross-reactive human neutralizing antibodies elicited by the 2025-2026 influenza vaccine.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41757210}, abstract = {An H3N2 variant, named subclade K, continues to circulate widely during the 2025-2026 influenza season. This virus possesses a hemagglutinin (HA) protein that has eleven substitutions relative to the HA of the Northern Hemisphere 2025-2026 H3N2 vaccine strain. Many of these substitutions are in epitopes in well-characterized HA antigenic sites. Despite this, interim vaccine effectiveness studies indicate that the 2025-2026 influenza vaccine provides moderate protection against H3N2 subclade K infection. We previously reported that many individuals who received the 2025-2026 influenza vaccine produced antibodies that inhibit H3N2 subclade K virus cellular attachment. Here, we show these individuals also produced antibodies that neutralize H3N2 subclade K virus infection, and we observed a strong correlation between hemagglutination-inhibition titers and neutralizing antibody titers. We completed additional specificity studies using samples from individuals who did or did not have antibodies that cross-reacted to H3N2 subclade K viruses. Using high-throughput neutralization assays, we determined that antibodies that bound to the vaccine strain but not H3N2 subclade K viruses typically targeted antigenic site B of HA. Conversely, we found that cross-reactive neutralizing antibodies elicited by vaccination commonly targeted antigenic site A, D, and E of HA that are conserved between the vaccine strain and H3N2 subclade K viruses. Additional electron microscopy-based polyclonal epitope mapping studies confirmed that cross-reactive antibodies elicited by vaccination typically target epitopes on the side of HA. Together, our studies provide an immunological explanation of why the 2025-2026 influenza vaccine was partially effective against antigenically advance H3N2 subclade K viruses. Our data suggest that vaccine strains for subsequent seasons need to be carefully considered, since subclade K viruses have already started to acquire additional substitutions in HA antigenic sites targeted by cross-reactive antibodies.}, }
@article {pmid41758580, year = {2026}, author = {Cai, Y and Surapaneni, A and Vasconcelos, AG and Johnson, M and Hsu, L and Sun, W and Kooperberg, C and Yu, B and Yeo, WJ and Auer, PL and Grams, ME and Franceschini, N and Raffield, LM and Reiner, AP}, title = {Alterations of Plasma Metabolites Associated with Sickle Cell Trait.}, journal = {Clinical journal of the American Society of Nephrology : CJASN}, volume = {}, number = {}, pages = {}, pmid = {41758580}, issn = {1555-905X}, support = {X01HL153408, 3R01HL-117626-02S1, HHSN268201800002I, R01HL-120393, U01HL-120393, HHSN268201800001I/HB/NHLBI NIH HHS/United States ; R01-DK117445 and R01-MD012765/NH/NIH HHS/United States ; U01-HG011720 and R01-HL146500/NH/NIH HHS/United States ; R01-DK124399 and K24-HL155681/NH/NIH HHS/United States ; }, abstract = {KEY POINTS: We identified 69 plasma metabolites associated with sickle cell trait, including markers of eGFR and/or related to oxidative stress pathways. Twenty-five percent or 39% of the sickle cell trait-associated metabolites were replicated in the Atherosclerosis Risk in Communities study. Sickle cell trait-associated metabolites individually or in aggregate were associated with better prediction of incident kidney failure in those with sickle cell trait.<br><br>BACKGROUND: Sickle cell trait (SCT) is the heterozygous carrier state for sickle cell disease (SCD) and is common among individuals of African ancestry. Although SCT is a known risk factor for CKD and ESKD, the mechanisms underlying this phenotypic association have not been fully characterized. We used metabolomic profiling to gain insight into the pathobiology of SCT.<br><br>METHODS: We used a nontargeted metabolomics approach (Metabolon Global Discovery Panel) to measure baseline plasma levels of 851 metabolites in 986 older Black women with SCT (mean age 61&#xb1;7 years) compared with 998 age- and race-matched controls without SCT from the prospective Women's Health Initiative (WHI) study. Age-adjusted linear regression was used to assess the association between metabolite levels and SCT. Replication was performed in an independent sample of 1070 Black men and women (including 70 with SCT) from the Atherosclerosis Risk in Communities study.<br><br>RESULTS: In age-adjusted models, 69 metabolites were significantly associated with SCT in WHI after correction for multiple testing. Many of the SCT-associated metabolites are markers of kidney glomerular filtration (eGFR) and/or related to oxidative stress metabolic pathways are known to be altered in SCD homozygotes. Of the 64 SCT-associated metabolites available for replication, 25 or 39% were replicated in the Atherosclerosis Risk in Communities study. Inclusion of SCT-associated metabolites was associated with significantly better risk prediction of incident ESKD in WHI among SCT individuals compared with a baseline model adjusted for age+eGFR.<br><br>CONCLUSIONS: We identified and replicated metabolites associated with SCT, many of which are related to eGFR and/or pathways altered in SCD (e.g ., oxidative stress, membrane remodeling). These results suggest that plasma metabolomic profiling may be useful in ESKD risk stratification for individuals with SCT, meriting validation in larger cohorts.}, }
@article {pmid41758981, year = {2026}, author = {Gill, H and Palandri, F and Ross, DM and Göthert, JR and Cochrane, T and Larsen, SR and Halpern, AB and Shortt, J and Rossetti, JM and Liang, J and Marchetti, M and Wilson, AJ and Innes, AJ and Hanna, M and Vianelli, N and Stevenson, WS and Vannucchi, AM and Kleppe, M and Flynn, J and Natsoulis, G and Harrison, CN and Rienhoff, HY}, title = {Phase 2 study of the lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat for essential thrombocythemia.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025017575}, pmid = {41758981}, issn = {2473-9537}, abstract = {Novel treatments that can improve disease course of essential thrombocythemia (ET) are needed. In this phase 2 trial, participants with ET who required cytoreduction and had inadequate response to or were intolerant of ≥1 standard therapy received bomedemstat at a starting dose of 0.6 mg/kg per day, titrated to achieve a target platelet count (200-400×109/L). Primary end points were safety and response, defined as a platelet count ≤400×109/L without new thromboembolic events. Seventy-three participants received bomedemstat. At 24 weeks, 49 of 64 evaluable participants (77%) had a response. Durable reductions in platelet count (≤400×109/L for ≥12 weeks) were observed in 52 of 72 participants (72%). Durable reduction in white blood cell count (<10×109/L for ≥12 weeks) was observed in 61 of 72 participants (85%); of 10 participants with elevated white blood cell count at baseline, 9 had normal white blood cell count (<10×109/L) at week 24. Hemoglobin levels remained stable. After 24 weeks of treatment, a decrease in variant allele frequency of CALR, JAK2, or MPL was observed in 39 of 46 (85%) evaluable participants. By week 24, 2 of 73 participants (3%) had experienced ≥1 thrombotic event and 15 of 73 (21%) experienced ≥1 hemorrhagic event. During overall treatment period, grade 3 or 4 adverse events (AEs) occurred in 34 of 73 participants (47%). AEs led to temporary treatment interruption in 29 participants (40%) and permanent discontinuation in 11 (15%). No participants died due to AEs. Bomedemstat had clinically relevant activity and manageable safety in participants with ET. Registration: NCT04254978 (Study of Bomedemstat in Participants With Essential Thrombocythemia [IMG-7289-CTP-201/MK-3543-003]).}, }
@article {pmid41760378, year = {2026}, author = {Cook, AJ and Wellman, RD and Marsh, T and Tiwari, RC and Nguyen, MD and Russek-Cohen, E and Peng, Y and Nelson, JC}, title = {Estimating Risk Differences Using Large Healthcare Data Networks for Medical Product Post-Market Safety Outcomes in a Distributed Data Setting and Allowing for Active Post-Market Surveillance.}, journal = {Statistics in medicine}, volume = {45}, number = {6-7}, pages = {e70440}, doi = {10.1002/sim.70440}, pmid = {41760378}, issn = {1097-0258}, support = {HHSF223200910006I/FD/FDA HHS/United States ; 75D30122D15428/CC/CDC HHS/United States ; }, mesh = {Humans ; *Product Surveillance, Postmarketing/methods/statistics &amp; numerical data ; United States ; United States Food and Drug Administration ; Risk Assessment/methods ; Propensity Score ; Computer Simulation ; Centers for Disease Control and Prevention, U.S. ; }, abstract = {Risk differences allow decision makers to easily estimate the excess safety risk associated with a medical product relative to the potential benefits. However, in post-market observational surveillance studies that actively monitor (e.g., sequentially over time) for safety risk of new medical products, available methods target a relative measure (e.g., odds ratio and relative risk), which can be especially unstable in the rare event setting. These studies are typically conducted within distributed healthcare networks (e.g., Food and Drug Administration [FDA] Sentinel and Centers for Disease Control [CDC] Vaccine Safety Datalink) with patient-level data protected behind firewalls, but sharing of aggregate, deidentified data for centralized analyses. We propose an inverse probability of treatment weighting (IPTW) method that uses site-specific propensity scores to estimate site-specific risk differences that are combined to create an overall stratified risk difference estimate. This method is tailored to the rare event setting and requires minimal data sharing. The stratified IPTW approach is then extended to the active post-market surveillance setting by incorporating group sequential monitoring boundaries using a novel permutation approach. A simulation study is conducted to evaluate the performance of the new methods relative to two centralized analysis approaches, and the methods are applied to a safety surveillance study comparing the risk of febrile seizure between two vaccines using FDA Sentinel Data from three healthcare organizations.}, }
@article {pmid41760865, year = {2026}, author = {Mandrik, O and Thomas, C and Bessey, A and Brennan, A and Carvalho, AL and Castilla-Rodríguez, I and Doroshenko, O and Hill, H and Kunst, N and Nagy, B and Payne, K and Pollard, D and Ramsey, SD and Roitberg, F and Shinkins, B and Smitht, RA and Howard, T and Whyte, S}, title = {Ten Recommendations for Modelling Cost Effectiveness of Screening: Perspectives of an International Stakeholder Group.}, journal = {PharmacoEconomics}, volume = {}, number = {}, pages = {}, pmid = {41760865}, issn = {1179-2027}, support = {189350//University of Sheffield/ ; }, abstract = {Modelling the cost effectiveness of screening interventions presents unique challenges. These relate to a lack of knowledge about underlying health states and disease progression in the absence of screening, added costs arising from incidental findings, screening recall and follow-up diagnostics, imperfect uptake, potential harms to otherwise healthy people, and impacts on resource capacity and equity. No specific but generalisable advice currently exists to help guide health economic modellers working in this area. There is a need for tailored recommendations beyond the widely used, health economic modelling frameworks. We aimed to develop a set of recommendations for modelling the cost effectiveness of screening programmes. In our iterative process, we first drafted a conceptual document outlining key issues requiring recommendations. This framework was then expanded based on additional themes identified through a survey of screening modelling experts. Next, the draft recommendations were shared with a broader international expert group, which included modellers, health economists and policy specialists. Finally, the core concepts were refined and agreed upon during a virtual stakeholder meeting. A set of ten recommendations and a checklist are presented. The document provides guidance on critical methodological requirements for modelling screening interventions. These guidelines are intended to help health economic modellers and screening policy makers working to evaluate screening interventions across a wide range of diseases and jurisdictions with clarity, rigour and consistency.}, }
@article {pmid41761831, year = {2026}, author = {Boeckh, M and Corey, L}, title = {Cytomegalovirus and Aging-How Can the Field Move Forward?.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiag099}, pmid = {41761831}, issn = {1537-6613}, }
@article {pmid41763306, year = {2026}, author = {Rosenthal, KJ and Felix-Sanchez, P and Forbush, K and Rhoads, N and Kang, M and Vicente, JJ and Smith, FD and Wordeman, L and Ong, SE and Cheung, KJ and Scott, JD}, title = {AKAP2 is required for assembly of cytoskeletal signaling complexes that promote growth and metastasis of triple-negative breast cancer.}, journal = {The Journal of biological chemistry}, volume = {302}, number = {4}, pages = {111329}, pmid = {41763306}, issn = {1083-351X}, support = {R01 GM129090/GM/NIGMS NIH HHS/United States ; S10 OD021502/OD/NIH HHS/United States ; }, abstract = {A Kinase Anchoring Proteins (AKAPs) that coordinate spatiotemporal signaling are increasingly implicated in cancer. Elevated AKAP2 protein correlates with an invasive phenotype in triple-negative breast cancer cell lines. A combination of biochemical, cellular, and omics approaches shows that AKAP2 cytoskeleton and focal adhesion-associated scaffolds contribute to the progression of basal-like triple-negative breast cancer. Proximity proteomics identifies AKAP2 as an element of focal adhesions in MDA-MB-231 cells. Molecular and immunofluorescent microscopy studies demonstrate that AKAP2 indirectly constrains focal adhesion kinase (FAK). Gene silencing of AKAP2 not only decreases FAK levels but also attenuates the phosphorylation of the cell motility adapter protein paxillin on Tyr118. Cell-derived xenograft studies in mice establish that AKAP2 is required for triple-negative breast cancer growth and metastasis, phenotypes that are linked to FAK action. These findings discover a new role for focal adhesion-associated AKAP2 in triple-negative breast cancer pathology.}, }
@article {pmid41763313, year = {2026}, author = {Kirtane, K and Kalos, M and Billups, R and Chapuis, AG and Coutinho, V and Feldman, SA and Gastman, B and Haanen, J and Hanley, PJ and Hegde, P and Hopewell, EL and Levine, BL and Locke, FL and Maus, MV and Nair, NV and Nathenson, M and Perales, MA and Rivière, I and Sikder, D and Tendler, C and Yee, C and Luke, J and O'Cearbhaill, RE}, title = {Advancing Cell Therapies for Solid Tumors: A Pathway to Overcome Biological, Operational, and Regulatory Hurdles.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.02.054}, pmid = {41763313}, issn = {2666-6367}, abstract = {Cellular therapies have revolutionized the treatment of hematologic malignancies and are now emerging as potentially promising interventions for solid tumors. While considerable learnings can be leveraged from hematologic applications to inform the development of cell therapies in solid tumors, a number of biological and operational challenges-such as target-antigen heterogeneity; off-tumor target-mediated toxicity; immunosuppressive microenvironment; limited trafficking and persistence; tissue accessibility; and significantly larger patient populations-necessitate innovative clinical, manufacturing, regulatory, and operational strategies to deliver effective cell therapies for solid tumors. This white paper, informed by the 2025 Summit on Advancing Cell Therapy for Solid Tumors-co-sponsored by American Society for Transplantation and Cellular Therapy (ASTCT) and Society for Immunotherapy of Cancer (SITC)-proposes a framework for cellular therapy development in solid tumors, with an emphasis on logistical, operational, and regulatory considerations unique to this setting. The paper lays out an innovative, collaborative operational model to leverage collective experience and knowledge; emphasize standardization; invest in both prospective and retrospective banking of materials; engage in regulatory data-driven recalibration; engage payers before therapy begins; and establish regional manufacturing hubs and tailored accreditation pathways to support scalability and quality assurance. Operational innovations that can streamline access include hub-and-spoke clinical networks-where a central specialized facility is connected to smaller, more accessible locations-as well as early patient referrals. To safely implement new therapies, it is essential for providers to undergo enhanced training to manage cellular therapy-specific and delayed toxicities. Regulatory recalibrations-including streamlined evaluation of long-term follow-up requirements and proactive payer engagement for comprehensive reimbursement-are equally vital. Finally, cell therapy experts must lead cross-disciplinary education to ensure equitable and safe access as indications for cellular therapy expand across solid-tumor types, autoimmune diseases, and other disease types. Collaborative efforts across clinical, operational, regulatory, and policy initiatives are vital in order to unlock the full potential of cellular therapy for diverse patient populations.}, }
@article {pmid41763494, year = {2026}, author = {Lee, S and Shu, X and Derkach, A and Reiner, AS and Liang, X and Woods, M and Concannon, P and Lynch, CF and Malone, KE and Knight, JA and John, EM and Deasy, JO and Bernstein, JL and Oh, JH}, title = {Integrating Genomic and Nongenomic Data to Stratify the Risk of Contralateral Breast Cancer After Radiation Therapy.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, pmid = {41763494}, issn = {1879-355X}, support = {R21 CA234752/CA/NCI NIH HHS/United States ; R01 CA097397/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA083178/CA/NCI NIH HHS/United States ; R01 CA285801/CA/NCI NIH HHS/United States ; R01 CA129639/CA/NCI NIH HHS/United States ; R01 CA206464/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Women treated with radiation therapy (RT) for breast cancer have an increased risk of developing radiation-associated contralateral breast cancer (CBC). Predicting CBC events is challenging because of the complex interplay of genomic, treatment, personal, and clinical factors. This study investigated computational methods that integrate genome-wide single-nucleotide polymorphisms and nongenomic data to develop a risk stratification model for developing CBC in women treated with RT for their first primary breast cancer.<br><br>METHODS AND MATERIALS: This study used a subset of the population-based Women's Environmental Cancer and Radiation Epidemiology study that included 633 CBC cases and 1253 individually matched unilateral breast cancer controls who were treated with RT and had single-nucleotide polymorphism data available from a genome-wide association study. The study population was split into training, validation, and test sets for rigorous modeling and validation. Three data integration methods were compared in terms of their ability to stratify CBC risk: (1) naive integration; (2) sequential integration; and (3) sequential iterative integration. A biological analysis of the final model was performed using gene set enrichment analysis and protein-protein interaction analysis with gene annotation information informed by the model.<br><br>RESULTS: The best-performing integration method was the sequential iterative integration equipped with the mixed-effect random forest algorithm. This approach achieved an area under the curve of 0.64 to stratify CBC risk in the test set, representing moderate predictive power. Calibration analysis showed good agreement between the lowest and highest risk bins stratified using sorted predicted values in the test set, resulting in an odds ratio of 3.27 for both predicted and observed CBC occurrence. Gene set enrichment analysis and protein-protein interaction analysis revealed that genes with high importance scores were associated with pathways relevant to lipid and fatty acid metabolism as well as breast cancer sensitivity to tamoxifen.<br><br>CONCLUSIONS: The mixed-effect random forest approach demonstrated the potential for integrating high-dimensional genomic and low-dimensional nongenomic data to stratify CBC risk.}, }
@article {pmid41767406, year = {2026}, author = {Haddox, HK and Abdel Aziz, O and Galloway, JG and Kent, J and Cooper, CR and Jennings-Shaffer, C and Dumm, W and Temple, SD and Bloom, JD and Matsen, FA}, title = {Clonal interference and changing selective pressures shape the escape of SARS-CoV-2 from hundreds of antibodies.}, journal = {Virus evolution}, volume = {12}, number = {1}, pages = {veaf104}, pmid = {41767406}, issn = {2057-1577}, abstract = {SARS-CoV-2 has evolved increased resistance to human polyclonal antibody responses. But, how it escaped individual monoclonal antibodies from these responses has not been thoroughly explored. Cao et al. used deep mutational scanning to identify mutations that allow SARS-CoV-2 to escape individual antibodies, doing so for hundreds of different antibodies. Here, we use these data to reconstruct how the virus escaped each antibody in nature. For each antibody, we predict how levels of escape changed in the global SARS-CoV-2 population over time. For many antibodies, these levels dramatically fluctuated due to escape mutations being displaced by clade-turnover events. We validate predicted patterns using pseudovirus neutralization data. Fitness effects estimated from natural sequences suggest that mutations are displaced due to clonal interference between clades and that the order in which mutations arose is shaped by changing selective pressures. Overall, this work suggests that SARS-CoV-2 evaded polyclonal responses via complex evolutionary dynamics.}, }
@article {pmid41770651, year = {2026}, author = {Abrams, HR and Loggers, ET and Wagner, MJ and Kim, EY and Schaub, SK and Roberts, JL and Brinkmann, E and Thompson, M and Moore, R and Johnson, R and Baroudi, M and Morin, N and Gooley, T and Cranmer, LD}, title = {A Phase 1 Study of Neoadjuvant Cabozantinib in Combination With Radiation Therapy for Sarcomas of the Extremities.}, journal = {American journal of clinical oncology}, volume = {}, number = {}, pages = {}, pmid = {41770651}, issn = {1537-453X}, abstract = {OBJECTIVES: Cabozantinib demonstrates activity in multiple soft tissue sarcoma (STS) subtypes, but use with concurrent radiation therapy (RT) has been limited by concern for risk of fistula or perforation. This phase 1 trial evaluated the safety of concurrent cabozantinib and RT as neoadjuvant therapy in patients with extremity STS.<br><br>METHODS: Adults with newly diagnosed localized extremity STS planned for neoadjuvant RT and surgical resection were eligible. Participants received radiation with 5000 to 5040&#xa0;cGy with conventional fractionation and cabozantinib 40&#xa0;mg or 60&#xa0;mg daily. Patients were observed for dose-limiting toxicity (DLT) up to 28 days after completion of concurrent cabozantinib/RT. The primary objective was to identify a recommended phase 2 dose (RP2D) of cabozantinib for combination with RT, and secondary objectives included estimating rates of treatment-related adverse event (TRAE), margin positivity, and objective response.<br><br>RESULTS: Six patients were enrolled with histologic subtypes of undifferentiated pleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, and myxoid liposarcoma. No DLT due to the combination of cabozantinib and radiation was observed, but 3/6 (50%) patients required dose-reduction due to TRAE of cabozantinib alone. No grade &#x2265;3 toxicities were attributed to RT. The RP2D was cabozantinib 60&#xa0;mg. Six (100%) patients demonstrated stable disease at 12 weeks, and 5 (83%) underwent R0 resection. Two (33%) patients experienced metastatic relapse, and 1 (17%) died without relapse; 3 (50%) patients survived without relapse by last contact. No local recurrences occurred.<br><br>CONCLUSIONS: In this phase 1 trial, concurrent cabozantinib/RT was feasible and demonstrated an acceptable safety profile for patients with extremity STS.}, }
@article {pmid41770790, year = {2026}, author = {Minnie, S and Ho, K and Boiko, JR and Adams, RC and Ensbey, KS and Nemychenkov, NS and Legg, SR and Schmidt, CR and Comstock, ML and Lyons, J and Sekiguchi, T and Koyama, M and Spencer, A and Green, DJ and Hill, GR}, title = {CSF-1R inhibition and lenalidomide synergize to promote myeloma control after autologous stem cell transplantation.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025030207}, pmid = {41770790}, issn = {1528-0020}, abstract = {Autologous stem cell transplantation (ASCT) with maintenance lenalidomide remains the mainstay of consolidation therapy for eligible multiple myeloma (MM) patients but preventing disease relapse remains a critical unmet need. Here we investigated whether immunosuppressive myeloid populations in bone marrow (BM) correlated with ASCT outcomes. We identified a subset of CD64+CD169+CD163+ macrophages that expressed CSF-1R, PD-L1, and CD155, and were expanded in patients who relapsed post-ASCT. Using a preclinical ASCT model with suboptimal endogenous anti-myeloma activity, we demonstrated that while neither CSF-1R inhibition nor lenalidomide monotherapy significantly improved outcomes, their combination synergistically attenuated disease progression and prolonged survival. Single-cell RNA sequencing revealed that lenalidomide expanded NK-like CD8+ T-cells but paradoxically also increased the frequency of Csf1r+ macrophages. Cell-cell communication analyses identified Csf1r+ macrophages as suppressors of these NK-like and effector-like exhausted (Tphex) CD8 T-cell populations through CD94/NKG2A and PD-L1/PD-1, respectively. CSF-1R blockade depleted these immunosuppressive macrophages, which correlated with decreased expression of inhibitory receptors and enhanced expression of activation markers in Tphex. Given the FDA approval of axatilimab for chronic GVHD, combining CSF-1R blockade with lenalidomide maintenance represents a readily testable strategy to improve progression-free survival after ASCT.}, }
@article {pmid41771028, year = {2026}, author = {Kamat, AM and Hensley, PJ and Maiorano, BA and Li, R and Psutka, SP and Mouw, KW and Horowitz, A and Gupta, S and Necchi, A}, title = {Bacillus Calmette-Guérin (BCG) and Beyond: Is Systemic Immunotherapy for BCG-Naïve Non-Muscle-Invasive Bladder Cancer Progress or Overreach?.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2502670}, doi = {10.1200/JCO-25-02670}, pmid = {41771028}, issn = {1527-7755}, }
@article {pmid41771133, year = {2026}, author = {Tosteson, ANA and Stout, NK and Su, YR and van Ravesteyn, NT and Lowry, KP and Abraham, L and Alagoz, O and DiFlorio-Alexander, R and de Koning, HJ and Hampton, JM and Henderson, L and Mandelblatt, JS and Onega, T and Schechter, CB and Sprague, BL and Stein, S and Trentham-Dietz, A and Miglioretti, DL and Kerlikowske, K and Lee, CI}, title = {Outcomes of Density-Targeted Supplemental Breast Magnetic Resonance Imaging Screening by Breast Cancer Risk: Long-Term Health and Economic Considerations.}, journal = {Annals of internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.7326/ANNALS-25-00792}, pmid = {41771133}, issn = {1539-3704}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; R01 CA248068/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Federally mandated breast density notifications motivate consideration of supplemental breast magnetic resonance imaging (MRI).<br><br>OBJECTIVE: To evaluate supplemental breast MRI strategies.<br><br>DESIGN: Simulation of women at average to 4 times higher-than-average relative risk (RR) for breast cancer incidence undergoing screening digital breast tomosynthesis (DBT) with or without supplemental MRI.<br><br>DATA SOURCES: Breast Cancer Surveillance Consortium and literature.<br><br>TARGET POPULATION: Women aged 40 years or older.<br><br>TIME HORIZON: Lifetime.<br><br>PERSPECTIVE: U.S. federal payer.<br><br>INTERVENTION: Screening with DBT with or without breast density-targeted MRI by starting age (40, 45, or 50 years) and interval (annual or biennial).<br><br>OUTCOME MEASURES: Breast cancer deaths averted, false-positive biopsy recommendations, harm-benefit ratios, and incremental cost-effectiveness ratios (ICERs).<br><br>RESULTS OF BASE-CASE ANALYSIS: Across all starting ages and intervals, DBT averted 7.4 to 10.5 breast cancer deaths per 1000 average-risk women screened and 23.2 to 33.6 per 1000 women with 4 times higher-than-average risk. Across all RR levels, DBT with supplemental MRI for women with extremely dense breasts (DBT+MRId) averted 0.1 to 0.8 additional breast cancer deaths and resulted in 22 to 186 additional false-positive biopsy recommendations. False-positive biopsies per breast cancer death averted for biennial DBT+MRId for women with 2 times higher-than-average risk were similar to those associated with DBT in average-risk women. For all risk groups, biennial DBT+MRId starting at age 50 years was more effective but less cost-effective than DBT starting at age 45 years.<br><br>The ICERs were sensitive to cancer risk, MRI costs, and false-positive biopsy rates.<br><br>LIMITATION: Subgroups considered risk and breast density only.<br><br>CONCLUSION: Supplemental MRI for women aged 40 years or older with extremely dense breasts and higher-than-average risk (RR &#x2265;2.0) had harm-benefit ratios similar to biennial DBT alone and could be cost-effective if MRI costs and false-positive biopsy rates are reduced.<br><br>PRIMARY FUNDING SOURCE: National Cancer Institute.}, }
@article {pmid41774321, year = {2026}, author = {Chrostek, MR and Robinson, J and Krishnan, R and Yu, EY and Nordquist, LT and Vandross, AL and Salkeni, MA and Schehr, J and Mannino, M and Hintz, A and Caceres, J and Vatani, M and Emamekhoo, H and Nelson, P and Markey, C and Coates, E and Breitmeyer, J and Fong, L and De Bono, JS and Lang, JM and Zhao, SG}, title = {Phase I multi-center clinical and biomarker study of the dual-action androgen receptor inhibitor ONCT-534.}, journal = {Investigational new drugs}, volume = {}, number = {}, pages = {}, pmid = {41774321}, issn = {1573-0646}, support = {P50 CA269011/CA/NCI NIH HHS/United States ; T32GM140935/GF/NIH HHS/United States ; P50CA269011/GF/NIH HHS/United States ; DP2 OD030734/GF/NIH HHS/United States ; T32 GM140935/GM/NIGMS NIH HHS/United States ; }, abstract = {ONCT-534 is a dual-action androgen receptor inhibitor (DAARI) that combines AR antagonism and degradation via N-terminal domain binding, additionally targeting AR splice variants. In this study patients received ONCT-534 daily ranging from 40 to 1200 mg. The primary objectives were safety and dose-limiting toxicities (DLTs). Additional objectives included antitumor activity and AR signaling biomarkers. Adverse events (AEs) were assessed within the first 28 days for DLTs. Clinical activity was evaluated by PSA and radiographic progression per PCWG3 and RECIST v1.1. The trial was stopped early and not all patients were evaluated per protocol. Twenty-one patients received ONCT-534 across six doses. The most common AEs were anemia, back pain, and fatigue. While no DLTs were observed within 28 days, Grade 3/4 AEs occurred later in 9 patients (anemia most frequently). One patient discontinued due to treatment-related AE. No radiographic or PSA-based responses were observed; however, three patients showed PSA declines at week 4, with one achieving a PSA50 at time of study closure. Of 10 patients with baseline AR protein data, the median change was - 40.59% in AR protein levels at week 4. In the 300 mg cohort, 3 patients showed concordant decreases in AR protein and AR gene expression. Here, PSA levels correlated positively with AR target gene and AR gene expression. ONCT-534 had acceptable safety and demonstrated biological activity through AR protein degradation and AR signaling suppression in mCRPC patients. Although clinical responses weren't observed, these findings provide proof-of-concept for examining AR protein changes in patients receiving DAARIs.}, }
@article {pmid41774512, year = {2026}, author = {Becilli, M and Merli, P and Algeri, M and Del Bufalo, F and Pagliara, D and Bertaina, V and Agrati, C and Rosignoli, C and Cefalo, MG and Boccieri, E and Di Cecca, S and Iaffaldano, L and Lee, Y and De Angelis, B and Meshinchi, S and Quintarelli, C and Campana, D and Locatelli, F}, title = {Anti-CD7 fratricide-resistant chimeric antigen receptor T cells for relapsed/refractory acute myeloid leukemia.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025032299}, pmid = {41774512}, issn = {1528-0020}, abstract = {Autologous second-generation CD7-directed CAR T-cells, expressing an anti-CD7 protein expression blocker to prevent self-killing fratricide, were infused in three pediatric/young adult patients with relapsed/refractory CD7+ acute myeloid leukemia resulting in measurable residual disease negativity. The safety profile was favorable.}, }
@article {pmid41774517, year = {2026}, author = {Crombie, JL and Ahmed, S and Frigault, MJ and Hunter, BD and Palomba, ML and Mirza, AS and Lunning, MA and Egini, O and Odstrcil Bobillo, MS and Kallam, A and Kambhampati Thiruvengadam, S and Lee, D and Dahiya, S and Hamadani, M and Herrera, AF and Lee, CJ and Patel, K and Patel, SS and Reagan, PM and Shadman, M and Bernasconi, D and Kim, S and Liu, FF and Roy, D and Pasquini, MC and Isufi, I}, title = {Real-world outcomes for lisocabtagene maraleucel in patients with relapsed or refractory large B-cell lymphoma.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025031733}, pmid = {41774517}, issn = {1528-0020}, abstract = {This study assessed real-world effectiveness and safety of lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), including those with high-risk disease, secondary central nervous system (sCNS) involvement, comorbidities, and poor fitness, using data in the Center for International Blood and Marrow Transplant Research Registry from 5 Feb 2021 to 4 Feb 2025. Eligible patients (N=1116) received liso-cel and had ≥1 effectiveness and safety assessment after infusion, including 195 in the second-line setting, 71 with sCNS, and 257 with transformed LBCL. Median age was 71.1 years (range, 21.5‒91.2), with 72.3% ≥65 years. Within the overall population, 6.6% had Eastern Cooperative Oncology Group performance status of ≥2, 53.4% had ≥1 comorbidity, and median number of prior lines of therapy was 3 (range, 1‒16). Median study follow-up was 12.6 months (95% confidence interval [CI], 12.5‒12.8). Among effectiveness-evaluable patients (n=1109), objective response rate was 81.2% and complete response rate was 71.3%. Duration of response, progression-free survival, and overall survival rates (95% CI) at 12 months were 60.2% (56.4‒63.9), 51.2% (48.0‒54.4), and 67.6% (64.5‒70.6), respectively. Cytokine release syndrome was reported in 51.0% of patients, with grade ≥3 events in 2.5%. Immune effector cell-associated neurotoxicity syndrome was reported in 26.6% of patients, with grade ≥3 events in 9.2%. The 12-month nonrelapse mortality rate was 6.1% (95% CI, 4.6‒7.8). These real-world data reinforce the effectiveness and safety of liso-cel in this broad population of patients with R/R LBCL, including younger patients and those with high-risk disease features.}, }
@article {pmid41774708, year = {2026}, author = {Hsieh, YP and O'Keefe, IP and Wang, Z and Sun, W and Yang, H and Vu, LM and Smalley, NE and Ernst, RK and Dandekar, AA and Malik, HS}, title = {Magnesium depletion by Candida albicans unleashes two unusual modes of colistin resistance in Pseudomonas aeruginosa with different fitness costs.}, journal = {PLoS biology}, volume = {24}, number = {3}, pages = {e3003673}, pmid = {41774708}, issn = {1545-7885}, mesh = {*Pseudomonas aeruginosa/drug effects/genetics/metabolism ; *Colistin/pharmacology ; *Magnesium/metabolism ; *Candida albicans/metabolism/drug effects/genetics ; *Drug Resistance, Bacterial/genetics ; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/metabolism/genetics ; Mutation ; Lipid A/metabolism/biosynthesis ; Genetic Fitness ; Microbial Sensitivity Tests ; }, abstract = {Increasing bacterial resistance to colistin, a vital last-resort antibiotic, is an urgent challenge. Previous studies have shown that Mg2+ depletion enables Pseudomonas aeruginosa to become resistant to colistin. Here, we show that magnesium sequestration by Candida albicans also enables P. aeruginosa to evolve a nearly hundredfold higher level of colistin resistance through genetic changes in lipid A biosynthesis-modification pathways and a putative magnesium transporter. These mutations synergize with the Mg2+-sensing PhoPQ two-component signaling system to remodel lipid A structures of the bacterial outer membrane in previously uncharacterized ways. One predominant mutational pathway involves early mutations in htrB2, a non-essential gene involved in lipid A biosynthesis, which enhances resistance but compromises outer membrane integrity, resulting in fitness costs and increased susceptibility to other antibiotics. A second pathway achieves increased colistin resistance independently of htrB2 mutations without compromising membrane integrity. In both cases, reduced colistin binding to the bacterial membrane underlies resistance. Our findings reveal that Mg2+ scarcity triggers novel evolutionary trajectories, leading to extremely high colistin resistance in P. aeruginosa.}, }
@article {pmid41775429, year = {2026}, author = {Flores, TF and Tonorezos, ES and Bhatia, S and Brahmer, JR and Cappelli, LC and Cooper, M and Davies, M and Guild, S and Gunturu, K and Haanen, JBAG and Johnson, DB and Lacouture, ME and Leidner, R and Mitchell, S and Moledina, DG and Moslehi, J and Naidoo, J and Obeid, M and Postow, M and Puzanov, I and Reid, ME and Santomasso, BD and Schadendorf, D and Silk, AW and Sullivan, RJ and Walunas, T and Wang, Y and Ascierto, PA and Ernstoff, MS}, title = {Where is the data? Delayed and chronic irAE surveillance and management after cessation of ICIs: expert insights from SITC on survivorship care and the need for long-term data.}, journal = {Journal for immunotherapy of cancer}, volume = {14}, number = {3}, pages = {}, pmid = {41775429}, issn = {2051-1426}, mesh = {Humans ; *Immune Checkpoint Inhibitors/adverse effects/therapeutic use ; Survivorship ; *Neoplasms/drug therapy ; Cancer Survivors ; }, abstract = {Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, offering durable responses and prolonged survival. However, these therapies also present unique challenges, particularly with the onset of immune-related adverse events (irAEs), which can manifest during treatment either acutely and/or become chronic or emerge long after treatment cessation. Delayed, chronic, and re-emergent irAEs often require tailored survivorship care, including coordination across multiple disciplines focused on oncology, specialty care, and primary care. Despite the increased usage of ICIs, there is limited longitudinal data guiding the surveillance, diagnosis, attribution, and management of irAEs after ICI treatment. To address these gaps, the Society for Immunotherapy of Cancer convened an Expert Panel to deliberate best practices and identify research opportunities for improving post-treatment care. This paper outlines these expert insights into irAE surveillance, coordination and continuity across care transitions and settings, and clinical management strategies. The paper also underscores the importance of clinicians' understanding of irAE onset patterns, multidisciplinary coordination, and the urgent need in the field for the development of a comprehensive irAE registry. By addressing these critical gaps, the oncology community can better support the growing population of ICI-treated cancer survivors, ensuring improved quality of life and care outcomes.}, }
@article {pmid41775684, year = {2026}, author = {Suarez-Carmona, M and Hampel, M and Zhang, XW and Pöchmann, A and Grauling-Halama, SA and Valous, NA and Charoentong, P and Ferber, D and Wissfeld, J and Höflich, A and Goriely, S and Detavernier, A and Azouz, A and Rongvaux, A and Zukunft, S and Fleming, I and Okun, JG and Baracos, V and Heikenwalder, M and Zitvogel, L and Xu, X and Xu, C and Volkmar, M and Schraivogel, D and Steinmetz, L and Hamanishi, J and Mandai, M and Gaida, M and Mokry, T and Nattenmüller, J and Sedlaczek, O and Monje, N and Schwab, R and Hasenburg, A and Mavratzas, A and Boger, RJ and Marmé, F and Schott, S and Halama, N}, title = {Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer.}, journal = {Signal transduction and targeted therapy}, volume = {11}, number = {1}, pages = {}, pmid = {41775684}, issn = {2059-3635}, support = {Zukunftsthema//Helmholtz Association/ ; ERDF 2022-2027 WAL IMAGIN SYST-IMM//F&#xe9;d&#xe9;ration Wallonie-Bruxelles (French Community of Belgium)/ ; 318346496//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {Humans ; Female ; Animals ; Mice ; *Immunotherapy ; *Omentum/pathology/immunology ; *Ovarian Neoplasms/immunology/pathology/therapy/genetics ; Tumor Microenvironment/immunology/drug effects ; *Lipid Metabolism/immunology ; *Carcinoma, Ovarian Epithelial/immunology/pathology/therapy/genetics ; Tumor-Associated Macrophages/immunology ; Neoplasm Metastasis ; Signal Transduction ; }, abstract = {Immunotherapy with immune checkpoint blockade (ICB) in epithelial ovarian carcinoma (EOC) shows limited clinical benefit only for a small subset of patients. Overall response rates are low, so that overcoming immunotherapy resistance and improved stratification are key. In this study, we investigated the immunometabolic landscape of EOC with a focus on omental metastases, identifying lipid-laden macrophages as central elements for actionable therapeutic vulnerabilities and giving rise to biomarkers for improved patient stratification. Using patient-derived explants, we demonstrated a functional dichotomy inside the typically lipid-rich microenvironment of omental metastases: augmented maintenance of effector T cell function, while lipid uptake and processing by tumor-associated macrophages (TAMs) induces oxidative stress-dependent signaling programs, which drive macrophage dysfunction and immune suppression. Pharmacological modulation of lipid-driven signaling pathways through CCR5 inhibition (inflammation modulation through maraviroc) or blockade of the lipid scavenger receptor CD36 reprograms TAMs, restores T cell activity, and enhances antitumor immune responses within lipid-rich tumor niches. Mechanistically, studies in humanized mouse models reveal that maraviroc-mediated CCR5 inhibition induces transcriptional programs associated with immune activation in stressed, lipid-laden human TAMs. Consistent with these mechanistic insights, we demonstrated that the specific immunometabolic niche in omental metastases is clinically associated with responsiveness to ICB. We propose a non-invasive radiomics and machine-learning-based analysis of imaging data to assess omental involvement for patient stratification.}, }
@article {pmid41776157, year = {2026}, author = {Frouard, J and Telwatte, S and Luo, X and Gill, N and Thomas, R and Arneson, D and Roychoudhury, P and Butte, AJ and Wong, JK and Hoh, R and Deeks, SG and Lee, SA and Roan, NR and Yukl, SA}, title = {HIV-seq reveals gene expression differences between HIV-transcribing cells from viremic and suppressed people with HIV.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41776157}, issn = {2041-1723}, support = {P01AI169606//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01DK120387//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01AI132128//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01AI147777//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01DK131526//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01AI183286//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R21AI170166//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UM1AI164559//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UM1AI164567//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; UM1AI164560//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P30AI027763//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01AI183666//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01AI194343//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; BB19-SF-009/A135087//California HIV/AIDS Research Program (CHRP)/ ; }, mesh = {Humans ; *HIV Infections/drug therapy/virology/immunology/genetics ; *Viremia/virology/genetics ; *HIV-1/genetics ; RNA-Seq/methods ; Single-Cell Analysis/methods ; RNA, Viral/genetics ; CD4-Positive T-Lymphocytes/virology/immunology ; Transforming Growth Factor beta/metabolism ; Interferons/metabolism ; }, abstract = {HIV-transcribing cells can perpetuate chronic inflammation in ART-suppressed people with HIV (PWH) and likely contribute to viral rebound after ART interruption. However, these cells are difficult to study using single-cell RNA-seq (scRNA-seq) due to their low frequency and low levels of HIV transcripts, which are usually not polyadenylated. By spiking in capture sequences targeting conserved regions of HIV during scRNA-seq - a new method we call "HIV-seq" - we detect double the mean number of HIV reads per cell from PWH. HIV RNA+ cells are enriched among T effector memory cells during both viremia and ART suppression but exhibit a cytotoxic signature during viremia only. In contrast, HIV-transcribing cells from ART-suppressed timepoints exhibit a distinct anti-inflammatory signature involving elevated TGF-β and diminished IFN signaling. These findings demonstrate that HIV-seq is a useful tool to better understand the mechanisms by which HIV-transcribing cells can persist during ART.}, }
@article {pmid41777872, year = {2025}, author = {Muno, BA and Haris, M and Zegeye, A and Behailu, R and Hassan, SA and Islam, JY and Smith, MD and Picou, B and Nnaji, C and Barnes-Balenciaga, J and Miller, M and Sawyer, S and McCullough, D and Mares, L and Burley Iii, U and Bijole, P and Haddock, IL and Hall, BW and Warren, M and Duncan, DT and Jacobs, SEW and Camacho-Rivera, M and Jaiswal, J and Patel, RC}, title = {Manifestations and Lived Experiences of Structural Racism for Racial and Ethnic Minority Communities Affected by HIV Across the United States.}, journal = {Health equity}, volume = {9}, number = {1}, pages = {474-490}, pmid = {41777872}, issn = {2473-1242}, support = {R01 MH131542/MH/NIMH NIH HHS/United States ; }, abstract = {OBJECTIVE: To elucidate some of the manifestations of structural racism as a root cause of racialized inequities in HIV in the context of COVID-19, centered through the lens of community members with lived experiences.<br><br>METHODS: We partnered with eight community-based organizations to conduct focus group discussions structured around COVID-19 and HIV-related experiences. We utilized inductive coding and thematic analysis.<br><br>RESULTS: We conducted 10 focus group discussions (98 participants) across the United States between February and May 2023; 65% were ages 18-39, over 90% identified as Black, 39% were female, and 66% were cisgender. First, participants emphasized that structural racism intersects with other systems of oppression. Second, three main themes emerged as manifestations of structural racism: (1) lack of representation in state and federal decision-making levels, (2) differential access to resources, and (3) intergenerational mistrust and trauma.<br><br>CONCLUSION: The intersecting impact of the HIV epidemic and COVID-19 pandemic underscores the pervasive effects of structural racism that manifests in the United States.<br><br>HEALTH EQUITY IMPLICATIONS: More than ever, researchers must champion the experiences and needs of racial and ethnic minority communities to affect structural change.}, }
@article {pmid41779000, year = {2026}, author = {Yu, EY and Narayan, V and Esposito, G and Szmulewitz, R and Lu, Y and Lilly, MB and Calais, J and Bratslavsky, G and Menda, Y and Vasanawala, M and Pouliot, F and Laidley, D and Fleshner, N and Saad, F and Provost, JC and Teslenko, I and Rawat, NK and Ulaner, G}, title = {131I-LNTH-1095 Radioligand Therapy Plus Enzalutamide vs. Enzalutamide Alone in Men With PSMA-Avid Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Study.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-4948}, pmid = {41779000}, issn = {1557-3265}, abstract = {PURPOSE: The phase 2 ARROW study was designed to evaluate radioligand therapy with 131I-LNTH-1095, an iodine-131-labeled small molecule targeting PSMA, in combination with enzalutamide in subjects with metastatic castration-resistant prostate cancer after progression on prior abiraterone therapy.<br><br>PATIENTS AND METHODS: Men &#x2265;18 years with PSMA-positive prostate cancer (PSMA PET tracer uptake >1&#xd7; liver SUVmean in all CT-measurable lesions) were randomized 2:1 to 131I-LNTH-1095 (4 cycles of 3.7 GBq/dose every 8 weeks)+enzalutamide (160 mg po qd) vs. enzalutamide alone. The primary endpoint was PSA50 response. Secondary endpoints included rPFS, ORR, OS, and safety.<br><br>RESULTS: Of 177 screened subjects, 120 were randomized (80: 131I-LNTH-1095+enzalutamide; 40: enzalutamide-monotherapy). PSA50 response was 62.9% (95% CI, 50.5-74.1) for 131I-LNTH-1095+enzalutamide vs. 31.3% (16.1-50.0) for enzalutamide alone (P=.003). Median rPFS was 14.0 months (95% CI: 8.64-18.20) for 131I-LNTH-1095+enzalutamide vs. 11.5 months (2.79-18.43) for enzalutamide alone (P=.10). Incidence of grade &#x2265;3 treatment-emergent adverse events (TEAEs) was 65.8% for 131I-095+enzalutamide vs. 41.0% for enzalutamide-monotherapy; the most frequent TEAEs were fatigue (75.0 vs. 53.8%), nausea (59.2 vs. 33.3%), thrombocytopenia (51.3 vs. 0%), and decreased appetite (48.7 vs. 17.9%), respectively. Two deaths in the 131I-LNTH-1095+enzalutamide group were considered treatment-related. The study was not powered to detect rPFS and OS differences.<br><br>CONCLUSIONS: 131I-LNTH-1095+enzalutamide was associated with a statistically significant improvement in PSA50 response compared to enzalutamide alone despite a lower dosing schedule (4 cycles of 3.7 GBq/dose every 8 weeks) than the other approved PSMA RLT agents. Grade &#x2265;3 adverse events were more frequent with combination therapy, particularly hematologic toxicity. NCT03939689.}, }
@article {pmid41779777, year = {2026}, author = {Ramsey, EL and Dobersch, S and Freie, B and Hong, NH and Wu, X and Kugel, S and Eisenman, RN and Carroll, PA}, title = {MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {10}, pages = {e2524659123}, pmid = {41779777}, issn = {1091-6490}, support = {R37 CA241472/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; 465590102//DKFZ | Heidelberger Zentrum f&#xfc;r Personalisierte Onkologie Deutsches Krebsforschungszentrum In Der Helmholtz-Gemeinschaft (DKFZ-HIPO)/ ; R35 CA231989/CA/NCI NIH HHS/United States ; PF-24-1196662-01-RMC//American Cancer Society (ACS)/ ; }, mesh = {Humans ; *Pancreatic Neoplasms/genetics/metabolism/pathology ; *Proto-Oncogene Proteins c-myc/genetics/metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; *Carcinoma, Pancreatic Ductal/genetics/metabolism/pathology ; Apoptosis/genetics ; Animals ; Activating Transcription Factor 4/genetics/metabolism ; Transcription, Genetic ; Mice ; *Stress, Physiological/genetics ; Cell Proliferation/genetics ; Gene Regulatory Networks ; *Transcription Factors/metabolism/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism/genetics ; }, abstract = {MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m[6]A) of messenger RNA (mRNA). MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Reestablishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Last, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.}, }
@article {pmid41779832, year = {2026}, author = {Rodriguez Chevez, HJ and Remington, AJ and Gray, MD and Alam, R and Gilmour, MW and Morningstar, C and Alencar, GF and Pulliam, T and McClure, EM and Singh, N and Urselli, F and Ouellette, S and Poljakov, K and Smythe, KS and Kulikauskas, RM and Robinson, KL and Moshiri, AS and Yeung, CCS and Lin, M and Shimp, KR and Schwartz, A and Macy, AM and Tooley, MR and Baker, ML and Carter, JJ and Hopwo, K and Singhi, N and Bakhtiari, J and Ruterbusch, M and Shasha, C and Iuliano, M and Mullen, LJ and DeBuysscher, BL and Veatch, JR and Koelle, DM and Galloway, DA and Nghiem, P and Taylor, JJ}, title = {Response of B cells specific for polyomavirus-derived oncoprotein is predictive of Merkel cell carcinoma tumor control.}, journal = {Cancer immunology research}, volume = {}, number = {}, pages = {}, pmid = {41779832}, issn = {2326-6074}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA044579/CA/NCI NIH HHS/United States ; }, abstract = {Merkel cell carcinomas (MCC) typically arise from clonal integration of the Merkel cell polyomavirus. Immunogenic viral oncoproteins then lead to tumorigenesis. Oncoprotein-specific T cells are essential for anti-MCC immunity, but it is unclear whether B cells promote tumor control. Here, we analyzed the frequency and phenotype of viral oncoprotein-specific and total B cells in blood samples from 47 patients with MCC and tumor samples from another 19 patients with MCC. The phenotype of blood B cells did not correlate with MCC patient outcomes. In contrast, all 11 patients with robust oncoprotein-specific antibody-secreting and/or germinal center B cells in tumors experienced long-term MCC control. In vitro, B cells engineered to be specific for viral oncoproteins increased the sensitivity of oncoprotein-specific CD4+ T cells by over 50-fold. Together, our findings suggest that cancer-specific B cells promote antitumor immunity via increased responses by T cells and that cancer-specific augmentation of B cells could be therapeutically relevant.}, }
@article {pmid41779867, year = {2026}, author = {Dosey, A and Dadonaite, B and Gillespie, RA and Leaf, EM and Vukovich, MJ and McGowan, J and Grey, E and Muramatsu, H and Jun, RHJ and Pardi, N and Kanekiyo, M and Bloom, JD and King, NP}, title = {Stabilization of the H5 clade 2.3.4.4b hemagglutinin improves vaccine-elicited neutralizing antibody responses in mice.}, journal = {Science translational medicine}, volume = {18}, number = {839}, pages = {eaea8770}, doi = {10.1126/scitranslmed.aea8770}, pmid = {41779867}, issn = {1946-6242}, support = {P01 AI167966/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; U19 AI181881/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Antibodies, Neutralizing/immunology ; *Influenza Vaccines/immunology ; *Hemagglutinin Glycoproteins, Influenza Virus/immunology/chemistry ; Mice ; Mutation/genetics ; Antibodies, Viral/immunology ; Female ; Humans ; Protein Stability ; Mice, Inbred BALB C ; Epitope Mapping ; Cryoelectron Microscopy ; }, abstract = {Transmission of highly pathogenic avian influenza from H5 clade 2.3.4.4b has expanded in recent years to infect large populations of birds and mammals, heightening the risk of a human pandemic. Influenza viruses that are adapted to transmission in birds and a variety of mammals tend to have a less stable hemagglutinin (HA) than seasonal influenza viruses, enabling membrane fusion at comparatively higher pH levels. Here, we combined five mutations in the H5 HA that increased its melting temperature and promoted stable closure of the HA trimer. Structural analysis by cryo-electron microscopy revealed that the stabilizing mutations create several new hydrophobic interactions while maintaining the local HA structure. We found that vaccinating mice with stabilized H5 HA immunogens resulted in higher hemagglutination inhibition and neutralization titers than nonstabilized comparators. Epitope mapping of vaccine-elicited polyclonal antibody responses using negative-stain electron microscopy and deep mutational scanning showed that site E on the side of the HA receptor binding domain was immunodominant across all groups; however, the stabilized immunogens shifted responses toward the receptor binding site, which elicited a higher proportion of neutralizing antibodies. Consistent with these findings, stabilized H5 HA immunogens delivered as messenger RNA-lipid nanoparticle (mRNA-LNP) vaccines protected mice against H5N1 challenge. These findings highlight that H5 HA-stabilizing mutations enhance the quality of antibody responses across different vaccine formats, underscoring their potential to improve pandemic preparedness vaccines targeting viruses from this widely circulating clade.}, }
@article {pmid41780060, year = {2026}, author = {Daodu, RO and Chang, J and Prescott, JB and Reinert, K and Kühnert, D}, title = {Lassa virus live tracking and lineage assignment: how nextstrain can enhance surveillance and public health in Africa and beyond.}, journal = {Emerging microbes &amp; infections}, volume = {15}, number = {1}, pages = {2640699}, pmid = {41780060}, issn = {2222-1751}, mesh = {*Lassa virus/genetics/classification/isolation &amp; purification ; *Lassa Fever/epidemiology/virology ; Humans ; Phylogeny ; Africa/epidemiology ; Animals ; Public Health ; Disease Outbreaks ; Epidemiological Monitoring ; Phylogeography ; }, abstract = {Lassa virus (LASV), a zoonotic, bi-segmented arenavirus endemic to West Africa, causes seasonal epidemics with substantial morbidity and mortality. Increasing frequency of exported cases emphasizes the need for near real-time genomic surveillance to support outbreak response and clinical decision-making. We developed a suite of open-access resources on the Nextstrain and Nextclade platforms tailored to LASV. These include live phylogenetic and phylogeographic visualization, as well as Nextclade builds for rapid mutation detection and lineage assignment based on the L and S segments and the glycoprotein complex (GPC). A dedicated GPC phylogeny enables tracking of clinically relevant mutations, including immunologically relevant variants such as alanine at position 76 (A76), which is prevalent in lineage II and is implicated in reduced binding of monoclonal antibody 25.10C. The Nextclade tools distinguish LASV from other mammarenaviruses and assign lineages with Matthews correlation coefficients exceeding 85%. These tools are available at https://nextstrain.org/lassa for immediate use in surveillance, data annotation, outbreak response, and potentially support clinical decision-making in both endemic regions and exported-case scenarios. A key limitation is dependence on genomic data quality and recency. Although sampling-to-submission delays have decreased over the past 40 years, the average delay in the past five years remains ∼2 years. In many endemic LASV regions, challenges, such as limited resources, infrastructure, and previous experiences of stigmatization and political repercussions linked to outbreak reporting, restrict data sharing. The resulting disparities and delays may hinder comprehensive surveillance and timely response, with implications for global public health.}, }
@article {pmid41780572, year = {2026}, author = {DeBerg, HA and Baloh, CH and DeGottardi, Q and Hou, J and Johansson, A and Newell, E and Laidlaw, TM and Sanda, S and Shamji, M and Durham, S and Togias, A and Kwok, WW}, title = {Differential effects of subcutaneous and sublingual immunotherapy on timothy grass-specific TH2 CD4[+] T-cell subsets.}, journal = {The Journal of allergy and clinical immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jaci.2026.02.026}, pmid = {41780572}, issn = {1097-6825}, support = {R01 AI095074/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Allergen-specific CD4[+] T cells are a highly heterogenous population. Depletion of these cells has been proposed as essential to achieve allergen desensitization in allergen immunotherapy.<br><br>OBJECTIVE: The overall aim of this study was to characterize the heterogeneity of timothy grass (Phleum pratense) allergen-specific CD4[+] T cells and determine how the frequency and phenotype of these cells change in response to sublingual (SLIT) and subcutaneous (SCIT) immunotherapy. Correlations between frequencies of these cells with Total Nasal Symptom Score and grass-specific serum immunoglobulin were also investigated.<br><br>METHODS: Mass cytometry with lanthanides-tagged peptide major histocompatibility complex class II multimers and CD154 upregulation assays were used to examine changes in the frequency and phenotype of Phl p-specific CD4[+] T cells in longitudinal peripheral blood mononuclear cell samples from a randomized, double-blind, placebo-controlled trial of SLIT and SCIT. Supervised and unsupervised clustering was used for data analysis.<br><br>RESULTS: Phenotypes of Phl p-specific T cells were highly heterogenous but could be categorized into two major metaclusters, CRTH2[hi]CD27[lo] and CRTH2[lo]CD27[hi], each with distinct phenotypic profiles. Weak positive correlations between Total Nasal Symptom Score and frequencies of T cells within both subsets were observed. SCIT preferentially depleted CRTH2[hi]CD27[lo] cells, whereas SLIT depleted CRTH2[lo]CD27[hi] cells. CRTH2[hi]CD27[lo] cell frequency correlated with Phl p-specific IgE and IgG4, but not IgA, levels.<br><br>CONCLUSION: Unsupervised clustering revealed distinct subpopulations of allergen-specific T cells that were differentially targeted and depleted by SCIT and SLIT, suggesting that SCIT and SLIT act through overlapping but distinct immunologic pathways.}, }
@article {pmid41781474, year = {2026}, author = {Naderi, E and Watt, GP and Knight, JA and Malone, KE and Lynch, CF and John, EM and Shu, X and Nguyen, TL and Oh, JH and Woods, M and Liang, X and Derkach, A and Pike, MC and Bernstein, JL}, title = {Evaluating mammographic density polygenic risk score for contralateral breast cancer risk prediction.}, journal = {Scientific reports}, volume = {16}, number = {1}, pages = {}, pmid = {41781474}, issn = {2045-2322}, abstract = {UNLABELLED: Survivors of breast cancer face a substantially increased risk of developing contralateral breast cancer (CBC). We assessed whether risk prediction models for CBC are improved by integrating mammographic density (MD) and polygenic risk scores (PRS). We analyzed data from 399 European-ancestry breast cancer survivors in the WECARE Study, an international, population-based case-control study. Cases were women who developed CBC, and controls were women with unilateral breast cancer (UBC). All participants had genome-wide genotyping and MD measurements at three intensity levels (Cumulus, Altocumulus, and Cirrocumulus) using the CUMULUS software. A weighted PRS was constructed comprised of 64 previously identified genome-wide significant single nucleotide polymorphisms (SNPs) associated with MD (PRS_MD). Linear and logistic regression models were used to assess the associations between PRS_MD, MD measurements, and CBC risk, adjusting for potential confounders. PRS_MD was significantly associated with Cumulus and Altocumulus densities, but not Cirrocumulus. In multivariable-adjusted predictive models, the inclusion of PRS_MD improved adjusted R-squared values for Cumulus (from 20.6% to 22.8%) and Altocumulus (22.7% to 24.7%). However, for Cirrocumulus the PRS_MD was not a significant predictor of CBC risk, with an effect estimate of 0.27 (95% CI: -0.9,1.4; P = 0.69). PRS_MD was not independently associated with CBC risk and adding it to MD models resulted in only small, non‑significant gains in AUC. Exploratory interaction analyses did not indicate that PRS_MD modified the association between MD and CBC risk. MD remains a robust independent predictor of CBC risk. Although PRS_MD captures inherited predisposition to MD, the current PRS explains only a small fraction of MD variance and does not enhance CBC risk prediction beyond measured MD. Further research is needed to elucidate the genetic underpinnings of MD and their relevance to CBC susceptibility.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-42365-7.}, }
@article {pmid41782345, year = {2026}, author = {Likasitwatanakul, P and Blinka, SM and Zarka, JG and Gebrael, G and Weg, E and Longoria, O and Moore, JA and Sharp, A and de Bono, J and Sternberg, CN and Agarwal, N and Swami, U and Orme, JJ and Schweizer, MT and Sloan, L and Hwang, JH and Antonarakis, ES}, title = {Molecular landscape of prostate cancers with clival metastases.}, journal = {The oncologist}, volume = {31}, number = {4}, pages = {}, pmid = {41782345}, issn = {1549-490X}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; 219594/Z/19/Z//Wellcome Trust Clinical Research Career Development Fellowship/ ; }, mesh = {Humans ; Male ; Aged ; *Prostatic Neoplasms/pathology/genetics ; Middle Aged ; Retrospective Studies ; *Cranial Fossa, Posterior/pathology ; *Skull Base Neoplasms/secondary/genetics ; Aged, 80 and over ; Prostatic Neoplasms, Castration-Resistant/pathology/genetics ; Biomarkers, Tumor/genetics ; }, abstract = {BACKGROUND: Clival metastases are a rare and clinically aggressive manifestation of advanced prostate cancer, associated with cranial nerve palsy and poor survival. The molecular features of prostate cancers giving rise to clivus metastases remain unknown.<br><br>PATIENTS AND METHODS: We performed a multi-center retrospective study across six institutions, identifying prostate cancer patients with radiographically confirmed clival metastases and available next-generation sequencing (NGS) data. Baseline characteristics and clinical outcomes were collected. Genomic alterations from tissue- and/or blood-based assays were aggregated at the patient level and compared with a publicly available metastatic castration-resistant prostate cancer (mCRPC) cohort (SU2C/PCF).<br><br>RESULTS: Fifty-nine patients with clival metastases contributed 87 molecular assays. More than half of patients had Gleason grade group 5 cancer and presented with de novo metastatic (M1) disease. The median interval from initial prostate cancer diagnosis to clival metastasis was 71.4&#x2009;months (95% CI, 42.0-101.7), while median overall survival following clival involvement was only 15.3&#x2009;months (95% CI, 6.9-22.8). Compared with the SU2C/PCF mCRPC cohort, clival metastases showed significant enrichment of BRAF and CHEK2 alterations as well as homologous recombination repair (HRR) with relative depletion of AR-related, PI3K pathway, and G2-M pathway alterations.<br><br>CONCLUSION: Prostate cancers giving rise to clival metastases exhibit a distinct molecular profile enriched for DNA damage-repair and RAF kinase alterations, suggesting unique metastatic biology and potential therapeutic vulnerabilities.}, }
@article {pmid41782488, year = {2026}, author = {Grint, DJ and White, RG and Churchyard, G and Fiore-Gartland, A and Rangaka, M and Garcia-Basteiro, AL and Cobelens, F}, title = {Imprecision in tuberculosis infection outcomes: implications for non-inferiority vaccine trials.}, journal = {International journal of epidemiology}, volume = {55}, number = {2}, pages = {}, pmid = {41782488}, issn = {1464-3685}, mesh = {Humans ; *Tuberculosis/prevention &amp; control ; *Tuberculosis Vaccines ; Sensitivity and Specificity ; *BCG Vaccine ; *Equivalence Trials as Topic ; Infant ; Computer Simulation ; *Randomized Controlled Trials as Topic ; Biomarkers ; Research Design ; Infant, Newborn ; }, abstract = {BACKGROUND: Randomized trials comparing new vaccines against tuberculosis for use in neonates and infants, for whom Bacille Calmette-Guérin vaccination is established practice, are using tuberculosis infection as the primary endpoint in a non-inferiority design. Markers of tuberculosis infection have imperfect sensitivity and specificity. Flaws in the non-inferiority trial design typically bias towards non-inferiority, which may result in falsely declaring non-inferiority.<br><br>METHODS: We conducted a statistical simulation study to assess the impact of imperfect markers of tuberculosis infection on the interpretation of tuberculosis vaccine trials testing a non-inferiority hypothesis of an infection primary outcome in a two-arm randomized comparison. Data were generated in three 2-year cumulative risk of tuberculosis infection scenarios (2%, 5%, and 8%). The specificity of tests of tuberculosis infection was assumed to range from 100% to 85%, while the sensitivity was assumed to range from 100% to 64%. Log-binomial regression was used to estimate the relative risk of tuberculosis infection.<br><br>RESULTS: With 100% sensitivity and specificity, type I error and power were both approximately equal to the expected values (2.5% and 80%, respectively) in all three cumulative tuberculosis risk scenarios. With modest deviations from perfect sensitivity and specificity (95% for both), the risk of falsely declaring non-inferiority was 96.8%, 53.2%, and 27.8% in the 2%, 5%, and 8% cumulative tuberculosis risk infection scenarios, respectively.<br><br>DISCUSSION: Tuberculosis vaccine non-inferiority trials using an infection primary outcome must be designed and interpreted accounting for the specificity of the tools used to measure infection, otherwise they risk declaring non-inferiority by default.}, }
@article {pmid41785305, year = {2026}, author = {Yan, Y and Chen, W and Ge, X and Sun, J and Yu, L and Garcia-Mansfield, K and Zhang, X and Yu, Y and Xiong, W and Zou, D and An, G and Jia, Z and Pirrotte, P and Li, JJ and Yu, Z and Hao, M and Qiu, L and Qi, J and Wang, L and Yi, S}, title = {Proteogenomic features define subtypes of mantle cell lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018701}, pmid = {41785305}, issn = {2473-9537}, support = {R35 GM140888/GM/NIGMS NIH HHS/United States ; }, abstract = {Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. While genomics and transcriptomics have delineated parts of the MCL disease spectrum, the proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 MCL patients and 4 healthy donors to investigate the translational and post-translational dimensions of MCL. Our study identified 1,296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed IGHV mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multi-omics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared to single-omics models (concordance index 0.83 vs. 0.74). This study provides the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.}, }
@article {pmid41785374, year = {2026}, author = {Muffly, LS and Lee, CJ and Gandhi, A and Varma, A and Scott, BL and Patel, SS and Shiraz, P and Youn, M and Yanagiba, C and Arulprakasam, J and Le, A and Kwon, HS and Long-Boyle, JR and Shizuru, JA and Pang, W and Artz, AS}, title = {Nonmyeloablative Conditioning Combined with Anti-CD117 Antibody Briquilimab in Older Adults with High-Risk AML and MDS.}, journal = {Blood}, volume = {}, number = {}, pages = {}, doi = {10.1182/blood.2025031858}, pmid = {41785374}, issn = {1528-0020}, abstract = {Briquilimab is a monoclonal antibody inhibiting stem cell factor (SCF) binding to CD117 (c-Kit). Based on preclinical data demonstrating the antibody clears hematopoietic stem and progenitor cells (HSPC) and myeloid malignant cells, we conducted a phase 1 trial examining briquilimab plus non-myeloablative fludarabine (flu) and total body irradiation (TBI) as conditioning for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing matched donor allogeneic hematopoietic cell transplantation (HCT). Briquilimab was infused 10-14 days before transplant day (TD) 0; fludarabine 30mg/m2 and TBI 2-3 Gy were administered on TD -4 to -2 and TD0, respectively. Graft-versus-host disease prophylaxis consisted of tacrolimus, sirolimus, and mycophenolate mofetil. Thirty-two patients enrolled (n=13 AML in complete remission [CR], n=3 AML in relapse, n=16 MDS). Median age was 70 years and most had detectable measurable residual disease at screening. There were no briquilimab infusion reactions, dose limiting toxicities, or primary graft failure events; briquilimab clearance was predictable across patients. Among the AML in CR cohort, 1-year EFS was 69.2% (95% CI, 37.3, 87.2); 1-year OS was 75% (95% CI, 40.8, 91.2). Among the MDS cohort, 1-year EFS was 53.8% (26.8, 74.8); 1-year OS was 76.4% (42.7, 91.8). One of 3 AML patients in relapse experienced a transient response. Marrow samples obtained before and after briquilimab and prior to flu/TBI demonstrated AML/MDS HSPC depletion (mean 62.4±22.7%) with resultant 3-fold increase in serum SCF. In summary, we demonstrate the feasibility, safety, and proof of concept of CD117 targeting with briquilimab as HCT conditioning for AML/MDS. The trial is registered at clinicaltrials.gov; using identifier: NCT04429191.}, }
@article {pmid41785446, year = {2026}, author = {Khor, S and Yu, K and Fedorenko, CR and Ramsey, S and Rivers, Z and Kreizenbeck, K and Khan, HM and Li, L and Kestner, ST and Kwendakwema, CN and Shankaran, V}, title = {Financial Hardship Before Diagnosis: Influence on Late-Stage Cancer Presentation and the Role of Screening.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {12}, pages = {1130-1138}, doi = {10.1200/JCO-25-01360}, pmid = {41785446}, issn = {1527-7755}, mesh = {Humans ; Female ; Middle Aged ; *Early Detection of Cancer/economics ; Case-Control Studies ; Aged ; *Breast Neoplasms/diagnosis/economics/pathology ; Neoplasm Staging ; Mammography/economics ; *Financial Stress/epidemiology/economics ; Male ; SEER Program ; Adult ; *Delayed Diagnosis/economics ; }, abstract = {PURPOSE: This study investigates the relationship between prediagnosis financial hardship (FH) and cancer stage, and the mediating role of cancer screening in breast cancer.<br><br>METHODS: This case-control study used linked, deidentified records from adult cancer patients diagnosed with stage I to IV solid tumors (2014-2017) from the Western Washington SEER registry, along with credit report data from TransUnion and health care claims, encompassing various cancers. FH was defined as at least one record of collections, charge-offs, delinquent mortgage payments, tax liens, foreclosures, repossessions, or bankruptcies within 2 years before diagnosis. We used multivariable log-binomial regression to assess the association between FH and late-stage diagnosis (stages III and IV) overall and by cancer screening category, and mediation analysis to evaluate the role of screening mammography in breast cancer.<br><br>RESULTS: Among 50,148 patients with cancer (mean age 64 years, 52% female, 85% non-Hispanic White), 30% experienced FH before diagnosis, which was associated with a 14% higher probability of late-stage diagnosis (adjusted risk ratio [aRR], 1.14 [95% CI, 1.11 to 1.17]). This association was stronger for cancers with organized screening (aRR, 1.25 [95% CI, 1.21 to 1.29]) and those detectable by physical examinations (aRR, 1.44 [95% CI, 1.31 to 1.59]), but not for cancers without these protocols (aRR, 1.00 [95% CI, 0.94 to 1.07]), with variations among individual sites. Among patients with breast cancer, 70% of the increased risk of late-stage diagnosis was attributable to the nonreceipt of screening.<br><br>CONCLUSION: FH significantly affects cancer stage at diagnosis, especially for cancers with organized screening and physical examinations. In breast cancer, this association is largely attributed to lack of screening. These findings underscore FH as an important social determinant of health and the need for targeted interventions to improve screening access.}, }
@article {pmid41785903, year = {2026}, author = {Kim, Y and Bates, JE and Yoon, HI and Grassberger, C}, title = {Cardiac radiosensitivity in the era of thoracic chemoradiotherapy and immunotherapy: a scoping review.}, journal = {The Lancet. Oncology}, volume = {27}, number = {3}, pages = {e130-e140}, doi = {10.1016/S1470-2045(25)00651-5}, pmid = {41785903}, issn = {1474-5488}, mesh = {Humans ; *Chemoradiotherapy/adverse effects ; *Immune Checkpoint Inhibitors/adverse effects ; *Cardiotoxicity/etiology ; *Immunotherapy/adverse effects ; *Lung Neoplasms/therapy/pathology ; *Carcinoma, Non-Small-Cell Lung/therapy/pathology ; *Radiation Tolerance/drug effects ; *Heart/radiation effects/drug effects ; *Thoracic Neoplasms/therapy ; Risk Factors ; }, abstract = {Concurrent chemoradiotherapy followed by immune checkpoint inhibitor (ICI) consolidation is now the standard of care for unresectable stage III non-small-cell lung cancer (NSCLC) and is increasingly applied to other thoracic malignancies. Although survival outcomes have improved, concerns about cardiac toxicity have emerged, as both chemoradiotherapy and ICIs are independently cardiotoxic and their combined effects remain unclear. This scoping review first examines chemoradiotherapy-associated and ICI-associated cardiac toxicity separately, and then evaluates their convergence in combined chemoradiotherapy and ICI therapy. For this examination and evaluation, we draw on ten clinical studies, two reviews, and five preclinical reports that together address six key questions: (1) does ICI add cardiac risks to chemoradiotherapy, (2) does previous radiotherapy increase cardiac risks with ICI, (3) does ICI alter the radiosensitivity of cardiac subregions, (4) how should cardiac endpoints be defined, (5) can molecular or pharmacological interventions mitigate toxicity, and (6) what are the major risk factors and management strategies? We also highlight four major gaps: extension beyond NSCLC, long-term survivorship, the potential of advanced radiotherapy techniques, and the interplay between lymphopenia and cardiotoxicity. The convergence of chemoradiotherapy and ICIs represents a new cardiac risk profile. Addressing these questions through larger, long-term studies is essential to balance oncological efficacy with cardiovascular safety.}, }
@article {pmid41786253, year = {2026}, author = {Engels, EA and Castenson, D and Luo, Q and Shiels, MS and Israni, A and Li, J and Madeleine, MM and Pawlish, K and Ramirez Aguilar, D and Zeng, Y and Pfieffer, RM}, title = {Population-level cancer trends among solid organ transplant recipients in the United States during 1995-2021.}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {}, number = {}, pages = {}, pmid = {41786253}, issn = {1600-6143}, support = {Z01 CP010150/ImNIH/Intramural NIH HHS/United States ; }, abstract = {Solid organ transplant recipients (SOTRs) experience elevated cancer risk from immunosuppression and underlying medical conditions. Medical management has improved over time, and SOTRs are living longer. We used registry data covering 693,718 SOTRs in the United States (US) to evaluate population-level cancer trends during 1995-2021. Compared with SOTRs in 1995-2003, those in 2013-2021 were living at older ages and were followed at a longer time since their transplant. Based on 65,081 cancers, cancer incidence in SOTRs was higher during 2013-2021 than 1995-2003 (unadjusted incidence rate ratio [IRR], 1.29; 95% confidence interval [95% CI], 1.26-1.32). However, cancer incidence was lower in 2013-2021 after adjustment for age (IRR, 0.93; 95% CI, 0.91-0.95) and multivariable adjustment (0.93, 0.90-0.96). Results for the 6 most common cancer types showed varying trends during 1995-2021. Overall cancer incidence was higher in SOTRs than in the US general population during 1995-2021 and, most recently, in 2013-2021 (standardized incidence ratio, 1.66; 95% CI, 1.64-1.67). In conclusion, after accounting for age, there was an encouraging decline in cancer incidence among US SOTRs during 1995-2021. However, incidence remained elevated compared with the general population in 2013-2021. Measures are needed to reduce the cancer burden as SOTRs live longer after transplantation and the population ages.}, }
@article {pmid41787039, year = {2026}, author = {Huang, SH and Seethala, RR and Patel, SG and O'Sullivan, B and Lydiatt, W and Ho, AS and Hosni, A and Vander Poorten, V and Glastonbury, CM and Bishop, J and Beadle, B and Ha, P and Kakarala, K and Rodriguez, CP and Ganly, I}, title = {Key Updates on the Version 9 AJCC/UICC Staging System for Salivary Gland Carcinoma.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, pmid = {41787039}, issn = {1534-4681}, abstract = {BACKGROUND: Multiple studies have identified limitations in the nodal (N) category definitions of the eighth-edition tumor-node-metastasis classifi cation (TNM8) for major salivary gland carcinoma (SGC). Minor SGCs have traditionally been staged according to site of origin despite distinct biology and patterns of spread, and the feasibility of a unified staging system for both major and minor SGCs had not been systematically evaluated. These shortcomings prompted a comprehensive reassessment of SGC staging.<br><br>METHOD: A multidisciplinary international expert panel, in collaboration with the American Joint Committee on Cancer (AJCC) Head and Neck Core Group, developed and validated a refined TNM classification for SGC. The proposed system was subsequently adopted by both the AJCC and the Union for International Cancer Control (UICC).<br><br>RESULTS: The ninth edition (TNM9) introduces the first unified SGC-specific staging system applicable to both major and minor SGCs. Key revisions include: (1) exclusion of extremely rare or non-salivary-origin histologies (e.g., squamous cell carcinoma, neuroendocrine carcinoma, and basosquamous carcinoma); (2) integration of major and minor SGCs into a single staging framework, with clarification of T3-T4 definitions to ensure applicability across both groups; (3) simplified N categorization based on lymph node count and extranodal extension (ENE): N0 (no nodal disease), N1 (1-3 nodes without ENE), and N2 (3 nodes or any ENE); and (4) restriction of stage IV exclusively to M1 disease, allowing future refinement of metastatic subcategories. Clinical TNM (cTNM) applies the same criteria as pathologic TNM (pTNM), incorporating radiologic assessment of abnormal lymph node count and imaging-detected ENE (iENE).<br><br>CONCLUSIONS: By establishing a unified, biologically relevant staging system with improved prognostic discrimination, TNM9 enhances clinical applicability and promotes more consistent management of both major and minor salivary gland carcinomas.}, }
@article {pmid41787068, year = {2026}, author = {Setiawan, T and Muhammad, JA and Julianto, NM and Wirawan, LM and Jun, N and Sari, IN and Oehler, VG and Kim, DW and Kwon, HY}, title = {Correction: Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.}, journal = {Leukemia}, volume = {40}, number = {4}, pages = {855}, doi = {10.1038/s41375-026-02909-2}, pmid = {41787068}, issn = {1476-5551}, }
@article {pmid41790934, year = {2026}, author = {Snyder, AJ and Garrison, SM and Kluesner, MG and Nutt, WS and Shasha, C and Ho, T and Marsh, SA and Linde, M and Wu, F and Meyer, L and Wilhelm, AR and Ortiz-Espinosa, S and Zepeda, V and Bingham, E and Malik, H and Mak, SR and Gad, E and Bhise, SS and Fan, E and Sarvothama, M and Wang, X and Potluri, S and Long, A and Elz, A and Ghajar, CM and Furlan, SN and Newell, EW and Srivastava, S}, title = {Modulating AP-1 enables CAR T cells to establish an intratumoral stemlike reservoir and overcomes resistance to PD-1 blockade.}, journal = {Science immunology}, volume = {11}, number = {117}, pages = {eadw7685}, doi = {10.1126/sciimmunol.adw7685}, pmid = {41790934}, issn = {2470-9468}, support = {F30 CA305905/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors/immunology ; Mice ; *Immunotherapy, Adoptive/methods ; *Receptors, Chimeric Antigen/immunology ; *Transcription Factor AP-1/immunology/metabolism ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; *Lung Neoplasms/immunology/therapy ; Drug Resistance, Neoplasm/immunology ; B7-H1 Antigen/immunology/antagonists &amp; inhibitors ; Mice, Inbred C57BL ; Cell Line, Tumor ; }, abstract = {Chimeric antigen receptor T (CAR T) cell therapy has shown limited synergy with immune checkpoint inhibitors, but the mechanisms underlying resistance remain unclear. Stemlike T cells coexpressing programmed cell death protein 1 (PD-1) and T cell factor 1 (TCF1) mediate responses to PD-1-PD-L1 (programmed death ligand 1) blockade and are maintained by major histocompatibility complex (MHC)-dependent interactions with dendritic cells in lymphoid tissues. Because CAR T cells recognize intact antigen rather than peptide-MHC, their activation is restricted to tumors, potentially limiting maintenance of this critical subset. In murine models of lung cancer, CAR T cells down-regulated TCF1, became exhausted, and were not enhanced by PD-L1 blockade. Overexpression of the transcription factor c-Jun increased intratumoral PD-1[+]TCF1[+] CAR T cells but did not prevent exhaustion, given that PD-1 induced posttranscriptional c-Jun down-regulation. PD-L1 blockade restored c-Jun levels, markedly increased CAR T cells, and enabled near-complete tumor clearance, revealing a mechanism by which MHC-independent CAR T cells can be engineered to overcome resistance to PD-1-PD-L1 blockade.}, }
@article {pmid41791098, year = {2026}, author = {Tsai, CS and Lee, H and Szewczyk, W and Palmer, JK and Putnam, S and Munson, SA and Heffner, JL and Vasbinder, A and Paullada, A and Yuwen, W and Reding, KW}, title = {Exploring Feature Priorities and User Needs in Developing Virtual Study Assistants.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e86945}, pmid = {41791098}, issn = {2561-326X}, mesh = {Humans ; *Artificial Intelligence ; *User-Computer Interface ; *Virtual Reality ; }, abstract = {This formative research explored health science researchers' perspectives on the development of an artificial intelligence-based virtual study assistant and identified 8 potential features and their priorities.}, }
@article {pmid41791419, year = {2026}, author = {Schiffer, JT and Esmaeili, S and Owens, K and Boeckh, M and Waghmare, A}, title = {Is it "time to eliminate" time to elimination of symptoms as a primary trial endpoint for respiratory virus targeting drugs?.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiag148}, pmid = {41791419}, issn = {1537-6613}, }
@article {pmid41792574, year = {2026}, author = {Azhideh, A and Haseli, S and Park, C and Lee, H and Kim, HS and Mirghaderi, P and Chalian, M}, title = {Comparative analysis of RADS classification systems for solitary bone lesions: malignancy risk stratification performance and clinical utility.}, journal = {European radiology}, volume = {}, number = {}, pages = {}, pmid = {41792574}, issn = {1432-1084}, abstract = {OBJECTIVE: To compare the malignancy risk stratification performance and inter-reader reliability of four Reporting and Data System (RADS) algorithms for solitary bone lesions: CT Bone-RADS, MRI Bone-RADS, Osseous Tumor (OT)-RADS, and Bone Tumor Imaging (BTI)-RADS.<br><br>MATERIALS AND METHODS: This retrospective analysis included patients with solitary bone lesions who underwent both CT and MRI between March 2005 and September 2021. Three radiologists independently categorized each lesion using CT Bone-RADS (1-4), MRI Bone-RADS (1-4), OT-RADS (2-5), and BTI-RADS (1-4). Categories were dichotomized into high- versus low-risk for malignancy. Diagnostic performance metrics and area under the receiver operating characteristic curve (AUC) were calculated for each reader as well as for a consensus interpretation generated using a majority-vote method. The reference standard was either histopathologic confirmation or imaging surveillance. Inter-reader reliability was assessed using Gwet's AC1 statistic.<br><br>RESULTS: A total of 207 patients (mean age, 49&#x2009;&#xb1;&#x2009;18 years; 111 men and 96 women) were included. Consensus malignancy risk stratification performance (AUC; sensitivity/specificity/positive predictive value/negative predictive value/accuracy, %) was as follows: CT Bone-RADS (0.52; 95/9/43/73/44), MRI Bone-RADS (0.60; 98/12/44/88/47), OT-RADS (0.91; 93/71/69/94/80), and BTI-RADS (0.89; 98/39/53/96/63). Inter-reader reliability (AC1) was excellent for CT Bone-RADS (0.978), MRI Bone-RADS (0.931), and BTI-RADS (0.822), and moderate for OT-RADS (0.585).<br><br>CONCLUSION: Among the evaluated bone tumor-RADS, OT-RADS demonstrated the most balanced diagnostic performance with moderate inter-reader reliability. CT Bone-RADS, MRI Bone-RADS, and BTI-RADS showed excellent inter-reader reliability.<br><br>KEY POINTS: Question Evaluation of solitary bone lesions is important but often challenging. This study compared four bone tumor-RADS algorithms to determine which provides the best malignancy risk stratification. Findings Among the four RADS algorithms, OT-RADS demonstrated the most balanced overall diagnostic performance in consensus analysis, while CT Bone-RADS, MRI Bone-RADS, and BTI-RADS showed excellent inter-reader reliability. Clinical relevance Knowledge of each RADS system's performance characteristics helps clinicians apply these algorithms appropriately to optimize the assessment of solitary bone lesions.}, }
@article {pmid41792585, year = {2026}, author = {Lee, HH and Avery, CL and Graff, M and Kim, D and Arias, J and Van Horn, L and Kooperberg, C and North, KE}, title = {Impact of Genetic Predisposition to Obesity on Long-Term Maintenance of Modest Weight Loss in Postmenopausal Women.}, journal = {Obesity (Silver Spring, Md.)}, volume = {34}, number = {4}, pages = {782-786}, pmid = {41792585}, issn = {1930-739X}, support = {75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D000//National Heart, Lung, and Blood Institute, National Institutes/ ; T32HL129982//National Heart, Lung, and Blood Institute, National Institutes/ ; /NH/NIH HHS/United States ; //U.S. Department of Health and Human Services/ ; //Intramural Research Program/ ; /CP/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; /NH/NIH HHS/United States ; /NH/NIH HHS/United States ; /CP/NCI NIH HHS/United States ; /CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; *Postmenopause/genetics ; *Obesity/genetics ; *Weight Loss/genetics ; Middle Aged ; *Genetic Predisposition to Disease ; Black or African American/genetics ; Body Mass Index ; White People/genetics ; Aged ; Weight Gain/genetics ; Longitudinal Studies ; White ; }, abstract = {OBJECTIVE: Long-term weight regain limits the population-level benefits of obesity interventions. We tested whether the polygenic risk score of BMI (PRSBMI) modifies weight trajectories following modest weight loss.<br><br>METHODS: The analytic sample included 9897 postmenopausal women from the Women's Health Initiative Dietary Modification Trial (6132 European American; 3749 African American). PRSBMI was derived from a trans-ancestry GWAS of ~2&#x2009;million participants. Longitudinal weight change (7&#x2009;years) was modeled using weighted GEE.<br><br>RESULTS: In European Americans, the PRSBMI&#x2009;&#xd7;&#x2009;randomization &#xd7; time interactions approached significance at the 95th percentile (p&#x2009;=&#x2009;0.052) and 85th percentile (p&#x2009;=&#x2009;0.07). No interaction was observed in African Americans. In analyses restricted to European Americans who lost &#x2265;&#x2009;5% of initial weight by year 1 (20%; n&#x2009;=&#x2009;1273), women in the &#x2265;&#x2009;95th percentile of PRSBMI regained nearly twice as much per year as those with average risk (0.94 vs. 0.48&#x2009;kg/year, p&#x2009;=&#x2009;0.0016).<br><br>CONCLUSIONS: A high PRSBMI was associated with faster weight regain following modest weight loss in European American women. While further validation is required in a diverse population, these results suggest the potential for genetics to inform targeted strategies for sustaining long-term weight management.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier: 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, and 75N92021D00005.}, }
@article {pmid41792766, year = {2026}, author = {Bouka, M and Nimptsch, K and Pham, TT and Bouras, E and Kanellopoulou, A and Phipps, AI and Van Guelpen, B and Brenner, H and Li, L and Le Marchand, L and Tsilidis, KK and Pischon, T}, title = {Associations of genetically predicted interleukin-6 and tumor necrosis factor signaling pathways with mortality among persons with colorectal cancer: a two-sample Mendelian randomization.}, journal = {BMC medicine}, volume = {24}, number = {1}, pages = {}, pmid = {41792766}, issn = {1741-7015}, mesh = {Humans ; *Colorectal Neoplasms/mortality/genetics ; Mendelian Randomization Analysis ; *Interleukin-6/genetics ; Polymorphism, Single Nucleotide ; *Tumor Necrosis Factor-alpha/genetics/metabolism ; Male ; *Signal Transduction/genetics ; Female ; Middle Aged ; Receptors, Interleukin-6/genetics ; Aged ; Cytokine Receptor gp130/genetics ; Genome-Wide Association Study ; }, abstract = {BACKGROUND: Despite significant progress in identifying risk factors for colorectal cancer (CRC), factors influencing survival in people with CRC remain less understood. Pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been implicated in cancer progression and may influence CRC outcomes. We investigated associations between genetically predicted levels of IL-6 and TNF-α signaling pathways and mortality in people with CRC.<br><br>METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using cis-acting single nucleotide polymorphisms (SNPs) associated with soluble IL-6 receptor alpha (sIL6-RA) and IL-6 signal transducer gp130 (IL6ST), representing IL-6 signaling, and with TNF-&#x3b1;, and its soluble receptors (sTNF-R1, sTNF-R2). SNPs were obtained separately from two large genome-wide association studies (GWAS): deCODE and UK Biobank (UKB). The outcome was CRC-specific mortality among 16,964 CRC cases (4010 deaths) in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Analyses were stratified by tumor site and stage. The inverse variance weighted (IVW) method, incorporating a correlation matrix for dependent SNPs, was used for primary analyses. Because literature links TNF-&#x3b1; to CRC incidence, we additionally performed a simulation study to evaluate the potential impact of collider bias resulting from restricting analyses to CRC cases.<br><br>RESULTS: Genetically predicted sIL6-RA was weakly positively associated with CRC-specific mortality (deCODE-SNPs (n&#x2009;=&#x2009;13) HR per 1 SD increase: 1.06; 95% CI: 1.00-1.12; UKB-SNPs (n&#x2009;=&#x2009;11) HR: 1.09; 95% CI: 1.02-1.17). Genetically proxied IL6ST levels showed no association with CRC-specific mortality in the overall sample (deCODE-SNPs (n&#x2009;=&#x2009;19) HR: 1.04; 95% CI: 0.90-1.21; UKB-SNPs (n&#x2009;=&#x2009;9) HR: 1.11; 95% CI: 0.87-2.42), while higher IL6ST levels were associated with increased mortality among patients with stage 2/3 disease (deCODE-SNPs (n&#x2009;=&#x2009;19) HR: 1.45; 95% CI: 1.10-1.91; UKB-SNPs (n&#x2009;=&#x2009;9) HR: 1.87; 95% CI: 1.22-2.89). No associations were observed for TNF-&#x3b1;, sTNF-R1, or sTNF-R2. Findings for all exposures were consistent across both GWAS datasets. Simulation analyses for TNF-&#x3b1; indicated collider bias was present but limited in magnitude.<br><br>CONCLUSIONS: Our findings suggest that IL-6 signaling may play a role in CRC progression although of limited magnitude, whereas TNF-related pathways appear less relevant for prognosis.}, }
@article {pmid41793312, year = {2026}, author = {Arthur, KC and Wilson, KB and Berry, B and Binion, B and Becker, M and Derus, A and Diop, SL and Gachuiri, M and Green, BB and Koné, A and Licitra, J and Liou, C and McCracken, CE and Nisotel, LE and Owens, SE and Piccorelli, AV and Ramsey, S and Schwartz, LB and Senturia, K and Svoboda, J and Volney, J and Williamson, BD and Hsu, C}, title = {Codesigning COVID-19 booster promotion materials in online workshops with long-term care staff: a process evaluation.}, journal = {Health education research}, volume = {41}, number = {2}, pages = {}, pmid = {41793312}, issn = {1465-3648}, support = {COVID-2021C2-13168/PCORI/Patient-Centered Outcomes Research Institute/United States ; }, mesh = {Humans ; *COVID-19/prevention &amp; control ; Female ; Male ; SARS-CoV-2 ; *COVID-19 Vaccines/administration &amp; dosage ; United States ; *Long-Term Care ; *Health Promotion/methods ; Middle Aged ; Adult ; *Health Personnel/education ; *Immunization, Secondary ; Focus Groups ; }, abstract = {When engaging communities in vaccine promotion efforts, it is critical to understand who has availability and interest in participating, and how participants experience the process. Guided by the Reach, Effectiveness, Adoption, Implementation, Maintenance framework, we evaluated an online codesign process with long-term care center staff to design coronavirus disease (COVID-19) booster promotion materials for their colleagues. Twenty-six staff joined codesign teams organized by self-identified race to culturally tailor materials during a cluster-randomized controlled trial with 40 centers in two US states. Data sources included surveys; interviews; screening, enrollment, and attendance data; fidelity assessment; codesigned materials; and focus groups. We report summary statistics and thematic analyses. We found that time constraints could impede enrollment. Most codesigners enjoyed collaborating and identified their individual contributions. Many linked having shared characteristics with their teammates (e.g. race, gender, age) to a feeling of connection. A few reported feeling motivated to engage in booster promotion. The process resulted in messages aligned with known psychological antecedents of vaccination. Considering recruitment challenges and limited participation of direct care staff, organizers should consider shorter codesign processes. Organizing teams based on shared characteristics could promote comfort. Community input should inform codesign structure and team composition to achieve optimum enrollment and engagement.}, }
@article {pmid41793956, year = {2026}, author = {Wu, AH and Wu, J and Tseng, C and Darst, BF and Park, SY and Stram, DO and Larson, T and Fruin, S and Setiawan, VW and Yu, X and Wilkens, LR and Hu, H and Haiman, C and Ritz, B and Crimmins, EM and Lim, U and Cheng, I and Marchand, LL}, title = {Racial and ethnic differences in the impact of air pollution on the risk of Alzheimer's disease and related dementias in the Multiethnic Cohort Study.}, journal = {Environment international}, volume = {209}, number = {}, pages = {110169}, doi = {10.1016/j.envint.2026.110169}, pmid = {41793956}, issn = {1873-6750}, support = {P30 AG066589/AG/NIA NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; UM1 CA164973/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Air Pollution/statistics &amp; numerical data/adverse effects ; *Alzheimer Disease/epidemiology/ethnology ; Male ; Female ; Particulate Matter/analysis ; Aged ; *Dementia/epidemiology/ethnology ; *Environmental Exposure/statistics &amp; numerical data ; Cohort Studies ; Air Pollutants/analysis ; California/epidemiology ; Incidence ; Ethnicity/statistics &amp; numerical data ; Risk Factors ; Aged, 80 and over ; Racial Groups/statistics &amp; numerical data ; Middle Aged ; }, abstract = {BACKGROUND AND OBJECTIVES: Meta-analysis results, based largely among Whites, suggested that fine particulate matter (PM2.5) exposure increases the risk of clinical dementia. This study investigated the association of air pollution and incidence of Alzheimer's disease and related dementias (ADRD) by race and ethnicity.<br><br>METHODS: We investigated incidence of AD (n&#xa0;=&#xa0;4,010) and other dementia (n&#xa0;=&#xa0;4,971) among 44,954 California Multiethnic Cohort (MEC) participants (28% African American, 14% Japanese American, 44% Latino, 14% White adults) who were enrolled in the fee-for-service component of Medicare (2001-2016). We used Cox proportional hazards regression to examine associations between exposure to PM, airport-related ultrafine particles (aUFP) and gaseous pollutants and incidence of AD, other dementia, and ADRD in a minimally- and fully-adjusted model, considering 12 established ADRD risk factors. We conducted stratified analyses to examine associations by sex, and race/ethnicity.<br><br>RESULTS: ADRD incidence was associated with PM2.5 (per 2&#xa0;&#xb5;g/m[3]), airport-related UFP (aUFP, per 4400 particles/cm[3]) and nitrogen dioxide (NO2, per 10&#xa0;&#xb5;g/m[3]) with hazard ratios (HRs, 95%CI), respectively, of 1.04 (1.02-1.06), 1.03 (1.01-1.05) and 1.09 (1.06-1.12). The AD-associations with PM2.5 and NO2, were stronger than the corresponding associations with other dementia (Pheterogeneity&#xa0;&#x2264;&#xa0;0.003). Similar patterns of results were observed by sex and across race and ethnicity. Statistically significant findings for ADRD with PM2.5, aUFP and NO2 were observed among African American (respective HRs 1.03, 1.04, 1.09), and Latino and White participants for NO2 (HR 1.10, 1.08). Results in all and African American participants remained statistically significant in fully-adjusted models. Although the effect of PM2.5 was diluted in a co-pollutant with NO2, both PM2.5 and aUFP were significantly associated with ADRD incidence in a co-pollutant model, and NO2 and aUFP (but not PM2.5) remained associated in a multipollutant model. We did not observe consistent modifying effects for any of the 12 established ADRD risk factors.<br><br>CONCLUSIONS: In this multiethnic population, incidence of ADRD increased with exposures to PM2.5, aUFP, and NO2 in all subjects and this pattern was most prominent among African American adults. These results emphasize that ADRD prevention should include not only individual-level factors but also population-wide policies and regulation to curb air pollution.}, }
@article {pmid41794050, year = {2027}, author = {Sabo, MC and Shah, JA and Lund, JM and McClelland, RS}, title = {Understanding the cervicovaginal immune response to Lactobacillus crispatus CTV-05.}, journal = {The Lancet. Microbe}, volume = {}, number = {}, pages = {101377}, doi = {10.1016/j.lanmic.2026.101377}, pmid = {41794050}, issn = {2666-5247}, }
@article {pmid41795834, year = {2026}, author = {Kang, DW and Courneya, KS and Swartz, MC and Maleki Vareki, S and Gordon, NB and Cesar Rosa Neto, J and Simpson, RJ and Baker, KS and Schadler, KL and LaVoy, EC}, title = {Chronic exercise training intensity, immune cells, and cancer outcomes: a scoping review.}, journal = {JNCI cancer spectrum}, volume = {10}, number = {2}, pages = {}, pmid = {41795834}, issn = {2515-5091}, support = {//Cancer Prevention Research Institute of Texas to EL, MS/ ; //Ontario Institute of Cancer Research/ ; //London Health Sciences Foundation Helen and Andy Spriet funds/ ; }, mesh = {Humans ; *Neoplasms/immunology/therapy ; *Exercise/physiology ; Killer Cells, Natural/immunology ; Randomized Controlled Trials as Topic ; *Exercise Therapy/methods ; Immunomodulation ; Treatment Outcome ; }, abstract = {BACKGROUND: Exercise has emerged as a potent, non-pharmacological intervention to enhance immune function in patients with cancer. The effects of exercise are likely influenced by patients' oncologic characteristics, such as cancer treatment, and intervention variables, such as exercise intensity, which can lead to heterogeneous outcomes. This scoping review aims to identify patterns, trends, and gaps in the literature regarding the relationship between chronic exercise training intensity and immune cell parameters in the context of treatment status.<br><br>METHODS: Reports were retrieved from PubMed, MEDLINE, and CINAHL. Eligible reports were controlled clinical trials of an exercise training intervention with more than 1 exercise session, included an objectively defined exercise intensity, and reported cellular immune outcomes.<br><br>RESULTS: Twenty-one articles (15 randomized controlled trials) were included. Results suggest a dose-response effect of intensity, where vigorous-intensity exercise (reported in 6 studies) elicited beneficial immunomodulation, such as enhanced natural killer cell cytotoxicity. Light-to-moderate and moderate-intensity exercise (reported in 8 studies) resulted in no significant immunological changes in 5 studies, particularly for patients undergoing active treatment. Comparisons across studies were difficult due to heterogeneity in patients' clinical characteristics, intervention details, and immune parameters. Few reported cancer clinical outcomes such as disease progression, and none directly examined the relationships between immune and clinical endpoints.<br><br>CONCLUSIONS: While direct comparisons of exercise intensities are lacking, these results suggest that vigorous exercise training may exert greater immune modulation than low-to-moderate intensity exercise training. Rigorously designed trials are needed to confirm these findings and establish the role of exercise in oncologic care.}, }
@article {pmid41796372, year = {2026}, author = {Zhang, X and Pan, L and Zhao, Y and Ma, R and Zhang, L and Zhang, Y and Li, G and Zhai, W and Ma, Q and Pang, A and Yang, D and Feng, S and Zhang, P and He, Y and Qin, G and Jiang, E and Han, M}, title = {Efficacy and safety of ruxolitinib for graft-versus-host disease prophylaxis in patients with aplastic anemia undergoing PBSC-only allogeneic stem cell transplantation: a prospective phase II study.}, journal = {Experimental hematology &amp; oncology}, volume = {15}, number = {1}, pages = {}, pmid = {41796372}, issn = {2162-3619}, support = {3332021055//Fundamental Research Funds for the Central Universities/ ; 82100225//National Natural Science Foundation of China/ ; 82070192//National Natural Science Foundation of China/ ; 2023ZD0502400//Noncommunicable Chronic Diseases-National Science and Technology Major Project/ ; 2023YFC2508900//National Key R&amp;D Program of China/ ; 2023-I2M-2-007//CAMS Innovation Fund for Medical Sciences/ ; 23JCZXJC00220//Tianjin Natural Science Foundation/ ; }, abstract = {BACKGROUND: While peripheral blood hematopoietic stem cell transplantation (PB-HSCT) supports rapid engraftment and reduces graft failure risk in aplastic anemia (AA) patients, it compromised higher risk of acute graft-versus-host disease (aGVHD), highlighting the need for more effective prophylactic strategies. This phase II clinical trial was designed to assess the efficacy and safety of ruxolitinib, a JAK1/2 inhibitor, as part of GVHD prophylaxis regimen following PB-HSCT.<br><br>METHODS: This open-label, single-arm, Phase II clinical trial (ClinicalTrials.gov: NCT05914714) enrolled patients with AA between June 2023 and December 2024. Ruxolitinib was initiated at the start of conditioning and continued for 3&#xa0;months post-transplant at a dose of 5&#xa0;mg twice daily. A historical control cohort receiving standard GVHD prophylaxis between January 2019 and May 2023 was included for comparison. To address baseline imbalances, propensity score-based inverse probability of treatment weighting (IPTW) was applied. The primary objective was the incidence of aGVHD six months after HSCT. Secondary endpoints included one-year overall survival (OS) and GVHD-free, failure-free survival (GFFS). Immune reconstitution-including T cells, B cells, NK cells-and levels of pro-inflammatory cytokines were also evaluated to explore potential mechanisms.<br><br>RESULTS: A total of 82 patients were enrolled (ruxolitinib group n&#x2009;=&#x2009;46, historical control cohort n&#x2009;=&#x2009;36). Comparative analysis showed that ruxolitinib significantly reduced the cumulative incidence of grade II-IV aGVHD (HR 0.24; p&#x2009;=&#x2009;0.004) and severe aGVHD (0% vs 15.8%; p&#x2009;=&#x2009;0.008) compared with the control group. At a median follow-up of 417&#xa0;days (range: 112-725), the ruxolitinib group demonstrated significantly superior 1-year GFFS (91.6% vs. 72.1%; HR 0.23, weighted log-rank p&#x2009;=&#x2009;0.012). Notably, the ruxolitinib group not only exhibited more rapid recovery of CD4&#x2009;+&#x2009;Tregs at 3&#xa0;months post-HSCT. Notably, but also suppressed proinflammatory cytokine levels during engraftment.<br><br>CONCLUSIONS: The peri-transplantation addition of ruxolitinib to the standard GVHD prophylaxis regimen in PB-HSCT for AA patients has shown to be a safe and effective approach to reducing both the incidence of aGVHD, while improving patient outcomes. Our study suggests that ruxolitinib may offer a promising strategy for improving survival and immune recovery. Trial registration clinicaltrials.gov identifier: NCT05914714.}, }
@article {pmid41796432, year = {2026}, author = {Lam, BD and Ryu, J and Jafari, O and Kim, RB and Ma, S and Ranjan, M and Jiang, JY and Li, A}, title = {Epidemiology of Cancer-Associated Venous Thromboembolism Across the United States.}, journal = {American journal of hematology}, volume = {101}, number = {5}, pages = {1005-1018}, pmid = {41796432}, issn = {1096-8652}, support = {K23 HL159271/HL/NHLBI NIH HHS/United States ; R01 HL180402/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Venous Thromboembolism/epidemiology/etiology/mortality ; United States/epidemiology ; *Neoplasms/complications/epidemiology/mortality ; Female ; Male ; Middle Aged ; Risk Factors ; Aged ; Incidence ; Adult ; Aged, 80 and over ; }, abstract = {Prior epidemiological studies on cancer-associated venous thromboembolism (VTE) were limited by homogenous patient populations. We leverage Cosmos, a collaborative dataset of Epic electronic health record systems, to conduct an updated evaluation of cancer-associated VTE in the United States (US). Cosmos includes patients from all 50 states, and the dataset is representative of the US census in terms of age, race, ethnicity, and insurance coverage. We included patients in the US with a new cancer diagnosis between 2018 and 2023. We computed the cumulative incidence of VTE at 6 and 12 months after the diagnosis date and used Cox regression to identify risk factors and examine the association between VTE type within the first year and mortality. We identified 1 628 626 patients, with a cumulative incidence of VTE at 6 months of 2.7% and at 12 months of 3.7%. Major risk factors included prior VTE, cancer type, advanced stage, and chemotherapy-based treatment regimens. The occurrence of VTE within the first year of cancer diagnosis was independently associated with increased mortality.}, }
@article {pmid41797392, year = {2026}, author = {Vega, P and Bhattacharyya, P and Lieberman, JA and Kuczmarski, TM and Yoke, LH and So, LM and Smith, HZ and Lengermann, R and Cohen, S and Fredricks, DN and Pergam, SA}, title = {Fusariosis in Patients With Hematologic Malignancies in the Era of Antifungal Prophylaxis.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70203}, doi = {10.1111/tid.70203}, pmid = {41797392}, issn = {1399-3062}, support = {T32AI118690//National Institute of Allergy and Infectious Diseases of the National Institutes of Health/ ; P30-CA015704//National Cancer Institute Cancer Center/ ; }, abstract = {BACKGROUND: Invasive fusariosis (IF) is an uncommon but frequently fatal infection among patients with hematologic malignancies (HM). Despite widespread mould-active prophylaxis, breakthrough infections and treatment failures may occur. We aim to describe the clinical epidemiology, diagnostic approaches, antifungal management strategies, and outcomes of IF in the era of routine antifungal prophylaxis.<br><br>METHODS: We conducted a retrospective study of all cancer patients diagnosed with IF at a tertiary cancer center that met probable/proven criteria for IF from 2015 to 2024. We collected data on demographics, oncologic history, diagnostics, therapy, and outcomes.<br><br>RESULTS: Twenty-two patients met criteria for proven IF. Most had acute myeloid leukemia (73%), and many underwent prior hematopoietic cell transplant (36%); nearly all were neutropenic (96%, median:48 days). Skin was the most common clinical site of infection&#xa0;(68%), followed by sino-pulmonary involvement (41%); fungemia occurred in 32%. Fever (77%) and skin nodules (64%) were frequent, while serum galactomannan was uniformly negative. Most common species complex was Fusarium fujikuroi. In our cohort, 82% occurred during antifungal prophylaxis, most often posaconazole. Minimum inhibitory concentrations were high for azoles and lower for amphotericin B and terbinafine. Antifungal regimens ranged from monotherapy to triple therapy. Overall mortality was 68%, of which 45% of deaths were attributed to IF. Mortality did not differ by antifungal regimen, species complexes, or presence of fungemia.<br><br>CONCLUSIONS: IF remains a life-threatening infection in patients with HM, often presenting as disseminated disease, despite prophylaxis. High azole MICs and the observed diversity of antifungal regimens highlight the ongoing uncertainty regarding optimal treatment and the need for prospective studies to define the role of combination therapy.}, }
@article {pmid41798119, year = {2026}, author = {Ronsley, R and Choe, M and Wright, J and Seidel, K and Lee, A and Wendler, J and Annesley, C and Jensen, MC and Park, JR and Vitanza, NA and Gust, J}, title = {Tumor inflammation-associated neurotoxicity in children with diffuse intrinsic pontine glioma receiving B7-H3-targeting CAR T cells on BrainChild-03.}, journal = {Neuro-oncology practice}, volume = {13}, number = {1}, pages = {105-111}, pmid = {41798119}, issn = {2054-2577}, support = {R37 CA289981/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy is a promising treatment for central nervous system (CNS) tumors like diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG). Unlike systemic administration, locoregional CAR T therapy may result in tumor inflammation-associated neurotoxicity (TIAN), which was recently defined. This study retrospectively applies TIAN criteria to patients with DIPG/pontine DMG treated with intraventricular B7-H3 CAR T cells in the BrainChild-03 (BC-03) trial (NCT04185038).<br><br>METHODS: A retrospective analysis of DIPG/pontine DMG patients treated with locoregional B7-H3 CAR T cells in BC-03 was conducted. Neurological symptoms, headache, fever, hydrocephalus, and inflammatory markers were extracted from case reports and medical records. TIAN was classified as type 1 (mechanical damage) or type 2 (electrophysiologic dysfunction), and symptom patterns, resolution, imaging findings, and management were analyzed.<br><br>RESULTS: Among 21 patients (ages 2-22) receiving &#x2265;1 infusion, 16 (76%) met TIAN criteria at least once. TIAN occurred in 49 of 152 infusions (32%), mostly grade 1 (n&#x2005;=&#x2005;34) or grade 2 (n&#x2005;=&#x2005;14), with one grade 3 event. Common symptoms included headache with fever (51%) and neurologic changes with headache (31%). In most patients, Type 1 vs Type 2 TIAN could not be defined; however, 1 patient required CSF diversion (type 1 TIAN), and 13 had worsening preexisting deficits (type 2). Median symptom resolution was <24 h (range: 0-33).<br><br>CONCLUSIONS: TIAN was common within this cohort but mostly low-grade and transient. Refining its classification and understanding its clinical impact will aid safety assessments and trial comparisons for CNS-directed CAR T therapies.}, }
@article {pmid41802176, year = {2026}, author = {Mukasa, D and Kinuthia, J and Meisner, A and Matemo, D and Schaafsma, T and Morton, J and Wandera, C and Budiawan, E and Kemuto, V and Irine, C and Odhiambo, S and Bii, M and Oduor, B and Achieng, E and Oyombra, T and Ukah, UV and Mugwanya, KK and , }, title = {Oral preexposure prophylaxis use and the risk of bacterial sexually transmitted infections and HIV among African women: A prospective observational cohort study.}, journal = {PLoS medicine}, volume = {23}, number = {3}, pages = {e1004962}, pmid = {41802176}, issn = {1549-1676}, mesh = {Humans ; Female ; *Pre-Exposure Prophylaxis/methods ; Adult ; *HIV Infections/prevention &amp; control/epidemiology/diagnosis ; Prospective Studies ; Kenya/epidemiology ; Young Adult ; Adolescent ; Administration, Oral ; *Sexually Transmitted Diseases, Bacterial/epidemiology/prevention &amp; control ; Sexual Behavior ; Risk Factors ; *Sexually Transmitted Diseases/prevention &amp; control/epidemiology ; Incidence ; }, abstract = {BACKGROUND: Oral preexposure prophylaxis (PrEP) effectively reduces HIV incidence when used with sufficient adherence, but does not protect against bacterial sexually transmitted infections (STIs). Several studies have documented high rates of bacterial STIs among individuals initiating and using PrEP. We evaluated the association between PrEP use and the risk of STI among African women accessing family planning clinics.<br><br>METHODS AND FINDINGS: We conducted a prospective cohort study nested within a large pragmatic stepped-wedge cluster randomized trial of PrEP delivery in Kenyan family planning clinics, with participant enrollment from June 18, 2021, to May 18, 2023, and follow-up through February 02, 2024 (ClinicalTrials.gov: NCT04666792). The study population included sexually active HIV-negative women aged &#x2265;15 years at elevated HIV risk per Kenyan PrEP guidelines. Participants were offered standard-of-care oral PrEP with the option to decline and followed quarterly for 12 months with assessments of HIV status, sexual behavior, and PrEP use. Urine samples were batch tested for Neisseria gonorrhoeae and Chlamydia trachomatis using the GeneXpert CT/NG real-time polymerase chain reaction nucleic acid amplification test assay. The primary exposure was self-reported PrEP initiation and PrEP use consistency through 6 months, categorized as never used PrEP, inconsistently on PrEP, or consistently on PrEP. Multivariable modified Poisson generalized estimating equation (GEE) models with robust standard errors were used to estimate associations between PrEP use and incident STI; clinic-level intracluster correlation coefficients were negligible. The secondary outcomes were incident HIV infection and sexual behaviors, which included condomless sex at last sex, sex with any new partners in the past 3 months, and multiple sex partners. HIV testing was performed at each scheduled visit, at enrollment, and 1, 3, 6, 9, and 12 months following the Kenya national HIV testing algorithm, using Determine HIV-1/2 and Fast Response test kits. All models for the primary outcome were adjusted for baseline covariates determined apriori as potential confounders, which included age, STI diagnosis at enrollment, any contraceptive use, number of sexual partners (categorized as any more than one sexual partner), education status, marital status, last partner HIV status, any transactional sex in 3 months pre-enrollment, and clinic site. Among 650 women enrolled, 60.0% (389) initiated PrEP at baseline and 14.6% (38/261) initiated post-enrollment. Median age was 26 years (IQR 23-30), 40% (262/650) were aged &#x2264;24 years, and 67% (436/648) did not know their primary partner's HIV status. At baseline, 11% (74/650) had an STI, including 9.9% (23/232) of consistent PrEP users, 9.2% (13/141) of inconsistent users, and 14.0% (38/277) of women who declined PrEP. During follow-up, 19.1% (114/597) had at least one STI diagnosis, with similar risk among women who initiated PrEP at baseline compared with those who declined (19.2% [68/354] versus 18.9% [46/244]; aRR 1.11, 95% CI 0.76-1.61; p&#x2009;=&#x2009;0.580). Compared with non-PrEP users (12.7% [25/195]), STI risk was 6.0% (12/200) among consistent PrEP users (aRR 0.56, 95% CI 0.27-1.19; p&#x2009;=&#x2009;0.130) and 16.5% (17/103) among inconsistent users (aRR 1.43, 95% CI 0.73-2.77; p&#x2009;=&#x2009;0.290). Chlamydia accounted for 87.7% (100/114) of STI diagnoses. STI risk was higher among women aged &#x2264;24 years (aRR 1.47, 95% CI 1.04-2.07; p&#x2009;=&#x2009;0.029) and those with a baseline STI (aRR 2.96, 95% CI 2.12-4.14; p&#x2009;<&#x2009;0.001). Four HIV infections occurred over 594 person-years (incidence 0.67, 95% CI 0.18-1.72 per 100 person-years), including three among women who declined PrEP (incidence 1.25, 95% CI 0.26-3.66 per 100 person-years). The main study limitation was oral PrEP use was assessed based on client self-report and not objectively through drug levels testing.<br><br>CONCLUSIONS: In this prospective cohort study among African women at elevated risk for HIV, 60% initiated PrEP at baseline and 14.6% (38/261) post-enrollment. PrEP use was not associated with increased risk for STI diagnosis through one year of follow-up. HIV incidence was low overall, consistent with expanded PrEP availability in similar populations.}, }
@article {pmid41802242, year = {2026}, author = {Hurvitz, SA and Layman, RM and Curigliano, G and André, F and Cristofanilli, M and Kim, SB and Martínez Rodríguez, JL and Nadal, JC and Kim, GM and Lo, L and Remolina-Bonilla, YA and Rosselli, G and Emile, G and Korbenfeld, E and Puig, JM and Wesolowski, R and Martin, M and Ring, A and Han, HS and Giordano, A and Mutka, SC and Moss, K and Suzuki, S and Sullivan, B and Gorbatchevsky, I and Pistilli, B and , }, title = {VIKTORIA-1 Trial of Gedatolisib Plus Fulvestrant With or Without Palbociclib in Hormone Receptor-Positive/HER2-/PIK3CA Wild-Type Advanced Breast Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {44}, number = {12}, pages = {1108-1119}, pmid = {41802242}, issn = {1527-7755}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/genetics/pathology/enzymology ; Fulvestrant/administration &amp; dosage/adverse effects ; Piperazines/administration &amp; dosage/adverse effects ; Pyridines/administration &amp; dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Middle Aged ; *Class I Phosphatidylinositol 3-Kinases/genetics ; Erb-b2 Receptor Tyrosine Kinases/metabolism ; Aged ; Adult ; Receptors, Estrogen/metabolism ; Receptors, Progesterone/metabolism ; Aged, 80 and over ; Progression-Free Survival ; }, abstract = {PURPOSE: Gedatolisib potently targets all four class I PI3K isoforms and mTORC1 and mTORC2 to comprehensively block the PI3K/AKT/mTOR pathway and has shown compelling activity in early clinical trials with palbociclib and fulvestrant.<br><br>METHODS: This phase III randomized trial (VIKTORIA-1; ClinicalTrials.gov identifier: NCT05501886) evaluated the efficacy of gedatolisib-based therapy, comparing gedatolisib, palbociclib, and fulvestrant (gedatolisib triplet) and gedatolisib plus fulvestrant (gedatolisib doublet) with fulvestrant monotherapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HER2-), PIK3CA wild-type (WT) advanced breast cancer. Eligible patients had disease progression during or after CDK4/6 inhibitor and aromatase inhibitor treatment. Comparison of progression-free survival as assessed by blinded independent central review for gedatolisib triplet versus fulvestrant and gedatolisib doublet versus fulvestrant was the primary objective.<br><br>RESULTS: A total of 392 patients were randomly assigned 1:1:1. The median study follow-up was 10.1 months. The median progression-free survival was 9.3 months in the gedatolisib-triplet group, 2.0 months in the fulvestrant group (hazard ratio [HR] for progression or death, 0.24 [95% CI, 0.17 to 0.35]; P < .001), and 7.4 months in the gedatolisib-doublet group (HR, 0.33 [95% CI, 0.24 to 0.48]; P < .001 v fulvestrant). Grade &#x2265;3 treatment-related adverse events (TRAEs) reported in the gedatolisib-triplet and gedatolisib-doublet groups, respectively, included neutropenia (62.3%, 0.8%), stomatitis (19.2%, 12.3%), rash (4.6%, 5.4%), hyperglycemia (2.3%, 2.3%), and diarrhea (1.5%, 0.8%). Study treatment discontinuation because of TRAEs was reported in 2.3% (triplet) and 3.1% (doublet) of patients.<br><br>CONCLUSION: The addition of gedatolisib to fulvestrant, with or without palbociclib, significantly reduced the risk of disease progression or death in patients with hormone receptor-positive/HER2-, PIK3CA WT advanced breast cancer.}, }
@article {pmid41802602, year = {2026}, author = {Treister, NS and Liang, L and Lee, SJ and Cutler, C and Gooley, TA and Hujoel, P and Gbujie, D and Oh, UY and Bennett-Johnson, L and Hagstrom, MK and Rothen, M and Lloid, M and Dean, D and Sroussi, H}, title = {Tooth Loss and Oral Health-related Quality of Life in a Sub-cohort Within the Chronic Graft-Versus-Host Disease Consortium.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, pmid = {41802602}, issn = {2666-6367}, support = {R01 DE028336/DE/NIDCR NIH HHS/United States ; }, abstract = {Chronic graft-versus-host-disease (cGVHD) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) that frequently affects the oral cavity with manifestations of oral mucosal inflammation, salivary gland hypofunction, and trismus. However, the long-term consequences of oral cGVHD on oral health outcomes are not defined. This report assesses long-term tooth loss and oral health-related quality of life (OHRQL) measures in patients who have received alloHCT. Participants were evaluated at an initial post-transplant dental visit which consisted of dental and periodontal examination, oral mucosal examination, and panoramic radiographs. The National Institutes of Health (NIH) Modified Oral Mucosa Rating Scale (OMRS) and World Health Organization (WHO) Oral Health Assessment for Adults were used for diagnosis and grading of oral cGVHD and dental status. Pretransplant dental records were available and utilized to calculate tooth loss data. Participants also completed the Oral Health Impact Profile-14 (OHIP-14) questionnaire, the NIH mouth sensitivity score, the Lee Symptom Scale (oral cavity items), and the shortened summated Xerostomia Inventory (XI). This study enrolled 70 participants at a median of 8.8 years after alloHCT (range 6.7 to 11.8 years); 19 (27.1%) had no past oral cGVHD, 22 (31.4%) had past but no current oral cGVHD, and 29 (41.4%) had current oral cGVHD. Patients with current oral cGVHD had a mean tooth loss of 2.3, patients with past but no current oral cGVHD had a mean tooth loss of 1.0, and patients with no past oral cGVHD had a mean tooth loss of 2.1 (P = .54, ANOVA). The mean overall OHIP-14 scores for the current, past but no current, and no past oral cGVHD groups were 13.6, 6.3, and 6.3, respectively (P = .02, ANOVA). Oral cGVHD significantly impacted various aspects related to eating and meal choices. The rate of tooth loss was not definitively different based on past/current oral cGVHD status. Further efforts at mitigating the adverse impacts of oral cGVHD on nutrition and oral-health-related quality of life has the potential to improve the lives of alloHCT recipients.}, }
@article {pmid41803327, year = {2026}, author = {Zhang, W and Allen, EK and Li, S and Tarasova, I and Farrukee, R and Kedzierski, L and Gilbertson, B and McQuilten, HA and Habel, JR and Allen, LF and Rockman, S and Londrigan, SL and Kent, SJ and Wheatley, AK and Trubiano, JA and Kotsimbos, TC and Cheng, AC and Schroeder, J and Crawford, JC and Thomas, PG and Kedzierska, K and Nguyen, THO}, title = {IFN-gene signatures in B cells following influenza A and B virus infection and influenza vaccination.}, journal = {EMBO molecular medicine}, volume = {18}, number = {4}, pages = {1456-1477}, pmid = {41803327}, issn = {1757-4684}, support = {2033783//DHAC | National Health and Medical Research Council (NHMRC)/ ; 1194036//DHAC | National Health and Medical Research Council (NHMRC)/ ; 2016491//DHAC | National Health and Medical Research Council (NHMRC)/ ; 2026762//DHAC | National Health and Medical Research Council (NHMRC)/ ; 2012463//DHAC | National Health and Medical Research Council (NHMRC)/ ; 2038242//DHAC | National Health and Medical Research Council (NHMRC)/ ; T11-712/19-N//Theme-based Research Scheme of the Research Grants Council of the Hong Kong Special Administrative Region (HKSAR), China/ ; 1U01AI144616-01//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; HHS-NIH-NIAID-BAA2018//HHS | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *B-Lymphocytes/immunology ; *Influenza Vaccines/immunology/administration &amp; dosage ; *Influenza, Human/immunology/prevention &amp; control/virology ; *Influenza B virus/immunology ; *Interferons/genetics/immunology ; Vaccination ; *Influenza A virus/immunology ; Female ; Adult ; Male ; Middle Aged ; }, abstract = {Influenza viruses continue to cause a substantial global disease burden. Despite influenza vaccination, some individuals succumb to life-threatening influenza or death. Yet our understanding of immune features elicited by vaccination and influenza A and B virus (IAV, IBV) infection is limited. To define molecular signatures of influenza-specific B-cells, we performed scRNA-sequencing of influenza-specific B-cells in vaccinees and hospitalized IAV/IBV-infected patients using HA-probes. We observed increased interferon-stimulated gene signatures (IF44L, IFITM1 and XAF1), in total B-cells from IBV-patients, but not at 1-month following patients' recovery or in IAV-patients or vaccinees. Phenotypic differentiation and isotype class-switching of HA-specific B-cells were observed following vaccination, with clonal sharing between memory and atypical B-cell phenotypes. In-vitro influenza virus infection experiments showed IBVs having higher infectivity of human PBMCs, including B-cells, and reduced B-cell proliferation compared to IAV, potentially associated with antiproliferative effect of IFITM1. We provide key insights into B-cell immunity towards IBV and IAV infections and vaccination, which will inform rational vaccine design and therapeutic strategies aimed at eliciting robust HA-specific B-cell responses, while minimizing adverse effects caused by natural infection.}, }
@article {pmid41804750, year = {2026}, author = {van Creij, NCH and Tymoszuk, P and Handle, F and Seeber, A and Sellemond, T and Martowicz, A and Comperat, E and Wafa, H and Ormanns, S and Günther, M and Parson, W and Noeparast, M and Santer, FR and Subiela, JD and Grivas, P and Li, R and Culig, Z and Pichler, R}, title = {Multi-omic profiling defines three distinct molecular subtypes of urothelial carcinoma with implications for precision therapy.}, journal = {Clinical and translational medicine}, volume = {16}, number = {3}, pages = {e70638}, pmid = {41804750}, issn = {2001-1326}, mesh = {Humans ; *Precision Medicine/methods ; *Urinary Bladder Neoplasms/genetics/classification ; Gene Expression Profiling/methods ; Cell Line, Tumor ; Transcriptome ; Multiomics ; }, abstract = {BACKGROUND: Urothelial carcinoma (UC) is a biologically heterogeneous disease, and current molecular classifications have limited integration into clinical decision-making. To further pursue precision oncology efforts in UC, we developed a molecular classification framework applicable to transcriptomic and proteomic data from non-muscle-invasive bladder cancer (NMIBC), muscle-invasive bladder cancer (MIBC) and urothelial cancer cell lines.<br><br>METHODS: Using a whole-transcriptome self-organised map and regularised semi-supervised clustering of 4439 bulk NMIBC and MIBC transcriptomes and proteomes, and 33 UC cell lines, we identified three molecular UC clusters. Making use of both in silico and in vitro approaches, we selected promising treatment approaches for each cluster.<br><br>RESULTS: The three developed clusters displayed distinct signatures of mRNA, proteins, biological processes, metabolism and essential driver genes. They also differed in prognosis and machine learning-predicted treatment vulnerabilities and resistance. High-risk, stroma-rich Cluster #1 cancers were predicted to respond to selected cytotoxic drugs, ferroptosis inducers and PARP inhibitors. For the aggressive, fast-proliferating, immune-infiltrated Cluster #2 tumours with basal/squamous differentiation, cytotoxic agents and EGFR/ERBB- and MEK/ERK-targeting therapies were proposed. Cluster #3 cancers of predominantly luminal papillary phenotype with scarce stroma and immune infiltration were enriched with NMIBC and low-risk malignancies. For patients with Cluster #3 tumours, selected epigenetic drugs or EGFR/FGFR inhibitors may represent attractive treatment options.<br><br>CONCLUSIONS: Our novel molecular taxonomy holds promise as a practical framework for patient risk stratification and clinical trials in UC. Our molecular classification scheme may facilitate personalised transcriptome- and proteome-based risk assessment and clinical trial design for the development of various therapeutics.<br><br>KEY POINTS: We developed three UC clusters, applicable for MIBC and NMIBC, which were validated using transcriptomic- and proteomic datasets. Publically available UC cell lines were assigned to the clusters, to have in vitro models representing each cluster. The clusters differ in molecular and biological signatures, with distinct prognostic and therapeutic characteristics.}, }
@article {pmid41804865, year = {2026}, author = {Ma, J}, title = {Inference for microbe-metabolite association networks using a latent graph model.}, journal = {Biometrics}, volume = {82}, number = {1}, pages = {}, pmid = {41804865}, issn = {1541-0420}, support = {R01 GM145772/GF/NIH HHS/United States ; }, mesh = {Algorithms ; Computer Simulation ; Humans ; *Models, Statistical ; Female ; *Microbiota ; *Metabolic Networks and Pathways ; Stochastic Processes ; }, abstract = {Correlation networks are commonly used to infer associations between microbes and metabolites. The resulting $p$-values are then corrected for multiple comparisons using existing methods such as the Benjamini &amp; Hochberg (BH) procedure to control the false discovery rate (FDR). However, most existing methods for FDR control assume the $p$-values are weakly dependent. Consequently, they can have low power in recovering microbe-metabolite association networks that exhibit important topological features, such as the presence of densely associated modules. We propose a novel inference procedure that is both powerful for detecting significant associations in the microbe-metabolite network and capable of controlling the FDR. Power enhancement is achieved by modeling latent structures in the form of a bipartite stochastic block model. We develop a variational expectation-maximization (EM) algorithm to estimate the model parameters and incorporate the learned graph in the testing procedure. In addition to FDR control, this procedure provides a clustering of microbes and metabolites into modules, which is useful for interpretation. We demonstrate the merit of the proposed method in simulations and an application to bacterial vaginosis.}, }
@article {pmid41805422, year = {2026}, author = {Hunter, NB and Parsons, HA and Cope, L and Canzoniero, JV and Navarro, FCP and El-Refai, S and Anampa, JD and Sparano, JA and Rimawi, M and Storniolo, AM and Mainor, C and Nanda, R and DeMichele, A and Gupta, GP and Stringer-Reasor, EJ and Lynce, F and Cobain, EF and Puhalla, S and Jankowitz, R and Rexer, B and Mayer, I and Hwang, ES and Blackwell, K and El Ayass, W and Lee, Y and Tweed, C and Wilkinson, M and Pennisi, A and Sun, B and Wright, P and Gralow, JR and Chen, R and Boyle, SM and Stearns, V and Wolff, AC and Park, BH}, title = {The Pathologic Response Evaluation and Detection in Circulating Tumor-DNA Study: Ultrasensitive Circulating Tumor-DNA Assessment of Breast Cancer Minimal Residual Disease.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2502934}, doi = {10.1200/JCO-25-02934}, pmid = {41805422}, issn = {1527-7755}, abstract = {PURPOSE: Patients with stage II/III human epidermal growth factor receptor 2 (HER2)-positive or triple-negative breast cancer (TNBC) frequently receive neoadjuvant therapy (NAT). Although pathologic complete response (pCR) correlates with improved outcomes, many non-pCR patients have long-term survival. Circulating tumor-DNA (ctDNA) minimal residual disease (MRD) assessment may provide additional or superior risk stratification.<br><br>METHODS: Pathologic Response Evaluation and Detection in Circulating Tumor-DNA is a prospective, multicenter study evaluating ctDNA as a biomarker of treatment response using a tumor-informed, ultrasensitive (<100 parts per million) assay. The primary objective was to determine whether the negative predictive value (NPV) of post-NAT ctDNA for pCR was &#x2265;90%. A prespecified secondary objective for the TNBC cohort was to assess associations between ctDNA and 5-year invasive disease-free survival (IDFS). ctDNA was evaluated at baseline, after NAT before surgery, and after surgery.<br><br>RESULTS: Of 227 enrolled patients, 220 were evaluable for pCR (48% HER2-positive; 52% TNBC) and 91 patients (41%) had pCR. The primary objective was not met. Although all patients with pCR were ctDNA-negative after NAT, 40% of non-pCR patients were also ctDNA-negative (NPV, 60% [95% CI, 0.50 to 0.69]). However, the prespecified secondary objective was met. Detectable ctDNA after NAT was prognostic for recurrence (hazard ratio [HR], 8.9 [95% CI, 2.4 to 33]; P = .001), independent of pCR. Additionally, detectable ctDNA after surgery identified patients at extremely high recurrence risk (HR, 128 [95% CI, 15 to 1,083]; P < .001), while ctDNA-negative patients after surgery had 94% 5-year IDFS.<br><br>CONCLUSION: In HER2-positive breast cancer and TNBC, ctDNA after NAT does not discriminate pCR from non-pCR. However, ctDNA provides markedly superior prognostic stratification, identifying patients with exceptional outcomes and those at extreme risk. These findings support ctDNA-guided therapeutic de-escalation and escalation strategies.}, }
@article {pmid41807764, year = {2026}, author = {Hurlburt, NK and Lubow, J and Goo, L and Pancera, M}, title = {Structural basis for antibody cross-neutralization of Dengue and Zika viruses.}, journal = {Communications biology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s42003-026-09805-6}, pmid = {41807764}, issn = {2399-3642}, abstract = {Safe and effective vaccines against co-circulating mosquito-borne orthoflaviviruses such as Zika virus (ZikV) and the four serotypes of Dengue virus (DenV1-4) must elicit broadly neutralizing antibodies (bnAbs) to prevent the risk of enhancement of infection by non-neutralizing antibodies. We recently discovered new orthoflavivirus-directed bnAbs, including F25.S02, which neutralizes DenV1-4 and ZikV with comparable or superior potency to the previously characterized E dimer epitope (EDE) bnAbs. Here, we used cryoEM and X-ray crystallography to understand the basis of cross-neutralization of F25.S02 at the molecular level. We obtained a ~ 4.2 Å cryoEM structure of F25.S02 Fab bound to a stabilized DenV3 soluble E protein dimer and a 2.3 Å crystal structure of F25.S02 Fab bound to ZikV soluble E protein dimer. Like previously described EDE1 bnAbs, the structural epitope of F25.S02 is at the E dimer interface, encompassing predominantly conserved regions in domain II, including the fusion loop. However, unlike EDE1 bnAbs, F25.S02 binding is almost entirely dependent on the heavy chain and is shifted slightly away from the dimer symmetry axis. Our findings emphasize the importance of this cross-neutralizing site of vulnerability for DenV and ZikV that can facilitate rational design of vaccines and therapeutics.}, }
@article {pmid41808348, year = {2026}, author = {Frutoso, M and DeJong, CS and Shree, R and McCartney, SA and Prlic, M}, title = {Phenotypically similar but functionally distinct NK cell populations within the human maternal-fetal interface.}, journal = {ImmunoHorizons}, volume = {10}, number = {3}, pages = {}, pmid = {41808348}, issn = {2573-7732}, support = {1R01AI179712/NH/NIH HHS/United States ; R21AI144677/NH/NIH HHS/United States ; }, mesh = {Humans ; *Killer Cells, Natural/immunology/metabolism ; Female ; Pregnancy ; *Decidua/immunology/cytology ; *Placenta/immunology/cytology ; Cytokines/metabolism ; Interferon-gamma/metabolism ; Placentation/immunology ; Lymphocyte Activation ; Phenotype ; Flow Cytometry ; }, abstract = {Natural killer (NK) cell function within tissues extends beyond exerting cytotoxicity, encompassing a range of functions that are just starting to become fully elucidated. In the context of human placentation, NK cells play a key role in enabling initial placentation, which is associated with the acquisition of tolerance-like properties. If and to which extent NK cells maintain these tolerance-like properties over the course of human pregnancy is still poorly understood. We asked if NK cells isolated from the decidual-placental interface of full-term human pregnancies are able to exert effector function. We observed a significant and striking lack in the ability of NK cells isolated from the decidual-placental interface (DPI) to produce interferon-g (IFN-γ) in response to the activating cytokines interleukin (IL)-12, IL-15, and IL-18. In contrast, NK cells from the decidua retained their responsiveness to cytokine-mediated activation. Notably, CD103+CD69+ tissue-resident NK cells were present in both DPI and decidua, yet exhibited distinct effector function from one another. Using high-parameter flow cytometry and single-cell sequencing, we found that this functional discrepancy was not directly predictable based on their cell surface phenotype or cell transcript. Together, our findings reveal the presence of distinct functional resident NK cell populations in 2 anatomically adjacent tissues at healthy full-term pregnancies.}, }
@article {pmid41808921, year = {2026}, author = {Hudson, A and Carone, M and Shojaie, A}, title = {Inference on function-valued parameters using a restricted score test.}, journal = {Journal of the Royal Statistical Society. Series B, Statistical methodology}, volume = {}, number = {}, pages = {}, pmid = {41808921}, issn = {1467-9868}, support = {R01 GM114029/GM/NIGMS NIH HHS/United States ; R01 GM133848/GM/NIGMS NIH HHS/United States ; R01 HL137808/HL/NHLBI NIH HHS/United States ; RF1 AG090462/AG/NIA NIH HHS/United States ; }, abstract = {It is often of interest to make inference on an unknown function that is a local parameter of the data-generating mechanism, such as a density or regression function. Such estimands can typically only be estimated at a slower-than-parametric rate in nonparametric and semiparametric models, and performing calibrated inference can be challenging. In many cases, these estimands can be expressed as the minimizer of a population risk functional. Here, we propose a general framework that leverages such representation and provides a nonparametric extension of the score test for inference on an infinite-dimensional risk minimizer. We demonstrate that our framework is applicable in a wide variety of problems. As both analytic and computational examples, we describe how to use our general approach for inference on a mean regression function under (i) nonparametric and (ii) partially additive models, and evaluate the operating characteristics of the resulting procedures via simulations. Assessment of effect heterogeneity, inference on density functions, and conditional independence testing are discussed as additional examples.}, }
@article {pmid41812087, year = {2026}, author = {Owens, CA and Ludmir, EB and Liu, Q and Qiu, W and Gupta, AC and Smith, SA and Rigaud, B and Brock, KK and Bates, JE and Meyers, TG and Paulino, AC and Peterson, CB and Kry, SF and Teepen, JC and Ronckers, CM and Neglia, JP and Leisenring, WM and Oeffinger, KC and Nathan, PC and Turcotte, LM and Hodgson, DC and Hudson, MM and Robison, LL and Moskowitz, CS and Armstrong, GT and Henderson, TO and Yasui, Y and Howell, RM}, title = {Reply to: Methodologic Considerations for Subsequent Colorectal Cancer in Survivors of Childhood Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {}, number = {}, pages = {JCO2600051}, doi = {10.1200/JCO-26-00051}, pmid = {41812087}, issn = {1527-7755}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, }
@article {pmid41813924, year = {2026}, author = {Feder, AF and DeWitt, WS}, title = {Context dependency is essential for predicting intrahost evolution.}, journal = {Nature ecology &amp; evolution}, volume = {10}, number = {3}, pages = {389-391}, pmid = {41813924}, issn = {2397-334X}, }
@article {pmid41816837, year = {2026}, author = {Oehler, VG and Berman, E and Huang, IJ}, title = {Management of chronic myeloid leukemia with tyrosine kinase inhibitors: adverse events, toxicities and therapy dosing.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.288334}, pmid = {41816837}, issn = {1592-8721}, abstract = {Targeted therapies have made near normal life span an attainable goal for many patients with chronic phase (CP) chronic myeloid leukemia (CML). Most patients require years of therapy and not everyone may be able to discontinue treatment permanently without CML recurrence. BCR::ABL1 targeted tyrosine kinase inhibitors (TKIs) including ATP binding site and allosteric inhibitors that bind to the myristoyl pocket are associated with treatment-emergent adverse events (TEAEs) that may compromise quality of life and well-being. Although alternative treatment options exist, side effects may persist, or new ones occur after a therapy switch. Using a case-based approach, this review examines the incidence of non-hematologic and hematologic TEAEs with specific therapies, provides guidance on AE management, and describes the impact of therapy dose reduction on efficacy and tolerability.}, }
@article {pmid41816965, year = {2026}, author = {Cheung, C and Anita, NZ and Filigrana, P and Fornage, M and Gonzalez, KA and Gallo, LC and Isasi, CR and Kaplan, RC and Li, X and Márquez, F and Parada, H and Perreira, KM and Ramos, AR and Rundek, T and Tarraf, W and Testai, FD and DeCarli, C and González, HM and Sofer, T}, title = {APOE and plasma AD biomarkers: The role of genetic ancestry in Hispanics/Latinos.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {3}, pages = {e71213}, doi = {10.1002/alz.71213}, pmid = {41816965}, issn = {1552-5279}, support = {R01 AG048642/AG/NIA NIH HHS/United States ; R01 AG080598/AG/NIA NIH HHS/United States ; R01AG075758//National Institute on Aging (NIA)/ ; R01 AG075758/AG/NIA NIH HHS/United States ; R56AG048642//National Institute on Aging (NIA)/ ; R01AG048642//National Institute on Aging (NIA)/ ; }, mesh = {Humans ; *Hispanic or Latino/genetics ; Female ; Male ; *Alzheimer Disease/genetics/blood/ethnology ; Biomarkers/blood ; tau Proteins/blood ; Aged ; Amyloid beta-Peptides/blood ; *Apolipoproteins E/genetics ; Glial Fibrillary Acidic Protein/blood ; Neurofilament Proteins/blood ; Middle Aged ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Peptide Fragments/blood ; White ; }, abstract = {BACKGROUND: Apolipoprotein E (APOE) alleles are well-established genetic risk factors for Alzheimer's disease (AD), but their effects on AD biomarkers (amyloid beta [Aβ]42/40, phosphorylated tau [p-tau]181, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) may vary across populations due to ancestry-, age-, and sex-related differences. We hypothesized that these effects vary across Hispanic/Latino background groups with distinct ancestral admixture.<br><br>METHODS: We analyzed &#x3b5;2 and &#x3b5;4 allele associations with AD biomarkers using survey-weighted linear regression models, adjusting for demographic covariates. Secondary analyses examined genetic analysis group- and ancestry-specific effects.<br><br>RESULTS: &#x3b5;4 was associated with lower A&#x3b2;42/40 and higher p-tau181and GFAP levels, but not with NfL, suggesting its role in A&#x3b2; and tau deposition and neuroinflammation. &#x3b5;4 associations were stronger in those with higher European and lower African ancestry.<br><br>DISCUSSION: These findings expand on prior studies suggesting that genetic ancestry modifies APOE-associated AD risk in Hispanic/Latino populations and highlight the importance of capturing ancestry-based heterogeneity in AD biomarker research.}, }
@article {pmid41817149, year = {2026}, author = {Banerjee, R and Dhodapkar, MV}, title = {Reading the "T" Leaves: Predicting Outcomes with Bispecific Antibodies in Multiple Myeloma.}, journal = {Blood cancer discovery}, volume = {}, number = {}, pages = {OF1-OF3}, doi = {10.1158/2643-3230.BCD-26-0041}, pmid = {41817149}, issn = {2643-3249}, abstract = {In this issue of Blood Cancer Discovery, Frenking and colleagues demonstrate the prognostic potential of three risk score models to predict hematotoxicity, infections, response rates, and survival following bispecific T-cell engager (TCE) therapy in multiple myeloma. These risk score models, which the authors validated using retrospective real-world data from 278 patients, can easily be calculated using routine blood testing and offer the potential to improve the efficacy and safety of TCE therapy. See related article by Frenking et al., p. XX .}, }
@article {pmid41817312, year = {2026}, author = {McKay, RR and Nazari, SS and Elliott, A and Smith, N and Barata, P and Kilari, D and Garje, R and Haffner, MC and Morrissey, C and Rupnow, BA and Basu, S and Drake, C and Rose, B and Bagrodia, A and Agarwal, N and Antonarakis, ES and Beltran, H}, title = {Molecular Characterization of KLK2 RNA Expression in Prostate Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-4293}, pmid = {41817312}, issn = {1557-3265}, abstract = {PURPOSE: KLK2 is an androgen-regulated gene critical in prostate cancer biology with multiple KLK2-targeted therapies in clinical development. We investigated KLK2 RNA expression patterns and associations with molecular features to provide context for emerging KLK2-targeted treatments.<br><br>EXPERIMENTAL DESIGN: DNA/RNA next-generation sequencing was performed on 7,078 prostate cancer specimens. KLK2-high/low RNA expression was defined as &#x2265;75th/<25th percentiles (transcripts per million, TPM). KLK2 expression was evaluated across histologic subtypes, disease states, and metastatic sites, with correlative analyses of genomic alterations, RNA signatures, and clinical outcomes.<br><br>RESULTS: KLK2 gene expression varied significantly by histology, with highest levels in adenocarcinoma (8.79 log2[TPM+1]) and minimal expression in histologic neuroendocrine prostate cancer (0.33 log2[TPM+1]). Expression was significantly higher in androgen deprivation therapy (ADT)/androgen receptor pathway inhibitor (ARPI)-sensitive versus ADT/ARPI-exposed tumors (8.97 vs. 8.38 log2[TPM+1], q<0.001). Localized tumors demonstrated higher expression than lymph node (8.93 vs. 8.76 log2[TPM+1]) or distant metastases (8.23 log2[TPM+1]), with visceral metastases showing the lowest levels. In the overall cohort, KLK2 expression correlated positively with androgen receptor signaling (r=0.25-0.47) and negatively with neuroendocrine signaling. High KLK2 expression was associated with significantly improved overall survival (93.9 vs. 74.4 months, hazard ratio 0.68, p<0.001) in the total cohort, with similar patterns in patients with ADT/ARPI-sensitive and ADT/ARPI-exposed disease.<br><br>CONCLUSIONS: This large-scale clinico-genomic analysis reveals distinct KLK2 expression patterns across prostate cancer histologies, tumor sites, and clinical states. These findings provide a molecular framework understanding KLK2 as a therapeutic target in prostate cancer.}, }
@article {pmid41817876, year = {2026}, author = {Donzella, SM and Newton, CC and VoPham, T and Peoples, AR and Bodelon, C and Shams-White, MM and Patel, AV and Zhong, C and Phipps, AI}, title = {Change in sleep duration following a cancer diagnosis.}, journal = {Cancer causes &amp; control : CCC}, volume = {37}, number = {4}, pages = {}, pmid = {41817876}, issn = {1573-7225}, mesh = {Humans ; Female ; Middle Aged ; Male ; *Neoplasms/diagnosis/epidemiology ; Adult ; Aged ; *Sleep/physiology ; Prospective Studies ; Follow-Up Studies ; United States/epidemiology ; Time Factors ; Incidence ; Registries ; Sleep Duration ; }, abstract = {INTRODUCTION: The objective of this study was to investigate how the experience of a cancer diagnosis impacts sleep duration among Cancer Prevention Study-3 (CPS-3) participants.<br><br>METHODS: CPS-3 is a prospective cohort of US adults aged 30-65&#xa0;years. At baseline (2006-2013), 2015, and 2018, participants reported their average sleep duration during the prior year. Cancer incidence was determined via linkage to state registries. Participants who experienced a cancer diagnosis during study follow-up with complete sleep data prior to (pre-reference) and after cancer diagnosis (post-reference) were included. We matched individuals with a cancer diagnosis to participants without a cancer diagnosis during follow-up (1:4 ratio) based on age, sex, cohort entry year, and timepoint of sleep duration measures. Change in sleep duration was calculated as the difference between average sleep duration measurements at two survey timepoints (pre- and post-reference) (decrease, no change [ref], increase). We used multivariable multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between receiving a cancer diagnosis (exposure) and change in sleep duration (outcome) adjusted for demographic, lifestyle, and health factors.<br><br>RESULTS: Among the 20,210 included CPS-3 participants (4,042 cancer survivors), participants who received a cancer diagnosis had higher odds of increasing sleep duration (OR&#x2009;=&#x2009;1.16, 95% CI 1.07, 1.27) compared to participants who did not receive a cancer diagnosis. Restricting to female participants with a diagnosis of any cancer and breast cancer only showed similar results.<br><br>CONCLUSION: The experience of a cancer diagnosis may contribute to increased sleep duration beyond expected age-related changes.}, }
@article {pmid41818265, year = {2026}, author = {Depierreux, DM and Ruiz, F and Lilly, M and Guenthoer, J and Chohan, V and Overbaugh, J}, title = {Determinants of natural killer cell-mediated antibody dependent cellular cytotoxicity in SARS-CoV-2 antibodies.}, journal = {PLoS pathogens}, volume = {22}, number = {3}, pages = {e1014026}, pmid = {41818265}, issn = {1553-7374}, mesh = {*Antibody-Dependent Cell Cytotoxicity/immunology ; Humans ; *SARS-CoV-2/immunology ; *Killer Cells, Natural/immunology ; *Antibodies, Viral/immunology ; *COVID-19/immunology ; Spike Glycoprotein, Coronavirus/immunology ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; Epitopes/immunology ; }, abstract = {A growing body of evidence underscores the role of antibody-dependent cellular cytotoxicity (ADCC) in antiviral immunity. Yet, the mechanisms underlying the ability of certain antibodies (Abs) to mediate potent ADCC activity remain poorly characterized. In particular the contribution of features within the antigen-binding Fab region remains largely unexplored. In this study, we leveraged a collection of 142 SARS-CoV-2 monoclonal Abs to systematically dissect the determinants of ADCC activity. We analyzed their epitope domain target, binding characteristics, neutralization potency, somatic hypermutation (SHM) and CDR3 length to determine the contribution of these features to ADCC activity. We found that ADCC activity is primarily shaped by epitope target - particularly targeting of the S2 domain of the Spike glycoprotein. ADCC potency was not associated with the degree of SHM or neutralization. Notably, ADCC activity was not correlated with binding activity and moderate binding to antigen was sufficient for ADCC activity. By integrating these analyses, we provide a comprehensive framework for understanding the molecular and functional determinants of ADCC. Together, these findings offer novel insights into the mechanisms that underpin ADCC functions, with implications for vaccine design and therapeutic Abs development.}, }
@article {pmid41819545, year = {2026}, author = {Chae, YK and Othus, M and Lyu, J and Lee, S and Paik, S and Dietrich, E and Jung, CM and Chung, LI and Patel, S and Kurzrock, R}, title = {Evaluation of mixed response in tumor size and survival in patients with rare cancers treated with dual checkpoint inhibitor therapy (DART SWOG S1609).}, journal = {Journal for immunotherapy of cancer}, volume = {14}, number = {3}, pages = {}, pmid = {41819545}, issn = {2051-1426}, mesh = {Humans ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Male ; Female ; *Neoplasms/drug therapy/mortality/pathology ; Middle Aged ; Retrospective Studies ; Aged ; Nivolumab/therapeutic use/pharmacology ; Adult ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Ipilimumab/therapeutic use/pharmacology ; Response Evaluation Criteria in Solid Tumors ; *Rare Diseases/drug therapy/mortality ; Tumor Burden ; }, abstract = {BACKGROUND: Mixed response, where different lesions within the same patient show discordant responses to treatment, remains poorly understood. To better understand the complex effects of mixed response on patient survival, we devised three different definitions of mixed response. This retrospective analysis provides the first evaluation of the association between mixed response and survival outcomes in patients with rare cancers treated with dual checkpoint blockade using ipilimumab plus nivolumab, based on data from 52 baskets in the DART SWOG S1609 trial.<br><br>METHODS: We included 438 patients with Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1-measurable disease and at least two target lesions, after exclusions for ineligibility, early death, or missing data. Overall survival (OS) and progression-free survival (PFS) were compared using log-rank tests and Cox regression, stratified by basket and using a day 65 landmark. A mixed response was evaluated using three definitions: Method 1-RECIST discordance across lesions; Method 2-presence of &#x2265;1 lesion with >5&#x2009;mm increase or &#x2265;1 with >5&#x2009;mm decrease; and Method 3-same as Method 2 but with a 1&#x2009;mm cut-off.<br><br>RESULTS: Mixed response was significantly associated with worse OS and PFS using both Method 1 (OS: HR 1.80; PFS: HR 1.58) and Method 2 (OS: HR 1.55; PFS: HR 1.57) compared with "all SD/stable per lesion". Among patients classified as "SD by RECIST", those who exhibited a mixed per lesion response according to Method 1 had significantly worse OS (median 9.9 months (8.8-12.4)) than those with a non-mixed per lesion response (median 22.7 months (19.2-32.0)). Further stratification showed that any lesion increasing >5&#x2009;mm was linked to worse outcomes (OS: HR >2.37, p<0.05).<br><br>CONCLUSIONS: Mixed response was significantly associated with worse survival outcomes in patients treated with dual immune checkpoint inhibitors, even among those with RECIST-defined stable disease. Our findings suggest that the "worst"-responding lesion drives prognosis, underscoring the limitations of RECIST in capturing clinically relevant heterogeneity. This study highlights the need to incorporate lesion-level assessment into immunotherapy decision-making and provides a foundation for guiding earlier transition to the next line therapies or other therapeutic options. Future studies integrating molecular biomarkers are warranted to refine response evaluation criteria and optimize immune checkpoint inhibitor-based strategies.}, }
@article {pmid41819830, year = {2026}, author = {Ghodsi, A and Demirci, RA and Gulati, R and Nelson, PS and Raychaudhuri, R and Cheng, HH and Sunkara, R and Khan, H and Rios, RN and Hsieh, A and Grivas, P and Montgomery, B and Yezefski, TA and Yu, EY and Schweizer, MT and Chen, DL and Iravani, A}, title = {Prognostic Value of Cycle 1 SPECT SUVmean in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with [177]Lu-PSMA-617.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.125.271593}, pmid = {41819830}, issn = {1535-5667}, abstract = {This study aimed to determine whether SPECT SUVmean measured after the first cycle of [177]Lu-PSMA-617 is associated with oncologic outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: This retrospective study included 192 consecutive patients with mCRPC treated with [177]Lu-PSMA-617 who underwent SPECT 24 h after cycle 1. Associations of total tumor SPECT SUVmean with a decline of 50% or more from baseline in prostate-specific antigen (PSA) levels (PSA50), PSA progression-free survival (PSA-PFS), and overall survival (OS) were evaluated using logistic and Cox regression adjusted for prostate-specific membrane antigen PET SUVmean and scan interval. Results: Higher SPECT SUVmean quartiles were independently associated with greater odds of PSA50 response (odds ratios of 4.45, 10.2, and 17.1 for quartiles 2 (Q2), 3 (Q3), and 4 (Q4), respectively (P < 0.05 for all), longer PSA-PFS (hazard ratios of 0.52, 0.29, and 0.17 for Q2-Q4, respectively; P < 0.05 for all), and longer OS (hazard ratios of 1.03, 0.82, and 0.42 for Q2-Q4, respectively; P < 0.05 for Q4 only). Conclusion: SPECT SUVmean measured after the first cycle of [177]Lu-PSMA-617 in patients with mCRPC was prognostic for PSA50 and PSA-PFS, independent of the prostate-specific membrane antigen PET SUVmean, whereas its association with OS was limited and observed only in the highest quartile.}, }
@article {pmid41820080, year = {2026}, author = {Henikoff, S and Hahn, S}, title = {RNA polymerase II: the elephant in the room.}, journal = {Trends in genetics : TIG}, volume = {42}, number = {4}, pages = {311-313}, doi = {10.1016/j.tig.2026.01.008}, pmid = {41820080}, issn = {0168-9525}, mesh = {*RNA Polymerase II/genetics/metabolism ; Humans ; Epigenesis, Genetic ; Animals ; Histones/metabolism/genetics ; Protein Kinases/metabolism/genetics ; Transcription, Genetic ; }, abstract = {How genes respond to external signals is poorly understood, with transcription factors and histones proposed as mediators of signals to RNA polymerase II (Pol II). However, recent work shows that Pol II is the direct target of more than 100 protein kinases, a previously underappreciated mechanism for generating epigenetic complexity.}, }
@article {pmid41821238, year = {2026}, author = {Williams, DM and Reilly, S and Lord, T and Ayers, K and Kissiah-Grove, S and Robinson, M and Fong, L and Angel, J}, title = {"Give me the sense that I matter:" Queer women's recommendations for an ideal cervical cancer screening exam and pathways to screening equity.}, journal = {Women's health (London, England)}, volume = {22}, number = {}, pages = {17455057261428108}, pmid = {41821238}, issn = {1745-5065}, mesh = {Humans ; Female ; Young Adult ; Adult ; Middle Aged ; *Uterine Cervical Neoplasms/diagnosis/prevention &amp; control ; *Early Detection of Cancer/psychology ; *Sexual and Gender Minorities/psychology ; *Healthcare Disparities ; *Patient Acceptance of Health Care/psychology ; Qualitative Research ; Interviews as Topic ; Professional-Patient Relations ; }, abstract = {BACKGROUND: Cervical cancer screening is a powerful tool in the prevention, early detection, and diagnosis of precancers and cancer. There is mounting evidence, however, demonstrating that Queer cisgender women experience disparities in cervical cancer screening access and uptake compared to their heterosexual counterparts. To close gaps in screening, Queer women's voices and visions must foreground recommendations aimed at remedying screening inequities.<br><br>OBJECTIVES: This study aims to explore perceptions on an ideal cervical cancer screening exam among a racially and ethnically diverse group of Queer women.<br><br>DESIGN: This qualitative interview study is led in partnership with a multidisciplinary community steering committee. Our work is grounded in the Reproductive Justice Framework.<br><br>METHODS: We held in-depth interviews with 19 Queer women to understand their recommendations for improving cervical cancer screening experiences for their community. Data from these interviews were analyzed through thematic analysis.<br><br>RESULTS: We identified five themes around creating an ideal cervical cancer screening experience among Queer women: (1) community outreach and education, (2) cues of affirmation and safety, (3) Queer patient navigation and advocacy, (4) Queer-affirming and knowledgeable providers, and (5) trauma-informed care.<br><br>CONCLUSION: Engaging Queer women in developing solutions to address screening disparities is a missing link in cervical cancer prevention and the advancement of reproductive health equity. We share actionable strategies at the healthcare professional, community, and organizational levels to support healthcare systems in translating Queer women's visions into practice. Our findings also inform medical organizations, expert panels, and health authorities on patient-defined strategies and pathways to remedying screening inequity.}, }
@article {pmid41821313, year = {2026}, author = {Bridge, J and Johnson, MJ and Kar, B and Kim, J and Wenthe, S and Krueger, J and Wick, B and Kluesner, MG and Crane, AT and Bell, J and von Dissen, L and Stelljes, E and Skeate, JG and Moriarity, BS and Webber, BR}, title = {Efficient multiplex non-viral engineering and expansion of polyclonal γδ CAR-T cells for immunotherapy.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2026.03.007}, pmid = {41821313}, issn = {1525-0024}, support = {F30 CA305905/CA/NCI NIH HHS/United States ; }, abstract = {Gamma delta (γδ) T cells are defined by their unique ability to recognize a limited repertoire of non-peptide, non-MHC-associated antigens on transformed and pathogen-infected cells. In addition to their inability to mediate GvHD, γδ T cells exhibit properties distinct from other lymphocyte subsets, prompting significant interest in their development as an off-the-shelf cellular immunotherapeutic. However, their low abundance in circulation, heterogeneity, limited methods for ex vivo expansion, and under-developed methodologies for genetic modification have hindered basic study and clinical application of γδ T cells. Here, we implement a feeder-free, scalable approach for ex vivo manufacture of polyclonal, non-virally modified, gene edited chimeric antigen receptor (CAR)-γδ T cells for therapeutic application. Engineered CAR-γδ T cells demonstrate robust functionality in vitro and in vivo. Longitudinal in vivo pharmacokinetic profiling of adoptively transferred polyclonal CAR-γδ T cells uncover subset-specific responses to IL-15 cytokine armoring and multiplex base editing. Our results present a robust platform for genetic modification of polyclonal CAR-γδ T cells and present unique opportunities to further define synergy and the contribution of discrete, engineered CAR-γδ T cell subsets to therapeutic efficacy in vivo.}, }
@article {pmid41822160, year = {2026}, author = {Lu, SZ and Vermani, A and Sanno, K and Lu, J and Matsen, FA and Jagota, M and Song, YS}, title = {Conditionally Site-Independent Neural Evolution of Antibody Sequences.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {41822160}, issn = {2331-8422}, abstract = {Common deep learning approaches for antibody engineering focus on modeling the marginal distribution of sequences. By treating sequences as independent samples, however, these methods overlook affinity maturation as a rich and largely untapped source of information about the evolutionary process by which antibodies explore the underlying fitness landscape. In contrast, classical phylogenetic models explicitly represent evolutionary dynamics but lack the expressivity to capture complex epistatic interactions. We bridge this gap with COSINE, a continuous-time Markov chain parameterized by a deep neural network. Mathematically, we prove that COSINE provides a first-order approximation to the intractable sequential point mutation process, capturing epistatic effects with an error bound that is quadratic in branch length. Empirically, COSINE outperforms state-of-the-art language models in zero-shot variant effect prediction by explicitly disentangling selection from context-dependent somatic hypermutation. Finally, we introduce Guided Gillespie, a classifier-guided sampling scheme that steers COSINE at inference time, enabling efficient optimization of antibody binding affinity toward specific antigens.}, }
@article {pmid41822483, year = {2026}, author = {Brackett, C and Zhang, L and Do, BTN and Baral, S and Fisher, LH and Hahn, WO and Carnacchi, AJ and Hilliard, S and Li, SS and Premkumar, L and Greninger, AL and Hyrien, O and Seaton, KE and Tomaras, GD}, title = {Early rise in nasal secretory IgA associated with shorter duration of SARS-CoV-2 virus shedding in an acute infection cohort.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1722585}, pmid = {41822483}, issn = {1664-3224}, mesh = {Humans ; *Virus Shedding/immunology ; *COVID-19/immunology/virology ; *SARS-CoV-2/immunology/physiology ; *Immunoglobulin A, Secretory/immunology/blood ; Male ; Female ; *Antibodies, Viral/immunology/blood ; Adult ; Middle Aged ; Immunity, Mucosal ; Cohort Studies ; Spike Glycoprotein, Coronavirus/immunology ; *Nasal Mucosa/immunology ; Nasal Lavage Fluid/immunology ; }, abstract = {INTRODUCTION: Understanding the role of mucosal immune responses in preventing coronavirus replication is essential for the development of broad-spectrum therapeutics and vaccines capable of interrupting transmission. Investigating the relationship between mucosal antibodies and viral shedding may provide critical insights into protective mechanisms against SARS-CoV-2 and inform strategies for enhancing mucosal immunity.<br><br>METHODS: In a subset of the larger CoVPN 5001 cohort, 143 participants from the US, Mexico, and South America were characterized as either short (<7 days), intermediate (7-21 days), or prolonged (>21 days) virus shedders based on RT-qPCR measurements over the first month of acute SARS-CoV-2 infection. We measured systemic circulating serum IgA and secretory IgA (SIgA) in serially collected nasal lavage fluids to 15 SARS-CoV-2 antigens, including spike variants, receptor binding domain (RBD), and N-terminal Domain (NTD) and evaluated the relationship between antibody titers and duration of viral shedding using multivariate and binary logistic regression modeling. We also assessed antibody responses to RBD proteins of endemic alpha and beta coronaviruses to compare variations in antibody kinetics throughout the course of infection.<br><br>RESULTS: We found that increased serum IgA and mucosal secretory IgA antibody titers during the earliest phase of acute infection were associated with decreased viral shedding duration, with nasal IgA responses to the spike NTD being the strongest factor associated with viral shedding (adjusted p<0.1). In contrast, antibody titers against endemic human coronaviruses remained stable throughout the course of infection, consistent with a specific role for newly elicited SARS-CoV-2 antibodies in virus control.<br><br>DISCUSSION: These findings demonstrate that early rises in serum and mucosal IgA titers are associated with reduced duration of viral shedding. Notably, nasal secretory IgA responses targeting the spike N-terminal domain were most strongly associated with shorter shedding, suggesting a potentially protective role for SARS-CoV-2-specific nasal IgA during acute SARS-CoV-2 infection. These results highlight the importance of mucosal immunity for limiting viral transmission and shedding, offering future insights for pan-coronavirus therapeutics and vaccine development aimed for enhancing SARS-COV-2 mucosal antibody responses.}, }
@article {pmid41826235, year = {2026}, author = {Yorke, AA and Ignatius, K and Schreiner, JL and Kron, T}, title = {Estimating the Carbon Footprint of External Beam Radiotherapy: Should This Be a Concern for LMICs?.}, journal = {Journal of medical imaging and radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1111/1754-9485.70083}, pmid = {41826235}, issn = {1754-9485}, abstract = {PURPOSE: This study aims to estimate the carbon footprint associated with external beam radiotherapy in a low- and middle-income country (LMIC) context, specifically at the Uganda Cancer Institute (UCI), and to evaluate whether sustainability should be a priority alongside treatment access in such radiation therapy settings.<br><br>METHODOLOGY: A carbon footprint analysis was conducted for patients treated for locally advanced cervical cancer at UCI between 2023 and 2024. The assessment included emissions from three key components: (1) patient travel to and from the facility, (2) pre-treatment imaging using CT and 2D simulation and (3) energy consumption by three Varian TrueBeam linear accelerators during treatment and idle times. Emission estimates were calculated using activity data and standard global warming potential (GWP) conversion factors.<br><br>RESULTS: Patient travel emerged as a major contributor to carbon emissions due to the centralisation of services in Kampala and the lack of regional treatment centres. Energy use from LINACs and imaging contributed less significantly, owing in part to Uganda's low-carbon electricity grid powered largely by hydropower. CT scans generated approximately 0.105&#x2009;kg CO2 per scan, and LINAC operations added modest emissions depending on usage patterns and machine idle time.<br><br>CONCLUSION: While radiotherapy-related emissions in LMICs like Uganda are relatively modest compared to high-income countries, they are non-negligible and expected to rise with growing access to cancer care. Incorporating sustainability considerations into the future planning of radiotherapy infrastructure and service expansion is both feasible and necessary. Carbon-conscious planning should be integrated into decisions around siting and radiotherapy expansion to promote environmentally responsible cancer care in LMICs.}, }
@article {pmid41826733, year = {2026}, author = {Kousa, AI and Jahn, L and Zhao, K and Flores, AE and Acenas, D and Lederer, E and Argyropoulos, KV and Lemarquis, AL and Granadier, D and Cooper, K and D'Andrea, M and Sheridan, JM and Tsai, J and Sikkema, L and Lazrak, A and Nichols, K and Lee, N and Ghale, R and Malard, F and Andrlova, H and Velardi, E and Youssef, S and Burgos da Silva, M and Docampo, M and Sharma, R and Mazutis, L and Wimmer, VC and Rogers, KL and DeWolf, S and Gipson, B and Gomes, ALC and Setty, M and Pe'er, D and Hale, L and Manley, NR and Gray, DHD and van den Brink, MRM and Dudakov, JA}, title = {Author Correction: Age-related epithelial defects limit thymic function and regeneration.}, journal = {Nature immunology}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41590-026-02489-4}, pmid = {41826733}, issn = {1529-2916}, }
@article {pmid41827907, year = {2026}, author = {Chesney, KM and Whiteaker, JR and Hood, B and Zhou, M and Zhang, H and Rivero-Hinojosa, S and Paulovich, AG and Conrads, TP and Rood, BR}, title = {Longitudinal Detection of Tumor-Specific Peptides in Cerebrospinal Fluid for Pediatric Brain Tumor Surveillance.}, journal = {Cells}, volume = {15}, number = {5}, pages = {}, pmid = {41827907}, issn = {2073-4409}, support = {R50 CA211499/CA/NCI NIH HHS/United States ; U01 CA271407/CA/NCI NIH HHS/United States ; 44844//Lilabean/ ; 44568//Jeff Gordon/ ; }, mesh = {Humans ; *Brain Neoplasms/cerebrospinal fluid/diagnosis ; Child ; Male ; *Peptides/cerebrospinal fluid ; Female ; *Biomarkers, Tumor/cerebrospinal fluid ; Child, Preschool ; Medulloblastoma/cerebrospinal fluid ; Proteomics/methods ; Longitudinal Studies ; Adolescent ; Infant ; }, abstract = {Pediatric brain tumor survivors remain at high risk of recurrence, yet current surveillance strategies relying on neuroimaging and cerebrospinal fluid (CSF) cytology have limited sensitivity for early or minimal disease. Tumor-specific peptides (TSPs) derived from individual tumors represent a promising class of highly specific biomarkers for longitudinal disease monitoring through CSF-based proteomic analysis. In this study, tumor tissue and serial CSF samples from six pediatric brain tumor patients (five medulloblastomas and one atypical teratoid/rhabdoid tumor (ATRT)) were analyzed using an integrated proteogenomic workflow combining discovery and targeted mass spectrometry. TSPs were identified from resected tumor tissue and matched against shotgun CSF proteomic datasets to nominate candidate biomarkers. High-confidence peptides were synthesized as isotopically labeled standards and quantified longitudinally using targeted multiple reaction monitoring. Two TSP biomarkers derived from individualized pediatric brain tumors (one medulloblastoma and one ATRT) demonstrated robust detection in serial CSF samples and exhibited temporal concordance with radiographic disease course, declining with treatment response and increasing during disease progression. These findings establish the feasibility of detecting and longitudinally quantifying TSPs in CSF and support further investigation of individualized proteomic biomarkers for treatment response monitoring and disease surveillance in pediatric brain tumors.}, }
@article {pmid41827933, year = {2026}, author = {McHenry, PR and Fakhruddin, N and Homer, K and Gil da Costa, RM and True, LD and Morrissey, C}, title = {Characterization and Evaluation of CD24 and NPY as Biomarkers for Metastatic Castration-Resistant Prostate Cancer.}, journal = {Diagnostics (Basel, Switzerland)}, volume = {16}, number = {5}, pages = {}, pmid = {41827933}, issn = {2075-4418}, support = {PO1CA163227/GF/NIH HHS/United States ; }, abstract = {Background/Objectives: Prostate cancer is the most diagnosed and third most deadly cancer among men in Europe. Metastatic castration-resistant prostate cancer (mCRPC) is incurable and resistant to standard androgen ablation therapy. More biomarkers are needed to select patients for novel personalized treatments. Previous whole-genome RNA sequencing results indicated a possible role for cluster of differentiation 24 (CD24) and neuropeptide Y (NPY) as diagnostic or prognostic biomarkers in androgen receptor-positive (AR[+]) mCRPC. Methods: We analyzed tissue microarrays representing 127 primary prostate cancers (with matched adjacent benign prostatic glands) and 124 metastases (from 34 patients) using immunohistochemistry to detect CD24 or NPY. Results: CD24 was more highly expressed in primary prostate cancer than in adjacent benign tissue for nuclear (p: <0.001), cytoplasmic (p: <0.001), and membranous staining (p: <0.001), while NPY showed no difference. Average NPY scores were lower in prostate cancers that later recurred (geometric mean 17.6, 95% CI: 9.5-32.5) compared to those that did not (38.7, CI: 23.2-64.4; p: 0.044, d: 0.773). In mCRPC, CD24 was detectable in 76% of cores at the cell membrane and in 58% in the nucleus. NPY was detectable in the cytoplasm of 17%. Scores for NPY and nuclear (but not membranous) CD24 were higher in AR[+] mCRPC. In the RNA sequencing results, CD24 did not correlate with AR or kallikrein-related peptidase 3 (KLK3), while NPY positively correlated with AR (rs: 0.313; p: <0.004) and KLK3 (rs: 0.400; p: <0.004). NPY and CD24 scores did not correlate with neuroendocrine mCRPC markers. Nuclear and membranous CD24 showed differential expression by metastatic site. Conclusions: We did not find strong evidence to support the use of CD24 or NPY alone as clinical biomarkers. Membranous and nuclear CD24 were expressed in the majority of mCRPC specimens, while NPY expression was more limited. NPY and nuclear CD24 were more highly expressed in AR[+] mCRPC than AR[-] neuroendocrine disease, and nuclear CD24 displayed site-specific expression, suggesting a potential role for nuclear CD24 in promoting AR[+] mCRPC.}, }
@article {pmid41830051, year = {2026}, author = {Ong, SC and Kosmach-Park, B and Alomar, O and Woodside, K and Blosser, CD and Twombley, K and Basu, A and Herrera, N and Jittirat, A and Merzkani, M and George, R and Alhamad, T}, title = {Perspectives and Practices in Pediatric to Adult Healthcare Transition in Kidney Transplantation: An American Society of Transplantation (AST) Member Survey.}, journal = {Pediatric transplantation}, volume = {30}, number = {3}, pages = {e70286}, doi = {10.1111/petr.70286}, pmid = {41830051}, issn = {1399-3046}, mesh = {Humans ; *Kidney Transplantation ; *Transition to Adult Care ; Adolescent ; Adult ; United States ; Young Adult ; Male ; Surveys and Questionnaires ; Female ; Child ; Societies, Medical ; *Attitude of Health Personnel ; Middle Aged ; }, abstract = {BACKGROUND: Adolescent and young adult (AYA) kidney transplant recipients (KTR) are susceptible to risk-taking behaviors that peak during transfer from pediatric to adult healthcare, resulting in poorer outcomes. Professional guidelines support healthcare transition (HCT) practices to mitigate this risk; however, HCT perspectives and practices among providers, especially adult providers caring for KTR in the US, have not been widely studied.<br><br>METHODS: An online survey of American Society of Transplantation (AST) members was conducted targeting both adult providers (AP) and pediatric providers (PP).<br><br>RESULTS: The survey was completed by 135 respondents (predominantly US), including 61 PP and 74 AP. US respondents who disclosed their center ID represented 30% of all programs. Providers agreed that HCT was important (PP 97%, AP 94%) and a shared responsibility (PP 91% and AP 84%). Respondents to our survey frequently worked within transition programs (PP 70% vs. AP 48%), but the majority did not have a formal HCT policy to guide them (PP 43%, AP 21%). Multidisciplinary transition clinics were rare (PP 27%, AP 23%). Only 64% of PP included targeted HCT education either as part of a routine visit or a HCT session. Perceived barriers to providing HCT interventions were similar in both groups, including a lack of provider resources, outcomes tracking, provider communication, and patient/caregiver feedback.<br><br>CONCLUSION: Providers recognize the importance of HCT and the joint responsibility of PP and AP but have difficulty following best practices. A multipronged approach will be necessary to address barriers. Our survey reminds us of the gap that persists in providing AYAs with a seamless transfer from pediatric to adult care.}, }
@article {pmid41831609, year = {2026}, author = {Keenan, BP and Fan, Z and Le, BK and Harris, Q and Chen, J and Clark, M and Lea, A and Zhang, L and Cheung, A and Lara, F and Gordan, JD and Bracci, P and Behr, SC and Fong, L and Venook, AP and Kim, EJ and Kelley, RK}, title = {Phase II trial with nivolumab and sorafenib in HCC identified enrichment of immunosuppressive monocytes in patients with Child-Pugh B liver dysfunction.}, journal = {JHEP reports : innovation in hepatology}, volume = {8}, number = {5}, pages = {101817}, doi = {10.1016/j.jhepr.2026.101817}, pmid = {41831609}, issn = {2589-5559}, abstract = {BACKGROUND &amp; AIMS: Immune checkpoint inhibition (ICI) and anti-angiogenic therapies are active in hepatocellular carcinoma (HCC), although patients with impaired hepatic function have worse outcomes.<br><br>METHODS: We conducted an open-label phase II clinical trial to assess the safety and efficacy of the multikinase inhibitor, sorafenib, combined with nivolumab, in patients with advanced HCC and varying liver function. In a Part 1 safety lead-in, we investigated the maximum-tolerated dose (MTD) of the combination in patients with Child-Pugh A or B7. In Part 2, we enrolled patients with Child-Pugh B7-9 HCC with the primary endpoint of grade &#x2265;3 treatment-related adverse event (TRAE) incidence. Exploratory endpoints included immunological biomarkers.<br><br>RESULTS: Overall, 25 patients were consented and 16 eligible patients enrolled. In Part 1, dose-limiting toxicity occurred in one of six patients in Dose Level -1, and two of five patients in Dose Level 1; Dose Level -1 was determined to be the MTD. In total, 69% of patients experienced a grade &#x2265;3 TRAE, with similar distribution for patients with Child-Pugh A and B (70%, 95% CI: 0.35-0.93 vs. 66.7%, 95% CI: 0.22-0.96). The objective response rate was 6% and median overall survival was 12.99 months (Child-Pugh A: 15.26 and Child-Pugh B: 10.41). We found that patients with Child-Pugh B liver disease harbored more circulating suppressive CD14[+] monocytes at baseline compared with those with Child-Pugh A disease.<br><br>CONCLUSIONS: Although combination sorafenib and nivolumab demonstrated acceptable safety at the MTD in both Child-Pugh subgroups, the objective response rate was below the prespecified threshold to be declared worthy of further exploration. A distinct immune cell profile in patients with Child-Pugh B disease might define mechanisms of resistance and potential therapeutic targets in this population with unmet clinical need.<br><br>IMPACT AND IMPLICATIONS: This study addresses the crucial need for effective therapies for patients with advanced HCC and compromised liver function, a population historically excluded from many clinical trials. The findings suggest that, although the combination of sorafenib and nivolumab demonstrated acceptable safety across different liver function subgroups, there was a low response rate overall. Importantly, the discovery of distinct immune profiles, particularly an increase in suppressive immune cells in patients with worse liver function, provides insights into potential mechanisms of resistance to immunotherapy. These results are crucial for understanding how we can improve the treatment of advanced HCC, especially in patients with impaired liver function.<br><br>CLINICAL TRIAL: NCT03439891.}, }
@article {pmid41832336, year = {2026}, author = {Kimura, A and Peck, A and Bell-Brown, A and Todd, K and Akinsoto, NO and Fang, V and Wood, J and Issaka, RB}, title = {Navigation activities in an organized colorectal cancer screening program improve follow-up colonoscopy completion.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-44477-6}, pmid = {41832336}, issn = {2045-2322}, support = {K08CA241296/CA/NCI NIH HHS/United States ; }, }
@article {pmid41832601, year = {2026}, author = {Anderson, AK and Georgakopoulou, A and Kuhlmann, AS and Wang, H and Riker, A and Karuppusamy, KV and Radtke, S and Bui, JK and Kiem, HP and Lieber, A and Li, C}, title = {In vitro and in vivo base editing of CCR5 in hematopoietic stem cells confers HIV-1 resistance.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ymthe.2026.03.018}, pmid = {41832601}, issn = {1525-0024}, abstract = {Here, we present an HIV gene therapy strategy by in vivo precision gene editing in hematopoietic stem cells (HSCs). We successfully generated a panel of helper-dependent adenoviral vectors expressing all-in-one base editors (HDAd-BEs) targeting the CCR5 gene. In an HIV-permissive cell line, transduction with the HDAd-BE vector led to near-complete target site editing, CCR5 knockout, and inhibition of HIV infection. In HSC-enriched human CD34[+] cells from mobilized donors or cord blood, we measured efficient precision base editing after HDAd-BE transduction and selection. Following in vitro T cell differentiation and HIV infection, we demonstrated that HIV genome titers were significantly lower with precision CCR5 base editing. Importantly, in a humanized mouse model, in vivo transduction with the HDAd-BE vector followed by selection resulted in ∼50% base editing at the CCR5 target site in bone marrow mononuclear cells, which conferred ∼12-fold lower HIV plasma titers than control animals after HIV challenge. No significant off-target editing and adverse effects associated with the treatment were observed. By targeting HSCs to precisely engineer HIV-resistant cells in vivo, our strategy represents an efficient, durable, and affordable approach to achieve a functional cure for HIV infection.}, }
@article {pmid41834265, year = {2026}, author = {Bradley, R and A Staab, C and E Jamieson, P and O Langley, B and O Metz, T and F Stevens, J}, title = {Safety and Tolerability of Xanthohumol in Adults With Crohn's Disease: Results of a Triple-Masked, Randomized, Placebo-Controlled Phase 2 Trial.}, journal = {Molecular nutrition &amp; food research}, volume = {70}, number = {6}, pages = {e70438}, pmid = {41834265}, issn = {1613-4133}, support = {T90 AT008544/AT/NCCIH NIH HHS/United States ; R01AT010271/AT/NCCIH NIH HHS/United States ; K24AT011568/AT/NCCIH NIH HHS/United States ; R01HL146549/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Propiophenones/adverse effects/therapeutic use ; *Crohn Disease/drug therapy ; Adult ; Male ; Female ; *Flavonoids/adverse effects/therapeutic use ; Middle Aged ; Double-Blind Method ; Young Adult ; gamma-Glutamyltransferase/blood ; Body Mass Index ; Humulus/chemistry ; }, abstract = {Xanthohumol (XN), a flavonoid from hops (Humulus lupulus), exhibits mucosal anti-inflammatory, antioxidant, and microbiome-modulating effects, making it a candidate therapeutic for inflammatory bowel disease. We assessed the safety and tolerability of XN in adults with Crohn's disease (CD) over 8 weeks. In this randomized, triple-masked, placebo-controlled phase 2 trial, 20 adults with unremitted CD received either 24 mg/day XN or placebo for 8 weeks. Primary outcomes included clinical laboratory toxicology parameters, vital signs and adverse events (AEs). Disease activity was screened and assessed using the Crohn's Disease Activity Index (CDAI). XN was well tolerated, with adherence exceeding 95%. Neither halting nor stopping criteria were met, and all laboratory elevations were minor and transient in both groups. There were no attributable serious AEs in either group, and all moderate AEs were short-term and self-resolving. Between-group comparisons demonstrated differences for changes in BMI and gamma-glutamyltransferase (GGT), favoring XN: BMI: -0.67 (0.0, 1.3), p = 0.04 and GGT: -4.8 U/L, 95% CI 0.8-8.8, p = 0.02, which may reflect beneficial effects on hepatic and metabolic health in CD. XN at 24 mg/day was safe and well tolerated in adults with active CD, supporting further research in inflammatory bowel disease.}, }
@article {pmid41837286, year = {2026}, author = {Pache, L and Bui, JK and Klouser, LM and Fennessey, CM and Noyola, AC and Einhaus, T and Zhu, H and Stensland, L and Leguizamo, I and Koroma, AA and Teriete, P and Chang, WLW and Hyrien, O and Duggan, NN and Heimann, D and Pérez-Osorio, AC and Bar, KJ and Cosford, ND and Keele, BF and Hartigan-O'Connor, DJ and Farzan, M and Gardner, MR and Jerome, KR and Chanda, SK and Kiem, HP and Peterson, CW}, title = {Smac mimetic combined with eCD4-Ig reverses latency without reducing SHIV reservoirs in rhesus macaques.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {6}, pages = {}, pmid = {41837286}, issn = {1558-8238}, support = {R01 DA056770/DA/NIDA NIH HHS/United States ; U42 OD010990/OD/NIH HHS/United States ; }, mesh = {Animals ; Macaca mulatta ; *Simian Immunodeficiency Virus/physiology/drug effects/genetics ; *Simian Acquired Immunodeficiency Syndrome/drug therapy/virology/genetics ; *Virus Latency/drug effects ; Dependovirus/genetics ; Apoptosis Regulatory Proteins ; Viremia ; *Mitochondrial Proteins ; Humans ; }, abstract = {Despite the success of antiretroviral therapy in controlling HIV replication, latent viral reservoirs persist, presenting a major barrier to a cure. Current treatment approaches that aim to reactivate latent virus and eliminate infected cells, termed "shock and kill," hold promise but have yet to demonstrate meaningful reservoir reduction in vivo. In this study, we explored combining ciapavir, a Smac mimetic latency-reversing agent, with adeno-associated virus-delivered (AAV-delivered) eCD4-Ig to treat antiretroviral therapy-suppressed, SHIV-infected rhesus macaques. We could demonstrate that a Smac mimetic can induce modest reactivation of the latent SHIV reservoir, as evidenced by transient increases in plasma viremia. However, while AAV-expressed eCD4-Ig conferred partial protection against intrarectal SHIV challenge in uninfected animals, neither eCD4-Ig nor ciapavir reduced the viral reservoir in SHIV-infected rhesus macaques, as determined by total SHIV DNA and a 5-target intact provirus detection assay. Animals treated with the combination showed no significant differences in viral rebound kinetics post-analytical treatment interruption compared with controls. Additionally, repeated ciapavir dosing resulted in adverse effects in some animals, suggesting potential toxicity with repeat administration. These findings highlight the challenges in reducing viral reservoirs using this shock-and-kill approach, particularly in SHIV-infected models, and suggest that further optimization of both latency-reversing agent and immune-mediated clearance strategies is required.}, }
@article {pmid41838964, year = {2026}, author = {Filigrana, P and Moon, JY and Gallo, LC and González, HM and Lipton, RB and Tarraf, W and Kaplan, RC and Daviglus, ML and Testai, FD and Marquine, MJ and Cai, J and Perreira, KM and Stickel, AM and DeCarli, C and Isasi, CR}, title = {Contribution of Life-Course Socioeconomic Position to Later-Life Brain Volumes in US Hispanic/Latino Adults.}, journal = {Neurology}, volume = {106}, number = {7}, pages = {e214716}, pmid = {41838964}, issn = {1526-632X}, support = {N01 HC065236/HL/NHLBI NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; RF1 AG054548/AG/NIA NIH HHS/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; R01 AG077639/AG/NIA NIH HHS/United States ; N01 HC065233/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Brain/diagnostic imaging/anatomy &amp; histology ; Middle Aged ; Magnetic Resonance Imaging ; *Hispanic or Latino ; Aged ; Longitudinal Studies ; United States ; Organ Size ; *Social Class ; Aged, 80 and over ; Adult ; White ; }, abstract = {BACKGROUND AND OBJECTIVES: Low life-course socioeconomic position (SEP) has been associated with worse cognitive function in older age. However, its association with brain structure remains unclear. We assessed whether SEP at 3 periods of the life-course and socioeconomic mobility are associated with later-life MRI-derived brain volumes.<br><br>METHODS: We used longitudinal data from the Hispanic Community Health Study/Study of Latinos and its Investigations of Neurocognitive Aging-MRI ancillary study. We determined childhood SEP using participant self-reports of their parent's educational attainment (<high school vs &#x2265;high school). We used indexes combining participant's education, employment, household income, and assets to determine adult SEP at visits 1 (2008-2011) and 2 (2014-2017). Using childhood and adult SEP at visit 1, we classified participants into 4 socioeconomic mobility categories (stable low or high SEP, upward or downward mobility). We also used the discrepancy between attained height and genetically predicted height (e.g., height residuals) as a biomarker of childhood environment. A higher residual would indicate a more favorable environment for growth and development. Using 3T MRI scans, we quantified (2018-2022) brain volumes (e.g., total brain volume, total gray matter volume [TGMV], total cortical gray volume, hippocampal volume, and white matter hyperintensity volume [WMHV]). We fitted linear marginal structural models accounting for the complex sampling design and covariates to quantify the association between life-course SEP and z-scored brain volumes.<br><br>RESULTS: We included 2,400 adults aged 50-85 years. Higher childhood SEP (TGMV 0.13; 95% CI 0.02-0.24) and higher height residuals (TGMV 0.17; 95% CI 0.09-0.24) were associated with larger brain volumes. Similarly, higher adult SEP at visit 1 (TGMV 0.18; 95% CI 0.05-0.31) and visit 2 (TGMV 0.16; 95% CI 0.04-0.29), upward socioeconomic mobility, and stable high SEP were associated with larger brain volumes. Higher adult SEP at visit 2 (log-WMHV -0.16; 95% CI -0.29 to -0.02) and upward mobility were also associated with smaller log-WMHV.<br><br>DISCUSSION: This study highlights the contribution of higher life-course SEP to greater brain health as indexed by larger brain volumes in later life. Our results suggest that the effect of early-life socioeconomic disadvantages persists beyond socioeconomic conditions in adulthood.}, }
@article {pmid41839859, year = {2026}, author = {Gupta, A and Morella, N and Sutormin, D and Li, N and Gaisser, K and Robertson, A and Ispolatov, Y and Seelig, G and Dey, N and Kuchina, A}, title = {Dynamics of phage-host interactions in Bacteroides fragilis resolved by single-cell transcriptomics.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-70381-8}, pmid = {41839859}, issn = {2041-1723}, support = {R35GM150994//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; DE-SC0023091//DOE | SC | Biological and Environmental Research (BER)/ ; DE-SC0023091//DOE | SC | Biological and Environmental Research (BER)/ ; Postdoctoral Fellowship//Washington Research Foundation (WRF)/ ; U54 CA274374/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {The interactions between lytic phages and their hosts are typically studied in bulk culture, which obscures cell-cell differences in infection susceptibility or expression of protective factors. Here, we use bacterial single-cell RNA sequencing to profile the transcriptomes of ~50,000 cells from cultures of a human pathobiont, Bacteroides fragilis, infected with a lytic bacteriophage. From a single sampling, we quantified the asynchronous progression of phage infection in individual bacterial cells and reconstructed the infection timeline, characterizing both host and phage transcriptomic changes as infection unfolded. Further, we discovered phenotypic subpopulations of bacteria that remained uninfected. Each cell's vulnerability to phage infection was influenced by expression of multiple genetic loci, most prominently phase-variable capsular polysaccharide (CPS) biosynthesis pathways and an operon predicted to encode fimbrial genes. These findings uncovered genome-wide phase variation and stochasticity that enable bacterial survival and re-growth without acquiring additional mutations. Overall, we establish bacterial single-cell RNA sequencing as a powerful platform for investigating the dynamics of host-phage interactions and revealing the roles of phase variation and stochasticity in bacterial defenses.}, }
@article {pmid41840226, year = {2026}, author = {Turcsanyi, L and Zhang, XS and Kudelka, M and Kubikova, K and Radvansky, M and Yang, S and Kriegova, E and Juranova, J and Mayer, J and Klamova, H and Belohlavkova, P and Karas, M and Stejskal, L and Cmunt, E and Othus, M and Gale, RP and Jiang, Q and Faber, E}, title = {Chronic myeloid leukaemia: have basophils gone the way of the Dodo bird?.}, journal = {Leukemia}, volume = {40}, number = {4}, pages = {713-716}, pmid = {41840226}, issn = {1476-5551}, support = {IGA_LF_2025_014//Univerzita Palack&#xe9;ho v Olomouci (Palack&#xfd; University Olomouc)/ ; IGA_LF_2025_14//Univerzita Palack&#xe9;ho v Olomouci (Palack&#xfd; University Olomouc)/ ; IGA_LF_2025_05//Univerzita Palack&#xe9;ho v Olomouci (Palack&#xfd; University Olomouc)/ ; MH CZ - DRO (FNOL, 00098892)//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky (Ministry of Health of the Czech Republic)/ ; MH CZ-DRO (FNOL 00098892)//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky (Ministry of Health of the Czech Republic)/ ; MH CZ (FNOL, 00098892)//Ministerstvo Zdravotnictv&#xed; Cesk&#xe9; Republiky (Ministry of Health of the Czech Republic)/ ; }, }
@article {pmid41841734, year = {2026}, author = {Banerjee, R and Dong, S and McCaughan, G and Mehra, N and Wang, B and Sperling, AS and Cowan, AJ and Anderson, LD and Rajkumar, SV and Kaur, G}, title = {Preferred standard-of-care carfilzomib dosing in multiple myeloma: An international survey of haematologists/oncologists.}, journal = {British journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/bjh.70435}, pmid = {41841734}, issn = {1365-2141}, support = {UL1 TR002319/NH/NIH HHS/United States ; }, }
@article {pmid41844245, year = {2026}, author = {Tran-Kiem, C and Perofsky, AC and Lessler, J and Bedford, T}, title = {Characterizing the informativeness of pathogen genome sequence datasets about transmission between population groups.}, journal = {Proceedings. Biological sciences}, volume = {293}, number = {2067}, pages = {}, doi = {10.1098/rspb.2025.2983}, pmid = {41844245}, issn = {1471-2954}, support = {/TW/FIC NIH HHS/United States ; //EPSRC/ ; /CC/CDC HHS/United States ; /GATES/Gates Foundation/United States ; /HHMI/Howard Hughes Medical Institute/United States ; //National Institute of General Medical Sciences (NIH)/ ; }, mesh = {Mutation ; Phylogeography ; }, abstract = {Pathogen genome analysis helps characterize transmission between population groups. The information carried by pathogen sequences comes from the accumulation of mutations within their genomes; thus, the pace at which mutations accumulate should determine the granularity of transmission processes that pathogen sequences can characterize. Here, we investigate how the complex interplay between mutation, transmission, population mixing and sampling impacts study power. First, we develop a conceptual probabilistic framework to quantify the ability of pairs of sequences in capturing between-group transmission history. This allows us to comprehensively explore the space of possible phylogeographic analyses by explicitly considering the pace at which mutations accumulate and the pace at which between-group transmission events occur. Using this framework, we identify a pathogen-intrinsic limit in the mixing scale at which their sequence data remain informative, with faster mutating pathogens enabling finer spatial characterization. Second, we perform a simulation study exploring a range of assumptions regarding sequencing intensity. The sample size further imposes a limit on the characterization of between-group transmission processes. This work highlights inherent horizons of resolvability for population mixing processes that depend on the interaction between evolution, transmission, mixing and sampling. Such considerations are important for the design of pathogen genomic studies.}, }
@article {pmid41844546, year = {2026}, author = {Safyan, RA and White, RA and Gonda, TA and Lee, SM and Han, J and Kuriakose, N and Yamamoto, NK and Kugel, S and Jamison, JK and Manji, GA and Schwartz, GJ and Oberstein, PE and Bates, SE}, title = {Phase 2 study of azacitidine plus pembrolizumab as second-line treatment in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma.}, journal = {The oncologist}, volume = {31}, number = {4}, pages = {}, pmid = {41844546}, issn = {1549-490X}, support = {//Merck &amp; Co., Inc/ ; }, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology/administration &amp; dosage ; Male ; Female ; *Carcinoma, Pancreatic Ductal/drug therapy/pathology ; Middle Aged ; *Pancreatic Neoplasms/drug therapy/pathology ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/pharmacology ; *Azacitidine/therapeutic use/pharmacology/administration &amp; dosage ; Adult ; Aged, 80 and over ; }, abstract = {BACKGROUND: Epigenetic regulators represent a novel strategy to modulate the tumor immune microenvironment in pancreatic ductal adenocarcinoma (PDAC). In preclinical models, DNA hypomethylating agents enhance cytotoxic T-cell infiltration, synergize with PD-1 blockade, and improve survival when combined with immune checkpoint blockade. This single-institution, phase II study evaluated the safety, efficacy, and biomarkers of azacitidine plus pembrolizumab in patients with previously treated PDAC.<br><br>METHODS: Patients with locally advanced or metastatic PDAC after one prior regimen received 50&#x2009;mg/m2 subcutaneous azacitidine on days 1-5 of a 28-day cycle, starting week 1, and pembrolizumab 200&#x2009;mg intravenously every 3&#x2009;weeks starting week 3. Baseline and on-treatment blood and tumor was collected for exploratory biomarker analysis.<br><br>RESULTS: Thirty-six patients enrolled between October 2017 and September 2021 (median age: 62.5&#x2009;years); 34 were evaluable for safety; 31 for efficacy. Treatment was generally well-tolerated, with Grade 1-2 fatigue and diarrhea most common AEs. Three patients (9.7%) had a partial response, and the disease control rate was 35.5%. Median progression-free and overall survival was 1.51 and 4.83&#x2009;months, respectively. Exploratory analysis suggested higher baseline CD8+ T cells and lower tumor Ki-67 was associated with response, whereas low baseline CD8+ T cell and Granzyme B infiltration correlated with higher exponential tumor growth rate. PD-L1 and CD68 expression were not predictive of benefit.<br><br>CONCLUSION: Azacitidine plus pembrolizumab demonstrated limited clinical activity in second line, locally advanced or metastatic PDAC. Biomarker analysis suggests higher baseline CD8+ T-cell infiltration and lower proliferative index may identify patients more likely to benefit. Clinical trial registration number: NCT03264404.}, }
@article {pmid41845032, year = {2026}, author = {Chanda, A and Song, Y and Nazir, J and Lin, C and Cheng, A and Sargent, J and Sikora, AE}, title = {Comparable immunogenicity from murine blood collection methods in intranasal gonococcal vaccination with ACP and MtrE supports refinement of preclinical vaccine studies.}, journal = {Scientific reports}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41598-026-44505-5}, pmid = {41845032}, issn = {2045-2322}, support = {R01-AI117235//National Institute of Allergy and Infectious Diseases/ ; }, }
@article {pmid41846317, year = {2026}, author = {Choi, SH and Ramesh, S and Reed, S and Menyah, G and Ganschow, P and Henderson, V and Dunnenberger, HM}, title = {Breaking barriers to completing genetic testing for inherited breast cancer among at-risk Black women using a community-based participatory research approach.}, journal = {HGG advances}, volume = {7}, number = {2}, pages = {100591}, pmid = {41846317}, issn = {2666-2477}, mesh = {Humans ; Female ; *Breast Neoplasms/genetics/diagnosis ; *Genetic Testing/methods ; Community-Based Participatory Research ; Middle Aged ; Adult ; *Genetic Predisposition to Disease ; Black or African American ; Early Detection of Cancer ; White ; }, abstract = {National guidelines from the US Preventive Services Task Force and the National Comprehensive Cancer Network recommend the use of family-health-history (FHH)-based risk assessment tools to guide genetic testing (GT) among women with an increased risk of inherited cancer and inform personalized cancer risk management. Prior research has focused on attitudes toward and decisions about initial uptake of GT in Black patients but little is known about the factors that impact the subsequent completion of GT after they have already provided consent. Using a community-based participatory research (CBPR) approach, we aimed to identify barriers and actionable strategies to improve GT completion offered through the Breast Health Assessment (BHA), an FHH screening tool administered at routine mammography visits. We conducted semi-structured interviews with 12 Black women who screened high-risk for inherited breast cancer and consented to GT through the BHA, but did not complete saliva sample collection. Thematic analysis revealed that lack of dedicated support throughout the BHA workflow emerged as a key obstacle to sample collection, whereas medical mistrust, shame, and limited knowledge were largely regarded as cultural barriers that had no impact on GT completion. Low utilization among participants reflected logistical challenges highlighting the need to evaluate multi-level implementation processes to better understand and address inequities in GT completion. Participants suggested implementing early educational outreach, culturally relevant messaging, and interpersonal touchpoints to promote GT uptake. By applying a CBPR approach, we translated these findings into actionable, equity-focused strategies to improve GT completion within a population genetic screening program.}, }
@article {pmid41846968, year = {2026}, author = {Santos, JJS and Souza, CK and Zanella, GC and Goulart, DB and Arruda, B and Boggiatto, P and Palmer, MV and Snyder, CA and Kristula, MA and Dickens, C and Webb, TL and Atkinson, RK and Dadonaite, B and Dwivedi, G and Alameh, MG and Bloom, JD and Weissman, D and Althouse, GC and Baker, AL and Hensley, SE}, title = {Evaluation of an H5 influenza virus mRNA-lipid nanoparticle (LNP) vaccine in lactating dairy cows.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41846968}, issn = {2692-8205}, abstract = {Highly pathogenic avian influenza (HPAI) clade 2.3.4.4b H5N1 virus has recently emerged in dairy cattle in the United States. The virus replicates primarily in the mammary gland of infected cattle, leading to dramatic reductions in milk production. It is thought that the virus transmits from animal to animal through viral shedding in milk, and therefore, vaccines that decrease the amount of virus in milk can potentially limit the current outbreak and reduce the risk of H5N1 spillover into humans. Here, we assess the immunogenicity and efficacy of a clade 2.3.4.4b H5 mRNA-LNP vaccine in lactating dairy cows. We found that the H5 mRNA-LNP vaccine elicited robust antibody responses in sera and milk and significantly reduced viral replication and disease caused by clade 2.3.4.4b H5N1 intramammary infection.}, }
@article {pmid41848013, year = {2026}, author = {Janakiram, M and Fan, L and Ghosh, S and Alegria, V and Perciavalle, M and Emond, B and Maitland, J and Bixby, T and Nagar, SP and Qureshi, ZP and Dima, D}, title = {Real-world healthcare resource utilization and clinical outcomes among patients with relapsed/refractory multiple myeloma receiving ciltacabtagene autoleucel after four or more prior lines of therapy in inpatient versus outpatient settings.}, journal = {Journal of medical economics}, volume = {29}, number = {1}, pages = {871-884}, doi = {10.1080/13696998.2026.2640811}, pmid = {41848013}, issn = {1941-837X}, mesh = {Humans ; Male ; *Multiple Myeloma/drug therapy/therapy ; Female ; Middle Aged ; Aged ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; Adult ; Retrospective Studies ; *Immunotherapy, Adoptive/methods ; *Health Resources/statistics &amp; numerical data/economics ; }, abstract = {BACKGROUND: Ciltacabtagene autoleucel (cilta-cel) has demonstrated remarkable efficacy in relapsed or refractory multiple myeloma (RRMM). Outpatient (OP) administration of cilta-cel is increasingly used to improve access and reduce healthcare resource utilization (HCRU) compared to inpatient (IP) administration. We compared all-cause HCRU and clinical outcomes of IP versus OP administration of cilta-cel in patients with RRMM after ≥4 prior lines of therapy (LOT) in clinical practice.<br><br>METHODS: We identified adults receiving cilta-cel between 02/28/2022 and 06/30/2024 after &#x2265;4 prior LOT using Komodo Research Database claims data and classified patients into cohorts by setting of administration (IP/OP). All-cause HCRU, treatment-free interval (TFI), overall survival (OS), and clinical events (e.g. cytokine release syndrome [CRS], immune effector cell-associated neurotoxicity syndrome [ICANS]) were assessed. Outcomes were compared using multivariate regression and reported as incidence rate ratios (IRR) with 95% confidence intervals (CI).<br><br>RESULTS: Among 242 patients, 148 (61.2%) received cilta-cel in IP and 94 (38.8%) in OP. Baseline characteristics were comparable between cohorts. Of patients in the OP cohort, 31.9% did not require an IP admission within 3&#x2009;months post-infusion. During this period, the OP cohort had significantly fewer IP days per-patient-per-month (2.4 vs. 6.6; IRR [95% CI]: 0.37 [0.28; 0.48], p&#x2009;<&#x2009;0.001) and more OP days (8.5 vs 5.4; IRR [95% CI]: 1.43 [1.26; 1.63], p&#x2009;<&#x2009;0.001) than the IP cohort. From the fourth month post-infusion, no significant differences in HCRU were observed. Rates of CRS and ICANS, and long-term outcomes including 6 and 12&#x2009;month TFI and OS were similar.<br><br>CONCLUSION: OP administration of cilta-cel yielded similar effectiveness and safety outcomes relative to IP administration, while significantly reducing IP resource use. These findings support the feasibility of OP administration of cilta-cel in treating RRMM patients and its potential to reduce the burden on the healthcare system.}, }
@article {pmid41848929, year = {2026}, author = {Richman, DH and Zhang, C and Matsen, FA}, title = {Vector Encoding of Phylogenetic Trees by Ordered Leaf Attachment.}, journal = {Bulletin of mathematical biology}, volume = {88}, number = {4}, pages = {}, pmid = {41848929}, issn = {1522-9602}, support = {AI162611/NH/NIH HHS/United States ; S10OD028685//Office of Research Infrastructure Programs, National Institutes of Health/ ; }, mesh = {*Phylogeny ; Mathematical Concepts ; *Models, Genetic ; Computational Biology ; Machine Learning ; Algorithms ; }, abstract = {As part of work to connect phylogenetics with machine learning, there has been considerable recent interest in vector encodings of phylogenetic trees. We present a simple new "ordered leaf attachment" (OLA) method for uniquely encoding a binary, rooted phylogenetic tree topology as an integer vector. OLA encoding and decoding take linear time in the number of leaf nodes, and the set of vectors corresponding to trees is a simply-described subset of integer sequences. The OLA encoding is unique compared to other existing encodings in having these properties. The integer vector encoding induces a distance on the set of trees, and we investigate this distance in relation to the NNI and SPR distances.}, }
@article {pmid41849087, year = {2026}, author = {Ogata, S and Manson, JE and Rist, PM and Hamaya, R and Aragaki, AK and Allison, M and Haring, B and Martin, LW and Nishimura, K and Clar, A and Sesso, HD and , }, title = {Cocoa flavanol supplementation and prevention of cardiovascular disease: a novel analysis of the COSMOS randomized trial using "win ratio".}, journal = {European journal of epidemiology}, volume = {}, number = {}, pages = {}, pmid = {41849087}, issn = {1573-7284}, support = {AG050657//National Institutes of Health, Bethesda/ ; AG071611//National Institutes of Health, Bethesda/ ; EY025623//National Institutes of Health, Bethesda/ ; HL157665//National Institutes of Health, Bethesda/ ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; JP22K17821//JSPS KAKENHI/ ; 25K02863//JSPS KAKENHI/ ; }, abstract = {Cocoa flavanols may reduce cardiovascular disease (CVD) risk, yet large randomized trials remain inconclusive. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) suggested a modest, nonsignificant benefit using Cox models, which do not account for event severity in composite outcomes. To address this, we applied generalized pairwise comparison (GPC), or "win ratio" (WR), to assess cocoa flavanols versus placebo on hierarchical CVD outcomes among healthy older US adults. This secondary analysis of COSMOS, a randomized, placebo-controlled, 2 × 2 factorial trial of cocoa extract and multivitamins for preventing CVD and cancer, included 21,442 adults (women ≥ 65, men ≥ 60 years) followed for a median of 3.6 years. The primary outcome was a hierarchical composite of total CVD, prioritizing: fatal CVD, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, carotid surgery, peripheral artery surgery, and hospitalized unstable angina. Analyses followed the intention-to-treat principle. GPC estimated WRs and net treatment benefits (NTBs) for cocoa flavanols versus placebo. GPC analyses showed cocoa flavanol wins of 3.41% and placebo wins of 2.87%, yielding a reciprocal WR of 0.84 (95% CI 0.72-0.99) and negative NTBs of - 0.54% (- 1.04 to - 0.03), p = 0.037. Sensitivity analyses prioritizing stroke over MI produced similar findings. By contrast, Cox regression of the same composite yielded a nonsignificant hazard ratio of 0.90 (95% CI 0.79-1.03), suggesting standard time-to-first-event models underestimated benefit. GPC "WR" analyses showed cocoa flavanols significantly reduced CVD events by accounting for event severity in the composite CVD outcome, whereas Cox regression marginally missed these effects.}, }
@article {pmid41849329, year = {2026}, author = {Jisuvei, CS and Kinuthia, J and Richardson, BA and Srinivasan, S and Lokken, EM and Mandaliya, K and Jaoko, W and Munch, M and Fiedler, TL and Fredricks, DN and McClelland, RS}, title = {Association between vaginal washing and group B Streptococcus colonization from periconception through the first trimester of pregnancy in a cohort of Kenyan women.}, journal = {PloS one}, volume = {21}, number = {3}, pages = {e0344736}, pmid = {41849329}, issn = {1932-6203}, mesh = {Humans ; Female ; Pregnancy ; Adult ; Kenya/epidemiology ; *Streptococcus agalactiae/isolation &amp; purification/genetics ; Pregnancy Trimester, First ; *Streptococcal Infections/epidemiology/microbiology ; *Vagina/microbiology ; Young Adult ; *Vaginal Douching/adverse effects ; *Pregnancy Complications, Infectious/epidemiology/microbiology ; Prevalence ; Cohort Studies ; RNA, Ribosomal, 16S/genetics ; }, abstract = {INTRODUCTION: Vaginal washing has been associated with adverse reproductive health outcomes including pelvic inflammatory disease, reduced fecundability, and HIV acquisition. This analysis tested the hypothesis that vaginal washing is associated with increased risk of group B streptococcus (GBS) colonization.<br><br>METHOD: Women planning pregnancies contributed monthly visits during which vaginal fluid specimens were collected and urine pregnancy testing was performed. In women who became pregnant, additional samples were collected at 9-12 weeks gestation. Broad-range 16S rRNA gene PCR with next generation sequencing (NGS) was performed to identify vaginal bacterial species. Generalized estimating equations with a log link, Poisson family, independent correlation structure and robust errors were used to generate prevalence ratios comparing the prevalence of GBS detection at vaginal washing visits versus non-vaginal washing visits.<br><br>RESULTS: The 189 women who became pregnant contributed 506 samples used in this analysis. Samples were collected at periconception 196 (38.9%), early first trimester 151 (29.8%), and late first trimester visits 159 (31.4%). The prevalence of GBS during the three time periods was 20/196 (10.2%), 11/151 (7.3%) and 2/159 (1.3%) respectively. Vaginal washing was practiced by 51/196 (26.0%), 27/151 (17.9%) and 32/159 (20.1%) participants during the three time periods. Compared to visits with no vaginal washing, there was no increased prevalence of GBS detection at visits where vaginal washing with water was reported (prevalence ratio [PR] 0.51, 95% confidence interval [CI] 0.16-1.62). However, the prevalence of GBS detection was nearly five-fold higher at visits when vaginal washing using water and soap was reported (PR 4.66, 95% CI 1.51, 14.33).<br><br>CONCLUSION: Vaginal washing with soap and water was associated with&#xa0;a nearly five-fold increase in GBS prevalence. Future studies should evaluate this association in later pregnancy and peripartum. Cessation or modification of vaginal washing practices could be a useful strategy for decreasing GBS colonization.}, }
@article {pmid41849750, year = {2026}, author = {O'Neill, AF and Zeme, EL and Abou-Alfa, GK and Baretti, M and Bondoc, AJ and Church, A and Ferrone, CR and Fitzgerald, M and Geller, JI and Gill, AE and Harris, WP and Kim, HB and Lee, SS and Liu, KX and Ortiz, MV and Rangaswami, A and Riehle, KJ and Rosenberg, AR and Torbenson, MS and Yarchoan, M and Gordan, JD}, title = {Clinical guideline for the diagnosis and treatment of fibrolamellar carcinoma.}, journal = {Hepatology (Baltimore, Md.)}, volume = {}, number = {}, pages = {}, pmid = {41849750}, issn = {1527-3350}, }
@article {pmid41850278, year = {2026}, author = {Dai, Y and Brouillard, J and Jaycox, JR and Yeon, SM and Huck, JD and Yandamuri, SS and Zhong, Z and O'Connor, KC and Burnina, I and Henkel, C and LeMay, AK and Lilov, A and McGurk, E and Morrill, M and Parker, L and Sackett, T and Sandberg, C and Sivasubramanian, A and Geoghegan, JC and Ring, AM}, title = {Off-target reactivity in clinical monoclonal antibodies.}, journal = {Structure (London, England : 1993)}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.str.2026.02.012}, pmid = {41850278}, issn = {1878-4186}, abstract = {Biologics, including monoclonal antibodies (mAbs), are widely used therapeutics due to their high specificity, yet off-target interactions remain an underappreciated risk for safety and efficacy. To systematically assess antibody specificity, we applied rapid extracellular antigen profiling (REAP) to evaluate 174 FDA-approved and clinical-stage antibodies against 6,172 human extracellular proteins. We found a substantial burden of off-target reactivity, with 28% of antibodies exhibiting at least one off-target hit. Structural and biophysical analyses revealed that off-target binding arises from antibody intrinsic properties and epitope mimicry, either within related protein families or across structurally unrelated proteins. We further identified new off-target interactions of tanezumab and engineered its variable domains to eliminate off-target binding while preserving target affinity and developability. These findings highlight the prevalence of specific off-target reactivity in therapeutic antibodies and underscore the importance of evaluating specificity early in biologic drug development.}, }
@article {pmid41851041, year = {2026}, author = {Kundu, P and Zhu, C and Huentelman, M and Deoni, SCL and Naymik, M and Taguinod, F and De Both, M and Lewis, CR and Müller, HG}, title = {Brain volume trajectories in young children are associated with polygenic scores for late-onset Alzheimer's disease risk.}, journal = {Alzheimer's &amp; dementia : the journal of the Alzheimer's Association}, volume = {22}, number = {3}, pages = {e71279}, doi = {10.1002/alz.71279}, pmid = {41851041}, issn = {1552-5279}, support = {DMS-2014626//National Science Foundation/ ; DMS-2310450//National Science Foundation/ ; }, mesh = {Humans ; *Alzheimer Disease/genetics/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Male ; Female ; *Brain/pathology/diagnostic imaging/growth &amp; development ; Child, Preschool ; *Multifactorial Inheritance/genetics ; *Genetic Predisposition to Disease/genetics ; Longitudinal Studies ; Organ Size ; Gray Matter/diagnostic imaging/pathology ; Child ; Genome-Wide Association Study ; White Matter/pathology/diagnostic imaging ; Cohort Studies ; }, abstract = {INTRODUCTION: Polygenic risk scores (PRSs) for Alzheimer's disease (AD) capture an individual's genetic susceptibility to AD. Although thoroughly studied in older populations, there exists a notable gap in comprehensively exploring the association of AD PRS with early brain development.<br><br>METHODS: We examined longitudinal brain magnetic resonance imaging (MRI) data from 348 typically developing children in the RESONANCE cohort. Proportional cerebrospinal fluid (pCSF), white matter (pWM), and gray matter (pGM) volumes were analyzed using functional concurrent regression and Riemannian functional principal component analysis. AD-PRS scores (AD25 and AD54) were computed using genome-wide data.<br><br>RESULTS: Higher AD PRS was significantly associated with reduced pCSF during early childhood (ages 2.5 to 5.5 years for AD54). Energy and distance-based tests revealed overall significant differences in brain volume trajectories between moderate and low AD54 risk groups.<br><br>DISCUSSION: These findings suggest that genetic risk for late-onset AD is linked to early neurodevelopmental patterns, indicating that AD vulnerability may originate during critical windows of early brain maturation.}, }
@article {pmid41855168, year = {2026}, author = {Templin, T and Song, S and Fort, S and Sinnott-Armstrong, N}, title = {Participatory-informed preference optimization (PiPrO): A reinforcement learning simulation study.}, journal = {PLOS digital health}, volume = {5}, number = {3}, pages = {e0001294}, pmid = {41855168}, issn = {2767-3170}, abstract = {Artificial intelligence (AI) has transformative potential in public health, but its impact is limited by models that implicitly prioritize a single stakeholder perspective and do not make explicit and tunable trade-offs between community and clinician endorsement. To address this gap, we introduce Participatory-informed Preference Optimization (PiPrO), a large language model embedding-based calibration framework that generates a single clinical outcome prediction while explicitly accounting for differences between community and physician interpretations of the same scenario. PiPrO takes as input two embeddings derived from a large language model representing a community-facing context and a physician-facing context. It then applies a shared lightweight feedforward predictor to produce per-stakeholder scores which are then mixed using a single global mixing weight (alpha). Alpha controls how strongly the final prediction reflects the community versus physician responses and is learned using a policy-gradient update driven by an abundant but noisy community text and a sparse and biased physician text. PiPrO reliably learned stable alpha values and a consistent reward signal. Alpha shifts systematically toward physician weighting as community feedback becomes noisier and shifts toward community weighting as physician feedback becomes more biased. Our results suggest PiPrO's potential to produce more transparent, and context-sensitive AI-driven healthcare recommendations. Future research should validate this approach using real-world community inputs to ensure generalizability and practical impact.}, }
@article {pmid41855500, year = {2026}, author = {Baek, G and Varma, G and Yamshon, S and van Besien, HJ and Bartlett, NL and Watkins, MP and Shah, HR and Baron, K and Merryman, RW and Falade, AS and Svoboda, J and Prischak, S and D'Angelo, CR and Lukowski, JD and Advani, RH and Yeung, AH and Rosenberg, MC and Voutsinas, JM and Di, M and Lynch, RC and Poh, C and Raghunathan, V and Shadman, M and Smith, SD and Till, BG and Ujjani, CS and Diefenbach, C and Gopal, AK}, title = {Real-World Evidence for Pembrolizumab Gemcitabine Vinorelbine and Liposomal Doxorubicin in Classical Hodgkin Lymphoma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018267}, pmid = {41855500}, issn = {2473-9537}, }
@article {pmid41856415, year = {2026}, author = {Liu, L and Sathees, S and Sobel, A and Pepper, G and Greninger, AL and Jerome, KR and Fong, Y and Roychoudhury, P}, title = {BlotDx: A deep learning tool for Western blot-based diagnostics.}, journal = {Journal of virological methods}, volume = {343}, number = {}, pages = {115385}, doi = {10.1016/j.jviromet.2026.115385}, pmid = {41856415}, issn = {1879-0984}, mesh = {*Deep Learning ; Humans ; *Herpesvirus 1, Human/immunology/isolation &amp; purification ; *Blotting, Western/methods ; *Herpesvirus 2, Human/immunology/isolation &amp; purification ; *Herpes Simplex/diagnosis/virology ; Serologic Tests/methods ; Sensitivity and Specificity ; }, abstract = {BACKGROUND: Western blot (WB) is the gold standard for herpes simplex virus (HSV-1/HSV-2) serology but requires manual interpretation by trained laboratory personnel, which is time-consuming and variable. This study presents BlotDx, a deep learning tool to assist in HSV WB interpretation to improve efficiency and diagnostic consistency.<br><br>METHODS: BlotDx uses a two-stage approach: (1) instance segmentation or object detection to identify blots from input images, and (2) classification models to determine positive or negative serostatus for HSV-1 and HSV-2, excluding indeterminate results. We developed three classifiers that differ in how information flows between stages. The primary dataset consisted of 926 blot pairs derived from samples collected between 2016 and 2017 and photographed in 2018; and a second institutional validation dataset containing 185 blot pairs from samples collected between 2019 and 2024 and photographed in a different laboratory space in 2025.<br><br>RESULTS: Evaluated against the ground truth of expert human review by three independent technicians, BlotDx demonstrated high diagnostic accuracy by 5-fold cross validation in both the primary dataset (98.8% for HSV-1, 95% confidence interval (CI): 97.9%-99.3%; and 98.9% for HSV-2, 95% CI: 98.0%-99.4%), and in the institutional validation dataset (97.3% for HSV-1, 95% CI: 93.8%-98.8%; and 96.2% for HSV-2, 95% CI: 92.4%-98.1%).<br><br>CONCLUSIONS: This study highlights the utility of AI as a diagnostic assistant for image-based assays like HSV Western blots, with potential applications in other diseases. The proposed two-stage approach, combined with modern deep learning techniques is scalable and offers a step towards transforming traditional diagnostic workflows by reducing costs and increasing efficiency.}, }
@article {pmid41856486, year = {2026}, author = {Barachini, S and Cassano Cassano, R and Ronca, F and Petrini, I and Galimberti, S and Buda, G}, title = {The Role of Microenvironment in Bispecific Antibodies Treatment in Multiple Myeloma.}, journal = {European journal of haematology}, volume = {}, number = {}, pages = {}, doi = {10.1111/ejh.70168}, pmid = {41856486}, issn = {1600-0609}, abstract = {Multiple myeloma (MM) is a clonal plasma cell malignancy that remains largely incurable despite major therapeutic advances. T-cell-redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T (CAR-T) cells have recently emerged as highly effective therapies in relapsed/refractory MM, inducing deep responses even in heavily pretreated patients. However, disease relapse, limited durability of response, and treatment-related toxicities remain frequent, underscoring the need to better understand mechanisms of resistance. Accumulating evidence indicates that the tumor microenvironment (TME) plays a central role in shaping BsAb efficacy in MM. Immunosuppressive cellular components, including regulatory T-cells, myeloid-derived suppressor cells, and dysfunctional antigen-presenting cells, as well as inhibitory cytokines, hypoxia, and metabolic constraints within the TME, profoundly impair T-cell activation, expansion, and persistence following BsAb engagement. In addition, chronic CD3 stimulation within the TME may promote T-cell exhaustion, contributing to suboptimal responses and disease progression. This review focuses on the dynamic interplay between BsAbs and the MM TME, highlighting how microenvironment-driven immune suppression, antigen escape, and impaired T-cell fitness influence clinical outcomes. We further discuss emerging strategies designed to overcome these barriers, including rational combination approaches, immunomodulatory agents, and next-generation trispecific antibodies that enhance co-stimulation or dual-antigen targeting. Understanding and therapeutically modulating the TME represents a critical step toward improving the depth, durability, and safety of BsAb-based therapies in MM.}, }
@article {pmid41856667, year = {2026}, author = {Gogebakan, KC and Kunst, N and Ghodsi, A and Owens, L and Iravani, A and Etzioni, R}, title = {Cost-Effectiveness Analysis of [177]Lu-PSMA-617 Versus Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer from a U.S. Health Care Perspective.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {}, number = {}, pages = {}, doi = {10.2967/jnumed.125.271825}, pmid = {41856667}, issn = {1535-5667}, abstract = {The TheraP trial demonstrated that [177]Lu-PSMA-617 improved progression-free survival (PFS) compared with cabazitaxel, with no significant difference in overall survival (OS). However, [177]Lu-PSMA-617 was associated with fewer severe adverse events, better patient-reported outcomes, and lower health care utilization rates. In this study, we evaluated the impact of these benefits on the cost-effectiveness of [177]Lu-PSMA-617 versus cabazitaxel from a U.S. health care perspective. Methods: A partitioned survival model was developed to estimate lifetime costs and health outcomes associated with [177]Lu-PSMA-617 versus cabazitaxel over a 60-mo horizon. OS and PFS associated with[177]Lu-PSMA-617 were derived from a retrospective cohort, and relative treatment effects (hazard ratios [HRs]) from the TheraP trial were applied to generate outcomes for patients treated with cabazitaxel. Health state utilities, adverse-event disutilities, and costs were obtained from published sources. Outcomes included total costs, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit at willingness-to-pay (WTP) thresholds up to $200,000/QALY. Results: In the base case analysis, [177]Lu-PSMA-617 was not cost-effective compared with cabazitaxel (incremental cost-effectiveness ratio, $358,990/QALY). Cost-effectiveness results were most sensitive to the OS HR, the per-cycle cost of [177]Lu-PSMA-617, and the per-cycle cost of cabazitaxel. [177]Lu-PSMA-617 would become cost-effective if the per-cycle treatment cost was $27,656 or if the OS HR improved to 0.76 at a WTP threshold of $200,000/QALY. Probabilistic analyses found that [177]Lu-PSMA-617 was cost-effective in 19.7% of iterations at a WTP threshold of $200,000/QALY, 4.7% at $100,000/QALY, and 2.2% at $50,000/QALY. Conclusion: Although [177]Lu-PSMA-617 was not cost-effective compared with cabazitaxel in the base case analysis, it may achieve cost-effectiveness under more favorable assumptions of survival benefit or reduced cost per cycle. Probabilistic analyses further highlighted substantial uncertainty, with a low likelihood of cost-effectiveness.}, }
@article {pmid41856883, year = {2026}, author = {Wang, Y and Ouyang, WO and Wang, C and Nourmohammad, A and Liu, G and Wu, NC}, title = {Experimental immunologists in the era of artificial intelligence.}, journal = {Trends in immunology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.it.2026.01.003}, pmid = {41856883}, issn = {1471-4981}, abstract = {While artificial intelligence (AI) is transforming biological science, its full potential in immunology has yet to be realized due to limited data and the need for extensive experimental validation. This review provides a practical guide for experimental immunologists to actively contribute to AI development, with a focus on applications for B- and T-cell receptors. It not only gives an overview of common AI techniques in immunology but also highlights the important role of high-throughput experimental methodologies. Overall, we believe that the synergy between AI and experimental innovation will be a crucial catalyst for advancing the field of immunology.}, }
@article {pmid41858873, year = {2026}, author = {Sanchez-Cespedes, M and Lockwood, WW and Suda, K and Gardner, EE and Mitsudomi, T and Politi, K and Rolfo, C and Sen, T and Sos, ML and Tammela, T and Wynes, MW and Tsao, MS and Berger, AH}, title = {Tolerance and Resistance to Targeted Therapy in NSCLC: Emerging Concepts and Strategies.}, journal = {JTO clinical and research reports}, volume = {7}, number = {4}, pages = {100944}, pmid = {41858873}, issn = {2666-3643}, abstract = {The discovery of EGFR mutations two decades ago launched an era of rapid development and clinical application of targeted therapies in NSCLC. Today, increasing numbers of targeted therapies against somatic aberrations involving nine different genes have become available for treating patients with lung cancer and have improved their outcomes. However, acquired resistance and tumor tolerance to these therapies remains one of the biggest challenges in lung cancer treatment today. Most, if not all, targeted therapies have limited durability, which we now recognize is due to both genetic and non-genetic mechanisms of resistance. The state of our current understanding of resistance and new approaches to prevent or overcome resistance were recently presented at the International Association for the Study of Lung Cancer Hot Topics Meeting. Here, we summarize and discuss the emerging concepts and new strategies for combating drug tolerance and resistance in targeted therapies, including our understanding of the role of genetics, drug-tolerant persister cells, tumor plasticity and lineage transformation, spatial and temporal heterogeneity, microenvironmental influence, and novel therapeutic approaches.}, }
@article {pmid41859811, year = {2026}, author = {Coronado, GD and Rutter, C and Nascimento De Lima, P}, title = {Response to Piscitello et al.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag075}, pmid = {41859811}, issn = {1460-2105}, }
@article {pmid41860387, year = {2026}, author = {Blew, RM and Ziller, SG and Odegaard, AO and Caan, BJ and Chen, Z and Roe, DJ and Manson, JE and Rohan, TE and Felix, AS and Harris, HR and Luo, J and Lane, DS and Bea, JW}, title = {DXA-Derived Abdominal Adiposity and Obesity-Related Cancer Risk Among Postmenopausal Women in the Women's Health Initiative.}, journal = {Obesity (Silver Spring, Md.)}, volume = {}, number = {}, pages = {}, doi = {10.1002/oby.70168}, pmid = {41860387}, issn = {1930-739X}, support = {R01CA253302//National Cancer Institute at the National Institutes of Health/ ; R01CA253302-02S1//National Cancer Institute at the National Institutes of Health/ ; R25CA217725//National Cancer Institute at the National Institutes of Health/ ; P30CA023074//National Cancer Institute at the National Institutes of Health/ ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01AG055018//National Institute on Aging of the National Institutes of Health/ ; }, abstract = {OBJECTIVE: Obesity is associated with the risk of several cancers, yet conventional anthropometric measures do not distinguish the contributions of different compartments of abdominal adipose tissue. This study examined the relationship between visceral (VAT) and subcutaneous (SAT) abdominal adiposity and the incidence of 13 obesity-related cancers (ObRCs) in postmenopausal women.<br><br>METHODS: Data from 9950 postmenopausal participants in the Women's Health Initiative (WHI) dual-energy X-ray absorptiometry (DXA) cohort were analyzed. Abdominal VAT and SAT were quantified from DXA scans using validated imaging software. Fine and Gray competing-risks models estimated associations with ObRC incidence over 177,295 person-years of follow-up.<br><br>RESULTS: Higher abdominal VAT was significantly associated with higher ObRC risk, independently of BMI, waist circumference (WC), and other confounders. Each 100-cm[2] increase in VAT corresponded to a 32% higher risk, with a nearly twofold increase for women in the highest VAT quartile. SAT and the VAT/SAT ratio were also significantly associated with risk, though more modestly. Findings were consistent across BMI, WC, age, and race/ethnicity strata and in time-varying models.<br><br>CONCLUSIONS: Visceral adiposity has a strong, independent association with ObRC risk in postmenopausal women. Incorporating imaging-based body composition measures may improve cancer risk stratification and guide targeted prevention strategies.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov identifier:&#xa0;NCT00000611 https://clinicaltrials.gov/study/NCT00000611.}, }
@article {pmid41860999, year = {2026}, author = {Henikoff, S and Henikoff, JG}, title = {Superabundant microRNAs are transcribed from human rDNA spacer promoters insulated by CTCF.}, journal = {Science advances}, volume = {12}, number = {12}, pages = {eaec1451}, pmid = {41860999}, issn = {2375-2548}, mesh = {Humans ; *MicroRNAs/genetics ; *Promoter Regions, Genetic ; *CCCTC-Binding Factor/metabolism/genetics ; *Transcription, Genetic ; RNA Polymerase II/metabolism/genetics ; *DNA, Ribosomal/genetics ; *DNA, Ribosomal Spacer/genetics ; }, abstract = {microRNAs are ~22-nucleotide RNAs processed from primary transcripts and exported from the nucleus to repress gene expression by base-pairing to mRNAs. Unexpectedly, we find that the highest levels of RNA polymerase II (Pol II) at human microRNA genes are within the ribosomal gene repeat arrays (rDNAs). Alignment of public nascent transcript data to the hs1 human genome assembly reveals a 50-nucleotide transcript for both miR-1275 and miR-6724, which exits from the nucleus with exceptional rapidity. We show that the miR-1275/miR-6724 transcription unit is closely flanked by CCCTC-binding factor (CTCF) within a <400-bp span of the rDNA spacer promoter. miR-1275/miR-6724 and microRNA precursors expressed from the 5' external transcribed spacer (5'ETS) are exported independently of known RNA processing activities and are detected in exosomes and as circulating cancer biomarkers. We propose that the rDNA spacer promoter and 5'ETS microRNA genes have evolved for general regulatory functions in recipient cells.}, }
@article {pmid41861692, year = {2026}, author = {Lam, AC and Li, Y and Brown, MC and Deng, Y and Hueniken, K and Leighl, NB and Shepherd, FA and Murison, K and Wang, Z and Kothari, J and Wenzlaff, AS and Liu, H and Kohno, T and Pesatori, AC and Harris, C and Ma, H and Dai, J and Barnett, MJ and Diver, R and Leal, LF and Fernandez-Tardon, G and Pérez-Ríos, M and Davies, MP and Holleczek, B and Brennan, P and Zaridze, D and Holcatova, I and Lissowska, J and Świątkowska, B and Mates, D and Savic, M and Brenner, H and Andrew, AS and Taylor, F and Field, JK and Ruano-Ravina, A and Shete, SS and Tardon, A and Wang, Y and Marchand, LL and Reis, RM and Schabath, MB and Neuhouser, ML and Shen, H and Landi, MT and Shiraishi, K and Zhang, J and Schwartz, AG and Tsao, MS and Christiani, DC and Yang, P and Hung, RJ and Xu, W and Liu, G}, title = {Evaluating eight smoking metrics for modelling survival in non-small cell lung cancer.}, journal = {Cancer epidemiology}, volume = {102}, number = {}, pages = {103052}, doi = {10.1016/j.canep.2026.103052}, pmid = {41861692}, issn = {1877-783X}, support = {R01 CA087895/CA/NCI NIH HHS/United States ; R01 CA060691/CA/NCI NIH HHS/United States ; R01 CA085997/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; U01 CA209414/CA/NCI NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; U19 CA203654/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: Smoking is a strong modifiable prognostic factor for lung cancer survival. We compared eight smoking metrics to determine which metric best models the relationship between smoking exposure with overall survival (OS) and lung cancer-specific survival (LCSS). These metrics included cigarettes-per-day, smoking duration, pack-years, square-root pack-years, logcig-years, the comprehensive smoking index, age-of-initiation, and years-since-quit.<br><br>MATERIALS/METHODS: This retrospective, pooled analysis included 25 International Lung Cancer Consortium studies between June 1, 1983-December 31, 2019. The performance of smoking metrics for modelling OS was compared based on 1) strength and significance in adjusted Cox-proportional hazard models and 2) linearity based on the goodness-of-fit assuming the log-hazard varies linearly with each smoking metric (i.e. the hazard ratio is constant across different values of the smoking metric) compared to models using non-linear splines. This process was repeated across clinicodemographic subgroups and for LCSS.<br><br>RESULTS: In total, 28,702 lung cancer patients were included (median age 64 [IQR: 57-71]; 53% male). Logcig-years (log(cigarettes/day+1)&#xb7;years-smoked) had the highest adjusted hazard ratio per standard deviation (aHR 1.11; 95% CI: 1.09-1.13) and best goodness-of-fit when modelled linearly. Square-root pack-years had a similar effect size (aHR 1.11; 95% CI: 1.09-1.13) and had a strong linear relationship on visual assessment of spline curves. In subgroup analyses, logcig-years had a large effect size and maintained a linear relationship regardless of age, sex, stage, and histology. For lung cancer-specific survival (LCSS), logcig-years again had the highest aHR (1.09; 95% CI: 1.05-1.12) and the best linear goodness-of-fit, while square-root pack-years demonstrated the most linear relationship on visual assessment.<br><br>DISCUSSION: Logcig-years best modelled the relationship between smoking exposure and OS as well as LCSS, and had consistent associations across clinicodemographic subgroups. Logcig-years should be considered in clinical and research applications for quantifying smoking exposure in lung cancer.}, }
@article {pmid41862775, year = {2026}, author = {Rees, MJ and Cassano, RC and Tan, M and Zolotov, E and Sidana, S and Dima, D and Kort, J and Afrough, A and Gaballa, M and Pasvolsky, O and Mikkilineni, L and Khouri, J and Raza, S and Zanwar, SS and Ferreri, CJ and Kumar, S and Khan, AM and Atrash, S and Portuguese, AJ and Rana, MS and Banerjee, R and Freeman, C and Blue, B and Patel, KK and Anderson, LD and Puglianini, OC and Shune, LO and Biran, N and Hansen, DK and Lin, Y}, title = {The Safety and Efficacy of Commercial BCMA-Directed CAR T-Cell Therapy in Systemic AL Amyloidosis With Concurrent Myeloma.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70294}, pmid = {41862775}, issn = {1096-8652}, }
@article {pmid41864146, year = {2026}, author = {Raizenne, BL and Koshkin, VS and Zhu, A and Ben-David, R and Dufault, SM and Eraky, A and Friedlander, TW and Hong, JC and Wong, AC and Chou, J and Chu, C and Mar, N and Ma, TM and Sfakianos, JP and Porten, S and Seyedin, SN}, title = {Prognostic Utility of ctDNA for Trimodality Therapy Outcomes in Muscle Invasive Bladder Cancer.}, journal = {Clinical genitourinary cancer}, volume = {24}, number = {4}, pages = {102524}, doi = {10.1016/j.clgc.2026.102524}, pmid = {41864146}, issn = {1938-0682}, }
@article {pmid41864782, year = {2026}, author = {Vertosick, EA and Goodman, P and Tangen, CM and Till, C and Thompson, IM and Lucia, MS and Eastham, J and Lilja, H and Vickers, AJ}, title = {Estimating the Effect of Finasteride on Kallikrein Marker Levels in Blood and the Use of Converted Markers in the Four-Kallikrein Model.}, journal = {European urology focus}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euf.2026.03.005}, pmid = {41864782}, issn = {2405-4569}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND OBJECTIVE: Although the effects of 5-α-reductase inhibitors (5-ARIs) on prostate-specific antigen (PSA) have been well-studied, the effects on other kallikrein markers have not been firmly established. Accordingly, a statistical model based on blood measurements of four kallikreins-known commercially as the "4Kscore"-cannot be used for men taking 5-ARIs. We investigated how finasteride affects kallikrein markers and whether suitably adjusted marker levels could be used in the four-kallikrein model to accurately predict the prostate biopsy results.<br><br>METHODS: We analyzed 500 participants from the Prostate Cancer Prevention Trial (PCPT) with PSA &#x2264;3&#xa0;ng/ml before finasteride and who had marker measurements after 1&#xa0;yr on finasteride. Conversion factors were generated from this cohort to estimate prefinasteride marker levels in a separate PCPT cohort of 459 men on finasteride biopsied for cause. Adjusted marker levels were entered into the prespecified 4K model and performance characteristics assessed for predicting high-grade prostate cancer on biopsy.<br><br>KEY FINDINGS AND LIMITATIONS: Finasteride use halved total PSA (&#x3b2; 0.51, 95% confidence interval 0.49, 0.54). human kallikrein 2 was also halved (&#x3b2; 0.50); free PSA and intact PSA were slightly more than halved (&#x3b2; 0.44 for both). Predictions from the 4K model using adjusted markers improved discrimination over adjusted total PSA alone (AUC 0.734 vs 0.595; p&#xa0;<&#xa0;0.001). While this cohort underwent only sextant biopsy, the ProtecT model, created on 10-12 core biopsies was still well-calibrated at clinically important thresholds. In decision-curve analysis, the 4K model had the highest net benefit for risk thresholds of &#x2265;7%.<br><br>The 4K model can be used to inform prostate biopsy decision-making in men taking 5-ARIs for at least 3&#xa0;mo by incorporating adjusted kallikrein levels into the scoring algorithm.}, }
@article {pmid41865485, year = {2026}, author = {De Rosa, SC and Gravett, RM and Hahn, WO and Villaran, M and Huang, Y and Schmitzberger, L and Montefiori, D and Domin, E and Tomaras, GD and Heptinstall, J and Seaton, KE and Ferrari, G and Ozorowski, G and Ward, AB and Lee, WH and van der Maas, L and Polakowski, L and Frank, I and Tieu, HV and Kalams, SA and Garcia, NMG and Huang, J and Ghosh, S and Purwar, M and Kulp, D and Humeau, L and Kwong, PD and McElrath, MJ and Corey, L and Weiner, D and , }, title = {DNA electroporation of HIV Env elicits robust T cell responses and memory B cell responses with muted serum antibody levels that can be boosted with recombinant protein.}, journal = {Vaccine}, volume = {79}, number = {}, pages = {128487}, doi = {10.1016/j.vaccine.2026.128487}, pmid = {41865485}, issn = {1873-2518}, abstract = {Broadly neutralizing antibodies against the HIV envelope protein exhibit the potential to prevent HIV-1 acquisition, a concept demonstrated both in non-human primate (NHP) challenge models and in human clinical trials. The use of DNA for vaccination, in combination with IL-12 and delivered via intradermal (ID)-adaptive electroporation (EP), has resulted in excellent cellular and humoral immunogenicity. HVTN 304 (NCT05828095) is a first-in-human, phase 1 clinical trial that evaluated the safety and immunogenicity of a novel vaccination regimen of a synthetic DNA-encoded stabilized HIV-1 Env native-like trimer (sD-NLT-AB05) adjuvanted with IL-12 DNA, either alone or in combination with a recombinant protein HIV-1 Env (Trimer 4571) adjuvanted with 3M-052-AF/Alum as a boost, in 20 participants without HIV. The DNA vectors were delivered via ID EP. The regimen did not induce autologous neutralizing antibodies in serum. Binding antibodies to Env were induced in over half of the participants receiving DNA only and in all participants who received the Trimer 4571 boost; the magnitude was increased by the second protein boost. The DNA-induced antibodies were primarily directed to the Env base; some Trimer protein-induced antibodies were directed to other regions of Env and the base. Env-specific CD4+ T cells expressing IFN-γ and/or IL-2 were detected in all participants, with CD8+ T cells detected in up to 75% of participants. The CD4+ T cell response included cells expressing IL-21. This study demonstrates that the DNA modality, in combination with a closely related heterologous boost, may be another modality to enable iterative testing of new vaccine regimens for HIV-1, as it primes a B cell response and a CD8+ T cell response without inducing high titers of serum antibody.}, }
@article {pmid41866129, year = {2026}, author = {Shah, PD and Schwartz, J and Bacci, JL and Calo, WA and Ko, LK and Glascock, M and Li, L and Watabayashi, K}, title = {Improving pharmacy-based HPV vaccine delivery through communication training: Findings from a pilot feasibility study.}, journal = {Journal of the American Pharmacists Association : JAPhA}, volume = {}, number = {}, pages = {103078}, pmid = {41866129}, issn = {1544-3450}, support = {P30 CA014089/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: HPV vaccination coverage among U.S. adolescents remains below national targets. Community pharmacies are highly accessible vaccination venues, but staff need to enhance practical skills to identify vaccine-eligible adolescents and communicate effectively with parents.<br><br>OBJECTIVES: To evaluate the acceptability and feasibility of a team-based HPV vaccine communication training for pharmacy staff.<br><br>METHODS: We used a single-group pre/post-test design in three community pharmacies in Washington state between December 2022-May 2023. The prerecorded online vaccine communication training integrated vaccine eligibility forecasting with 5A's counseling and Announcement Approach recommendation language. Pharmacy staff involved in adolescent immunizations completed baseline (n=18) and follow-up (n=13) online surveys assessing behavioral outcomes related to adolescent HPV vaccination before and after completing the training. Adolescent vaccination counts were audited for pre- (February-May 2022) and post-implementation (February-May 2023) periods.<br><br>RESULTS: The proportion of staff reporting strong HPV vaccine recommendations increased from 22% pre-implementation to 67% post-implementation (p=0.016). The proportion of staff recommending HPV vaccination starting at ages 9-12 increased from 33% to 50% for both female and male adolescents, though this was not statistically significant (p=0.324). Self-efficacy improved for personal interactions (mean 2.8 to 3.4; p=0.004), goal setting (2.7 to 3.5; p=0.004), and addressing hesitancy (2.6 to 3.3; p=0.010). Post-implementation, staff rated the acceptability (mean 4.1/5), appropriateness (4.0/5), and feasibility (4.1/5) of pharmacy-based HPV vaccination favorably. Vaccination audits showed increased HPV doses at one pharmacy (2 doses to 20 doses) and no change at the other pharmacy (1 dose to 1 dose). The third pharmacy did not administer any adolescent vaccinations during the post-implementation period.<br><br>CONCLUSION: A team-based HPV vaccine communication training was acceptable and feasible and improved staff-reported HPV recommendation behaviors, with heterogeneous short-term changes in HPV vaccination delivery. Larger multisite studies with longer observation periods are needed to evaluate effects on vaccination uptake.}, }
@article {pmid41867175, year = {2026}, author = {Hall, M and Probert, W and Abeler-Dörner, L and Wymant, C and Di Lauro, F and Xi, X and Sauter, R and Golubchik, T and Bonsall, D and Pickles, M and Cori, A and Bwalya, J and Floyd, S and Mandla, N and Shanaube, K and Yang, B and Bock, P and Donnell, D and Grabowski, MK and Pillay, D and Ratmann, O and Fidler, S and Ayles, H and Hayes, R and Fraser, C and , }, title = {The age and sex dynamics of heterosexual HIV transmission in Zambia: an HPTN 071 (PopART) phylogenetic and modelling study.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41867175}, abstract = {While much progress has been made in reducing the incidence of HIV-1 infection in sub-Saharan Africa in recent years, bringing the epidemic to an end will require identification of the demographic groups that continue to contribute to transmission. Pathogen phylogenetics and individual-based mathematical models (IBMs) of transmission are approaches that enable researchers to explore such questions. Here, we used both methods to characterise the ages and sexes of the individuals involved in heterosexual transmission in the context of the HPTN 071 (PopART) trial in Zambia. The two methods produced largely concordant results, strengthening confidence in both. A principal finding was that when the age gap in transmission (the difference of ages between the two individuals) was stratified by recipient age, the largest differences were for the youngest female recipients and the smallest for the youngest males. For women under 21 this stood at a male 9.87 years older (95% CI: 8.02 - 11.59) in the phylogenetics, compared to 6.93 (95% HDI: 6.56 - 7.32) in the IBM. As the age of female recipients increased, this gap decreased towards parity. Conversely, the under-21 male recipients saw the smallest gaps with the female older by 0.14 years (95% CI: -2.95 - 3.23) in the phylogenetics and 1.38 years (95% HDI: 0.98 - 1.68) in the IBM. As the age of male recipients decreased, this gap steadily increased. The consequence of this pattern is that transmission to new age cohorts first entering into sexual activity is driven predominantly by male-to-female transmission. We also showed that targeting interventions at younger adults captures most of the benefit of population-wide approaches. We used the IBM to simulate the PopART universal testing and treatment intervention into the future, showing that effective treatment of under-35-year-olds would account for 94.3% (95% HDI: 65.8% - 126.6%) of the reduction in incidence by 2039 that would be achieved by treating the entire population, while effective treatment of under-35 men accounts for 60% (95% HDI: 23.2% - 92.1%). Finally, we simulated a one-year cessation of ART treatment for the whole population, which resulted in an immediate increase in both incidence and the average age at transmission of both sources and recipients. The magnitude of this was 4.6 years (95% HDI: 2.17 - 6.24) for female recipients, 5.3 (95% HDI: 2.74 - 7.09) for male recipients, 5.24 (95% HDI: 2.78 - 6.97) for female sources, and 6.04 (95% HDI: 2.92 - 8.09) for male sources. These changes would be slow to reverse even after ART was restored. These findings indicate that substantial reductions in HIV incidence can be achieved through intensified testing and treatment of individuals aged under 35, and in particular young men, a group that drives the infection of younger women and for whom engagement with care remains disproportionately low.}, }
@article {pmid41867231, year = {2026}, author = {O'Brien, A and Kong, H and Patel, H and Ho, M and Patel, MB and Zhong, J and Xu, M and Papenberg, BW and Connelly, KE and Collins, I and Hennessey, R and Thakur, R and Sowards, H and Funderburk, K and Luong, T and Florez-Vargas, O and Myers, T and Jermusyk, A and Gorman, B and Luo, W and Jones, K and Das, S and ,  and ,  and Lan, Q and Rothman, N and McKay, JD and Hung, RJ and Amos, CI and Iles, MM and Koutros, S and Landi, MT and Law, MH and Stolzenberg-Solomon, RZ and Wolpin, BM and Hassan, M and Klein, AP and Antwi, SO and Orr, N and Chanock, SJ and Lindström, S and Hoskins, JW and Stern, MH and Andresson, T and Shi, J and Prokunina-Olsson, L and Choi, J and Brown, KM and Amundadottir, LT}, title = {Integrative screening identifies functional variants and VNTRs underlying GWAS signals at the 5p15.33 multi-cancer susceptibility locus.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {41867231}, abstract = {Chromosome 5p15.33 harbors several independent association signals which demonstrate antagonistic pleiotropy across cancer types, with causal mechanisms largely unresolved. To identify functional variants and enhancer elements at this locus, we performed statistical fine-mapping followed by massively parallel reporter assays (MPRA) and proliferation based CRISPRi screens. This approach identified eight multi-cancer functional variants (MCFVs) across three GWAS signals. Targeting rs421629 (part of the CLPTM1L signal marked by rs465498) with CRISPRi revealed opposing effects on TERT expression in pancreatic versus lung cancer cells, consistent with the antagonistic pleiotropy observed for this signal. Furthermore, CRISPRi nominated an intronic CLPTM1L variable number tandem repeat (VNTR) as a potent enhancer. Long-read sequencing established VNTR polymorphisms as potential causal variants for the rs465498 signal. We showed that Hippo-pathway transcription factors mediate VNTR enhancer activity in lung and pancreatic cancer cells. Together, these findings indicate that cancer susceptibility at 5p15.33 may be mediated by both SNPs and VNTRs and provide an integrated framework for resolving complex pleiotropic loci.}, }
@article {pmid41867486, year = {2026}, author = {Mirza, AS and Hosing, C and Foss, F and Kim, S and Moskop, A and Oloyede, T and Abid, MB and Afrough, A and Ahmed, S and Badar, T and Barba, P and Bhatt, VR and Brown, VI and Dahiya, S and Deol, A and Epperla, N and Ganguly, S and Grover, NS and Hashmi, H and Hashmi, S and Hematti, P and Hildebrandt, GC and Hill, JM and Hossain, NM and Ibrahim, U and Johnson, PC and Kharfan-Dabaja, MA and Krem, MM and Lekakis, LJ and Maziarz, RT and Murthy, HS and Riedell, PA and Salas, MQ and Shouse, G and Strouse, C and Thakar, MS and Turtle, CJ and Woolfrey, A and Wudhikarn, K and Yared, JA and Pasquini, MC and Gowda, L}, title = {Impact of age on outcomes after CD19 CAR T-cell therapy for large B-cell lymphomas.}, journal = {Blood neoplasia}, volume = {3}, number = {2}, pages = {100187}, pmid = {41867486}, issn = {2950-3280}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, abstract = {Age may influence clinical outcomes after CD19-directed chimeric antigen receptor (CAR) T-cell (CAR-T) therapy. Real-world data on the survival and toxicity outcomes of older patients receiving CAR-T therapy are limited. We used data from the Center for International Blood and Marrow Transplant Research for adults with diffuse large B-cell lymphoma who received CAR-T therapy from May 2018 to June 2020. Cumulative incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. Efficacy and safety outcomes were assessed using age as a continuous variable and among 4 age groups: 18 to 54, 55 to 64, 65 to 74, and ≥75 years. Nearly half (44%) of 1916 total recipients were aged ≥65 years. Patients received either axicabtagene ciloleucel (75%) or tisagenlecleucel (25%). Overall rates of CRS and ICANS were 75% and 43%, and severe rates of CRS and ICANS were 9% and 21%, respectively. For all patients, 12-month overall survival (OS), progression-free survival (PFS), and relapse rates were 62%, 42%, and 55%, respectively. As a continuous variable, older age did not affect OS, PFS, and CRS; however, the risk of ICANS increased with age (hazard ratio [HR], 1.03; P < .001). At age >64 years, risk for ICANS increases (HR, 1.65;95% confidence interval (CI), 1.33-2.1; P < .001). In a categorical analysis, the 65 to 74-year age group had lower relapse risk (HR, 0.77;95% CI, 0.64-0.93; P = .005) than younger patients. CD19 CAR-T therapy is effective for older adults, and older age does not worsen mortality. Older age is associated with higher ICANS risk and should guide patient selection.}, }
@article {pmid41867730, year = {2026}, author = {Hollis, JA and Stonick, JA and Topalidou, I and Young, JM and Moens, CB and Lehrbach, NJ and Campbell, MG and Malik, HS}, title = {Remote homology and functional genetics unmask deeply preserved Scm3/HJURP orthologs in metazoans.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41867730}, issn = {2692-8205}, abstract = {In most animals and fungi, centromere identity and function depend on the Scm3/HJURP chaperone, which deposits CENPA at centromeres. However, Scm3/HJURP orthologs appeared to be missing in insects, nematodes, many vertebrates, and other metazoans, suggesting radical chaperone replacement in these lineages. Here, we combine remote homology detection, AlphaFold-based structural modeling, and functional genetics in zebrafish and Caenorhabditis elegans to identify previously unknown Scm3/HJURP orthologs that localize to centromeres and whose loss causes catastrophic mitotic failure. We further show that Drosophila CAL1, long considered a functional analog, is instead a highly diverged Scm3/HJURP ortholog. Despite rapid primary-sequence divergence, predicted and known structures reveal a broadly conserved CENPA-H4-binding scm3 fold across fungi, vertebrates, nematodes, insects, and basally-branching metazoans. Our work demonstrates how rapid divergence can obscure the broad conservation of essential centromere machinery and provides a broadly applicable strategy to unmasking missing orthologs.}, }
@article {pmid41869074, year = {2026}, author = {Strauss, JD and Shetty, PB and Tsavachidis, S and Byun, J and Mack, SC and Xiangjun, X and Armstrong, TS and Gilbert, MR and ,  and Mirabello, L and Bhatia, S and Leisenring, WM and Morton, LM and Armstrong, GT and Foss-Skiftesvik, J and Hagen, CM and Bybjerg-Grauholm, J and ,  and Ghozal, M and Bonaventure, A and Clavel, J and Bondy, ML and ,  and Amos, CI and Hoang, TT and Scheurer, ME}, title = {Discovery of genetic susceptibility variants in pediatric and adult ependymoma.}, journal = {Neuro-oncology advances}, volume = {8}, number = {1}, pages = {vdag004}, pmid = {41869074}, issn = {2632-2498}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Ependymoma is a malignancy of the neuroepithelium-derived ependyma that lines the spinal cord and ventricles of the brain, occurring most frequently in young children and older adults. Genetic susceptibility to ependymoma has proven difficult to assess due to disease rarity.<br><br>METHODS: We performed genome-wide association studies (GWAS) of 478 ependymoma patients and 4,841 disease-free controls of European ancestry. Ependymoma patients consisted of 117 children (<18&#x2009;years old) with whole-genome sequencing (WGS), 142 children with genotyping, and 219 adults (&#x2265;18&#x2009;years old) with genotyping. Genotyped samples were imputed using the 1,000 Genomes Project as the reference panel and underwent quality control filtering. The GWAS was performed separately by age group and technology (genotyped or WGS). GWAS variants were considered significant at P&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10[-8].<br><br>RESULTS: Among pediatric subjects with WGS data, we identified a significant intronic variant in EDIL3 (rs149378, P&#x2009;=&#x2009;1.9&#x2009;&#xd7;&#x2009;10[-8]) and a nearly significant intronic variant in LHX4 (rs79008224, P&#x2009;=&#x2009;7.2&#x2009;&#xd7;&#x2009;10[-8]). In pediatric subjects with genotyped data, two significant intronic variants were detected: FAM149A (rs6852180, P&#x2009;=&#x2009;1.8&#x2009;&#xd7;&#x2009;10[-8]) and CYS1 (rs61052588, P&#x2009;=&#x2009;3.0&#x2009;&#xd7;&#x2009;10[-8]). Additionally, an intergenic variant near C1orf94 (rs1404350, P&#x2009;=&#x2009;1.2&#x2009;&#xd7;&#x2009;10[-14]) was highly significant. In genotyped adult subjects, a single variant was observed in KCNQ3 (rs79089725, P&#x2009;=&#x2009;2.0&#x2009;&#xd7;&#x2009;10[-8]).<br><br>CONCLUSION: Our analysis represents one of the most extensive ependymoma-specific GWAS conducted to date. Several significant intronic variants were harbored in genes associated with cancer and neurological disease. Future studies are needed to investigate the role of these age-specific alterations in ependymoma pathogenesis.}, }
@article {pmid41869811, year = {2026}, author = {Hughes, SM and Calienes, FL and Levy, CN and Pandey, U and Gornalusse, GG and Cranston, RD and Lama, JR and Pickett, J and Brand, RM and Hendrix, CW and Marzinke, MA and Dai, JY and Balar, B and Justman, JE and Nair, G and Berard, AR and Birse, K and Noel-Romas, L and Mayer, KH and Stekler, JD and Mackelprang, R and Burgener, AD and McGowan, I and Cameron, CM and Cameron, MJ and Woodrow, KA and Hladik, F}, title = {Mucosal tenofovir 1% gel stimulates cell proliferation and type I/III interferon pathways.}, journal = {Microbiology spectrum}, volume = {}, number = {}, pages = {e0168025}, doi = {10.1128/spectrum.01680-25}, pmid = {41869811}, issn = {2165-0497}, abstract = {UNLABELLED: Oral tenofovir is a key antiretroviral used for treatment and pre-exposure prophylaxis (PrEP) of human immunodeficiency virus (HIV). A gel form has been tested for vaginal and rectal PrEP. We have shown that 7 days of tenofovir 1% gel had broad-ranging effects on gene expression in the rectum, especially suppression of anti-inflammatory mediators and induction of cell proliferation. Similarly, oral PrEP induced type I/III interferon-stimulated genes in the gut. It is unknown how long these effects last and whether they occur in other relevant body compartments. We measured the transcriptomes and proteomes of tissue samples obtained before and after daily topical tenofovir 1% gel application for 14 days (Microbicide Trials Network [MTN]-014 trial, rectal and vaginal) or 56 days (MTN-017 trial, rectal). While many changes seen after 7 days diminish after 14 and 56 days, some remain, notably increases in cell proliferation- and type I/III interferon-related genes. Vaginal gel uniquely induces changes related to epithelial-mesenchymal transition and angiogenesis. Induction of type I/III interferon-related genes is the most consistent and persistent mucosal response to tenofovir, occurring after both oral and topical use and at all tested time points. Hypothetically, interferon induction could improve antiviral efficacy, but also contribute to an increased chronic disease burden in people with HIV.<br><br>IMPORTANCE: Analyzing gene expression data from three separate clinical trials, we find that the antiretroviral drug tenofovir, which belongs to the class of nucleotide analogue reverse transcriptase inhibitors, induces the type I/III interferon system of innate immunity in the mucosa. This effect occurs in the absence of HIV infection and manifests itself over various treatment durations and after both oral and topical drug delivery. Tenofovir and other related medications are important components of long-term antiretroviral treatment taken by people living with HIV. Therefore, this unexpected immunological effect might need to be considered as a potential contributor to comorbidities in people living with HIV, as well as an immunopharmacological co-factor when testing novel HIV cure interventions.<br><br>CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT01768962, NCT01687218, and NCT01232803.}, }
@article {pmid41870422, year = {2026}, author = {Evans, SR and Fleming, TR and Janes, H and Dodd, LE}, title = {Reflections on FDA Draft Guidance on Bayesian Methods in Trials-Protecting Scientific Integrity and Evidentiary Standards.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, doi = {10.1001/jama.2026.4175}, pmid = {41870422}, issn = {1538-3598}, }
@article {pmid41871339, year = {2026}, author = {Lau, N and Srinakarin, K and Hong, SJ and Aalfs, H and Roth, ME and Ingram, KM and Berkman, A and Chan, S and Patten, J and Iwata, W and Taylor, MR and Fann, JR and Chow, EJ and Palermo, TM}, title = {Mobile Health App Attitudes and Adoption Among Oncology Providers: Cross-Sectional National Survey.}, journal = {Journal of medical Internet research}, volume = {28}, number = {}, pages = {e85583}, pmid = {41871339}, issn = {1438-8871}, mesh = {Humans ; Cross-Sectional Studies ; *Mobile Applications ; Female ; Male ; Middle Aged ; *Telemedicine ; Adult ; *Attitude of Health Personnel ; United States ; Surveys and Questionnaires ; *Medical Oncology ; *Health Personnel/psychology ; }, abstract = {BACKGROUND: Mobile health (mHealth) apps can address health inequities and enhance access to care for individuals with immunocompromising conditions. Although hundreds of oncology apps exist, research on provider perspectives regarding their use in clinical care remains limited.<br><br>OBJECTIVE: This study aimed to describe oncology providers' recommended apps, mHealth attitudes and beliefs, and perceived barriers to and facilitators of mHealth adoption. Exploratory aims examined differences based on provider type (medical vs psychosocial), provider age (<45 vs &#x2265;45 years old), and patient population (pediatric vs adult).<br><br>METHODS: We conducted a cross-sectional survey administered via REDCap (Research Electronic Data Capture) to oncology providers across the United States between June and November 2024. Data were summarized using descriptive statistics. Pearson's chi-square analyses examined exploratory group differences based on provider type, provider age, and patient age.<br><br>RESULTS: Of 188 respondents, the majority self-identified as female (150/188, 79.8%), White (161/188, 85.6%), and non-Hispanic/Latino (174/188, 92.6%). Nearly all providers (178/188, 94.7%) reported either recommending or using mHealth apps with their patients, with primary use for patient-provider communication (139/188, 73.9%). Providers perceived potential benefit across a broad spectrum of holistic care functions. Providers, on average, reported a growth mindset and confidence in their ability to learn mHealth tools and in its potential to improve care access. Key facilitators included alignment with patient needs, increased accessibility, and cost-effectiveness, while barriers included disparities in technology access, digital health literacy, and data security and privacy. Exploratory analyses showed some significant group differences by provider role, provider age, and patient age. Psychosocial providers were significantly more likely to recommend or use apps for pain management (&#x3c7;[2]1=14.34, P<.001, &#x3c6;=0.28), mental health (&#x3c7;[2]1=50.54, P<.001, &#x3c6;=0.53), and sleep health (&#x3c7;[2]1=25.47, P<.001, &#x3c6;= 0.38). Psychosocial providers also perceived higher benefit for sleep health apps (&#x3c7;[2]1=6.40, P=.01, &#x3c6;=0.19). Medical providers were significantly more likely to perceive medication management apps as potentially beneficial (&#x3c7;[2]1=10.93, P<.001, &#x3c6;=0.25). Older providers (16/88, 18.2%) and adult care providers (8/32, 25%) were significantly more likely to recommend or use disease management apps compared to younger providers (5/100, 5%; &#x3c7;[2]1=8.20, P=.004, &#x3c6;=0.21) and pediatric care providers (6/101, 5.9%; &#x3c7;[2]2=9.22, P=.01, Cramer V=0.22), respectively. Pediatric care providers (83/101, 82.2%) were more likely to recommend or use medical team communication apps compared to adult care providers (15/32, 46.9%; &#x3c7;[2]2=15.66, P<.001, Cramer V=0.29).<br><br>CONCLUSIONS: Our study underscores the opportunity to develop inclusive mHealth solutions tailored to the diverse needs of individuals across the cancer care continuum, including those in active treatment and survivorship care. Engaging diverse medical and psychosocial providers is essential to inform clinical integration of mHealth technologies in oncology care.}, }
@article {pmid41871940, year = {2026}, author = {Mercinelli, C and Pavlick, D and Agarwal, N and Spiess, PE and Li, R and Kamat, AM and Grivas, P and Gupta, S and Maiorano, BA and Tateo, V and Cigliola, A and Piacentini, M and Jacob, JM and Bratslavsky, G and Basnet, A and Ross, JS and Necchi, A}, title = {Homologous recombination deficiency and genomic alterations in advanced prostate cancer: insights for precision therapy.}, journal = {The oncologist}, volume = {31}, number = {4}, pages = {}, doi = {10.1093/oncolo/oyag100}, pmid = {41871940}, issn = {1549-490X}, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/pathology/drug therapy ; *Homologous Recombination/genetics ; Precision Medicine/methods ; BRCA2 Protein/genetics ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Aged ; Middle Aged ; Genomics/methods ; Biomarkers, Tumor/genetics ; Microsatellite Instability ; Mutation ; }, abstract = {BACKGROUND: the homologous recombination deficiency signature (HRDsig) is emerging as a novel potential predictor of PARP-inhibitor (PARPi) response. We compared genomic alterations (GA) across BRCA2-loss, BRCA2 short variant-mutated (svmut), and BRCA2-wild type (wt) clinically advanced prostate carcinoma (CAPC) samples, combined with an assessment of HRDsig status to gain a better understanding of these biomarkers.<br><br>METHODS: Comprehensive genomic profiling (CGP) was performed on 22&#xa0;061 CAPC cases to evaluate all classes of GA. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic ancestry, were derived from sequencing data. HRDsig status was calculated using genome-wide copy number features. PD-L1 expression was assessed by IHC. Comparisons were performed using Fisher's exact test with Benjamini-Hochberg correction for false discovery.<br><br>RESULTS: Among 22&#xa0;061 CAPC cases, 10.2% were HRDsig+. HRDsig+ and were enriched for BRCA2, RB1, MYC, RAD21, and AR alterations, while SPOP, MSI-high, high TMB, and MMR signatures were more frequent in HRDsig- cases. Across BRCA2-defined subgroups, 597 (2.7%) were BRCA2-loss, 1085 (4.9%) BRCA2-svmut, and 20&#xa0;379 (92.4%) BRCA2-wt. Both BRCA2-loss and BRCA2-svmut were associated with higher GA burden and enrichment for RB1 alterations. BRCA2-loss cases displayed lower TMB-high incidence, while BRCA2-svmut showed higher MSI-high and TMB-high incidence. Most BRCA2 alterations were bi-allelic, with concurrent alterations in other HRR genes being rare.<br><br>CONCLUSIONS: BRCA2-loss CAPC displays a distinct genomic landscape, marked by robust HRD features, suggesting the potential of higher sensitivity to PARPi. These findings highlight the relevance of HRDsig, and routinely use of CGP in refining patient selection for PARPi and guiding the design of future clinical trials.}, }
@article {pmid41875138, year = {2026}, author = {Coronado, GD and Dickerson, JF and Tsou, MH and Shivaprakash, N and Rosales, AG and Voelkel, JL and Whyte, MA and Shuster, E and Petrik, AF and Llavona-Ortiz, JY and Jenkins, CL and Rutter, CM and Escaron, AL}, title = {Temporal and geographic analyses of colorectal cancer screening during and after the COVID-19 pandemic in a federally qualified health center.}, journal = {PloS one}, volume = {21}, number = {3}, pages = {e0345248}, pmid = {41875138}, issn = {1932-6203}, mesh = {Humans ; *COVID-19/epidemiology/virology ; Male ; *Colorectal Neoplasms/diagnosis/epidemiology ; Middle Aged ; Female ; Aged ; *Early Detection of Cancer/statistics &amp; numerical data/trends ; SARS-CoV-2 ; Pandemics ; Los Angeles/epidemiology ; Mass Screening ; Interrupted Time Series Analysis ; }, abstract = {BACKGROUND: The COVID-19 pandemic caused reductions in cancer screening services. We assessed the pandemic's impact on colorectal cancer screening in a large diverse federally qualified health center (FQHC) in Los Angeles, CA.<br><br>METHODS: We used interrupted time series regression to estimate trends in monthly colorectal cancer screening rates for four relevant COVID-19 pandemic periods: pre-pandemic (March 2018 - February 2020); early-pandemic (March - December 2020); vaccine-era (January 2021- May 2023); and post-pandemic (June 2023 - May 2024). We plotted spatial distribution patterns of screening across census tracts.<br><br>RESULTS: Participants were 83,430 unique individuals (55% male; 80% Hispanic) ages 50-75. Average monthly colorectal cancer screening rates dropped from 9.3% pre-pandemic to 5.9% early-pandemic. Monthly screening rates in the vaccine era (7.5%) never returned to pre-pandemic levels and further declined in the post-pandemic era (6.7%; p trend&#x2009;=&#x2009;0.09). Screening rates were consistently higher for males, ages 65-75, Hispanic individuals, and Spanish-preferring individuals in both pre-COVID (March 2018-Feb 2020) and post-COVID (July 2020-May 2024) periods. Increases in stool-based testing aligned with mailed outreach campaigns.<br><br>CONCLUSIONS: Monthly post-pandemic screening rates never reached pre-pandemic levels and declined from 2023 to 2024. Sharp increases in stool-based testing coincided with mailed outreach events, highlighting the importance of home-based screening methods during disruptive events.<br><br>IMPACT: Our findings can help shape healthcare response strategies to reduce screening delays in the context of future natural disasters.}, }
@article {pmid41875428, year = {2026}, author = {Bricker, JB and Santiago-Torres, M and Sullivan, BM and Mull, KE and Clark, HW and Fogel, CA and Hwang, SB and Keith, AR and Kornacki, C and Afraid Of Lightning-Craddock, T and Martinez, SA and Seneca, DS and Stanford, CM and Terry, C and Wilcox, SL and Nelson, L and Henderson, PN}, title = {Development of a Culturally Adapted Smartphone App (IndigeQuit) Designed to Help American Indian and Alaska Native People Quit Commercial Cigarettes: User-Centered Mixed Methods Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e88768}, pmid = {41875428}, issn = {2561-326X}, mesh = {Humans ; *Mobile Applications ; *Smoking Cessation/methods/ethnology/psychology ; Female ; Male ; Adult ; Middle Aged ; *Alaska Natives/psychology ; Community-Based Participatory Research ; Qualitative Research ; Smartphone ; United States ; *American Indian or Alaska Native/psychology ; User-Centered Design ; }, abstract = {BACKGROUND: Due to the colonization of tobacco plants by European settlers and the subsequent intensive marketing of commercial tobacco products to American Indian and Alaska Native (AI/AN) communities in the United States, commercial cigarette smoking accounts for half of all deaths among AI/AN people. Limited awareness, access to treatment, and the absence of culturally relevant, effective smoking cessation interventions contribute to these high death rates.<br><br>OBJECTIVE: This study aims to culturally adapt iCanQuit, a smartphone smoking cessation app proven efficacious for the general population, for AI/AN people.<br><br>METHODS: A user-centered and community-based participatory research (CBPR) mixed methods approach was applied to culturally adapt iCanQuit for AI/AN people in collaboration with a community advisory board (CAB) of AI/AN individuals using a 3-step process. Step 1 identified ways to culturally adapt the iCanQuit for AI/AN people through 1-on-1 qualitative interviews with 8 prior iCanQuit AI/AN participants. Step 2 involved developing prototypes of cultural refinements identified in step 1 through regular biweekly meetings of the CAB, research, and app development teams. The prototypes were then evaluated with a separate group of 4 prior iCanQuit AI/AN participants through 1-on-1 qualitative interviews. Step 3 involved beta testing the app through a 6-day diary study followed by 1-on-1 qualitative interviews with a nationally recruited group of 7 AI/AN adults who smoke commercial cigarettes. The development work associated with step 3 was further informed by the CAB and the research and app development teams.<br><br>RESULTS: Key findings identified 5 cultural refinements that informed subsequent app development and testing: (1) stories featuring AI/AN adults and elders emphasizing culture, spirituality, family, and community; (2) honoring the Earth as a motivator for cessation; (3) a guide character representative of AI/AN people; (4) clear distinction between ceremonial and commercial tobacco use; and (5) use of earth tones in visual design. In Step 3, all 7 (100%) diary study participants rated the beta version of the app as excellent or good/meets expectations (5/7, 71%, and 2/7, 29%, respectively) and that it felt made for them. They suggested 6 modifications which were incorporated into the final version of the app: (1) include vaping frequently asked questions, (2) feature motivation icons more prominently, (3) increase notification frequency, (4) track today's cigarettes rather than yesterday's, (5) allow users to update how much they spend per pack of cigarettes; and (6) rename the medications tool to reflect the inclusion of AI/AN traditional healing modalities.<br><br>CONCLUSIONS: A user-centered and CBPR development process yielded IndigeQuit-one of the first known apps developed specifically to help AI/AN adults quit commercial cigarette smoking.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT06145763; https://clinicaltrials.gov/ct2/show/NCT06145763.}, }
@article {pmid41876852, year = {2026}, author = {Kerlikowske, K and Lowry, KP and Miglioretti, DL}, title = {In what clinical settings are the MASAI trial results applicable?.}, journal = {Nature reviews. Clinical oncology}, volume = {}, number = {}, pages = {}, pmid = {41876852}, issn = {1759-4782}, }
@article {pmid41878702, year = {2026}, author = {Rosenbaum, A and Wibom, C and Hammermeister Suger, A and Pensch, R and Roy, A and Brännström, T and Rentoft, M and Forsberg-Nilsson, K and Lindblad-Toh, K and Lindström, S and Dahlin, AM and Melin, B}, title = {Rare germline variants contribute to glioma predisposition: Whole-genome analysis of a regional cohort of glioma patients.}, journal = {Neuro-oncology advances}, volume = {8}, number = {1}, pages = {vdag038}, pmid = {41878702}, issn = {2632-2498}, abstract = {BACKGROUND: Gliomas are the most common malignant primary tumor of the central nervous system and show a high mortality, particularly at higher grades. Cancer predisposition syndromes and common low-penetrance single nucleotide polymorphisms have been shown to contribute to glioma risk, but the contribution of rare germline variants remains incompletely understood. Here, we investigated rare germline variants in glioma patients.<br><br>METHODS: We performed whole-genome sequencing on 113 glioma patients from Northern Sweden, analyzing rare germline variants across 651 genes. Variants were compared to population controls (ACpop, gnomAD) and validated in TCGA glioma data, a UK Biobank glioma nested case-control study, and a separate cohort of 105 Swedish glioblastomas.<br><br>RESULTS: 17.6% of glioma cases carried a Pathogenic or Likely Pathogenic (P/LP) variant within 1 of the 651 genes, and the number of alleles carrying a P/LP was significantly more than in the reference data (P = 3.2 &#xd7; 10 - 3). Many of the observed candidate genes also harbored P/LP variants in our Swedish validation cohort. Overall, gene-based comparison of rare coding variants indicated an enrichment in several genes, including TP53, CREBBP, and DNMT3A.<br><br>CONCLUSIONS: Rare P/LP germline variants were more frequent among glioma patients than in the reference population within our predefined gene set. These results suggest a contribution of rare germline variants to glioma risk, particularly in genes involved in DNA repair. While several genes are indicated as enriched with rare variants, only TP53 validates across all 3 patient sets.}, }
@article {pmid41878771, year = {2026}, author = {Goldberg, ME and Dashnow, H and Harris, K and Quinlan, AR}, title = {The selective dynamics of interruptions at short tandem repeats.}, journal = {Genetics}, volume = {}, number = {}, pages = {}, doi = {10.1093/genetics/iyag080}, pmid = {41878771}, issn = {1943-2631}, support = {R00 HG012796/HG/NHGRI NIH HHS/United States ; }, abstract = {Short tandem repeats (STRs) are hotspots of genomic instability that mutate at rates orders of magnitude greater than non-repetitive loci due to frequent replication slippage. Expansions at some STR loci cause Mendelian diseases, while variation at other noncoding loci may affect complex traits, possibly by altering transcription factor occupancy of nearby binding sites. Accordingly, some STRs are inferred to be under purifying selection, regardless of their instability. One or more "interruptions", or bases that disrupt the locus's canonical repeat, significantly decrease an STR's mutability. For example, the onset of Huntington's Disease, a neurodegenerative disorder associated with somatic expansions of a trinucleotide coding STR, is delayed in individuals whose inherited alleles contain interruptions. Thus, interruptions that decrease mutation rate at some coding loci may broadly protect against deleterious phenotypes associated with locus instability. However, interruptions may themselves be deleterious at constrained loci, particularly at noncoding loci in gene regulatory elements, possibly disrupting the formation of secondary structures key to their function. We therefore hypothesized that the frequency of interruptions could depend on a locus's functional importance-at constrained loci, the fitness effects of expansions but also interruptions could be more deleterious than at neutral loci. To test this hypothesis, we examined the distribution of interruptions at ∼650,000 autosomal STRs. In the ∼2,500 3- or 6bp-motif coding STRs, we find that synonymous interruption density increases with purifying selection on the gene, while the opposite is true for missense-causing interruptions. In contrast, noncoding STRs in gene regulatory elements harbor fewer interruptions than elements that are unassociated with gene regulation and thus more likely to be evolving neutrally. Our findings indicate that the abundance of interruptions may be partially explained at coding STRs by the benefit of lower instability, whereas maintaining a core stretch of uninterrupted repeat may be key to the function of regulatory noncoding STRs, outweighing the benefits of stability.}, }
@article {pmid41879614, year = {2026}, author = {Abad, PJB and Posadas, JJB and Tumulak, MJR and Laurino, MY}, title = {A Filipinized view of the counselor-client relationship in genetic counseling.}, journal = {Journal of genetic counseling}, volume = {35}, number = {2}, pages = {e70197}, doi = {10.1002/jgc4.70197}, pmid = {41879614}, issn = {1573-3599}, mesh = {Humans ; *Genetic Counseling/psychology ; Philippines ; *Counselors/psychology ; *Professional-Patient Relations ; }, abstract = {While genetic counseling expands globally and serves increasingly diverse clients, its theory and practice remain shaped by an English-based, Western/European orientation. This is concerning because this assumes that the genetic counseling theory and practice appropriate in the Global North apply equally to the Global South. Recent calls urge decentering genetic counseling from Western foundations to reflect the lived realities of the clients it serves. We present an indigenized view of the genetic counselor-client relationship grounded in Filipino experiences, adopting loob (relational will) and kapwa (shared identity) from Sikolohiyang Pilipino (Filipino psychology) to explicate therapeutic relationships within the context of genetic counseling. This Filipinized view cultivates indigenous knowledge to reimagine genetic counseling as culturally sensitive and locally relevant. However, further research is needed to understand how these concepts manifest in practice.}, }
@article {pmid41880621, year = {2026}, author = {Annamalay, A and García González, I and Forsyth, C and Jenkins, I and Arteaga, M and Othieno-Abinya, NA and Desai, C and Duarte, F and Gangadharan, VP and Gundeti, S and Malhotra, H and Malhotra, P and Meliksetyan, K and Mojica, R and Zarza, J and Sabonge, JM and Santana, AL and Gebremedhin, A and Orellana Martínez, R and Martínez Miranda, M and Lima Valencia, MG and Garcia-Gonzalez, P and Radich, J}, title = {Treatment-free Remission in Chronic Myeloid Leukemia in Low- and Middle-Income Countries.}, journal = {The New England journal of medicine}, volume = {394}, number = {12}, pages = {1238-1240}, doi = {10.1056/NEJMc2518028}, pmid = {41880621}, issn = {1533-4406}, }
@article {pmid41881346, year = {2026}, author = {Liang, EC and Shen, MJ and Salit, RB and Onstad, L and Vo, P and Oshima, MU and Boiko, JR and Lee, CJ and Carpenter, PA and Gauthier, J and Simard, S and Lee, SJ}, title = {Fear of Cancer Recurrence in Hematopoietic Cell Transplantation Survivors.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.03.022}, pmid = {41881346}, issn = {2666-6367}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; }, abstract = {Fear of cancer recurrence (FCR) is a significant challenge faced by hematopoietic cell transplantation (HCT) survivors, yet it remains insufficiently characterized in this group, limiting the ability to develop interventions to reduce FCR. We aimed to determine the prevalence and correlates of clinically significant levels of FCR (csFCR) in a large cohort of long-term HCT survivors at a major cancer center. From July 1, 2023 through June 30, 2024, survivors who underwent HCT >1 year ago at Fred Hutch Cancer Center received an annual patient recovery questionnaire (PRQ) and FCR module that included Patient-Reported Outcomes Measurement Information System (PROMIS) instruments, the FCR Inventory-Short Form (FCRI-SF), and questions regarding adherence to healthcare maintenance and cancer screening. csFCR was defined as a score ≥16 on the FCRI-SF. We determined predictors of csFCR using logistic regression and compared PROs, healthcare maintenance, and cancer screening by presence of csFCR. Of 4514 participants, 1501 (33%) completed the PRQ and FCR module, and 513 (34%) reported csFCR. In univariate logistic regression, younger age at survey completion, shorter time from HCT, diagnosis, intermediate or high pre-HCT disease risk, current receipt of maintenance therapy, and history of post-HCT relapse were significantly associated with higher odds of csFCR. In multivariable logistic regression, younger age at survey completion, shorter time from HCT, and history of post-HCT relapse remained independently associated with higher odds of csFCR. Survivors with csFCR reported lower PROMIS physical and psychosocial function, greater anxiety before hematology/oncology appointments, and greater need for, yet reduced access to, psychological care. Rates of cancer screening did not differ significantly by presence of csFCR. HCT survivorship programs should integrate psychosocial support to address FCR and determine whether targeted interventions can mitigate FCR and improve quality of life.}, }
@article {pmid41881573, year = {2026}, author = {Schuurmans, F and Boros, MGM and van den Bijgaart, RJE and Wittner, A and Molkenboer-Kuenen, JDM and Lok, J and Tahk, S and Hopfner, KP and Heskamp, S and Adema, GJ}, title = {In-vivo analysis of neuroblastoma targeting potential of aGD2-SIRPα fusion antibodies for local CD47 blockade.}, journal = {Molecular cancer therapeutics}, volume = {}, number = {}, pages = {}, doi = {10.1158/1535-7163.MCT-25-1169}, pmid = {41881573}, issn = {1538-8514}, abstract = {Anti-GD2 monoclonal antibodies (aGD2 mAbs) are the standard immunotherapy for patients with high-risk neuroblastoma (NB). This treatment has improved 5-year overall survival, however, long-term efficacy still requires improvement. The don't eat me signal CD47 is upregulated on NB tumor cells and inhibits aGD2 mAb effector mechanisms. While GD2 is restrictively expressed on NB tumor cells CD47 expression is ubiquitous, resulting in an antigen sink and on-target off-tumor related cytotoxicities. Recently, we developed two aGD2-SIRPα fusion mAbs for the murine and human setting. In-vitro these aGD2-SIRPα fusion mAbs restrict CD47 blockade towards GD2+ NB tumor cells. Here we explored the tumor targeting ability of aGD2-SIRPα fusion mAbs in a syngeneic 9464D-Luc-GFP and newly developed SK-N-AS xenograft NB tumor model. Conventional aCD47 and aSIRPα mAbs encountered a dominant antigen sink in the 9464D-Luc-GFP model. Surprisingly, while aGD2 mAbs preferentially targeted to tumors, murine aGD2-mSIRPα fusion mAbs accumulated in similar organs as aCD47 mAbs. Binding analysis of murine aGD2-mSIRPα and human aGD2-hSIRPα fusion mAbs to red blood cells (RBCs) revealed strong binding of murine aGD2-mSIRPα to RBCs, whereas their human counterparts showed negligible binding. These data indicate species specific CD47-SIRPα binding patterns. Utilizing a newly developed SK-N-AS xenograft model we show effective tumor targeting of the human aGD2-hSIRPα fusion mAbs with hSIRPα in a C-terminal configuration. These data provide the first proof of principal for NB tumor targeted blockade of CD47 by aGD2-hSIRPα fusion mAbs in-vivo and support the further development of aGD2-hSIRPα mAbs as attractive therapeutics to improve aGD2 based NB immunotherapy.}, }
@article {pmid41884897, year = {2026}, author = {O'Brien, SN and Gillman, MG and Green, MD and Cruz, DE and Floyd, JS and Hankinson, S and Katz, DH and Liu, X and Odden, MC and Psaty, BM and Reiner, AP and Rotter, JII and Rich, SSS and Gerszten, RE and Shah, A and Sims, M and Tahir, UA and Tinker, LF and Wood, AC and Yu, B and Zannas, AS and Raffield, L and Glover, L}, title = {Plasma Proteins Associated With Psychosocial Factors and Heart Disease: The Jackson Heart Study.}, journal = {Arteriosclerosis, thrombosis, and vascular biology}, volume = {}, number = {}, pages = {}, doi = {10.1161/ATVBAHA.125.324125}, pmid = {41884897}, issn = {1524-4636}, support = {U24 DK137631/DK/NIDDK NIH HHS/United States ; T32 GM067553/GM/NIGMS NIH HHS/United States ; R01 AG075884/AG/NIA NIH HHS/United States ; R01 HL172495/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 HL172803/HL/NHLBI NIH HHS/United States ; R01 HL133870/HL/NHLBI NIH HHS/United States ; R01 HL144483/HL/NHLBI NIH HHS/United States ; U01 AG082042/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Knowledge of proteomic mechanisms explaining the link between psychosocial stress and cardiovascular disease is limited. This study aimed to (1) identify plasma proteins associated with psychosocial factors and (2) assess associational pathways between psychosocial factors, identified proteins, and incident cardiovascular disease events in a discovery cohort, JHS (Jackson Heart Study), and 2 replication cohorts, the CHS (Cardiovascular Health Study), and the MESA (Multi-Ethnic Study of Atherosclerosis).<br><br>METHODS: JHS participants from exam 1 (2000-2004) with SomaScan 1.3k platform proteomics data were included (n=2143, mean age=55.3). Depressive symptoms and perceived stress scores were measured via the 20-item Centers for Epidemiological Studies scale and an 8-item perceived stress scale adapted for the JHS, respectively. Multivariable linear regression models were used to test the association between psychosocial factors and plasma proteins, controlling for age, sex, proteomics batch, and estimated glomerular function. Meta-analyses were also performed across cohorts, using Bonferroni correction for multiple testing (P<3.782&#xd7;10[-5]). Mediation analyses with Cox proportional hazards models were used to evaluate potential proteomic pathways in the association between psychosocial factors and coronary heart disease, heart failure, and stroke in JHS.<br><br>RESULTS: Angiopoietin-2 (&#x1d6fd;=0.013, SE=0.002, P<0.001), contactin-5 (&#x1d6fd;=-0.013, SE=0.002, P<0.001), growth/differentiation factor 15 or macrophage inhibitory cytokine 1 (&#x1d6fd;=0.011, SE=0.002, P<0.001), neural cell adhesion molecule 120 (&#x1d6fd;=-0.012, SE=0.002, P<0.001), and KYNU (kynureninase; &#x1d6fd;=0.014, SE=0.003, P<0.001) were each significantly associated with depressive symptoms, with angiopoietin-2, contactin-5, macrophage inhibitory cytokine 1, and neural cell adhesion molecule 120 replicating in CHS and MESA. Leukotriene A-4 hydrolase was associated with perceived stress (&#x1d6fd;=-0.0235, SE=0.005, P<0.001). Macrophage inhibitory cytokine 1 partially accounted for the association between depressive symptoms and incident coronary heart disease in JHS (23%; P=0.0009).<br><br>CONCLUSIONS: Novel associations between psychosocial factors, plasma proteins, and cardiovascular disease were identified in JHS. Circulating proteomic profiles across 3 cardiovascular disease cohorts showed differences in protein concentrations by psychosocial measures. Future investigations should identify additional potentially targetable proteomic mechanisms by which psychosocial factors contribute to disease.}, }
@article {pmid41885027, year = {2026}, author = {Radich, JP and Chaturvedi, S and Sadek, I and Obourn, V}, title = {Predictive biomarkers of sustained treatment-free remission in chronic myeloid leukemia: gene expression analyses from the ENESTfreedom and ENESTop studies.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2025.300215}, pmid = {41885027}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid41885416, year = {2026}, author = {Ellis, AL and Stauss, M and Barros Tiburcio, P and Emmen, IE and Edlefsen, PT and Kosmider, E and Barlow, S and Goss, M and Temte, JL and Stachler, E and McMahon, K and Sabeti, P and O'Connor, DH and O'Connor, SL}, title = {Adaptation of the multiplexed CRISPR-Cas13 CARMEN RVP assay for longitudinal detection of respiratory pathogens from air samples.}, journal = {Applied and environmental microbiology}, volume = {}, number = {}, pages = {e0211725}, doi = {10.1128/aem.02117-25}, pmid = {41885416}, issn = {1098-5336}, abstract = {UNLABELLED: Air sampling is a non-invasive alternative to individual testing for respiratory pathogens. Alternative methods to the "gold standard" quantitative reverse transcription-PCR (qRT-PCR) are required to enable higher throughput, lower cost, and more multiplexed detection of pathogens. The multiplexed CRISPR-Cas13 CARMEN Respiratory Viral Panel (RVP) was described previously for high-throughput detection of nine respiratory pathogens from nasal swab samples. Here, we modified and optimized the CARMEN RVP assay to overcome the unique challenges of air samples, including low biomass and environmental inhibitors. We monitored for SARS-CoV-2 and influenza A (Flu A) via qRT-PCR in air samples from 15 schools within Dane County, Wisconsin (USA), during the 2023-2024 school year. SARS-CoV-2 was detectable throughout the entire sampling period, while Flu A detection was seasonal from November 2023 to March 2024. We then analyzed a subset of samples from seven schools using an optimized CARMEN RVP assay for air surveillance (RVP_air) and compared the results to qRT-PCR. The RVP_air assay detected several additional pathogens beyond our primary targets. The frequencies and patterns of SARS-CoV-2 positivity, but not Flu A positivity, were similar between qRT-PCR and RVP_air across the 2023-2024 sampling period. We developed a secondary panel (RVP_air_flu) to better detect both H1N1 and H3N2 subtypes. Finally, we compared air sample results to clinical nasal swabs collected from the same school district. For several pathogens (SARS-CoV-2, HCoV-OC43, Flu A), positive air detections coincided with positive nasal swabs. These findings demonstrate that the RVP_air assay can effectively detect airborne pathogens from infected individuals within indoor spaces.<br><br>IMPORTANCE: Air sampling offers a cost-effective alternative to individual testing for respiratory pathogens within congregate settings. Optimization and use of multi-pathogen assays are especially valuable for capturing the breadth of pathogens that may be present simultaneously in the same space. The modified CARMEN RVP assays (RVP_air and RVP_air_flu) detected SARS-CoV-2 and Flu A during similar sampling time periods compared to qRT-PCR, while also detecting several additional respiratory pathogens (seasonal coronaviruses, respiratory syncytial virus). Importantly, pathogens detected from air samples corresponded to those detected from nasal swabs collected from individuals in the same spaces. Together, these findings highlight the utility of the RVP_air and RVP_air_flu assays as alternatives to qRT-PCR for environmental surveillance, with applications extending to other congregate spaces (hospitals, long-term care facilities) and high-risk settings, better informing communities and improving public health.}, }
@article {pmid41886034, year = {2026}, author = {Huang, SH and Seethala, RR and Patel, SG and O'Sullivan, B and Lydiatt, W and Ho, AS and Hosni, A and Vander Poorten, V and Glastonbury, CM and Bishop, J and Beadle, B and Ha, P and Kakarala, K and Rodriguez, CP and Ganly, I}, title = {ASO Visual Abstract: Key Updates on the Version 9 AJCC/UICC Staging System for Salivary Gland Carcinoma.}, journal = {Annals of surgical oncology}, volume = {}, number = {}, pages = {}, doi = {10.1245/s10434-026-19531-2}, pmid = {41886034}, issn = {1534-4681}, }
@article {pmid41886488, year = {2026}, author = {Xiao, H and Bai, G and Liu, F and Cui, Y and Unger, JM}, title = {Policy stringency during the COVID-19 pandemic and healthcare services utilization in China: An interrupted time-series analysis.}, journal = {PLoS medicine}, volume = {23}, number = {3}, pages = {e1004672}, pmid = {41886488}, issn = {1549-1676}, mesh = {Humans ; *COVID-19/epidemiology/prevention &amp; control ; China/epidemiology ; Interrupted Time Series Analysis ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; *Health Policy ; Pandemics ; SARS-CoV-2 ; Hospitalization/statistics &amp; numerical data ; Ambulatory Care/statistics &amp; numerical data ; }, abstract = {BACKGROUND: The COVID-19 pandemic has profoundly impacted healthcare systems worldwide, with China presenting a unique case. As the first country to report COVID-19 cases and the last to lift its stringent Zero-COVID policy, China presents a distinctive context for understanding the long-term effects of the pandemic on healthcare utilization. This study provides a comprehensive analysis of healthcare utilization trends in China over more than four years of the pandemic, focusing on how different phases, including the Zero-COVID policy and its cessation.<br><br>METHODS AND FINDINGS: We conducted an interrupted time-series analysis of monthly healthcare utilization data from January 2015 to April 2024, including outpatient visits and inpatient discharges, across Mainland China, controlling for underlying secular trends and patterns. Hospital-based healthcare utilization data were sourced from the National Health Commission of China, and daily Policy Stringency Indices (higher values indicating stricter control policies) were obtained from Oxford's COVID-19 Government Response Tracker. We modeled changes in healthcare utilization using negative binomial regression, comparing actual outcomes with counterfactual estimates based on pre-COVID trends. We assessed healthcare utilization during key pandemic phases, including the post-Zero-COVID period. Healthcare utilization in China experienced substantial declines during the pandemic, with an estimated reduction of 1.21 billion (7%) outpatient visits and 140.9 million (13%) inpatient discharges compared to expected levels from January 2020 to April 2024. The most pronounced declines occurred during the initial pandemic waves and coincided with periods of stringent Zero-COVID measures. Negative associations between the Policy Stringency Index and healthcare utilizations were observed. Before the lifting of the Zero-COVID policy, a 10-point increase in the Policy Stringency Index was associated with a 7.2 percentage point decrease in outpatient visits and a 6.2 percentage point decrease in hospitalizations. Although healthcare utilization gradually rebounded following the cessation of the Zero-COVID policy, as of April 2024, utilization remained below expected levels in 20 (65%) of the 31 regions for outpatient visits and in 23 (74%) for inpatient discharges. Regional disparities were evident, with more developed areas, such as Shanghai and Beijing, experiencing the largest absolute reductions after adjusting for population size. In Shanghai, outpatient visits declined by 4,997 and hospitalizations by 241 per 1,000 people. In contrast, the largest relative reductions occurred in less developed regions, where outpatient visits dropped by 16% in Guizhou and hospitalizations declined by 27% in Shanxi. Use of aggregated routine health system data limited individual-level analyses, assessment of care quality, and disentangling of causal pathways.<br><br>CONCLUSIONS: The COVID-19 pandemic and Zero-COVID policies were associated with substantial and enduring disruptions to healthcare utilization in China, characterized by slow recovery and regional disparities in access. These findings underscore the importance of strengthening healthcare systems to enhance resilience and better balance public health interventions with the maintenance of essential healthcare services in anticipation of future public health crises. Continued targeted efforts are needed to address the delayed recovery, particularly in regions with already strained healthcare infrastructure, and to ensure equitable healthcare access across the country.}, }
@article {pmid41886688, year = {2026}, author = {Bagshaw, P and Potter, JD and Goddard, J and McDonald, F and Bagshaw, S and Roskruge, M and Ahiro, G}, title = {Is health a basic human right or a commodity? Travelling the difficult road towards equity of outcomes.}, journal = {The New Zealand medical journal}, volume = {139}, number = {1632}, pages = {92-100}, doi = {10.26635/6965.7355}, pmid = {41886688}, issn = {1175-8716}, mesh = {Humans ; New Zealand ; *Health Policy ; *Human Rights ; *Health Equity ; *Right to Health ; *Health Services Accessibility ; Social Determinants of Health ; }, abstract = {From 1938, Aotearoa New Zealand health policy committed to providing free universal access to secondary healthcare. This approach initially worked for all citizens except Māori and Pacific peoples, who had different unmet needs. From the 1980s, as a neoliberal agenda spread, it became clear that action was needed to protect the population from the scourge of health as a commodity. Those who could afford to buy healthcare already had better social determinants of health; however, ultimately inadequate legal processes failed to protect many people from the damage to our healthcare systems. The focus should have been on the ultimate goal of universal equity of health outcomes. To rebalance, we define health as a collective and individual legal right. The required laws to thus refresh the social contract should: i) bind rights and responsibilities of government and governed and protect all citizens; and ii) be enshrined against future whims of politicians. We suggest ways forward, including: i) open physician advocacy, starting with the medical colleges; ii) honouring the right of New Zealanders, individually and collectively, to health; iii) adhering to relevant international agreements and national laws; and iv) advancing a codified constitutional legal structure for Aotearoa New Zealand.}, }
@article {pmid41888481, year = {2026}, author = {Chen, YQ and Wang, Y and Zhang, X and Prentice, RL}, title = {Estimating attributable risk functions for censored time-to-event in disease prevention research.}, journal = {Lifetime data analysis}, volume = {32}, number = {2}, pages = {}, pmid = {41888481}, issn = {1572-9249}, support = {R01 MH105857/MH/NIMH NIH HHS/United States ; R01 CA172415/CA/NCI NIH HHS/United States ; R56 AI140953/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/transmission ; Male ; Homosexuality, Male ; Models, Statistical ; Computer Simulation ; Risk Factors ; Risk Assessment/methods ; Time Factors ; }, abstract = {In disease prevention research, researchers often need to assess a prevention strategy that targets key disease-associated risk factors to reduce a population's disease burden. In this article, the fraction of the total disease burden associated with the risk factors targeted by the prevention strategy is calculated by time-varying attributable risk functions (ARF) when the disease outcome is censored time-to-event. We study some generic ARFs and develop nonparametric and semiparametric model-based procedures to estimate, compare, and predict ARFs. In addition to numerical simulation studies, we demonstrate the use of ARFs for a human immunodeficiency virus (HIV) behavior intervention trial in prevention of HIV transmissions among men who have sex with men (MSM).}, }
@article {pmid41888514, year = {2026}, author = {Yang, X and Kim, MS and Zhu, X and Uddin, MM and Nakao, T and Cho, SMJ and Koyama, S and Xu, T and Reeskamp, LF and Zhang, R and Liu, Z and A, Y and de Vries, PS and Vasan, RS and Boerwinkle, E and Morrison, AC and Psaty, BM and Tracy, RP and Heckbert, SR and Cho, MH and Yun, JH and Palmer, ND and Bowden, DW and Murabito, JM and Levy, D and Heard-Costa, NL and O'Connor, GT and Becker, LC and Kral, BG and Yanek, LR and Raffield, LM and Hidalgo, B and Rotter, JI and Rich, SS and Taylor, KD and Post, WS and Kooperberg, C and Reiner, AP and Mitchell, BD and Kardia, SLR and Smith, JA and Peyser, PA and Bielak, LF and Yon, DK and Won, HH and Arnett, DK and Smith, AV and Gabriel, SB and Ellinor, PT and ,  and Natarajan, P and Wang, M and Fahed, AC}, title = {An integrated germline and somatic genomic model for coronary artery disease.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-70379-2}, pmid = {41888514}, issn = {2041-1723}, support = {R01 HL164629/HL/NHLBI NIH HHS/United States ; K08 HL161448/HL/NHLBI NIH HHS/United States ; }, abstract = {Multiple germline and somatic genomic factors are associated with risk of coronary artery disease, but there is no single measure of risk that integrates all information from a DNA sample. To address this gap, we develop an integrated genomic model that includes six germline and somatic genetic drivers for coronary artery disease, including polygenic risk score, genetically-proxied proteomic/metabolomic risk scores, and clonal hematopoiesis of indeterminate potential. We evaluated its predictive power in the UK Biobank (N = 391,536), and validate it using data from the TOPMed program (N = 34,177). The 10-year coronary artery disease risk based on the integrated genomic model profile ranges from 1.1% to 15.5% in the UK Biobank and from 3.8% to 33.0% in TOPMed, with a more pronounced gradient in males than females. The integrated genomic model captures the cumulative effect of multiple genetic drivers, identifying individuals at high risk for coronary artery disease despite lacking any single high-risk genetic factor, as well as individuals at low risk despite carrying known high-risk factors. In middle age, the integrated genomic model augments the performance of the Pooled Cohort Equations, a clinical risk calculator for coronary artery disease. While the integrated genomic model yields only modest incremental predictive value over polygenic risk score at the population level, it identifies approximately 13% of high-risk individuals not detected by polygenic risk score alone.}, }
@article {pmid41888548, year = {2026}, author = {Genah, S and Pellegrino, M and Giansanti, M and Mancusi, A and Taviani, A and Cardinale, A and Rosichini, M and Flamini, S and Catanoso, ML and Giorda, E and Volpe, G and Piccione, M and Nazio, F and Dudakov, JA and van den Brink, MRM and de Billy, E and Locatelli, F and Velardi, E}, title = {Proteasome inhibition promotes Foxn1 expression in thymic epithelial cells and induces thymic regeneration in mice.}, journal = {Cell death and differentiation}, volume = {}, number = {}, pages = {}, pmid = {41888548}, issn = {1476-5403}, support = {GR-2019-12369231//Ministero della Salute (Ministry of Health, Italy)/ ; RF-2016-02364388//Ministero della Salute (Ministry of Health, Italy)/ ; 29932//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; 27019//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; 21147//Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)/ ; PRIN ID 2017 WC8499_004//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca (Ministry of Education, University and Research)/ ; }, abstract = {The thymus plays a critical role in sustaining T-cell immunity, although its function is highly vulnerable to acute injury and physiologically declines with age, resulting in compromised immune responses. Impaired thymic function represents a major clinical challenge, particularly in settings of immunosuppression associated with cancer therapy and aging. Yet, effective strategies to rejuvenate the thymus remain limited. To explore novel regenerative approaches, we focused on FOXN1, a master regulator of thymic epithelial cell (TEC) development and function. By developing a custom screening platform, we tested a library of FDA-approved compounds for their ability to induce FOXN1 in TECs. Proteasome inhibition emerged as a potent and previously unrecognized mechanism for upregulating FOXN1 in both murine and human primary TECs. Among the hits identified in the screening, the antiparasitic drug nitazoxanide (NTZ) stood out for its proteasome inhibitory activity and for inducing Foxn1 expression while preserving cell viability, unlike other proteasome inhibitors. Mechanistically, NTZ-induced proteasome inhibition triggered endoplasmic reticulum stress (ER) and the adaptive unfolded protein response (UPR), ultimately engaging autophagy in TECs. In this context, the induction of autophagy acted as a compensatory mechanism to support cell survival in response to proteasome inhibition. Notably, when administered in mice, NTZ significantly accelerated functional thymic recovery after radiation-induced damage, promoting restoration of thymic architecture and cellularity of both stromal and hematopoietic compartments without disrupting physiological T-cell selection or tolerance mechanisms. Consistent with our in vitro findings, NTZ treatment induced Foxn1 and its downstream targets in TECs in vivo and conferred protection to TECs following irradiation. These findings uncover proteasome inhibition and, more broadly, modulation of ER stress and UPR pathways as a previously unrecognized mechanism regulating Foxn1 expression and position NTZ as a promising pharmacological strategy to enhance immunity in patients experiencing T-cell deficiencies due to cancer-related immunosuppression, infections, and age-related thymic atrophy.}, }
@article {pmid41889450, year = {2026}, author = {Gulleen, EA and Kabukye, J and Block Ngaybe, MG and Bwogi, F and Namirembe, C and Liu, C and Orem, J and Phipps, W}, title = {Utilizing Process Mapping as a Framework for Identifying and Prioritizing Barriers to Antibiotic Delivery in Resource-limited Settings.}, journal = {Open forum infectious diseases}, volume = {13}, number = {3}, pages = {ofag037}, pmid = {41889450}, issn = {2328-8957}, abstract = {In resource-limited settings, healthcare providers face unique structural barriers to antibiotic delivery. Process mapping (PM) is a low-cost, low-technology approach used to understand the antibiotic delivery process and systematically identify barriers to timely antibiotic initiation. In this paper, we will use a 5-phase PM framework to provide the readers with a guide to developing antibiotic delivery process maps, identifying barriers to antibiotic delivery, and prioritizing the order in which these barriers should be addressed. We will then use our experience at the Uganda Cancer Institute in Kampala, Uganda as a case study to describe how we used PM to identify barriers to antimicrobial delivery for patients with neutropenic fever. We will also provide information about how to use low-cost supplies and open-access software to develop and analyze the process map. By the end of the paper, the reader will have the necessary tools to develop and analyze their own antibiotic delivery process maps. This will allow the reader to systematically identify barriers to antimicrobial delivery and understand how to prioritize which barriers to address using targeted interventions.}, }
@article {pmid41889507, year = {2026}, author = {Bender Ignacio, R and Rowan, K and Cook, D}, title = {How would Mari Kondo design a protocol? In favor of subtractive change in clinical trials.}, journal = {Frontiers in medicine}, volume = {13}, number = {}, pages = {1776929}, pmid = {41889507}, issn = {2296-858X}, }
@article {pmid41889874, year = {2026}, author = {Liu, Y and Zhang, Z and Tao, Y and Rahgav, L and Gray-Gaillard, S and Hussaini, Y and Pan, M and Shamber, J and Kwak, J and Park, SL and Cramer, J and Stoltz, R and Patria, J and Swanger, J and Liu, K and Sannigrahi, MK and Houghton, AM and Rodriguez, CP and Carey, RM and Brody, R and Rajasekaran, K and Weinstein, G and Linette, GP and Carreno, BM and Painter, MM and Wherry, EJ and Clurman, B and Basu, D and Diab, A}, title = {Therapeutic scheduling of WEE1 inhibition preserves T cell function and promotes immune control of HPV[+] tumors.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41889874}, issn = {2692-8205}, support = {K99 DE030194/DE/NIDCR NIH HHS/United States ; P01 CA022443/CA/NCI NIH HHS/United States ; R00 DE030194/DE/NIDCR NIH HHS/United States ; R01 DE034056/DE/NIDCR NIH HHS/United States ; }, abstract = {Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV[+] OPC) is driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined, and the challenge of eliciting antitumor immunity without compromising immune fitness has limited clinical translation. Here, we show that WEE1 inhibition elicits durable antitumor immunity in immunocompetent models of HPV[+] OPC. Using murine and human preclinical systems, we demonstrate that the WEE1 inhibitor azenosertib (ZN-c3) mediates tumor control through both cell-autonomous cytotoxicity and immune-dependent mechanisms requiring T cells and conventional dendritic cells. Mechanistically, HPV[+] tumor cells are deficient in STING signaling and fail to mount canonical type I interferon responses. Instead, tumor cell-intrinsic cGAS drives immune activation through STING-competent host cells within the tumor microenvironment, revealing a non-cell-autonomous relay that circumvents viral immune evasion. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, and mice achieving complete responses develop immunologic memory capable of rejecting tumor rechallenge. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses in HPV-driven malignancies and provides a mechanistic rationale for combination with immunotherapy.}, }
@article {pmid41890019, year = {2026}, author = {Arora, S and Suresh, L and Thirimanne, HN and Glatzer, G and Jensen, M and Fatherree, JP and Konnick, EQ and Levine, KM and Brooks, AN and Hougton, AM and Pritchard, CC and MacPherson, D and Berger, AH and Holland, EC}, title = {Beyond Histology: A Unified Transcriptomic Atlas Defines Lung Cancer Biologic States and Subtypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41890019}, issn = {2692-8205}, abstract = {Lung cancer encompasses multiple histological entities with substantial molecular heterogeneity that remain incompletely resolved at population scale. Here, we constructed a unified reference landscape of lung cancer by analyzing raw RNA sequencing data from 1,558 tumors spanning adenocarcinoma (n=753), squamous cell carcinoma (n=540), small cell lung cancer (n=150), and unclassified non-small cell lung cancer (n=80). Following batch correction, samples were embedded using PaCMAP to generate a continuous molecular atlas annotated with clinical and biological metadata. Rather than segregating strictly by histology, tumors organized along conserved transcriptional axes defined by tumor-intrinsic proliferative or metabolic programs and immune-infiltrated states. Consensus clustering resolved nine robust molecular clusters, including a female non-smoker-enriched adenocarcinoma subgroup, a neuroendocrine-like adenocarcinoma marked by ASCL1 activation, immune-associated regions, and bifurcation of both small cell and squamous carcinomas into biologically distinct states. Spatially-restricted expression of clinically actionable targets revealed state-specific vulnerabilities. Projection of patient tumors and patient-derived xenografts onto the atlas demonstrated preservation of transcriptional identity and enabled quantitative assessment of model fidelity. This unified framework redefines lung cancer as a structured continuum of transcriptional states with translational relevance.}, }
@article {pmid41891315, year = {2026}, author = {Borad, A and Andersen, M and Guffey, D and Shang, H and Jiang, JY and Fernandez Turizo, MJ and Berry, J and Zwicker, JI and Patell, R and Li, A}, title = {The Impact of Anticoagulation in Patients With Isolated Cancer-Associated Splanchnic Vein Thrombosis: A Dual-Center Cohort Study.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70287}, pmid = {41891315}, issn = {1096-8652}, support = {K23 HL159271/HL/NHLBI NIH HHS/United States ; R01 HL180402/HL/NHLBI NIH HHS/United States ; }, abstract = {Data to guide management of isolated bland cancer-associated splanchnic vein thrombosis (CA-SpVT) are limited. We aimed to assess the role of anticoagulation (AC) and bleeding and thrombosis in patients with CA-SpVT. We conducted a dual-center retrospective cohort study of adults with incident, isolated, bland CA-SpVT from 2011 to 2020. The primary outcome was major bleeding (MB); other outcomes included usual-site venous thromboembolism (VTE) recurrence and progression/recanalization of CA-SpVT. Time-to-event outcomes were analyzed with weighted Cox models adjusting for cancer type, stage, SpVT location, and whether symptomatic. For SpVT recanalization/progression, differences were estimated using weighted average treatment effects (ATEs). After excluding tumor thrombus, we included 437 patients with notable characteristics of median age 60 years, portal vein thrombosis (81.2%), and underlying hepatocellular cancer (35.9%). Of these, 29.5% received therapeutic AC. At 6 months, there were 11.9% MB and 6.4% incident usual-site VTE events. Among 308 patients with follow-up imaging, the 1-year thrombus progression rate was 19.8% and thrombus recanalization was 28.6%. In the adjusted analysis, there were numerically higher rates of MB with AC (adjusted hazard ratio [aHR] 1.93, 95% confidence interval [CI] 0.97-3.87) and no significant difference in the incidence of VTE (aHR 1.41, 95% CI 0.56-3.51). AC was associated with significantly higher likelihood of venous recanalization (ATE +24% 95% CI 13%-35%) and significantly lower likelihood of thrombus progression (ATE -14% 95% CI -23% to -5%). In patients with isolated bland CA-SpVT, AC was associated with thrombus recanalization and limited thrombus progression; effects were offset by a potentially higher risk of MB.}, }
@article {pmid41892875, year = {2026}, author = {Swiecicki, PL and Othus, M and Patel, SP and Kwang-Chae, Y and Kurzrock, R}, title = {Baseline tumor burden and outcomes in patients with rare cancers treated with immunotherapy (Southwest Oncology Group trial S1609).}, journal = {Cancer}, volume = {132}, number = {7}, pages = {e70374}, pmid = {41892875}, issn = {1097-0142}, support = {5U01CA180888-08/CA/NCI NIH HHS/United States ; 5UG1CA233198-05/CA/NCI NIH HHS/United States ; U10CA180819/CA/NCI NIH HHS/United States ; U10CA180888/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Neoplasms/drug therapy/pathology/mortality/immunology ; Middle Aged ; *Tumor Burden/drug effects ; Aged ; Nivolumab/administration &amp; dosage/therapeutic use ; Adult ; Ipilimumab/administration &amp; dosage/therapeutic use ; *Immune Checkpoint Inhibitors/therapeutic use ; *Rare Diseases/drug therapy/pathology/mortality ; Progression-Free Survival ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Immunotherapy/methods ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {BACKGROUND: It has been suggested that baseline tumor burden may correlate with immune checkpoint inhibitor (ICI) outcome for individual tumor types in which ICIs are standardly used. The authors investigated whether pretreatment tumor burden correlates with overall survival (OS), progression-free survival (PFS), and tumor regression among patients who had rare cancers treated with dual ICIs.<br><br>METHODS: Southwest Oncology Group study S1609 was a phase 2, National Cancer Institute/Southwest Oncology Group basket study (>1000 sites) evaluating nivolumab plus ipilimumab in 53 cohorts of patients who had rare/ultrarare malignancies (ClinicalTrials.gov identifier NCT02834013). Overall, 722 patients were included in this secondary analysis, all of whom had measurable disease (Response Evaluation Criteria in Solid Tumors, version 1.1). Baseline tumor burden, defined as the sum of the greatest dimensions of target lesions at study registration, was analyzed based on quartiles observed in the data. The number of target lesions was also considered a secondary tumor burden measure. End points included OS and PFS.<br><br>RESULTS: Larger baseline tumor burden correlated with shorter OS, but not PFS (multivariable analysis). Higher baseline tumor burden quartiles had only a weak negative association with any tumor regression at first scan (Fisher exact test, p&#xa0;=&#xa0;.09), and multivariable analyses further indicated that both tumor burden and any tumor regression at first posttreatment scan were independently associated with OS in multivariable analysis (comparing a baseline tumor size &#x2265;12.9 cm vs. 1.0-4.8 cm; hazard ratio, 1.64; 95% confidence interval, 1.02-1.72; p&#xa0;=&#xa0;.032), but there was no evidence of an interaction between tumor burden and any tumor regression at the first scan (p for interaction&#xa0;>&#xa0;.65).<br><br>CONCLUSIONS: Larger baseline tumor burden was associated with worse OS, but not PFS, and was not predictive of tumor regression after dual ICI therapy in a large cohort with rare cancer types.}, }
@article {pmid41893849, year = {2026}, author = {Zheng, DJ and DelRocco, N and Han, R and Krailo, M and Aziz-Bose, R and Karvonen, KA and Kelly, CA and Newman, H and Umaretiya, PJ and Ilcisin, L and Reed, DR and Gorlick, R and Janeway, K and Bona, K}, title = {Sociodemographics and Attrition in Children With Osteosarcoma Enrolled in the AOST0331 Clinical Trial.}, journal = {JAMA network open}, volume = {9}, number = {3}, pages = {e263666}, pmid = {41893849}, issn = {2574-3805}, support = {U10 CA180899/CA/NCI NIH HHS/United States ; }, }
@article {pmid41895553, year = {2026}, author = {Bell-Brown, A and Ramsey, SD and Hershman, DL and Carlos, RC and Watabayashi, K and Manuel, G and Shankaran, V}, title = {Immediate Release of Radiology Results in Cancer Care: Insights From a National Study of Oncology Patients.}, journal = {Journal of the American College of Radiology : JACR}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jacr.2026.03.013}, pmid = {41895553}, issn = {1558-349X}, }
@article {pmid41895695, year = {2026}, author = {Wolff, D and Solano, C and Michonneau, D and Bonifazi, F and Mehra, V and Hall, K and Lazaryan, A and Lee, CJ and Logan, AC and van der Laan, M and Gruber, S and Kabadi, S and Khan, I and Nicholls, C and Rota, L and Nikai, E and Ponomareva, E and Koumas, A and Waller, EK and , }, title = {Transportability to the European Population of Efficacy of Belumosudil as Compared With Physician's Choice of Best Available Therapy for the Treatment of Chronic Graft Versus Host Disease.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.03.028}, pmid = {41895695}, issn = {2666-6367}, abstract = {Belumosudil was approved by US Food and Drug Administration in July 2021 for the treatment of relapsed/refractory chronic graft-versus-host disease (cGVHD) in patients aged ≥12 years after failure of at least 2 prior lines of therapy (LOTs). By comparing the treatment response pattern of patients between the Europe and US, this transportability analysis modelled belumosudil's effect in European patients based on the observed effect in real-world US patients. This ROCKreal study used a targeted maximum likelihood estimation-based transportability analysis to compare treatment-response pattern in Europe and US to evaluate the potential efficacy of belumosudil compared with BAT for treatment of cGVHD in European patients after failure of 2 to 5 prior LOTs. This analysis generalized US ROCKreal study findings to European patients. Data was collected on 196 US and 222 European patients ≥12 years of age with cGVHD treated with 2 to 5 prior LOTs with visits between March 2015 and 2024 from 8 US and 32 European sites. Sustained steroid reduction is recognized as a clinically meaningful indicator of benefit in late-line cGVHD, consistent with prior work examining composite clinical benefit measures. The primary endpoint was the adjusted (causal) ratio in 6-month overall response rate (ORR), defined using a prespecified sequential algorithm incorporating NIH consensus criteria, physician assessment, and ≥50% corticosteroid taper without progression. Because outcomes were not collected for European patients, efficacy endpoints were transported using US outcome models. A supplementary endpoint, the adjusted (causal) difference in 6-month ORR, was also evaluated. At LOT initiation, median age (52.6 versus 57.6 years) and rate of severe cGVHD (40% versus 51%) were lower in Europe than the US; otherwise, populations were well-balanced. Efficacy was defined as ORR at 6 months post-LOT initiation when treated with belumosudil versus best available therapy (BAT). Using targeted maximum likelihood estimation, an outcome model was trained on US data. Treatment-specific responses were predicted using European patient characteristics, resulting in an estimated ORR of 37.6% when treated with belumosudil versus 26.3% with BAT (ORR ratio = 1.427 95% CI: [1.05, ∞); P-value: .03]). In line with positive efficacy results observed in previous real-world evidence studies in US and European patients, findings from this transportability analysis indicate that the treatment-response pattern are similar in Europe compared to US and cGVHD patients treated with belumosudil would have significantly more clinical benefit compared to BAT in Europe.}, }
@article {pmid41896552, year = {2026}, author = {Portuguese, AJ and Davis, JA and Raza, S and Castaneda Puglianini, O and Freeman, C and Alsina, M and Wright, C and Blue, BJ and Baz, RC and Shain, KH and Goel, U and Khouri, J and Anwer, F and Ali, HM and Pasvolsky, O and Gaballa, M and Patel, K and Garcia-Pleitez, H and Mikulski, D and Fogel, L and Zolotov, E and Sannareddy, A and Afrough, A and Anderson, LD and Julian, K and Dima, D and Banerjee, R and Liang, EC and Cassano Cassano, R and Herr, MM and Hassan, H and Shune, L and Kort, J and Midha, S and Nadeem, O and Sidana, S and Lin, Y and Locke, FL and Hansen, DK and Sborov, D and Biran, N and Grajales-Cruz, A}, title = {Real-world outcomes with elranatamab in multiple myeloma: a multicenter analysis from the U.S. Multiple Myeloma Immunotherapy Consortium.}, journal = {Blood cancer journal}, volume = {16}, number = {1}, pages = {}, pmid = {41896552}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality ; Male ; Female ; Aged ; Middle Aged ; Retrospective Studies ; United States ; Aged, 80 and over ; Adult ; *Antibodies, Bispecific/therapeutic use/adverse effects/administration &amp; dosage ; Treatment Outcome ; Immunotherapy ; }, abstract = {Elranatamab, a BCMA-CD3 bispecific antibody, has demonstrated robust activity in relapsed/refractory multiple myeloma (RRMM), but real-world outcomes remain poorly defined. We conducted a multicenter retrospective study of 130 patients treated with commercial elranatamab across nine U.S. academic centers. The cohort was heavily pretreated (91% triple-class refractory, 49% penta-refractory), with 49% previously exposed to BCMA-targeted therapies. Only 22% would have met eligibility for MagnetisMM-3 cohort A. The overall response rate (ORR) was 65%, including ≥CR in 36%. Median progression-free survival (PFS) and overall survival (OS) were 4.3 and 14.6 months, respectively, shorter than MagnetisMM-3. Elevated LDH and low hemoglobin independently predicted poor outcomes and were incorporated into the novel ALPS (Anemia-LDH Prognostic System) score, which stratified patients into distinct risk groups for ORR, OS, PFS, and duration of response. Prior BCMA exposure reduced depth of response, with inferior OS observed in those treated within one year of prior therapy. Infections occurred in 38% of patients. Intravenous immunoglobulin supplementation, modeled as a time-dependent covariate, was associated with improved infection-free survival and PFS. While the incidence of CRS was modestly lower than in MagnetisMM-3, ICANS occurred more frequently in this real-world cohort. These findings highlight the efficacy, limitations, and supportive care needs of elranatamab in a frailer, more heterogeneous real-world RRMM population.}, }
@article {pmid41902502, year = {2026}, author = {Wang, Z and Taylor, KD and Rotter, JI and Rich, SS and Zheng, Y and Hou, L and Guo, X and Bressler, J and Raffield, LM and Liu, Y and Kaplan, R and Lloyd-Jones, DM and Morrison, AC and Fornage, M and Psaty, BM and Brody, JA and Sofer, T and , }, title = {Estimating population structure using epigenome-wide methylation data.}, journal = {Briefings in bioinformatics}, volume = {27}, number = {2}, pages = {}, pmid = {41902502}, issn = {1477-4054}, support = {R01 HL161012/HL/NHLBI NIH HHS/United States ; R01HL161012/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *DNA Methylation ; CpG Islands ; *Epigenome ; Genome-Wide Association Study ; Female ; Male ; Middle Aged ; *Epigenomics/methods ; *Epigenesis, Genetic ; Principal Component Analysis ; }, abstract = {Population stratification is one of the source of inflation in epigenome-wide association studies (EWAS) when not properly accounted for. To address this, we developed methylation population scores (MPSs) to predict genetic principal components (GPCs) using a feature selection approach. We used multi-ethnic DNA methylation data from Illumina EPIC arrays across five cohorts, including MESA (n = 929), CARDIA (n = 1123), JHS (n = 1365), ARIC (n = 2338), and HCHS/SOL (n = 1475), randomly splitting participants into training (85%) and test (15%) sets. Within each cohort, associations between GPCs and CpG sites were estimated using linear regression adjusting for age, sex, smoking and alcohol use, race/ethnicity, body mass index, and cell type proportions, followed by meta-analysis and selection of CpGs with FDR <0.05. We then applied a two-stage weighted least squares Lasso regression to construct MPSs, adjusting for the aforementioned covariates. In the test dataset, MPSs showed strong correlation with GPCs, with R[2] ranging from 0.27 (MPS7 vs. GPC7) to 0.98 (MPS1 vs. GPC1). Visualization demonstrated that MPSs recapitulated the pattern shown by GPCs in differentiating self-reported White, Black, and Hispanic/Latino groups and outperformed methylation-based principal components constructed using alternative published methods. Additionally, MPSs showed comparable performance to GPCs in reducing inflation in EWAS. Overall, MPSs uses supervised learning with covariate adjustment to capture genetic structure across diverse populations, and provide a reliable estimate of population structure in the data and can complement GPCs when genetic data are absent.}, }
@article {pmid41904118, year = {2026}, author = {Sholokhova, A and Kaveh, K and Bozic, I}, title = {Neoantigen evolution and response to checkpoint inhibitor immunotherapy in colorectal cancer.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71135-2}, pmid = {41904118}, issn = {2041-1723}, support = {WiSTEM2D Scholar Award//Johnson and Johnson (Johnson &amp; Johnson)/ ; DMS-2045166//National Science Foundation (NSF)/ ; }, abstract = {Checkpoint-blockade immunotherapy enables the immune system to recognize tumor cells that were previously invisible due to immune escape, but these therapies lead to heterogeneous patient outcomes. Focusing on colorectal cancer, in which two subtypes have markedly different responses to immunotherapy, we query the relationship between a tumor's mutagenic landscape and therapeutic outcomes. First, we model neoantigen evolution in growing tumors using a stochastic branching-process model and label each neoantigen by its predicted immunogenicity, giving each in-silico tumor a unique pre-treatment mutational landscape. Next, we use a dynamical systems model of tumor-immune interactions under checkpoint-blockade therapy, parameterized using clinical trial data, to simulate immunotherapy. We relate therapeutic outcomes to the heterogeneity of tumor mutational landscape, finding that a strong clonal neoantigen appears crucial for a successful response. Additionally, the minimal neoantigen quality across all neoantigens contributing to response dynamics is one of the strongest predictors of durable response.}, }
@article {pmid41904631, year = {2026}, author = {Wang, X and Sofer, T and Frei, O and Kaplan, R and Perreira, KM and Franceschini, N and Parada, H and Zhou, L and Andreassen, OA and Gonzalez, H and Dale, AM and Broce, IJ}, title = {Explicitly modeling genetic ancestry to improve polygenic prediction accuracy for height in a large, admixed cohort of US Latinos: Findings from HCHS/SOL.}, journal = {HGG advances}, volume = {}, number = {}, pages = {100597}, doi = {10.1016/j.xhgg.2026.100597}, pmid = {41904631}, issn = {2666-2477}, abstract = {Polygenic scores (PGS) offer moderate to high prediction accuracy for complex traits, but most are developed in European ancestry cohorts, reducing their performance in populations of other ancestries. This study aimed to improve standing height prediction, a heritable and ancestry-influenced trait, in an admixed Latino cohort: Hispanic Community Health Study/Study of Latinos (HCHS/SOL) by modeling ancestry using principal components (PCs) alongside PGS. SNPs were selected from a large European ancestry GWAS using various p-value thresholds, and weights were trained using traditional and penalized regression in the UK Biobank (UKB). PGS with PCs were trained separately in HCHS/SOL and UKB. Compared to PGS alone, modeling PGS with PCs moderately improved height prediction in HCHS/SOL (R[2] increase of ∼0.05), while mild improvements were observed in UKB (R[2] increase of ∼0.01). These results underscore the importance of incorporating genetic ancestry into predictive models for admixed populations, particularly when the trait exhibits ancestry-specific associations.}, }
@article {pmid41906220, year = {2026}, author = {Gillis, N and Colin-Leitzinger, C and Tang, YH and Otterstatter, M and Sherman, S and Zhang, L and Moscinski, LC and Walker, ME and Painter, JS and Abel, GA and Al Baghdadi, T and Deeg, HJ and Foran, JM and Gore, SD and Harrington, AM and Kroft, SH and Liu, JJ and Saber, W and Virani, S and Bejar, R and Lindsley, RC and Padron, E and Walter, MJ and Komrokji, R and DeZern, AE and Sekeres, MA}, title = {Clinical, Genetic, and Pathologic Variability in Myelodysplastic Syndromes and Precursor Conditions Across Race, Ethnicity, and Sex.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70279}, pmid = {41906220}, issn = {1096-8652}, support = {HHSN268201400003I/HL/NHLBI NIH HHS/United States ; HHSN268201400002I/HL/NHLBI NIH HHS/United States ; //National Cancer Institute (NCI)/ ; HHSN268201400003I/HL/NHLBI NIH HHS/United States ; HHSN268201400002I/HL/NHLBI NIH HHS/United States ; }, abstract = {The epidemiology of myelodysplastic syndromes/neoplasms (MDS) is challenging to define due to inconsistent reporting, complex diagnostic procedures, and evolving diagnostic criteria. Using the National MDS Natural History Study-a prospective cohort with centrally adjudicated histopathology and genetic variant review-we characterized the landscape of MDS across the United States and identified differences across demographics. Among 2115 participants, 64% (1346) had an MDS spectrum condition, including MDS (24%), MDS/myeloproliferative neoplasm (5%) and precursor conditions-clonal cytopenia of undetermined significance (22%) and idiopathic cytopenia/dysplasia of undetermined significance (13%). The median age was 74 years, and participants were predominantly male (66%), White (91%), and Non-Hispanic (92%). Myeloid-associated variants were detected in 68% of participants, most commonly in TET2, DNMT3A, ASXL1, SF3B1, and SRSF2. Black, compared to White, participants were younger at diagnosis (69 vs. 74 years, p = 0.01), had equal or increased prevalence of higher-risk MDS, lower hemoglobin, and higher peripheral blood blasts, yet were less likely to receive MDS-directed therapy (14% vs. 42%, p = 0.008). Black and Hispanic participants had fewer detectable gene mutations than White participants. Females had lower variant allele frequencies and fewer RNA splicing gene mutations than males. After multivariable adjustment, TP53 mutations, MDS diagnosis, and higher-risk disease were associated with worse progression-free and overall survival; age was also associated with overall survival. Black race trended toward improved progression-free survival. These findings highlight the need for enhanced understanding of MDS pathogenesis across patient groups and refined prognostic tools to improve personalized management of MDS spectrum conditions. Trial Registration: ClinicalTrials.gov identifier: NCT02775383.}, }
@article {pmid41908584, year = {2026}, author = {Kumar, S and Jiang, J and Donald-Paladino, MS and Chen, J and Gutierrez, A and Federation, AJ and Szulzewsky, F and Holland, EC and Ferguson, FM and Nabet, B}, title = {Development of PROTACs for targeted degradation of oncogenic TRK fusions.}, journal = {RSC chemical biology}, volume = {7}, number = {4}, pages = {596-614}, pmid = {41908584}, issn = {2633-0679}, abstract = {Chromosomal translocations leading to the fusion of tropomyosin receptor kinases (TRKs) with diverse partner proteins have been identified as oncogenic drivers in many adult and pediatric cancers. While first-generation TRK kinase inhibitors, such as entrectinib and larotrectinib, have shown positive responses in TRK fusion-positive cancers, resistance mutations against these inhibitors in the kinase domain limit their efficacy. Second-generation inhibitors are in clinical evaluation, highlighting a need for novel therapeutic modalities to achieve durable suppression of the oncogenic activity of TRK fusions. Here, we developed heterobifunctional small molecule degraders (PROTACs) to achieve targeted degradation of TRK fusions. By conjugating entrectinib to thalidomide, we identified JWJ-01-378 as a potent and selective cereblon (CRBN)-recruiting degrader of the TPM3-TRKA fusion. JWJ-01-378 induced TPM3-TRKA degradation through the ubiquitin-proteasome system and proteomics analysis confirmed the acute selectivity of JWJ-01-378 for achieving TPM3-TRKA degradation with minimal off-target effects. Importantly, JWJ-01-378 did not degrade CRBN neosubstrates that are targeted by existing TRK PROTACs including CG-428. While JWJ-01-378 was also able to degrade wild-type TRK, it was unable to degrade TRK inhibitor resistant mutants and ALK fusions. TPM3-TRKA degradation by JWJ-01-378 suppressed downstream signaling and reduced cancer cell viability, with improved responses compared to a heterobifunctional control compound that cannot degrade TPM3-TRKA. Together, our study expands the toolbox of selective compounds for evaluating targeted degradation of TRK fusions in diseases including cancer.}, }
@article {pmid41909516, year = {2026}, author = {Chaturvedi, S and Nagalla, S and Kolodny, S and Oladapo, A and Bernheisel, C and Swallow, E and Goldschmidt, D and Greatsinger, A and Ormenaj, L and Sareen, S and Ruiz Lopez, JN and Vredenburg, M and Levy, MY}, title = {Real-world avatrombopag use for immune thrombocytopenia in the United States: the REAL-AVA 2.0 multisite chart review study.}, journal = {Blood vessels, thrombosis &amp; hemostasis}, volume = {3}, number = {2}, pages = {100142}, pmid = {41909516}, issn = {2950-3272}, support = {R00 HL172303/HL/NHLBI NIH HHS/United States ; }, abstract = {The REAL-AVA 2.0 study was a retrospective multisite chart review evaluating avatrombopag (AVA) effectiveness among patients with primary immune thrombocytopenia (ITP) who underwent routine care in academic- and community-based practices in the United States and initiated AVA between 1 July 2019 and 30 June 2024. Treatment response was defined as achieving platelet counts (PC) ≥30 × 10[3]/μL, ≥50 × 10[3]/μL, or ≥100 × 10[3]/μL. The discontinuation of steroids and/or immunosuppressants after AVA initiation was evaluated. Analyses were performed in the overall population and among 2 stratified subgroups: ITP disease duration (acute, <3 months; persistent, 3-12 months; and chronic, ≥12 months) and prior thrombopoietin receptor agonists exposure status. Among the 177 patients included in the study, 90% achieved or maintained a PC ≥30 × 10[3]/μL response, 86% achieved or maintained a PC ≥50 × 10[3]/μL response, and 76% of patients achieved or maintained a PC ≥100 × 10[3]/μL response, with a median duration of response to AVA of 12.1, 12.4, and 10.0 months, respectively. The median durability of response was 96% at the PC ≥30 × 10[3]/μL threshold, 93% at the PC ≥50 × 10[3]/μL threshold, and 76% at the PC ≥100 × 10[3]/μL threshold. Almost all patients (98%) who used concomitant steroids at AVA initiation subsequently reduced the steroid dose (19%) or discontinued steroid use completely (79%), and 40% of those who used immunosuppressants discontinued them after AVA initiation. Results of the subgroup analyses were consistent with the overall sample. Findings show that AVA is an effective treatment option for patients with ITP, demonstrating durable PC response in a diverse population.}, }
@article {pmid41909709, year = {2026}, author = {Menezes, F and Chen, S and Grunenberg, N and Malahleha, M and Mngadi, K and Muyoyeta, M and Laher, F and Chirenje, ZM and Bekker, LG and Goepfert, P and Gray, GE and Tomaras, G and McElrath, MJ and Kallas, E and Roxby, AC and Moodie, Z}, title = {AS01B-, MF59-, and alum-based adjuvants and HIV vaccine immunogenicity: a post-hoc cross-protocol comparison of results from HVTN 100, 107, 120, and 702.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1768201}, pmid = {41909709}, issn = {1664-3224}, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage ; *Alum Compounds/administration &amp; dosage ; Adult ; Female ; Male ; *Adjuvants, Immunologic/administration &amp; dosage ; *HIV Infections/immunology/prevention &amp; control ; *Squalene/administration &amp; dosage ; *Polysorbates/administration &amp; dosage ; *Immunogenicity, Vaccine ; Middle Aged ; HIV Antibodies/immunology/blood ; Cross-Sectional Studies ; Retrospective Studies ; *Saponins/administration &amp; dosage ; Double-Blind Method ; *Adjuvants, Vaccine/administration &amp; dosage ; CD4-Positive T-Lymphocytes/immunology ; *HIV-1/immunology ; Immunoglobulin G/immunology ; Young Adult ; }, abstract = {INTRODUCTION: Vaccine adjuvants are crucial in HIV vaccine development, enhancing immune responses. Immune responses generated by different adjuvanted vaccines are rarely compared directly with the same vaccine antigens.<br><br>METHODS: This retrospective cross-protocol, cross-sectional analysis examined four randomized, controlled, double-blinded, multicenter trials (HVTN 100, 107, 120, and 702) of adults without HIV who received the ALVAC-HIV (vCP2438) vaccine and a bivalent gp120 protein booster with either MF59, Alum, or AS01B adjuvant. Participants received ALVAC-HIV at months 0, 1, 3, 6, and 12, and the adjuvanted protein at months 3, 6, and 12. Data from month 6.5 were compared for IgG V1V2 binding antibodies (bAb) and CD4+ T-cell responses, measured as IFN-&#x3b3; and/or IL-2 expression, using Wilcoxon and Barnard's tests with FDR p-value multiplicity adjustment. Reactogenicity and adverse event profiles were also assessed.<br><br>RESULTS: AS01B elicited higher CD4+ T cell magnitudes among positive responders than either MF59 or Alum adjuvant to the 3 antigens considered: 1086, TV1, ZM96. No statistically significant differences were observed between MF59 and Alum in CD4+ T-cell responses. Regarding IgG bAb responses, AS01B induced significantly higher magnitudes among positive responders compared to both MF59 and Alum for the C.1086C V1V2 and Con 6 gp120/B antigens. Additionally, AS01B elicited greater IgG bAb responses than MF59 for gp70-96ZM651.02 V1V2 and gp70_B.CaseA V1V2, although no significant differences were found between AS01B and Alum for these antigens. AS01B also showed a trend toward greater reactogenicity, though this difference did not reach statistical significance. Importantly, no serious adverse events occurred in any of the groups.<br><br>CONCLUSION: The AS01B adjuvant demonstrated superior IgG binding antibody and CD4+ T-cell responses compared with MF59 and Alum, when given with gp120 protein boost after ALVAC-HIV prime. These findings support AS01B as a superior adjuvant for HIV vaccine development, relative to MF59 and Alum.}, }
@article {pmid41910996, year = {2026}, author = {Abrams, HR}, title = {Audiences in the Electronic Medical Record.}, journal = {JAMA internal medicine}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamainternmed.2026.0289}, pmid = {41910996}, issn = {2168-6114}, }
@article {pmid41911315, year = {2026}, author = {Ortblad, KF and Wairimu, N and Culquichicon, C and Njeru, I and Malen, RC and Reedy, AM and Ekwunife, O and McGowan, M and Mwangi, M and Muthoni, A and Kiboi, D and Njoroge, S and Gao, F and Baeten, JM and Ngure, K}, title = {Effect of enhanced peer PrEP referral with HIV self-testing delivery among young Kenyan women: A randomized controlled trial of peer networks.}, journal = {PLoS medicine}, volume = {23}, number = {3}, pages = {e1005023}, pmid = {41911315}, issn = {1549-1676}, mesh = {Humans ; Female ; Kenya/epidemiology ; *HIV Infections/prevention &amp; control/diagnosis ; Adolescent ; *Peer Group ; Young Adult ; *Referral and Consultation ; *Pre-Exposure Prophylaxis/methods ; *Self-Testing ; Anti-HIV Agents ; Adult ; }, abstract = {BACKGROUND: Adolescent girls and young women (AGYW) in Africa experience high HIV acquisition risk and low engagement in prevention services. Knowledge of HIV-negative status paired with peer support might motivate AGYW-who are highly socially connected-to initiate HIV prevention services, including pre-exposure prophylaxis (PrEP).<br><br>METHODS AND FINDINGS: We conducted a randomized controlled trial (ClinicalTrials.gov: NCT04982250) of AGYW peer networks in Central Kenya. Index peers aged 16-24 years who had used oral PrEP in the past 12 months were randomized 1:1 to: (1) enhanced peer referral: group training on PrEP referral strategies and delivery of HIV self-testing (HIVST) kits (n&#x2009;=&#x2009;8 kits, 2 kits/peer); or (2) standard peer referral: informal PrEP referral strategies. Index peers were encouraged to refer four peers who could benefit from PrEP. Outcomes for referred peers-PrEP initiation (primary), PrEP continuation (i.e., month one refills), and HIV testing (any form following referral)-were reported by index peers three months later. Implementation outcomes and costs were also assessed. Risk differences (RDs) were estimated using generalized linear mixed-effects regression models with study group fixed effects and index peer random effects. From May 3, 2023 to February 16, 2024, 316 index peers were screened and 82 enrolled/randomized (median age 22 years, IQR 20-23): 40 to the enhanced group and 42 to the standard. No index peers were lost to follow-up. Index peers reported outcomes for 241 referred peers (median age 22 years, IQR 21-24): 137 in the enhanced group and 104 in the standard. At follow-up, there were no significant differences in PrEP initiation between the enhanced group (30%, 41/137) and the standard (41%, 41/104; RD -6%, 95% CI [-26%, 11%], p&#x2009;=&#x2009;0.51). Enhanced peer referral was not associated with PrEP continuation (RD 1%, 95% CI [-10%, 13%], p&#x2009;=&#x2009;0.82) but was associated with increased recent HIV testing (RD 39%, 95% CI [24%, 54%], p&#x2009;<&#x2009;0.001). Three referred peers, all in the enhanced group, tested HIV-positive; two social harms (verbal abuse among index peers, one in each group) were reported. Index and referred peers in both study groups found enhanced peer referral acceptable and feasible, but it cost almost eight times more per peer referred to PrEP than standard referral ($23 versus $3 USD). Relying on index peers to report outcomes for referred peers was a study limitation.<br><br>CONCLUSIONS: Enhanced peer PrEP referral with training and HIVST delivery did not increase PrEP initiation among Kenyan AGYW but was associated with increased HIV testing, suggesting opportunities to combine peer-delivered HIVST with additional implementation strategies to improve AGYW's PrEP engagement.}, }
@article {pmid41912411, year = {2026}, author = {Etzioni, R and Gogebakan, K and Gulati, R and Owens, L and Lange, J and Kessler, L and Smith, R and Schrag, D and Robbins, HA}, title = {Measuring and defining screening benefit in a new era of cancer early detection.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag100}, pmid = {41912411}, issn = {1460-2105}, abstract = {We are at a watershed moment in the history of early cancer detection in which many novel tests are poised to become available for population screening. An ongoing debate concerns how to properly evaluate these tests and specifically whether a shorter-term, incidence-based outcome might substitute for cancer mortality as an endpoint in randomized trials of screening test efficacy. An incidence-based endpoint promises to reduce time and resources, but there is no framework for how studies using this endpoint should report results and how they should be interpreted in terms of clinical utility. We consider whether publication of incidence-based results ahead of any mortality results could result in adoption of new screening tests ahead of reliable mortality results becoming available. We argue that guardrails are needed for this scenario, including standards for conduct and reporting of trials with incidence-based endpoints to assure valid interpretation of clinical utility. For example, information regarding the type and timing of tests used for diagnostic workup in screen and control groups will be needed. Clinicians and policy makers will need to determine acceptable measurements and magnitudes of this modified measure of test efficacy. The roles of incidence-based and mortality-based endpoints in determining practice standards will need to be defined, along with specifications for permissible adjunct evidence, such as modeling studies and real-world data. As screening trials for new multi-cancer tests will soon begin to report incidence-based results, resolution of these questions is a matter of urgency.}, }
@article {pmid41912885, year = {2026}, author = {Ahmad, Z and Carninci, P}, title = {Decoding the regulatory grammar of human gene promoters.}, journal = {Cell research}, volume = {}, number = {}, pages = {}, pmid = {41912885}, issn = {1748-7838}, }
@article {pmid41913502, year = {2026}, author = {Dussault, N and Morphew, J and Nwagwu, V and Gatta, B and Richardson, A and Payne, N and White-Chu, EF and Wilson, L and Dalton, H and Winstead-Derlega, CE and Ramos, K and Jones, CA}, title = {Top Ten Tips Palliative Care Clinicians Should Know About Wound Care.}, journal = {Journal of palliative medicine}, volume = {}, number = {}, pages = {10966218261436630}, doi = {10.1177/10966218261436630}, pmid = {41913502}, issn = {1557-7740}, abstract = {Wounds are a common and burdensome problem for patients with serious illness receiving palliative care and hospice services. Declining mobility, functional impairment, malnutrition, progression of underlying disease, and age-related skin changes all increase risk. Wound management can therefore be challenging for clinicians, patients, and caregivers. Symptoms such as pain, odor, drainage, functional limitations, and psychological distress can substantially worsen suffering. Optimal care requires an interdisciplinary approach that considers the patient's underlying illness, prognosis, and goals of care. Palliative care clinicians are well-positioned to reduce this distress and improve comfort through goal-concordant wound-care strategies. Given the high prevalence of wounds in palliative care populations and the need for skilled, patient-centered management, we convened a panel of palliative care clinicians, geriatricians, geropsychologists, and wound-care specialists to identify core principles and practical strategies for supporting patients with wounds. In this article, we outline key tips for assessing and managing wounds, including understanding prognosis and goals of care, evaluating care settings, tailoring management to the underlying disease process, and addressing symptoms such as pain, odor, and psychosocial distress. A thoughtful, interdisciplinary approach is essential to reduce the physical and emotional burden wounds place on patients and caregivers.}, }
@article {pmid41914866, year = {2026}, author = {Ghodsi, A and Owens, L and Demirci, RA and Gafita, A and Cheng, HH and Hawley, JE and Raychaudhuri, R and Khan, H and Sunkara, R and Hsieh, AC and Grivas, P and Montgomery, B and Yezefski, TA and Nelson, PS and Yu, EY and Schweizer, MT and Chen, DL and Gulati, R and Iravani, A}, title = {PSMA PET/CT-derived Tumor Volume for Predicting Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving [177]Lu-PSMA-617.}, journal = {Radiology}, volume = {318}, number = {3}, pages = {e250649}, pmid = {41914866}, issn = {1527-1315}, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/pathology/diagnostic imaging/radiotherapy ; *Positron Emission Tomography Computed Tomography/methods ; Aged ; *Lutetium/therapeutic use ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; *Dipeptides/therapeutic use ; Tumor Burden ; Middle Aged ; Radiopharmaceuticals/therapeutic use ; Retrospective Studies ; Prostate-Specific Antigen ; Predictive Value of Tests ; Treatment Outcome ; Radioisotopes/therapeutic use ; }, abstract = {Background Accurate prediction of the response of patients with metastatic castration-resistant prostate cancer (mCRPC) to lutetium 177 prostate-specific membrane antigen-617 (Lu-PSMA) therapy would be helpful for treatment selection. Purpose To evaluate the incremental value of total tumor volume (TTV) in prediction models developed for patients receiving Lu-PSMA. Materials and Methods Previously developed prediction models using baseline variables (time since diagnosis, chemotherapy status, hemoglobin, dichotomized number of metastases, tumor mean standardized uptake value, and bone and liver involvement) were externally validated in patients treated with Lu-PSMA between June 2022 and April 2024. The concordance index (ie, C index) for overall survival (OS), prostate-specific antigen (PSA) progression-free survival (PSA-PFS), and 50% or greater decline in PSA from baseline (PSA50) was assessed. The predictive value of prostate-specific membrane antigen PET/CT-derived TTV was evaluated by re-estimating previous models (Cox regression for OS and PSA-PFS; logistic regression for PSA50) and replacing the dichotomized number of metastases with the continuous number of metastases or TTV. Results Data from 168 patients (median age, 73 years [IQR, 68-78 years]) were analyzed. External validation of the original models achieved C indexes of 0.70 (95% CI: 0.64, 0.77) for OS, 0.68 (95% CI: 0.63, 0.73) for PSA-PFS, and 0.72 (95% CI: 0.64, 0.80) for PSA50. Replacing the dichotomized number of metastases with TTV increased the C index for OS by 0.04 (95% CI: 0.01, 0.07; P = .002). A higher TTV was associated with shorter OS (hazard ratio, 1.35 [95% CI: 1.08, 1.68]), whereas there was no evidence of an independent association between dichotomized number of metastases and OS (hazard ratio, 1.23 [95% CI: 0.64, 2.36]; P = .53). A higher TTV was associated with shorter PSA-PFS (hazard ratio, 1.25 [95% CI: 1.10, 1.42]) and lower PSA50 (odds ratio, 0.70 [95% CI: 0.53, 0.91]). Conclusion Previously developed models predicted OS, PSA-PFS, and PSA50 in patients with mCRPC receiving Lu-PSMA. The inclusion of TTV produces prediction models with better discriminatory ability than the dichotomized or continuous number of metastases. © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Vargas and Woo in this issue.}, }
@article {pmid41915825, year = {2026}, author = {Srinivasan, S and Munch, MM and Soge, OO and Sweeney, YTC and Proll, S and Hoffman, NG and Fredricks, DN and Patton, DL}, title = {The Vaginal Microbiota in Pig-Tailed Macaques and Colonization with Neisseria gonorrhoeae.}, journal = {Sexually transmitted diseases}, volume = {}, number = {}, pages = {}, doi = {10.1097/OLQ.0000000000002314}, pmid = {41915825}, issn = {1537-4521}, abstract = {BACKGROUND: Pig-tailed macaques (Macaca nemestrina) may serve as a useful animal model of Neisseria gonorrhoeae (GC) infection, but no such models are currently available. To aid in the development of a macaque model of gonorrhea, we characterized the macaque vaginal microbiota and evaluated the effect of streptomycin treatment on GC colonization.<br><br>METHODS: Six female pig-tailed macaques were observed for 96 days with cervicovaginal samples collected every 2-3 days. Samples were taken for one month prior to streptomycin treatment to characterize the vaginal microbiota using 16S rRNA gene sequencing over a menstrual cycle. The animals were treated intramuscularly with streptomycin for 22 days. They were challenged twice with a two-week interval with endocervical GC and once after cessation of antibiotics. GC colonization was assessed via 16S rRNA gene sequencing, nucleic acid amplification tests, and culture.<br><br>RESULTS: The macaque vaginal microbiota was diverse and heterogeneous with several anaerobes typically noted in the human vagina including Fannyhessea vaginae, Amygdalobacter indicium and Parvimonas micra. Streptomycin treatment resulted in changes in the diversity and composition of the microbiota, but prolonged GC colonization was not achieved in any animal. Changes in the microbiota were noted during menses.<br><br>CONCLUSIONS: Alternative approaches are needed to facilitate the establishment of GC infection in pig-tailed macaques.}, }
@article {pmid41918519, year = {2026}, author = {Mngadi, K and Broder, GB}, title = {Editorial: Community-centric strategies for HIV and STI prevention in key populations.}, journal = {Frontiers in reproductive health}, volume = {8}, number = {}, pages = {1798107}, pmid = {41918519}, issn = {2673-3153}, }
@article {pmid41918932, year = {2026}, author = {Hecht, JR and Molina, JR and Liechty, K and Welling, TH and Grierson, PM and Patel, SP and Kirtane, K and Morelli, MP and Locke, FL and Maloney, DG and Punekar, SR and Nikiforow, S and Lin, Y and Ulrickson, M and Specht, JM and Lozac'hmeur, A and Osterman, CK and Garde, RJ and Rangel, GA and Ng, EW and Welch, JS and Tebbets, JC and Go, WY and Simeone, DM}, title = {BASECAMP-1 screening study: a model for efficient enrolment in precision oncology clinical trials.}, journal = {BMJ oncology}, volume = {5}, number = {1}, pages = {e001033}, pmid = {41918932}, issn = {2752-7948}, abstract = {OBJECTIVE: Identifying eligible patients for precision oncology clinical trials is challenging, particularly for rare molecular subpopulations. To address this challenge, A2 Biotherapeutics developed BASECAMP-1 (NCT04981119), a non-interventional master screening study to identify patients eligible for interventional studies of logic-gated Tmod chimeric antigen receptor T-cell therapies. Eligible patients for these interventional trials have an advanced solid malignancy and are germline human leucocyte antigen (HLA)-A*02 heterozygous, with tumour-associated HLA-A loss of heterozygosity (LOH). HLA-A LOH occurs in ~16% of advanced solid malignancies; therefore, an efficient screening strategy is required. This report describes BASECAMP-1; compares the efficiency of two screening methods; and discusses the broader advantages of BASECAMP-1 beyond efficient enrolment.<br><br>METHODS AND ANALYSIS: Patients are identified for BASECAMP-1 using two approaches. In the traditional approach, common for clinical trials, investigators consent and screen all patients who might be good candidates for cell therapy trials, with no prior knowledge of patient HLA-A type or LOH status. To further optimise our approach, we co-developed with Tempus AI (Tempus) the bioinformatic programme Aware, which identifies potentially eligible patients with tumour-associated HLA-A*02 LOH within a clinico-genomic database that includes linked genomic and transcriptomic sequencing and clinical data collected during routine care.<br><br>RESULTS: Over 42 months of using a traditional approach to identify eligible patients, 1918 patients at 13 study sites were consented and screened for BASECAMP-1; of these, 30 patients with tumour-associated HLA-A*02 LOH were enrolled (~0.7 participants per month). Over the last 30 months of that same period, Tempus Aware screening was implemented and 55 patients with tumour-associated HLA-A*02 LOH were enrolled (~1.8 participants per month). The bioinformatic approach identified more patients than the traditional approach and used sequencing results produced as part of the standard clinical tumour sequencing workflow, reducing resource use and study staff burden. Additional advantages of using a screening study, such as BASECAMP-1, include manufacturing efficiencies and collection of a large dataset of molecular and clinical parameters that can be used to supplement trial analyses.<br><br>CONCLUSIONS: The BASECAMP-1 study demonstrates a clinico-genomic screening approach can more efficiently identify patients for precision oncology trials. Furthermore, precision oncology can be enhanced through collaborative data-sharing.<br><br>TRIAL REGISTRATION NUMBER: NCT04981119.}, }
@article {pmid41919503, year = {2026}, author = {Paschalis, A and Figueiredo, I and Bogdan, D and Lundberg, A and Santos, R and Gurel, B and Taha, T and Longoria, O and Ferreira, A and Bertan, C and Brittain, N and Nelson, R and Walker, L and Neeb, A and Welti, J and Yuan, W and Mitsopoulos, C and Plymate, SR and Haffner, MC and Sowalsky, AG and Carreira, S and Sharp, A and Gaughan, L and de Bono, J}, title = {Androgen receptor splice variant 7 expression levels distinguish AR-mutated from nonmutated metastatic castration-resistant prostate cancers.}, journal = {The Journal of clinical investigation}, volume = {136}, number = {7}, pages = {}, pmid = {41919503}, issn = {1558-8238}, mesh = {Humans ; Male ; *Receptors, Androgen/genetics/biosynthesis ; *Prostatic Neoplasms, Castration-Resistant/genetics/metabolism/pathology/drug therapy ; *Mutation ; *Alternative Splicing ; Neoplasm Metastasis ; *Gene Expression Regulation, Neoplastic ; Protein Isoforms/genetics/biosynthesis ; *Neoplasm Proteins/genetics/biosynthesis ; Cell Line, Tumor ; Aged ; }, abstract = {New androgen receptor (AR) pathway inhibitors (ARPIs) in clinical development, including AR degraders and CYP11A inhibitors, largely target ligand-dependent AR activation and have reported antitumor activity in metastatic castration-resistant prostate cancer (mCRPC) resistant to established ARPIs, predominately against tumors with AR mutations. We hypothesized that AR-mutated mCRPC exhibits lower AR splice variant 7 (AR-V7) expression and remains full-length-AR (FL-AR) driven, explaining, in part, the antitumor activity of these AR ligand-binding domain (LBD) targeting drugs. The data herein demonstrate that mCRPC tissue biopsies with detectable AR mutations express significantly lower levels of AR-V7 protein and associate with better overall survival and enhanced sensitivity to ARPIs. This is independent of differences in the total number of global splicing events but may be related to differences in splicing factor expression between AR-mutated and nonmutated mCRPC. In conclusion, AR-mutated mCRPC frequently exhibits low AR-V7 expression, arguably explaining the enhanced sensitivity to ARPIs observed in these cancers. Consequently, AR mutation status may serve as a biomarker to predict response to AR-directed therapies.}, }
@article {pmid41920173, year = {2026}, author = {Sanchez Mendez, J and Queme, B and Fu, Y and Morrison, JL and Lewinger, JP and Kawaguchi, ES and Mi, H and Obón-Santacana, M and Moratalla-Navarro, F and Martín, V and Moreno, V and Qu, C and Huyghe, JR and Newcomb, PA and Phipps, AI and Thomas, CE and Conti, DV and Wang, J and Platz, EA and Visvanathan, K and Keku, TO and Newton, CC and Um, CY and Kundaje, A and Gunter, MJ and Dimou, N and Papadimitriou, N and van Duijnhoven, FJB and Männistö, S and Rennert, G and Wolk, A and Hoffmeister, M and Brenner, H and Tian, Y and Le Marchand, L and Bouras, E and Tsilidis, KK and Bishop, DT and Maclnnis, RJ and Buchanan, DD and Ulrich, CM and Peoples, AR and Pellatt, A and Li, L and Devall, MA and Albanes, D and Berndt, SI and Gruber, SB and Ruiz-Narvaez, E and Song, M and Drew, DA and Chan, AT and Giannakis, M and Hsu, L and Peters, U and Stern, MC and Gauderman, WJ}, title = {TGF-β-pathway-based polygenic risk score modifies the association between red meat intake and colorectal cancer risk: Application of a novel pathway-based PRS method.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-1754}, pmid = {41920173}, issn = {1538-7755}, abstract = {BACKGROUND: Red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported over 200 variants associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways to construct pathway-based Polygenic Risk Scores (pPRS) to assess interactions with meat intake.<br><br>METHODS: A pooled sample of 30,812 cases and 40,504 CRC controls from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated interactions between pPRS and red or processed meat intake in relation to CRC risk.<br><br>RESULTS: A total of 30 variants were overrepresented in four pathways: Presenilin-Alzheimer disease, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-&#x3b2; signaling. We found a significant interaction between TGF-&#x3b2;-pPRS and red meat intake (ORint = 0.95; 95% CI = 0.92-0.98; p = 0.003). When variants in the TGF-&#x3b2; pathway were assessed, we observed significant interactions of red meat with rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.0005 &amp; 0.036, respectively). There was no evidence of pPRS x red meat interactions for other pathways or with processed meat Conclusions:This pathway-based interaction analysis revealed a statistically significant interaction between variants in the TGF-&#x3b2; pathway and red meat consumption that impacts CRC risk.<br><br>IMPACT: These findings shed light into the possible mechanistic link between red meat consumption and CRC risk.}, }
@article {pmid41920180, year = {2026}, author = {Thomas, CE and Loroña, NC and LaBrie, SD and Curtis, KR and Yin, H and Ma, N and Randolph, TW and Qu, C and Huyghe, JR and Thomas, S and Hsu, L and Koehne, AL and Nayemi, S and Ammar, H and Kahsai, OJ and Redwood, D and Li, CI and Li, L and Peters, U and Figueiredo, JC and Thomas, TK and Phipps, AI and Hullar, MAJ}, title = {The phylum Fusobacteriota is associated with CRC-specific mortality: Results from the Translational Research Program in Cancer Differences across Populations.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-1580}, pmid = {41920180}, issn = {1538-7755}, abstract = {BACKGROUND: The microbiome is an important component of the tumor microenvironment implicated in colorectal cancer (CRC). However, its relationship with CRC-specific mortality remains unclear.<br><br>METHODS: We included 581 participants with CRC (167 African American, 176 Alaska Native, 118 Hispanic, 120 non-Hispanic White) from the Translational Research Program in Cancer Differences across Populations (TRPCDP). We sequenced the V4 region of the 16S rRNA bacterial gene using DNA extracted from formalin-fixed paraffin embedded tumors. 204 participants died of CRC and 377 did not die of CRC. Participants who died of CRC were matched to participants who did not die of CRC during follow-up by age, sex, tumor site, tumor stage, year of diagnosis, and population group. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between bacterial presence with CRC-specific mortality, adjusting for matching factors and tissue macrodissection status.<br><br>RESULTS: Individuals who died from CRC were 1.71 times as likely to have bacteria from the Fusobacteriota phylum present in their tumors (OR=1.71, 95% CI: 1.19-2.47). Associations with Fusobacteriota were strongest among African American participants (OR=2.36, 95% CI: 1.14-4.99) compared to other populations, however this different was not statistically significant (OR range = 1.05-1.38, Pinteraction = 0.697). Candidate pathways of pyruvate fermentation to acetate and lactate II and peptidoglycan biosynthesis I were associated with higher odds of CRC death.<br><br>CONCLUSIONS: Fusobacteriota was significantly associated with CRC-specific mortality with noted differences across populations.<br><br>IMPACT: This finding highlights the tumor microbiome as a candidate for further investigation into CRC outcome disparities.}, }
@article {pmid41921118, year = {2026}, author = {Gupta, A and Till, C and LeBlanc, ML and Hershman, DL and Unger, JM}, title = {Composition of Health Care Contact Days and Mortality Prediction Among Older Adult Clinical Trial Participants.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2501182}, doi = {10.1200/OP-25-01182}, pmid = {41921118}, issn = {2688-1535}, abstract = {PURPOSE: Contact days exceeding trial protocol-mandated care may represent adverse clinical events and portend worse outcomes. Identifying patients at risk of poor outcomes could enable clinical teams to intervene early and support patients' needs.<br><br>MATERIALS AND METHODS: We linked data from 6 SWOG trials to Medicare claims. We calculated contact days (days with ambulatory, emergency department, inpatient, or facility-based care) and their composition using protocol calendars. Total contact days were delineated as protocol-mandated (planned) ambulatory or unplanned (including unplanned ambulatory v unplanned inpatient). Cox frailty landmark regression analysis was used in a random 60% training set to identify the optimal threshold (percentile) and landmark (months) for contact-day measures as the predictor based on the chi-square statistic. Candidate predictors were tested in the remaining 40% sample.<br><br>RESULTS: We included 1,429 patients (median age, 71 years, 7.6% Black, 21.4% female). In the first 3 months, among 15,301 contact days in the training set (6.4 contact days per person per month; 21.2% of total days), 4,102 (26.8%) were protocol-mandated ambulatory, and 11,199 (73.2%) were unplanned (including 7,328 [47.9%] ambulatory and 3,871 [25.3%] inpatient). The 2-month follow-up time at the 75th percentile threshold was the optimal model in the training set. In the test set, unplanned contact days, especially unplanned inpatient contact days, were associated with subsequent survival (&#x2265;1 unplanned inpatient contact days, adjusted hazard ratio, 1.25 [1.02-1.52], P = .014).<br><br>CONCLUSION: One in five trial follow-up days was a health care contact day, of which the majority were unplanned ambulatory contact days. Meaningfully decreasing contact-day burdens will require addressing uncoordinated unplanned ambulatory contact days. The low threshold (&#x2265;1 in the first 2 months) of unplanned inpatient days in predicting mortality highlights the adverse impact of any acute care use on survival.}, }
@article {pmid41921232, year = {2026}, author = {Do, OA and Huang, LC and Tam, LT and Raub, S and Ermoian, RP and Leary, SES and Werny, DM and Ellenbogen, RG and Emerson, S and Ferreira, M and Lee, A and Ruzevick, JJ and Ronsley, RJ}, title = {Postoperative Visual Outcomes in Pediatric Craniopharyngioma: A Comparison of Endoscopic Endonasal and Transcranial Approaches.}, journal = {Journal of pediatric hematology/oncology}, volume = {}, number = {}, pages = {}, doi = {10.1097/MPH.0000000000003195}, pmid = {41921232}, issn = {1536-3678}, support = {N/A//N/A/ ; }, abstract = {OBJECTIVE: To compare postoperative visual outcomes in pediatric patients undergoing resection of craniopharyngioma via endoscopic endonasal versus transcranial craniotomy approaches.<br><br>METHODS: We retrospectively reviewed 37 pediatric patients (74 eyes) who underwent resection of histologically confirmed craniopharyngioma at a tertiary center between 1995 and 2023. Ophthalmologic evaluations included best-corrected visual acuity (VA), optic nerve findings, and visual fields. Outcomes were assessed at early, intermediate, and long-term follow-up and compared by surgical approach.<br><br>RESULTS: Twenty-five patients (68%) underwent craniotomy and 12 (32%) endoscopic resection. Preoperatively, 51% had normal vision in both eyes, while 6 were legally blind. Postoperatively, no significant differences in VA or visual fields were observed between approaches at any interval. Optic nerve pallor was somewhat more frequent in the endoscopic group, though not statistically significant. Gross total resection was achieved in 66% of endoscopic versus 34% of craniotomy cases. Most craniotomies (88%) occurred before 2015, compared with 16% of endoscopic cases.<br><br>CONCLUSIONS: Both endoscopic and transcranial approaches yielded comparable visual outcomes in pediatric craniopharyngioma surgery. Rates of gross total resection were higher in the endoscopic cohort, suggesting that surgical approach should remain anatomy-driven, with either technique capable of preserving visual function in appropriately selected patients.}, }
@article {pmid41921603, year = {2026}, author = {Murphy, AJ and Chen, Y and Cameron, DB and Geiger, EJ and Ramsey, D and Green, DM and Howell, RM and Kieran, K and Krull, KR and Meacham, LR and Ness, KK and Oeffinger, KC and Yasui, Y and Armstrong, GT and Chow, EJ and Weldon, CB and Weil, BR}, title = {Late complications of treatment for childhood pelvic sarcoma: A report from the Childhood Cancer Survivor Study (CCSS).}, journal = {Journal of pediatric surgery}, volume = {61}, number = {7}, pages = {163117}, doi = {10.1016/j.jpedsurg.2026.163117}, pmid = {41921603}, issn = {1531-5037}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: Evaluate late effects in survivors of childhood pelvic sarcoma by disease origin (bony vs. soft-tissue) and local control modality (bone surgery, pelvic organ resection, radiotherapy).<br><br>METHODS: Among 5-year pediatric pelvic sarcoma survivors, we assessed long-term outcomes including late (>5 years) mortality, graded chronic health conditions (CHCs), subsequent malignant neoplasms (SMNs), physical function/activity, cancer-related pain, and pregnancy/siring a pregnancy. Associations with disease origin and local control modality were analyzed using cumulative incidence and Cox or multivariable logistic regression.<br><br>RESULTS: Among 745 eligible survivors, the 35-year cumulative incidence of late all-cause and health-related mortality was 25.7% (95%CI = 22.1%-29.3%) and 12.2% (95%CI = 9.4%-15.1%), vs. 2.5% (95%CI = 1.3%-3.7%) and 1.4% (95%CI = 0.5%-2.4%) in matched US population. Cumulative incidence of severe/life-threatening CHCs was 47.6% (95%CI = 43.0%-52.1%) for survivors vs. 12.2% (95%CI = 11.3%-13.2%) for siblings. Cumulative incidence of SMNs was 7.6% (95%CI = 5.0%-10.2%). Bone sarcomas were associated with increased all-cause mortality (HR = 1.92, 95%CI = 1.16-3.17), health-related mortality (HR = 2.12, 95%CI = 1.03-4.38), and CHCs (HR = 2.55, 95%CI = 1.65-3.95) vs. soft-tissue sarcomas. Analyzing all survivors, radiotherapy was associated with increased CHCs (HR = 2.42, 95%CI = 1.53-3.81), multiple CHCs (HR = 2.27, 95%CI = 1.03-4.97), functional impairment (OR = 2.21, 95%CI = 1.30-3.74), and pain (OR = 2.29, 95%CI = 1.33-3.93). Bone surgery was associated with functional impairment (OR = 2.64, 95%CI = 1.30-5.37), performance limitations (OR = 2.12, 95%CI = 1.19-3.79), and pain (OR = 2.59, 95%CI = 1.37-4.89). Pelvic organ resection was associated with decreased pregnancy (OR = 0.25, 95%CI = 0.10-0.63).<br><br>CONCLUSIONS: Late effects differed by pelvic sarcoma origin (bone vs. soft-tissue) and local control modality. The associations between local control choices and late effects in this study can guide counseling of patients and families at the time of diagnosis, treatment, local control, or after completion of therapy.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01120353.}, }
@article {pmid41921744, year = {2026}, author = {Hoobler, R and Tabung, FK and Lin, T and Gigic, B and Smith, KS and Woodruff, K and Crowder, SL and Hardikar, S and Byrd, DA and Coletta, AM and Sanchez, A and Chaix, A and Greathouse, KL and Ilozumba, MN and Ose, J and Damerell, V and Strehli, I and McLaws, M and Florou, V and Huang, LC and Shibata, D and Figueiredo, JC and Toriola, AT and Li, CI and Ulrich, CM and Playdon, MC}, title = {Dietary patterns associated with weight loss among patients with colorectal cancer during the first six months post-diagnosis: A cross-sectional analysis from the ColoCare Study.}, journal = {Journal of the Academy of Nutrition and Dietetics}, volume = {}, number = {}, pages = {156351}, doi = {10.1016/j.jand.2026.156351}, pmid = {41921744}, issn = {2212-2672}, abstract = {BACKGROUND: Unintentional weight loss following a cancer diagnosis is associated with increased risk of adverse clinical outcomes. Nutritional guidance for the prevention of weight loss post-cancer diagnosis is limited, particularly regarding optimal dietary patterns.<br><br>OBJECTIVE: To identify common dietary patterns among a cohort of patients with colorectal cancer (CRC) and evaluate their associations with weight loss in the six-months following CRC diagnosis.<br><br>DESIGN: A cross-sectional analysis of data from CRC patients enrolled in the ColoCare Study between 2010 to 2021.<br><br>PARTICIPANTS: /setting: 405 patients newly diagnosed with CRC from four study sites located in Washington, Utah, Missouri, and Los Angeles. Included participants completed a six-month Food Frequency Questionnaire and had self-reported weight data from study enrollment to six months.<br><br>MAIN OUTCOME MEASURES: The primary outcome was weight loss &#x2265;5% from study enrollment to six-month follow-up visit.<br><br>Principal Component Analysis was leveraged to identify common dietary patterns and Healthy Eating Index (HEI)-2020 scores were calculated as a reference dietary pattern. Associations between adherence to dietary patterns (scaled to compare the 90th versus 10th percentile) and six-month weight loss were evaluated using multivariable logistic regression. All tests were two-sided.<br><br>RESULTS: Four dietary patterns were identified: "Western," "Prudent," "Refined Grain, Sugar, and Dairy," and "High-Fat, High-Protein Foods." High compared to low adherence to the "Refined Grain, Sugar, and Dairy" dietary pattern was associated with greater odds of weight loss in the first six-months following CRC diagnosis (OR = 2.04, 95% CI 1.10-3.81, p = 0.02). There was evidence for effect modification by cancer type and history of unintentional weight loss at study enrollment.<br><br>CONCLUSION: These results highlight the potential for dietary patterns to influence weight loss in the first six months following a cancer diagnosis. Further research is needed to refine dietary guidance for CRC patients to improve clinical outcomes.}, }
@article {pmid41922350, year = {2026}, author = {Zwimpfer, TA and Fereday, S and Pandey, A and Ariyaratne, D and Jayawardana, MW and Twomey, L and Laumont, CM and Kennedy, CJ and Bolithon, A and Meagher, NS and Milne, K and Hamilton, P and Alsop, J and Antoniou, AC and Au-Yeung, G and Beckmann, MW and Berrington de Gonzalez, A and Bisinotto, C and Blome, F and Bodelon, C and Boros, J and Brand, AH and Carney, ME and Cazorla-Jiménez, A and Chiu, DS and Christie, EL and Chudecka-Głaz, A and Coulson, P and Cushing-Haugen, KL and Cybulski, C and Darcy, KM and David, C and Davidson, T and Ekici, AB and Elishaev, E and Emons, J and Engler, T and Farrell, R and Fischer, A and García-Closas, M and Gentry-Maharaj, A and Ghatage, P and Glasspool, R and Harter, P and Hartkopf, AD and Hartmann, A and Heikaus, S and Hernandez, BY and Hettiaratchi, A and Heublein, S and Huntsman, DG and Jimenez-Linan, M and Jones, ME and Kang, E and Kaznowska, E and Kluz, T and Kommoss, FKF and Konecny, G and Kruitwagen, RFPM and Kwon, J and Lambrechts, D and Lee, CH and Lester, J and Leung, SCY and Leung, Y and Linder, A and Lissowska, J and Loverix, L and Lubiński, J and Mateoiu, C and McNeish, IA and Moubarak, M and Nelson, GS and Nevins, N and Olawaiye, AB and Olbrecht, S and Orsulic, S and Osorio, A and Quinn, CM and Mohan, GR and Ray-Coquard, I and Rodríguez-Antona, C and Roxburgh, P and Ruebner, M and Salfinger, SG and Samra, S and Schoemaker, MJ and Sinn, HP and Sonke, GS and Steele, L and Stewart, CJR and Talhouk, A and Tan, A and Tarney, CM and Taylor, SE and Van de Vijver, KK and van der Aa, MA and Van Gorp, T and Van Nieuwenhuysen, E and Van-Wagensveld, L and Wahner-Hendrickson, AE and Walter, C and Wang, C and Welz, J and Wentzensen, N and Wilkens, LR and Winham, SJ and Winterhoff, B and Anglesio, MS and Berchuck, A and Candido Dos Reis, FJ and Cohen, PA and Conrads, TP and Crowe, P and Doherty, JA and Fasching, PA and Fortner, RT and García, MJ and Gayther, SA and Goodman, MT and Gronwald, J and Harris, HR and Heitz, F and Horlings, HM and Karlan, BY and Kelemen, LE and Larry Maxwell, G and Menon, U and Modugno, F and Neuhausen, SL and Schildkraut, JM and Staebler, A and Sundfeldt, K and Swerdlow, AJ and Vergote, I and Wu, AH and Brenton, JD and Pharoah, PDP and Pearce, CL and Pike, MC and Goode, EL and Ramus, SJ and Köbel, M and Nelson, BH and DeFazio, A and Friedlander, ML and Bowtell, DDL and Garsed, DW}, title = {Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71134-3}, pmid = {41922350}, issn = {2041-1723}, support = {GNT1186505, GNT2029088, 2009840, 2033042//Department of Health | National Health and Medical Research Council (NHMRC)/ ; 0297//Gottfried und Julia Bangerter-Rhyner-Stiftung (Bangerter-Stiftung)/ ; MCRF22018//Victorian Cancer Agency (VCA)/ ; 2025/OCRF0071//Ovarian Cancer Research Foundation (OCRF)/ ; }, abstract = {BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.}, }
@article {pmid41922703, year = {2026}, author = {Aczel, B and Szaszi, B and Clelland, HT and Kovacs, M and Holzmeister, F and van Ravenzwaaij, D and Schulz-Kümpel, H and Hoffmann, S and Nilsonne, G and Kosa, L and Torma, ZA and Abdelfatah, Y and Aberson, CL and Acar, OA and Acem, E and Adamkovic, M and Adamovich, T and Adiasto, K and Ahnström, L and Akil, AM and Al-Busaidi, AS and Al-Hoorie, AH and Albers, CJ and Allen, PJ and Alsalti, T and Altman, M and Alzahawi, S and Ambrosini, E and Anafinova, S and Anand, R and Angerer, M and Angulo-Brunet, A and Antonietti, A and Arato, J and Arenas, A and Aviña, MM and Azevedo, F and Bachl, M and Bago, B and Bahník, &#x160; and Baker, BJ and Balayan, E and Baldwin, CL and Banai, B and Banas, K and Bartoš, F and Baskin, E and Bastiaansen, JA and Bault, N and Bauman, CW and Beazer, QH and Behnke, M and Bendixen, T and Berger, S and Bernard, A and Bernardic, U and Bloom, PA and Boldt, A and Bosch-Rosa, C and Botvinik-Nezer, R and Bouyamourn, A and Bozkurt, O and Brehm, L and Breuer, J and Briggs, R and Brohmer, H and Buchanan, E and Buckenmaier, J and Buckley, J and Buczny, J and Burghart, M and Butt, BH and Byrd, N and Cafarelli, V and Callahan, P and Capitán, T and Carriere, K and Cataldo, AM and Cepaluni, G and Chan, E and Chandler, JJ and Chang, CC and Chen, X and Chen, SS and Chen, F and Chen, H and Chirkov, V and Cialfi, D and Clarke, B and Coelho, SG and Cohen, C and Collins, J and Cook, SW and Corlazzoli, G and Cummins, J and Czymara, C and D'hondt, J and Rosa, AD and Davis, AMB and Davis, CP and Day, MV and De Keyzer, F and de Leeuw, JR and de Vries, TR and Debnath, R and Dechterenko, F and Demiral, EE and Desgroseilliers, M and Dianovics, D and Diveica, V and Dochow-Sondershaus, S and Dohle, S and Dong, L and Dora, J and Dorrough, AR and Dreber, A and Du, H and Edlund, JE and Eerland, A and Efendić, E and Elder, J and Elsherif, MM and Ernst, M and Estrada, E and Eudave, L and Evans, TR and Farrera, A and Ferrouhi, EM and Fiala, L and Fialho, FM and Fiechter, JL and Fišar, M and Flores-Kanter, PE and Folwarczny, M and Fossum, JL and Franco, VR and Freichel, R and Freire, D and Frese, J and Furnas, AC and Gaebler, JD and Gajary, LC and Galang, CM and Ganschow, B and Garrison, SM and Gasiorowska, A and Ponne, BG and Gauriot, R and Geminiani, A and Geraldes, D and Gernsbacher, MA and Giani, C and Glerean, E and Gligorić, V and Gnambs, T and Godefroidt, A and González-Bustamante, B and Goreis, A and Graf-Vlachy, L and Grieder, M and Grigoryev, D and Grinschgl, S and Grüning, DJ and Guassi Moreira, JF and Guichet, C and Gurgand, L and Habibnia, H and Hafenbrack, AC and Hafenbrädl, S and Häffner, C and Hagemeister, F and Haigh, M and Hajdu, N and Hajimoladarvish, N and Hall, JD and Hamjediers, M and Hardwick, RM and Harma, M and Harp, NR and Hartvig, &#xc1;D and Heiberger, RH and Heim, A and Hernæs, &#xd8; and Hernaus, D and Heyman, T and Hicks, J and Hogeveen, J and Höpler, J and Houlihan, SD and Huber, C and Hughes, C and Hummler, T and Huth, K and Ingendahl, M and Ishii, T and Isler, O and Izydorczak, K and Jackson, IR and Jahn, A and Jain, M and Jakubow, A and Jang, D and Jang, J and Jekel, M and Jia, F and Jiménez-Leal, W and Johnson, R and Jones, A and Jungkunz, S and Kačmár, P and Kaiser, C and Kalaycı, Y and Kantorowicz, J and Karabulut, A and Karch, JD and Karimi-Rouzbahani, H and Karl, JA and Kažemekaitytė, A and Kazlou, A and Kekecs, Z and Kim, J and Kirchler, MH and Kiss-Dobronyi, B and Klasmeier, KN and Klein, JW and Koba, C and Kołczyńska, M and Kolias, P and Kolouch Grabovský, M and Korbmacher, M and Korda, &#x17d; and Kowal, M and Kretzschmar, A and Krivoshchekov, V and Krypotos, AM and Kubsch, M and Kunisato, Y and Lacko, D and Landwehr, JR and Lange, M and Lee, H and Lee, D and Lee, S and Lemay, EP and Lempert, D and Leo, A and Lesage, E and Levin, JM and Li, P and Lin, J and Lindsay, L and Lisovoj, D and Liu, M and Liu, S and Liu, T and Iacono, SL and Lodder, P and López-Bueno, R and Lopez-Nicolas, R and Loter, K and Lou, NM and Lovakov, A and Lu, JG and Ludwig, J and Luebber, F and Lukavský, J and Luo, CQ and Lyu, X and Maassen, E and Máčel, M and Mack, ML and Madan, CR and Mädebach, A and Maffly-Kipp, J and Mallinson, DJ and Marchetti, I and Marghetis, T and Marini, MM and Fages, DM and Martínez, M and Martinoli, M and Masiliunas, A and Massoni, S and Mathieu, KC and Mayer, S and Mayer, DJ and Mayer, M and McCormick, EM and McDonough, IM and McGowan, AL and McIntyre, MM and McKee, P and Meier, AN and Meier, PF and Melero, H and Merkle, C and Merz, R and Michaelides, MP and Michaelsen, P and Mikolajczak, G and Mill, W and Millroth, P and Miroshnik, KG and Misiak, M and Mora, YL and Moreau, D and Moreh, C and Morvinski, C and Mushtaq, F and Nagy, T and Nater, C and Naumann, E and Navarrete, G and Nebe, S and Nedderhoff, A and Nennstiel, R and Neugebauer, M and Nicolaisen-Sobesky, E and Nielsen, YA and Niso, G and Nowak, B and Okan, M and Ong, K and Onicas, AI and Oswald, C and Otten, K and Pandey, S and Pantazi, M and Papale, P and Pärnamets, P and Pauer, S and Pavlov, YG and Pawel, S and Peelle, JE and Peetz, HK and Peez, A and Pesciarelli, F and Peterson, BD and Petruželka, B and Petter, J and Pfänder, J and Pfuhl, G and Phillips, J and Pietryka, MT and Pirrone, A and Pit, IL and Plachti, A and Plank, IS and Ploner, M and Poldrack, RA and Pollmann, MMH and Porcher, S and Präg, P and Pua, AAY and Pugel, J and Puri, R and Püski, M and Radkani, S and Raes, L and Rafaï, I and Raiber, K and Rathje, S and Rehms, R and Reshetnikov, M and Reynolds, CJ and Reynolds, JP and Rigaud, K and Rioux, C and Rivera, S and Robertson, O and Román-Caballero, R and Ropovik, I and Röseler, L and Ross, RM and Rotella, A and Rüffer, FF and Rusche, F and Rusconi, M and Russo, I and Sahm, AHJ and Salamon, J and Samahita, M and Sanaei, A and Sangchooli, A and Sarafoglou, A and Scandola, M and Schaak, H and Schaerer, M and Schares, E and Schilling, HT and Schmalz, X and Schmidt, K and Schonberg, T and Schreiner, MR and Schröder, JM and Schubert, AL and Schuetze, B and Schultz, DH and Schulze, L and Schwartz, ST and Schwitter, N and Scoggins, B and Seetahul, Y and Seri, R and Shanks, DR and Shaw, ST and Shaw, J and Shen, Q and Siemroth, C and Sladekova, M and Somo, A and Sondhi, A and Sonmez, B and Spantig, L and Speekenbrink, M and Stamos, A and Stasielowicz, L and Steckermeier, LC and Steinkamp, SR and Stoevenbelt, AH and Street, CNH and Suchow, JW and Sunde, HF and Sundquist, J and Suschevskiy, V and Swain, SD and Szecsi, P and Szekely-Copîndean, RD and Szumowska, E and Tacconelli, A and Talbert, E and Tang, JP and Tendeiro, JN and Testori, M and Toffalini, E and Tomašević, A and Topel, S and Torkkeli, L and Tozzi, L and Traczyk, J and Trinidad, A and Trübutschek, D and Turek, K and Uhlich, M and Uhlmann, EL and Urbanska, K and Van Assche, J and van Assen, MALM and van Dongen, NNN and van Lieshout, K and van Veldhuizen, R and Varga, MA and Vaughn, LA and Venczel, F and Vezzoli, M and Vierus, P and Visalli, A and Voldal, E and Votta, F and Wagenmakers, EJ and Waldendorf, A and Walker, MJ and Wall, MB and Wallen, H and Wang, K and Wang, I and Wang, YA and Weinmann, M and Weiß, M and Westheide, C and Wichman, A and Wilcke, JC and Williams, BJ and Wisniewski, D and Woiczyk, TKA and Woźniak, M and Wright, JD and Youyou, W and Wulff, JN and Yang, T and Yeung, SK and Yuen, KSL and Zawistowski, M and Zein, RA and Zhao, X and Zheng, Z and Zhou, S and Ziller, C and Zimmerman, D and Zogmaister, C and Zultan, R and Fox, N and Errington, TM and Nosek, BA}, title = {Investigating the analytical robustness of the social and behavioural sciences.}, journal = {Nature}, volume = {652}, number = {8108}, pages = {135-142}, pmid = {41922703}, issn = {1476-4687}, support = {//Amsterdam Brain and Cognition/ ; //Czech Science Foundation/ ; //Marie Sk&#x142;odowska-Curie grant/ ; }, mesh = {*Social Sciences/standards/statistics &amp; numerical data/methods ; *Behavioral Sciences/standards/statistics &amp; numerical data ; Reproducibility of Results ; Humans ; *Research Design/standards ; *Behavioral Research/standards ; }, abstract = {The same dataset can be analysed in different justifiable ways to answer the same research question, potentially challenging the robustness of empirical science[1-3]. In this crowd initiative, we investigated the degree to which research findings in the social and behavioural sciences are contingent on analysts' choices. We examined a stratified random sample of 100 studies published between 2009 and 2018, in which, for one claim per study, at least five reanalysts independently reanalysed the original data. The statistical appropriateness of the reanalyses was assessed in peer evaluations, and the robustness indicators were inspected along a range of research characteristics and study designs. We found that 34% of the independent reanalyses yielded the same result (within a tolerance region of ±0.05 Cohen's d) as the original report; with a four times broader tolerance region, this indicator increased to 57%. Of the reanalyses conducted, 74% reached the same conclusion as the original investigation, 24% yielded no effects or inconclusive results and 2% reported the opposite effect. This exploratory study indicates that the common single-path analyses in social and behavioural research should not be simply assumed to be robust to alternative analyses[4]. Therefore, we recommend the development and use of practices to explore and communicate this neglected source of uncertainty.}, }
@article {pmid41922791, year = {2026}, author = {Contieri, R and Gontero, P and Hurle, R and Afferi, L and Albisinni, S and Babjuk, M and Birtle, A and Black, P and Brausi, M and Bruins, M and Čapoun, O and Carrion, A and Catto, J and Choudhury, A and Cimadamore, A and Comperat, E and Daneshmand, S and D'andrea, D and Del Giudice, F and Escrig, JLD and Hensley, P and Krajewski, W and Laukhtina, E and Li, R and Liedberg, F and Lotan, Y and Marcq, G and Mariappan, P and Mari, A and Martini, A and Lecomte, AM and Meijer, R and Mir, MC and Mori, K and Moschini, M and Mostafid, H and O'Donnell, M and Palou, J and Panebianco, V and Perdonà, S and Porten, S and Psutka, S and Rink, M and Roupret, M and Seisen, T and Soloway, M and Soukup, V and Steinberg, G and Stenzl, A and Teoh, JY and Tully, K and van der Heijden, T and van Rhijn, BWG and Witjes, A and Xylinas, E and Kamat, AM and Pradere, B and Mertens, LS}, title = {Active surveillance in low-grade NMIBC - results of an international two-round modified Delphi consensus.}, journal = {Nature reviews. Urology}, volume = {}, number = {}, pages = {}, pmid = {41922791}, issn = {1759-4820}, abstract = {Standard management for recurrent low-grade non-muscle-invasive bladder cancer (LG-NMIBC) often involves a substantial treatment burden, which is not justified by the relatively indolent course of the disease, prompting a need for de-intensification strategies. Active surveillance (AS) is an alternative approach aimed at reducing overtreatment in selected patients. However, the broader adoption of AS is hindered by a lack of standardized protocols for patient selection, monitoring and intervention. To address this gap, we conducted an international, two-round Delphi consensus among 51 bladder cancer experts to establish foundational statements for the use of AS. Consensus was achieved on 20 statements, providing clear recommendations for terminology; inclusion and exclusion criteria; follow-up monitoring; and exit criteria. This Delphi consensus provides the first expert-driven framework to standardize the clinical application of AS for LG-NMIBC. These statements could guide current clinical practice and unify the design of future trials.}, }
@article {pmid41923460, year = {2026}, author = {Jin, Y and Luedtke, A and Moodie, Z and Janes, H and Benkeser, D}, title = {Comparing HIV Vaccine Immunogenicity Across Trials With Different Populations and Study Designs.}, journal = {Statistics in medicine}, volume = {45}, number = {8-9}, pages = {e70495}, doi = {10.1002/sim.70495}, pmid = {41923460}, issn = {1097-0258}, support = {5UM1AI068635/NH/NIH HHS/United States ; }, mesh = {*AIDS Vaccines/immunology ; Humans ; *HIV Infections/prevention &amp; control/immunology ; *Immunogenicity, Vaccine ; *Randomized Controlled Trials as Topic/methods ; *Research Design ; Computer Simulation ; Vaccine Efficacy ; Models, Statistical ; }, abstract = {Safe and effective preventive vaccines have the potential to help stem the HIV epidemic. The efficacy of such vaccines is typically measured in randomized, double-blind phase IIb/III trials and described as a reduction in newly acquired HIV infections. However, such trials are often expensive, time-consuming, and/or logistically challenging. These challenges lead to a great interest in immune responses induced by vaccination, and in identifying which immune responses predict vaccine efficacy. These responses are termed vaccine correlates of protection. Studies of vaccine-induced immunogenicity vary in size and design, ranging from small, early-phase trials to case-control studies nested in a broader late-phase randomized trial. Moreover, trials can be conducted in geographically diverse study populations across the world. Such diversity presents a challenge for objectively comparing vaccine-induced immunogenicity. To address these practical challenges, we propose a framework that is capable of identifying appropriate causal estimands and estimators, which can be used to provide standardized comparisons of vaccine-induced immunogenicity across trials. We evaluate the performance of the proposed estimands via extensive simulation studies. Our estimators are well-behaved and enjoy robustness properties. The proposed technique is applied to compare vaccine immunogenicity using data from three recent HIV vaccine trials.}, }
@article {pmid41923535, year = {2026}, author = {Zhu, K and Chuen Gary Chan, K and Zhao, YQ and Zheng, Y}, title = {Two-Step Error-Controlling Classifiers With Application to Cost-Effective Disease Diagnosis.}, journal = {Statistics in medicine}, volume = {45}, number = {8-9}, pages = {e70498}, doi = {10.1002/sim.70498}, pmid = {41923535}, issn = {1097-0258}, support = {R01 CA236558/NH/NIH HHS/United States ; U24 CA288285/NH/NIH HHS/United States ; U24 CA086368/NH/NIH HHS/United States ; }, mesh = {Humans ; *Prostatic Neoplasms/diagnosis/classification ; Male ; *Cost-Benefit Analysis ; Biomarkers, Tumor ; }, abstract = {Accurate classifiers that use novel biomarkers and readily available predictors significantly enhance decision-making in various clinical scenarios, such as assessing the need for biopsies in cancer diagnosis. When classification performance is limited, a decision framework can be applied to rule in or rule out invasive diagnostic procedures while incorporating a neutral zone for indeterminate classifications. Building on this framework, we propose a new family of two-step classifiers that selectively use costly biomarker testing for a targeted subset of individuals undergoing multiple evaluations. The optimal solution expands upon the Neyman-Pearson Lemma, highlighting a vital trade-off between the costs of expensive biomarker measurements and improving classification performance while minimizing uncertainty in the decision process. We demonstrate the practical utility of our approach through a biomarker study focused on prostate cancer diagnosis.}, }
@article {pmid41924784, year = {2026}, author = {Khan, A and Schwartz, JY and Patel, D and Njoku, C and Bosse, K and Heidaran, M and Atkins, JW}, title = {Two decades of advancing safe and effective cell-based therapies: a review of the impact, promise, and current limitations of USA regulation 21 CFR Part 1271.}, journal = {Cytotherapy}, volume = {28}, number = {6}, pages = {102119}, doi = {10.1016/j.jcyt.2026.102119}, pmid = {41924784}, issn = {1477-2566}, abstract = {BACKGROUND AIMS: Over the past 20 years, USA regulation 21 CFR Part 1271 has served as the cornerstone regulation for human cells, tissues, and cellular and tissue-based products (HCT/Ps) in the United States. Designed to ensure public health safety while fostering innovation, the framework has significantly shaped the development and oversight of regenerative medicine.<br><br>METHODS: This paper examines the evolution of 21 CFR Part 1271 since its inception, highlighting key amendments, milestones, and regulatory challenges. It explores its impact on the industry, focusing on case studies that underscore its influence on clinical translation and commercialization.<br><br>RESULTS: The analysis shows that 21 CFR Part 1271 addresses ongoing controversies, such as compliance and enforcement challenges, and discusses how emerging technologies like exosomes, gene editing, and bioprinting may reshape its future.<br><br>CONCLUSION: By reflecting on two decades of regulatory experience, this paper provides insights into the successes and limitations of 21 CFR Part 1271 and proposes pathways for its modernization to address the growing complexity of regenerative medicine.}, }
@article {pmid41925553, year = {2026}, author = {Urujeni, C and Epplein, M and Li, CI and Pete, D}, title = {Racial and ethnic differences in gastric cancer by stage of diagnosis in the United States (2009-2019).}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-1356}, pmid = {41925553}, issn = {1538-7755}, abstract = {BACKGROUND: Despite the United States having a low overall gastric cancer (GC) incidence rate, there remain disparities by race/ethnicity. We examined the incidence of GC by stage at diagnosis among Hispanic, Asian/Pacific Islander (A/PI), American Indian/Alaska Native (AI/AN), and non-Hispanic Black (NHB) populations, compared to non-Hispanic White (NHW) population, during 2009-2019.<br><br>METHODS: Using Surveillance, Epidemiology, and End Results data, age-adjusted GC incidence rates, rate ratios (RRs) and 95% confidence intervals (CIs) were calculated by stage and race/ethnicity. Stratified analyses were performed by sex, age and anatomical site.<br><br>RESULTS: Compared to NHW individuals, incidence rates of regional and distant stage GC diagnosis were nearly two times higher in Hispanic (RRRegional, 1.87; 95% CI, 1.78-1.97; RRDistant, 1.92; 95% CI, 1.84-2.00), A/PI (RRregional, 2.17; 95% CI, 2.04-2.30; RRDistant, 1.58; 95% CI, 1.49-1.68), and NHB (RRregional, 1.78; 95% CI, 1.67-1.88; RRDistant, 1.80; 95% CI, 1.71-1.89) individuals. In stratified analyses, the increased rate of advanced-stage diagnosis for Hispanic, A/PI, and NHB individuals remained generally consistent by sex and age, although young AI/AN individuals also had a significantly higher rate of distant GC (RR, 2.38; 95% CI, 1.36-3.83). By site, the increased rates of advanced-stage diagnosis were limited to non-cardia and overlapping/unspecified GC, whereas these populations had lower rates of cardia GC than NHW individuals.<br><br>CONCLUSIONS: Hispanic, A/PI, and NHB individuals have disproportionately high advanced-stage non-cardia GC rates compared to NHW individuals.<br><br>IMPACT: This study has identified significant disparities in advanced-stage non-cardia GC, suggesting the need to identify strategies to improve early detection in these populations.}, }
@article {pmid41925563, year = {2026}, author = {Schaefer, DA and Guo, M and Keane, EP and Song, MT and Larizza, IS and Adri, F and Wolfe, ED and Saadeh, N and Boardman, AC and Acharya, NB and Waldman, LP and Monahan, JA and Ramirez-Gamero, AF and Diaz Gonzalez-Colmenero, F and Watson, J and Cronin, AE and Celano, CM and Brown, L and Lee, SJ and Stoto, MA and Gudenkauf, LM and Amonoo, HL}, title = {Supportive Care Interventions in Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026019724}, pmid = {41925563}, issn = {2473-9537}, abstract = {There is no comprehensive synthesis of supportive care interventions for patients with hematologic malignancies receiving transplantation and cellular therapies (TCTs). This systematic review and meta-analysis aimed to characterize randomized controlled trials (RCTs) of TCT supportive care interventions and examine effects on patient-reported outcomes (PROs). We systematically searched MEDLINE, Embase, CINAHL, PsycInfo, Web of Science, and CENTRAL databases. We used the Cochrane Risk of Bias 2.0 protocol, grouped findings by intervention and PRO types, and synthesized results narratively. We conducted exploratory random-effects meta-analyses to estimate pooled intervention effects on anxiety, depression, and quality of life (QOL). Fifty-three RCTs published from 1992 to 2025 met criteria. All RCTs included hematopoietic stem cell transplantation (HSCT) recipients; none were tested in patients receiving cellular therapies. Included studies reported a range of sample sizes (11-711), participant demographics (mean age 33-63 years; 22-64% female), and PROs. There were nine intervention categories: cognitive behavioral (n=5), exercise only (n=17), expressive helping (n=2), mind-body/stress management (n=7), multimodal (exercise plus another modality; n=6), music/art (n=12), palliative care (n=2), positive psychology (n=1), and self-management/self-efficacy (n=5). Interventions were mostly feasible and acceptable, with promising improvements in psychological distress, QOL, and physical outcomes. Meta-analysis showed non-significant trends toward exercise interventions improving QOL (SMD=0.09; 95% CI: -0.07 to 0.25) and music/art interventions reducing acute depressive symptoms (SMD=-0.26; 95% CI: -0.52 to 0.00). Among patients undergoing HSCT for hematologic malignancies, supportive care interventions show feasibility, acceptability, and promise for improving PROs. However, larger, rigorously designed trials using standardized PRO measures are needed to establish efficacy.}, }
@article {pmid41925941, year = {2026}, author = {Owens, GC and Contreras, EM and Kienzler, JC and Treger, J and Soto, H and Orpilla, JR and Qiao, C and Chang, JW and Lee, A and Kim, WJ and Sun, MZ and Peeters, SF and Bethel, JA and Kondajji, AM and Holland, EC and Becher, OJ and Liau, LM and Prins, RM and Wang, AC}, title = {Therapeutic efficacy of dendritic cell vaccination in a novel syngeneic mouse model of diffuse hemispheric glioma, H3 G34-mutant.}, journal = {Journal of neuro-oncology}, volume = {177}, number = {2}, pages = {}, pmid = {41925941}, issn = {1573-7373}, support = {P50 CA211015/CA/NCI NIH HHS/United States ; R25 NS079198/NS/NINDS NIH HHS/United States ; T32 CA009120/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: The prognosis for pediatric high-grade gliomas associated with mutations in the H3-3A gene is very poor. To investigate whether tumor lysate-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma H3 G34-mutant (DHG), we have developed a novel syngeneic mouse model.<br><br>METHODS: We used the RCAS/tv-A system to target the expression of H3G34R and PDGF&#x3b2; and knock out p53 in neural progenitors in C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages. Lethal tumor developed following intracranial injection.<br><br>RESULTS: Two cycles of DC vaccination with PD-1 blockade decreased tumor burden and increased survival. In treatment resistant tumors we found higher expression of several genes involved in remodeling the extracellular matrix compared with tumors from untreated animals, suggesting a causal link to resistance to immunotherapy in this tumor model.<br><br>CONCLUSION: Immunotherapy involving autologous dendritic cells pulsed with tumor lysate and combined with anti-PD-1 antibody might be an effective treatment for DHG. Treatment failure in our tumor model is associated with increased expression of genes implicated in remodeling extracellular matrix in the tumor microenvironment.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11060-026-05545-z.}, }
@article {pmid41929060, year = {2026}, author = {Farrell-Sherman, A and Azam, W and de la Force, N and White, EL and Sandel, DA and Rodriguez, AE and Figueroa, T and Dalhuisen, T and Williams, MC and Tai, V and Gruenhagen, GW and Abdellatif, A and Fragiadakis, GK and Samghabadi, P and De la Sancha Verduzco, C and Vohra, P and Gasper, C and Long, S and Caskey, M and Zhu, B and Shalek, AK and Hoh, R and Rutishauser, RL and Peluso, MJ and Deeks, SG and Cohn, LB}, title = {Early immune responses anticipate HIV rebound and precede viral control.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929060}, issn = {2692-8205}, abstract = {Sustained viral suppression following antiretroviral treatment (ART) cessation is a major goal of HIV cure research[1]. Rare individuals mount immune responses able to control viral rebound without intervention[2,3], however, the earliest moments in which these responses form remain poorly defined. We performed an intensively sampled, prospective analytical treatment interruption (ATI) to study the initial immune response to rebound and to understand its role in defining subsequent virus control. Profiling of peripheral blood mononuclear cells and plasma revealed consistent immune activation prior to systemic rebound, including upregulation of antiviral transcriptional pathways, expansion of CD16[++] non-classical monocytes, and increases of inflammatory and antiviral soluble plasma proteins. Individuals with prior viral control (controllers) diverged from non-controllers with a slower slope of rebound, a longer period of immune activity prior to rebound, and engagement of a multifaceted immune program with less systemic inflammation. An intermediate immune signature emerged in a separate ATI cohort of individuals who experienced delayed rebound after receiving broadly neutralizing antibodies[4], suggesting that immunotherapy can induce a potentially protective pre-rebound immune response. Together, these data resolve the earliest systemic host immune responses to HIV rebound and demonstrate broad immune differences associated with HIV control phenotypes.}, }
@article {pmid41929126, year = {2026}, author = {Head, ST and Nemani, A and Chang, YH and Harrison, TA and Bresnahan, ST and Rothstein, JH and Sieh, W and Lindström, S and Bhattacharya, A}, title = {Improving isoform-level eQTL and integrative genetic analyses of breast cancer risk with long-read RNA transcript assemblies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {41929126}, issn = {2692-8205}, abstract = {Most eQTL and TWAS analyses quantify expression using aggregate, tissue-agnostic transcript annotations and ignore isoform-level regulation, potentially obscuring or misattributing regulatory mechanisms. Here, we developed a framework leveraging publicly available long-read RNA-seq data to perform tissue-informed inference of genetic regulation and prioritize candidate causal isoforms for breast cancer risk. We quantified gene- and isoform-level expression in breast tumor (TCGA), non-cancerous mammary tissue, and cultured fibroblasts (GTEx) using three transcriptome annotations: standard GENCODE, tissue-specific long-read-derived assemblies, and combined annotations incorporating transcript-isoforms from both. While GENCODE cataloged over 250,000 pan-tissue isoforms, the tissue-specific long-read assemblies captured reduced sets of 74,717 isoforms in tumor, 48,057 in fibroblasts, and 22,941 in healthy breast. We performed eQTL mapping and fine-mapping, followed by colocalization with overall and subtype-specific breast cancer GWAS and isoform-level TWAS. While most eGenes were concordant across annotations, approximately 1/3 of lead cis-eQTLs for shared eGenes differed between long-read assemblies and GENCODE. Further, eIsoform discovery was highly annotation-specific. In healthy breast tissue, the gold standard tissue for building gene expression prediction models for TWAS of breast cancer, 46% of eIsoforms identified by the long-read annotation were unique to that annotation even though 93.7% of them are present in GENCODE. Despite combined annotations expanding the GENCODE catalog by only 0.6-7.6% depending on tissue source, 69% of unique significant isoform-trait associations were specific to a single annotation. Long-read-informed annotations uncovered regulatory associations entirely missed by GENCODE, including a candidate regulatory isoform at the MARK1 locus captured only in fibroblasts and a previously unannotated splice variant prioritized as the likely effector transcript at NUP107. These findings demonstrate that transcript annotation is not merely a technical consideration but critically defines the biological hypothesis space for regulatory mechanisms and shapes discovery. Incorporating tissue-resolved isoform annotations from long-read RNA-seq improves the specificity of regulatory inference and enhances identification of candidate causal isoforms at GWAS loci.}, }
@article {pmid41930736, year = {2026}, author = {Zou, R and D Williamson, B and M Shortreed, S and Coley, RY}, title = {Validation of a Risk-Prediction Model in the Presence of Outcome Misclassification.}, journal = {Statistics in medicine}, volume = {45}, number = {8-9}, pages = {e70377}, pmid = {41930736}, issn = {1097-0258}, support = {R01 MH125821/MH/NIMH NIH HHS/United States ; U19-MH121738/MH/NIMH NIH HHS/United States ; U19-MH099201/MH/NIMH NIH HHS/United States ; R01-MH125821/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Electronic Health Records/statistics &amp; numerical data ; *Models, Statistical ; Risk Assessment/methods/statistics &amp; numerical data ; Computer Simulation ; ROC Curve ; Bias ; Area Under Curve ; }, abstract = {Electronic health records (EHRs) provide a rich data source for building prediction models to improve the quality of care. However, EHR data are prone to measurement error, and outcomes used to evaluate prediction model performance may be misclassified. Comparing risk predictions to misclassified outcomes will result in unreliable estimates of a prediction model's performance. We propose a method that leverages a smaller chart review sample with gold-standard outcome measurements to adjust validation for outcome misclassification and provide more accurate prediction model evaluation. We derive formulae to estimate true positive rate (TPR), false positive rate (FPR), positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC) in the presence of outcome misclassification. Different scenarios of misclassification are explored, including when the misclassification is independent or dependent on features, and when misclassification is unidirectional (e.g., only missed diagnoses) or bidirectional. In simulation studies, we compare the bias and 95% confidence interval coverage of performance estimates obtained using our proposed method to those estimated with misclassified outcomes (without accounting for misclassification) or in the smaller chart review sample. Simulation results indicate that, across all misclassification scenarios examined, our proposed estimates have good accuracy and improved precision. Outcome misclassification should be considered when evaluating a prediction model's performance in order to accurately inform decision-making about whether and how to use a clinical prediction model.}, }
@article {pmid41932032, year = {2026}, author = {Geidel, G and Fekade, N and Raabe, K and Smit, DJ and Adam, L and Heidrich, I and Rünger, A and Kött, J and Zell, T and Amaral, T and Ascierto, PA and Corrie, P and Dummer, R and Eggermont, A and Guo, J and Hassel, JC and Jalving, M and Johnson, DB and Kandolf, L and Kirkwood, JM and Lebbé, C and Lee, R and Long, GV and Lorigan, P and Malvehy, J and Mangana, J and Mohr, P and Patel, SP and Rizos, H and Robert, C and Schadendorf, D and Sondak, VK and Svane, IM and Wainstein, A and Zager, JS and Pantel, K and Hauschild, A and Gebhardt, C and , }, title = {Translating ctDNA into cutaneous melanoma care: An international expert survey.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {239}, number = {}, pages = {116676}, doi = {10.1016/j.ejca.2026.116676}, pmid = {41932032}, issn = {1879-0852}, abstract = {BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker in melanoma, with higher sensitivity for tumor burden detection than conventional diagnostics. While well established in research, clinical routine implementation remains pending. Key global questions concern optimal clinical applications and barriers to adoption.<br><br>METHODS: A web-based survey of 116 members of the Melanoma World Society Study Group assessed international expert opinions on ctDNA utility across predefined clinical scenarios. The questionnaire included 18 general questions on ctDNA use and 5 clinical vignettes with de-identified patient data and retrospectively obtained ctDNA results.<br><br>RESULTS: ctDNA was rated most valuable for detecting minimal residual disease (mean score 3.63), surveillance of recurrent disease (3.85), and stage IV melanoma (3.82), with limited utility in early stages. Experts considered ctDNA superior to S100 and LDH for early relapse detection and identifying progressive disease. Most participants (80%) agreed that ctDNA correlates with radiographic response, and 82% favored its integration into routine follow-ups. In urgent high-tumor-burden settings, 82.8% would initiate BRAFi/MEKi therapy based on ctDNA if tissue analysis was pending, and 93.9% if unavailable. For central nervous system lesions, 62% did not support blood ctDNA, while 66% considered cerebrospinal fluid valuable. Pragmatic approaches with small to mid-size targeted panels and short turnaround times were preferred. Major barriers included the need for prospective trials (85%), standardized guidelines (83%), and reimbursement policies (82%).<br><br>CONCLUSION: Key opinion leaders regarded ctDNA as a valuable adjunct selected melanoma scenarios. Validation through prospective studies, guideline development, and reimbursement frameworks are essential for broader clinical implementation.}, }
@article {pmid41932899, year = {2026}, author = {Williamson, C and Moodley, C and Magaret, CA and Giorgi, EE and Rolland, M and Westfall, DH and Yssel, A and Deng, W and Rossenkhan, R and Mkhize, NN and Chen, L and Zhao, H and Bhattacharya, T and Pankow, A and Murrell, B and York, T and Gwashu-Nyangiwe, A and Ndabambi, N and Thebus, R and Cohen, P and Lambson, B and Kaldine, H and Bhebhe, S and Juraska, M and Bai, H and deCamp, AC and Miner, MD and Ludwig, J and Molitor, C and Beaume, N and Matten, D and Huang, Y and Zhang, L and Reeves, DB and Mayer, B and Karuna, ST and Hural, JA and Morris, L and Montefiori, D and Bumgarner, RE and Moore, PL and Edlefsen, PT and Edupuganti, S and Mgodi, N and McElrath, MJ and Cohen, MS and Corey, L and Gilbert, PB and Mullins, JI}, title = {Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-70888-0}, pmid = {41932899}, issn = {2041-1723}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; R01 AI152115/AI/NIAID NIH HHS/United States ; K25 AI155224, R01 AI186721-01//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01 AI157854/AI/NIAID NIH HHS/United States ; 1032144, INV-016189//Bill and Melinda Gates Foundation (Bill &amp; Melinda Gates Foundation)/ ; 2018-02381//Vetenskapsr&#xe5;det (Swedish Research Council)/ ; }, abstract = {In the antibody mediated prevention (AMP) trials, the broadly neutralizing antibody (bNAb) VRC01 demonstrated protective efficacy against susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, deep sequencing was performed on 172 participants (>100,000 gag-Δpol and rev-env-Δnef sequences), at diagnosis and over time, in the placebo and treatment arms of the African (HVTN703/HPTN081; NCT02568215) and Americas/Europe (HVTN704/HPTN085; NCT02716675) cohorts. A high frequency of multilineage infections was detected (38%), including co-infection with both VRC01 sensitive and resistant viruses. This high frequency is largely accounted for by low-abundance lineages. Although VRC01 does not significantly affect the genetic transmission bottleneck compared to placebo, higher VRC01 doses trend towards greater VRC01 neutralization differences among co-infecting lineages. Two-thirds of multilineage infections showed evidence of recombination at the diagnostic timepoint. In the treatment group there is evidence of recombinant viruses preferentially inheriting resistance-associated mutations. This study provides critical insights into viral genetic and antigenic diversity that needs to be targeted to achieve protection, and highlights the role of recombination in facilitating escape.}, }
@article {pmid41933174, year = {2026}, author = {Cummings, JL and Agadjanyan, MG and Barry, M and Corey, L and Doody, R and Hendrix, S and Mattke, S and Mattsson-Carlgren, N and McDade, E and Menetski, JP and Mohs, RC and Partrick, KA and Petrovsky, N and Selkoe, DJ and Silva, D and Sperling, RA and Tiede, B and Vradenburg, G}, title = {Target product profiles for treatments to delay or prevent symptomatic Alzheimer's disease.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {41933174}, issn = {1546-170X}, abstract = {Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated biomarkers who do not yet show symptoms. Multiple candidate interventions are now being evaluated in clinical trials in these settings, raising key questions around which populations are most appropriate and what criteria should guide regulatory and clinical decision-making. Data are expected within 1-2 years, underscoring the need for stakeholder alignment on clinically meaningful and acceptable characteristics of preventative therapies or other products. To address this need, the Global CEO Initiative on Alzheimer's Disease convened an international group of experts to develop target product profiles for therapies designed to delay or prevent the onset of clinical symptoms in AD. These target product profiles outline minimum and preferred characteristics, including intended use, target populations, safety expectations and efficacy benchmarks. This effort provides a foundational framework to accelerate therapeutic development and guide researchers, regulators and patients in the evaluation of emerging therapies for preventing symptomatic AD.}, }
@article {pmid41933184, year = {2026}, author = {Li, S and Ghajar, CM}, title = {A tumor-derived metabolite primes the leptomeningeal pre-metastatic niche.}, journal = {Nature cancer}, volume = {}, number = {}, pages = {}, pmid = {41933184}, issn = {2662-1347}, }
@article {pmid41934616, year = {2026}, author = {Núñez, ER and Triplette, M}, title = {Care Coordination as the Bridge: Closing the Gaps in Lung Cancer Screening.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, doi = {10.1093/annalsats/aaoag081}, pmid = {41934616}, issn = {2325-6621}, }
@article {pmid41934618, year = {2026}, author = {Singh Mahla, R}, title = {Comment on: Fcgamma-receptor-activation by circulating immune complexes in systemic autoimmune diseases and its reduction by CD19-CAR T-cell therapy.}, journal = {Rheumatology (Oxford, England)}, volume = {}, number = {}, pages = {}, doi = {10.1093/rheumatology/keag174}, pmid = {41934618}, issn = {1462-0332}, }
@article {pmid41936367, year = {2026}, author = {, }, title = {Global burden of cancer in children and adolescents aged 0-19 years, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023.}, journal = {Lancet (London, England)}, volume = {407}, number = {10536}, pages = {1360-1373}, doi = {10.1016/S0140-6736(26)00200-X}, pmid = {41936367}, issn = {1474-547X}, mesh = {Humans ; Adolescent ; Child ; *Neoplasms/epidemiology/mortality ; Child, Preschool ; Infant ; *Global Burden of Disease/trends ; Young Adult ; Infant, Newborn ; Male ; Disability-Adjusted Life Years ; Female ; Incidence ; Global Health/statistics &amp; numerical data ; Life Expectancy ; Prevalence ; Risk Factors ; }, abstract = {BACKGROUND: Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses.<br><br>METHODS: GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs).<br><br>FINDINGS: Globally, in 2023, there were an estimated 377&#x2008;000 incident childhood cancer cases (95% UI 288&#x2008;000-489&#x2008;000), 144&#x2008;000 deaths (131&#x2008;000-162&#x2008;000), and 11&#xb7;7 million (10&#xb7;7-13&#xb7;2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27&#xb7;0% (15&#xb7;5-36&#xb7;1) globally, from 197&#x2008;000 (173&#x2008;000-218&#x2008;000) in 1990, but increased in the WHO African region by 55&#xb7;6% (25&#xb7;5-92&#xb7;4), from 31&#x2008;500 (24&#x2008;900-38&#x2008;500) to 49&#x2008;000 (42&#x2008;600-58&#x2008;200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26&#xb7;5% (26&#xb7;5-26&#xb7;5) in GBD 2017 to 10&#xb7;5% (8&#xb7;1-13&#xb7;1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47&#xb7;3% (42&#xb7;2-52&#xb7;0) of global childhood cancer deaths in 2023.<br><br>INTERPRETATION: Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum.<br><br>FUNDING: St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.}, }
@article {pmid41936375, year = {2026}, author = {Umbleja, T and Zafar, MU and McCallum, S and Gattu, AK and Zanni, MV and Bloomfield, GS and Malvestutto, CD and Fichtenbaum, CJ and Currier, JS and Sponseller, CA and Diggs, MR and Chu, SM and Lu, AB and Glesby, MJ and Stapleton, JT and Frank, M and Nguyen, KL and Bender Ignacio, RA and Han, WM and Douglas, PS and Aberg, JA and Ribaudo, HJ and Grinspoon, SK}, title = {Pitavastatin effects on lipids in relation to major adverse cardiovascular events: a REPRIEVE secondary analysis.}, journal = {The lancet. HIV}, volume = {}, number = {}, pages = {}, doi = {10.1016/S2352-3018(26)00031-7}, pmid = {41936375}, issn = {2352-3018}, support = {UM1 AI068634/AI/NIAID NIH HHS/United States ; U01 HL123339/HL/NHLBI NIH HHS/United States ; UG3 HL164285/HL/NHLBI NIH HHS/United States ; P30 DK040561/DK/NIDDK NIH HHS/United States ; U01 HL123336/HL/NHLBI NIH HHS/United States ; U24 HL164284/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) found a 36% reduction in major adverse cardiovascular events (MACE) with pitavastatin in people with HIV. Little is known about the relationship between lipid lowering and MACE in this population. We evaluated pitavastatin effects on lipids and examined mediation of pitavastatin effects on MACE through lipid lowering.<br><br>METHODS: REPRIEVE was a randomised, double-blind, placebo-controlled phase 3 trial evaluating pitavastatin (4 mg daily) or placebo for prevention of MACE in people with HIV. Participants aged 40-75 years, on stable combination antiretroviral therapy (ART), and at low-to-moderate atherosclerotic cardiovascular disease risk with minimally elevated LDL were followed up for a median of 5&#xb7;6 years. Centrally tested fasting lipids were captured at entry and annually thereafter. The primary MACE outcome, reported previously, was time to first MACE. Here, we report secondary outcomes on fasting lipids. Linear mixed-effects models were used for assessment of the pitavastatin effect on lipids, Cox regression for relationship of lipids to MACE, and Vansteelandt method for mediation analysis.<br><br>FINDINGS: REPRIEVE enrolled 7769 participants from March 26, 2015, to July 31, 2019, in 12 countries across five Global Burden of Diseases super-regions. The median baseline LDL was 108 mg/dL, and similar across treatment groups. Pitavastatin effects were primarily observed on LDL, with a modest reduction in triglycerides and no apparent effect on HDL. Based on the longitudinal data modelling, the estimated treatment group difference in LDL at month 12 (pitavastatin minus placebo) was -30 mg/dL (95% CI -31 to -29), corresponding to a 30% reduction. The estimated risk of LDL of &#x2265;100 mg/dL at month 12 was 0&#xb7;18 in the pitavastatin group and 0&#xb7;57 in the placebo group (relative risk 0&#xb7;32, 95% CI 0&#xb7;30-0&#xb7;34). A 30% lower time-updated average LDL was associated with 20% lower risk of primary MACE (hazard ratio 0&#xb7;80, 95% CI 0&#xb7;68-0&#xb7;94). Of the pitavastatin effect on MACE, 68% was estimated to be mediated through LDL, although with low precision (95% CI 15-574).<br><br>INTERPRETATION: LDL is strongly related to MACE, and LDL lowering should be an important goal of primary cardiovascular prevention in people with HIV, even in those with minimally elevated LDL. Treatment should aim to achieve accepted primary care prevention targets for LDL.<br><br>FUNDING: US National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.}, }
@article {pmid41939159, year = {2025}, author = {Kumar, AS and Meyer, J and Babu, AD and Sankar, S and Marco, E}, title = {Commissioning and Quality Assurance of Catalyst[+] HD Surface-guided Radiotherapy on TrueBeam HyperArc Linear Accelerator: An Indian Experience in Precision Radiotherapy.}, journal = {Journal of medical physics}, volume = {50}, number = {2}, pages = {288-296}, pmid = {41939159}, issn = {0971-6203}, abstract = {OBJECTIVE: In this study, we describe and critically review our experience in the commissioning of the surface-guided radiation therapy (SGRT) system from C-RAD (Uppsala, Sweden), integrated with a Varian TrueBeam HyperArc linear accelerator (LINAC).<br><br>MATERIALS AND METHODS: The C-RAD SGRT system was commissioned according to the guidelines of the American Association of Physicists in Medicine Task Group 147 and the European Society for Radiotherapy and Oncology-Advisory Committee for Radiation Oncology Practice report. The commissioning tests included the isocenter, camera thermal drift, reproducibility, static localization accuracy with a 6-degree-of-freedom (DOF) couch, dynamic gating delivery, and an end-to-end test. The tools and phantoms employed for this verification included: (a) Sentinel 4DCT daily check device, (b) Catalyst&#x207a; HD daily check device, (c) Penta-guide, (d) gating phantom, (e) calibration board, (f) Winston-Lutz phantom, and (g) the Little John anthropomorphic phantom.<br><br>RESULTS/DISCUSSION: The reproducibility of both the Sentinel 4DCT and Catalyst&#x207a; HD cameras demonstrated accuracy within &#xb1; 1 mm. The radiation isocenter measurements for both the Sentinel 4DCT and Catalyst&#x207a; HD cameras were found to be <1 mm, well within the recommended reports of the relevant international guidelines. The static localization accuracy of the Catalyst&#x207a; HD camera with a 6DOF couch was determined to be 0.15 &#xb1; 0.13 mm, 0.42 &#xb1; 0.23 mm, and 0.20 &#xb1; 0.15 mm for the vertical, longitudinal, and lateral directions, respectively. The rotational accuracy for roll, pitch, and yaw was found to be 0.05&#xb0;&#xb1;0.05&#xb0;, 0.12&#xb0;&#xb1;0.18&#xb0;, and 0.13&#xb0;&#xb1;0.10&#xb0;, respectively. All results were within the tolerances recommended by the international recommendations and highlight the accuracy and precision of the C-RAD SGRT system in conjunction with the TrueBeam HyperArc LINAC.<br><br>CONCLUSION: The newly installed advanced C-RAD SGRT systems have been successfully integrated with the Varian TrueBeam LINAC for clinical use, marking a significant milestone as the first deployment of SGRT technology of its kind in India.}, }
@article {pmid41941252, year = {2026}, author = {Jhaveri, K and Eli, LD and Hurvitz, SA and Brufsky, A and Bose, R and de Miguel, M and Unni, N and Reid, S and Quinn, DI and Mahalingam, D and Saura Manich, C and García-Sáenz, J&#xc1; and Martínez-Bueno, A and Guerrero-Zotano, A and Trédan, O and Wildiers, H and Bischof, GF and Bebchuk, J and Solit, DB}, title = {Efficacy and Genomic Analysis of HER2-Mutant Metastatic Triple-Negative Breast Cancer Treated with Neratinib Alone or with Trastuzumab in the SUMMIT Basket Trial.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {}, number = {}, pages = {}, doi = {10.1158/1078-0432.CCR-25-4135}, pmid = {41941252}, issn = {1557-3265}, abstract = {PURPOSE: HER2 mutations occur in 1-3% of triple-negative breast cancers (TNBCs), representing a novel target for biomarker-directed treatment. In the SUMMIT basket trial (NCT01953926), patients with HER2-mutant, metastatic TNBC received neratinib (240 mg/day) or neratinib+trastuzumab (N+T; neratinib 240 mg/day, IV trastuzumab 8 mg/kg initially then 6 mg/kg q3w). We report final results from the neratinib and N+T TNBC cohorts.<br><br>EXPERIMENTAL DESIGN: Primary endpoint: investigator-assessed objective response rate at first post-baseline tumor assessment (ORRfirst); secondary endpoints included: confirmed ORR by investigator; clinical benefit rate (CBR); progression-free survival (PFS); exploratory endpoint: circulating tumor (ct) DNA collected at baseline, during treatment, and at end of treatment.<br><br>RESULTS: Twenty-seven patients were enrolled between July 2014 and September 2021. Confirmed ORRs were 40.0% (95%CI12.2-73.8) for neratinib (n=10) and 35.3% (95%CI 14.2-61.7) for N+T (n=17). CBRs were 40.0% (95%CI 12.2-73.8) and 47.1% (95%CI 23.0-72.2), respectively; median PFS was 2.89 (95%CI 0.95-5.52) and 6.24 months (95%CI 2.10-8.18), respectively. HER2 mutation variant allele frequencies in ctDNA from patients with response or stable disease decreased upon treatment and increased upon progression. Serial ctDNA sequencing revealed emergence or increase of on-pathway (ERBB3) and off-pathway (KRAS, TP53) mutations. The most common treatment-emergent adverse events were diarrhea, nausea, and constipation.<br><br>CONCLUSIONS: N+T in patients with HER2-mutant metastatic TNBC appeared to prolong responses versus neratinib alone, representing a novel approach for biomarker-defined metastatic TNBC patients. Based on these and previously published data, neratinib-based combinations are endorsed by NCCN guidelines for patients with hormone receptor-positive or -negative metastatic breast cancer with activating HER2 mutations.}, }
@article {pmid41941698, year = {2026}, author = {Einarsdottir, S and Fei, T and Singh, KH and Martens, MJ and Young, JH and Bhavsar, K and Kou, J and Chen, M and Lee, LW and Baluch, A and Dhodapkar, MV and Nakamura, R and Peyton, K and Shahid, Z and Armistead, PM and Westervelt, P and McCarty, J and McGuirk, JP and Hamadani, M and Sharon, E and Spahn, A and Toor, AA and Waldvogel, SL and Greenberger, LM and Auletta, JJ and Horowitz, MM and Riches, M and Hosszu, K and Hill, JA and DeWolf, S and Perales, MA}, title = {Antigen-specific T cell responses to SARS-CoV-2 vaccination after Hematopoietic Cell Transplant or CAR T cell Therapy.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026019614}, pmid = {41941698}, issn = {2473-9537}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {The optimal timing of SARS-CoV-2 vaccination after cellular therapies remains uncertain. In a prior prospective multicenter cohort (n=466), we found no differences in humoral or SARS-CoV-2-specific T cell receptor (TCR) responses between patients vaccinated early (<4 months) versus later (4-12 months) after allogeneic hematopoietic cell transplant (allo-HCT), autologous HCT (auto-HCT), or chimeric antigen receptor T cell (CAR-T) therapy. In this sub-study, we evaluated functional T cell responses in 68 patients (allo-HCT n=28, auto-HCT n=22, CAR-T n=18) that were clinically and immunophenotypically similar to the overall cohort. Antigen-specific CD4[+] and CD8[+] T cell responses to SARS-CoV-2 mRNA vaccination were assessed by spectral flow cytometry. Functional responses were correlated with baseline immune reconstitution parameters, antibody responses, and to SARS-CoV-2-specific TCR repertoire metrics. Vaccination induced significant increases in antigen-specific IFN-γ and TNF-α production by both CD4[+] and CD8[+] T cells across all cellular therapy groups. Responses were primarily driven by CD4[+] central memory and cytotoxic CD8[+] T cell subsets. Functional T cell responses correlated with baseline CD19[+] B cell counts (p=0.002) and post-vaccination antibody responses (p<0.01), but not with SARS-CoV-2-specific TCR breadth or depth. Notably, functional T cell responses were detectable even in patients with low B cell counts or absent antibody responses. We conclude that mRNA SARS-CoV-2 vaccination elicits functional, Th1-skewed T cell responses after allo-HCT, auto-HCT, and CAR-T therapy. Initiation of SARS-CoV-2 vaccination early after cellular therapy (<4 months) was not associated with impaired functional T cell responses.}, }
@article {pmid41941894, year = {2026}, author = {Yorke, AA and Nyflot, MJ and Apisarnthanarax, S and Sponseller, PA and Bowen, SR}, title = {Precision Radiotherapy for Hepatocellular Carcinoma: Exploring the Clinical Utility of Functional Liver Avoidance Planning (FLAP).}, journal = {Practical radiation oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.prro.2026.03.008}, pmid = {41941894}, issn = {1879-8519}, abstract = {PURPOSE: We assessed the utility of functional liver avoidance planning (FLAP) to meet clinical constraints and reduce dose to functioning liver tissue.<br><br>METHODS: Twenty patients (52-83 years, 6/20 female) with varying degrees of cirrhosis (Child-Pugh scores A5-B9) underwent [99mTc] sulfur colloid SPECT/CT imaging with generation of functional liver volumes (FLV) at 30%max thresholds, and FLV were co-registered onto planning CT scans. Half of patients received prior liver directed therapy (LDT). VMAT-SBRT (5 fx, 5 CP-A, 5 CP-B/C) conventional plans were optimized following ASTRO consensus guidelines and those that did not meet published functional liver dose constraints (FLV mean, FLV V20) were re-optimized for functional liver avoidance and scaled to the same target dose coverage. Scanning proton beam therapy (PBT) plans were similarly generated for hypo-fractionated regimens (15 fx, 5 CP-A, 5 CP-B/C). We characterized the associations between clinical characteristics and the probability of FLAP re-optimization and correlations with FLV dose reduction.<br><br>RESULTS: SBRT conventional plans for CP-A patients met all clinical and functional liver dose constraints, while 40% of CP-B/C SBRT plans, 40% of CP-A PBT plans, and 80% of CP-B/C PBT plans required re-optimization for FLV dose constraints. Compared to conventional plans, FLAP replans achieved a median reduction of 13% (range: 2%-30%) in FLV mean dose and 4% (range: 1%-10%) in FLV V20. Increasing likelihood of prior LDT correlated with a decrease in FLAP re-optimization frequency (Spearman R -0.95, p=0.05). This is reflected in CP-A SBRT patients requiring fewer functional liver avoidance replans (80% prior LDT, 0% FLAP replans) compared to CP-B/C PBT patients (10% prior LDT, 80% FLAP replans).<br><br>CONCLUSION: We successfully investigated the clinical utility of functional tissue avoidance in different groups of patients with HCC as a planning strategy to preserve liver function and mitigate hepatoxicity.}, }
@article {pmid41942445, year = {2026}, author = {Ozog, S and Krantz, EM and Tindbaek, K and Munoz, J and Liu, WL and Chalal, C and Pernikoff, S and Yahya, K and Stevens-Ayers, T and Dasgupta, S and Cowan, AJ and Green, DJ and Gauthier, J and Till, BG and Gardner, RA and Shadman, M and Bleakley, M and Boeckh, M and Boonyaratanakornkit, J and Turtle, CJ and Hill, JA}, title = {Influence of B cell-lineage targeted CAR-T cell therapy on humoral immunity and vaccine-induced antibody response.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71473-1}, pmid = {41942445}, issn = {2041-1723}, support = {U01 CA247548/CA/NCI NIH HHS/United States ; 5U01CA247548//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; T32 CA009351/CA/NCI NIH HHS/United States ; }, abstract = {Humoral immune-related adverse events, including hypogammaglobulinemia and B cell depletion, pose long-term infection risks after chimeric antigen receptor T cell therapy (CARTx) for hematologic malignancies. This prospective study evaluates the kinetics of pathogen-specific humoral immunity prior to and up to a year after CARTx targeting CD19 and CD20 (B cells) or BCMA (plasma cells) in 100 and 28 individuals, respectively. Antibodies are tested for 12 vaccine-preventable pathogens and using comprehensive high-throughput antibody profiling. A subset of 72 participants are evaluated for post-CARTx vaccine responses. Here, we show pathogen-specific humoral immunity does not significantly change after CD19-, CD20-, or BCMA-targeted CAR-T cell therapy (CARTx). However, seroprotective antibodies are absent for up to one-third of routine vaccine-preventable pathogens in CD19- and CD20-CARTx recipients and for nearly half of vaccine-preventable pathogens in BCMA-CARTx recipients by one-year post-CARTx. Pre-vaccination B cell count is the main predictor of vaccine response.}, }
@article {pmid41942608, year = {2026}, author = {Azam, S and Lamb, LR and Eliassen, AH and King, TA and Specht, M and Kraft, P and Lindstrom, S and Lehman, CD and Tamimi, RM}, title = {Performance of an image-only deep learning breast cancer risk model with the addition of a polygenic risk score.}, journal = {British journal of cancer}, volume = {}, number = {}, pages = {}, pmid = {41942608}, issn = {1532-1827}, abstract = {BACKGROUND: Mammograms contain imaging biomarkers that can predict future breast cancer risk using deep learning (DL) models. We evaluated whether adding a polygenic risk score (PRS) improves performance of the image-only DL breast cancer risk model Mirai.<br><br>METHODS: This nested case-control study within the Nurses' Health Study 2 included 902 women (270 cases, 632 controls) who underwent bilateral 2D digital screening mammography between 2001-2017. Risk was assessed using Mirai and, for clinical comparison, the Gail 5-year model. A PRS was calculated using 313 breast cancer-associated single-nucleotide polymorphisms. The primary outcome was incident breast cancer within five years of the index mammogram. Discrimination was evaluated using area under the receiver operating characteristic curve (AUC), with comparisons using the DeLong test.<br><br>RESULTS: Mean age was 55.5 years(SD 5.3). Among cases, median time from index mammogram to diagnosis was 2.0 years (IQR0.5-4.0). Mirai alone achieved an AUC of 0.66 (95% CI: 0.62-0.70), increasing to 0.73 (95% CI 0.67-0.78; P&#x2009;=&#x2009;0.05) with PRS. The Gail model improved from 0.52 (95% CI: 0.47-0.57) to 0.69 (95% CI: 0.62-0.76; P&#x2009;<&#x2009;0.001) with PRS. Mirai+PRS significantly outperformed Gail+PRS (P&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: Integrating PRS with DL-based mammographic models modestly improves risk discrimination and may enhance personalized screening.}, }
@article {pmid41944291, year = {2026}, author = {Matsen, FA and Dumm, W and Sung, K and Johnson, MM and Rich, DH and Starr, TN and Song, YS and Fukuyama, J and Haddox, HK}, title = {Separating selection from mutation in antibody language models.}, journal = {eLife}, volume = {15}, number = {}, pages = {}, pmid = {41944291}, issn = {2050-084X}, support = {R01-AI146028/NH/NIH HHS/United States ; R56-HG013117/NH/NIH HHS/United States ; R01-HG013117/NH/NIH HHS/United States ; DP2-AI177890/NH/NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; }, mesh = {*Mutation ; *Antibodies/genetics ; *Selection, Genetic ; Humans ; V(D)J Recombination ; Models, Genetic ; }, abstract = {Antibodies are encoded by nucleotide sequences that are generated by V(D)J recombination and evolve according to mutation and selection processes. Existing antibody language models, however, focus exclusively on antibodies as strings of amino acids and are fitted using standard language modeling objectives such as masked or autoregressive prediction. In this paper, we first show that fitting models using this objective implicitly incorporates nucleotide-level mutation processes as part of the protein language model, which degrades performance when predicting effects of mutations on functional properties of antibodies. To address this limitation, we devise a new framework: a deep amino acid selection model (DASM) that learns the selection effects of amino acid mutations while explicitly factoring out the nucleotide-level mutation process. By fitting selection as a separate term from the mutation process, the DASM exclusively quantifies functional effects: effects that change some aspect of the function of the antibody. This factorization leads to substantially improved performance on standard functional benchmarks. Moreover, our model is an order of magnitude smaller and multiple orders of magnitude faster to evaluate than existing approaches, as well as being readily interpretable.}, }
@article {pmid41945753, year = {2026}, author = {Verboon, L and Barwe, SP and Tavenner, M and Faust, JR and Issa, H and Goncalves-Dias, J and Schuschel, K and Bhayadia, R and van Berkel, PH and Sebastian, A and Ries, RE and Paczesny, S and Meshinchi, S and Hitzler, JK and Pikman, Y and Kolb, EA and Heckl, D and Klusmann, JH and Gopalakrishnapillai, A}, title = {DLK1 is a GATA1s-Driven Dependency and Therapeutic Target in Down Syndrome-Associated Myeloid Leukemia.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018830}, pmid = {41945753}, issn = {2473-9537}, abstract = {Children with Down syndrome have a markedly increased risk of developing myeloid leukemia (ML-DS). Although having an excellent prognosis, 10-20% develop relapsed or refractory disease with poor survival, highlighting the need for new targeted approaches. The pathogenesis of ML-DS is tightly linked to fetal hematopoiesis and mutations in GATA1, generating the truncated GATA1short(s) isoform. We identified Delta-like non-canonical Notch ligand 1 (DLK1) as a direct GATA1s target. DLK1, a paternally imprinted transmembrane protein, is highly expressed in fetal liver CD34[+] cells but absent in adult hematopoiesis, making it an attractive immunotherapeutic target. Chromatin profiling revealed GATA1s occupancy at a distal enhancer within the DLK1-DIO3 locus, driving aberrant DLK1 upregulation in ML-DS. Functional studies demonstrated that DLK1 is a leukemia dependency, as its genetic ablation impaired proliferation and engraftment, induced apoptosis, and altered Notch and β-catenin signaling. Therapeutically, a DLK1-directed antibody-drug conjugate (DLK1-ADC) induced selective cytotoxicity, abrogated colony formation, and significantly prolonged survival in refractory ML-DS PDX models, achieving durable remissions at higher doses. These findings establish DLK1 as a leukemia-specific vulnerability and provide preclinical proof-of-concept for DLK1-targeted therapies in ML-DS and other leukemias with fetal-like expression programs.}, }
@article {pmid41945755, year = {2026}, author = {Amonoo, HL and Keane, EP and Guo, M and Gudenkauf, LM and Boardman, AC and Larizza, IS and Wolfe, ED and Mate-Kole, MN and Healy, BC and Cutler, CS and Jim, HS and Lee, SJ and Greer, JA and Huffman, JC and El-Jawahri, A}, title = {A Pilot Randomized Clinical Trial of a Peer Support Intervention for Hematopoietic Stem Cell Transplantation.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2025018918}, pmid = {41945755}, issn = {2473-9537}, abstract = {Peer support has been associated with improved patient-reported outcomes (PROs), including reduced psychological distress, among patients undergoing hematopoietic stem cell transplantation. Structured interventions tailored for this population are limited. This study assessed the feasibility, acceptability, and preliminary effects of a scalable peer support intervention for reducing psychological distress and enhancing quality of life (QOL) post-HSCT. We conducted a pilot randomized clinical trial evaluating the Supporting Transplant Experiences with Peer Program (STEPP), a five-session, telephone-based intervention delivered by an HSCT survivor offering psychoeducation and coping strategies. Participants were recruited 1-2 weeks pre-HSCT admission and randomized to STEPP or usual care. Feasibility was defined as ≥60% enrollment and ≥60% completing ≥3 sessions. Acceptability was assessed using the Client Satisfaction Questionnaire (CSQ; ≥3/4 mean benchmark). PRO measures of anxiety, depression (HADS), post-traumatic stress (PCL-C), QOL (FACT-BMT), social support (SSEQ), and self-efficacy (CASE) were assessed pre-HSCT and at 30 and 60 days post-HSCT. Mixed-effects models explored STEPP's preliminary effects. We enrolled 77% (90/117) of eligible patients (STEPP n=45; usual care n=45). Twelve became ineligible due to HSCT cancellation or postponement. Among 78 active participants (mean age 58.9 years (SD=12.3); 57.7% women), all STEPP participants completed ≥3 sessions, and the mean CSQ score was 3.5. STEPP showed small-to-moderate improvements in Day 30 anxiety (d=-0.36) and Day 60 anxiety (d=-0.58), depression (d=-0.25), post-traumatic stress (d=-0.28), QOL (d=0.48), social support (d=0.36), and self-efficacy (d=0.46). STEPP exceeds feasibility and acceptability thresholds, showing promising psychosocial benefits warranting a fully powered multi-site efficacy trial. This study was preregistered on ClinicalTrials.gov (NCT06010017).}, }
@article {pmid41946999, year = {2026}, author = {Brain, JA and Vigil, ABG and Davidsen, K and Itokawa, A and Jurasin, AC and Kerbyson, HJ and Kobiesa, M and Hart, ML and Yoon, SJ and Bellotti, P and Maianti, JP and DeNicola, GM and Sullivan, LB}, title = {Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.}, journal = {Nature metabolism}, volume = {}, number = {}, pages = {}, pmid = {41946999}, issn = {2522-5812}, support = {P01CA250984//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R37CA230042//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R35 GM147118/GM/NIGMS NIH HHS/United States ; P30CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; T32GM007270//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, abstract = {Cancer cells with constitutive NRF2 activation take up excess cystine beyond the cysteine demands of conventional pathways, implying unknown metabolic fates. Here, we develop an unbiased approach for the identification of cysteine metabolic fates and find that both known and previously uncharacterized cysteine-derived metabolites accumulate in NRF2-activated cancer cells. We identify many of these unknown metabolites as conjugates formed between cysteine and endogenous sugar metabolites, which can also be generated in vitro. We confirm the presence of these cysteine-derived conjugates in murine lung cancer models and primary human lung cancer samples, and their enrichment in NRF2-activated tumours in each context. Mechanistically, NRF2 promotes cystine uptake by driving SLC7A11 expression, which increases intracellular cysteine levels to promote these cysteine fates in a panel of cancer cell lines. Finally, we show that NRF2 activation creates a sensitivity to high environmental cystine, which impairs cell proliferation through excess free cysteine, and can be mitigated by sequestration into cysteine-derived conjugates. Overall, these findings reveal a cancer-associated metabolic vulnerability to excess cysteine stress, and reveal unrecognized routes of cysteine metabolism.}, }
@article {pmid41947740, year = {2026}, author = {Pan, J and Bannick, M and Gao, F}, title = {Estimating HIV Cross-sectional Incidence Using Recency Tests from a Non-representative Sample.}, journal = {American journal of epidemiology}, volume = {}, number = {}, pages = {}, doi = {10.1093/aje/kwag075}, pmid = {41947740}, issn = {1476-6256}, abstract = {Cross-sectional incidence estimation based on recency testing is a widely used tool in HIV research. This method has been used to estimate "placebo" incidence in active-control HIV prevention trials by applying the cross-sectional estimator to the screening population data. The application of this approach faces challenges due to non-representative sampling, as individuals aware of their HIV-positive status may be less likely to participate in screening for an HIV prevention trial. To address this, recent phase 3 trials introduced a test-based criterion, excluding individuals who had recently taken an HIV test. To date, the theoretical and empirical validity of this criterion has yet been studied. We develop a statistical framework incorporating non-representative sampling and the testing-based criterion. We quantify the limiting estimation error in recency-based incidence estimates, and investigate the performance of cross-sectional HIV incidence estimation through simulations emulating realworld trial designs. We find that under non-representative sampling, the incidence estimator is unreliable unless all recently tested individuals are excluded. Additionally, we highlight a bias-variance trade-off: excluding more individuals may reduce estimation bias from non-representative sampling but increases the variability. Our findings emphasize careful application of the testing-based criterion and the importance of improved methods in future HIV prevention trials.}, }
@article {pmid41948817, year = {2026}, author = {Zhao, K and Pershad, Y and Xue, L and Vlasschaert, C and Corty, RW and Heimlich, JB and Kooperberg, C and Reiner, AP and Bick, AG}, title = {Clonal Hematopoiesis and Risk of Stroke: Evidence From Over 800 000 Individuals Across 3 Cohorts.}, journal = {Stroke}, volume = {}, number = {}, pages = {}, doi = {10.1161/STROKEAHA.125.054128}, pmid = {41948817}, issn = {1524-4628}, support = {DP5 OD029586/OD/NIH HHS/United States ; R01 AG083736/AG/NIA NIH HHS/United States ; R01 AG088657/AG/NIA NIH HHS/United States ; UG3 AG097155/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that increases risk for cardiovascular disease. However, its relationship with stroke remains uncertain.<br><br>METHODS: To resolve these conflicting findings, we analyzed genomic and clinical data from 800&#x2009;160 participants with genetic sequencing and medical records across 3 large-scale cohorts: the Vanderbilt BioVU biobank (United States; enrollment 2007-2022), the National Institutes of Health All of Us Research Program (United States; enrollment 2018-2023), and the UK Biobank (United Kingdom; enrollment 2006-2010). The median follow-up time was 4.4 years (interquartile range, 1.8-10.2) in BioVU, 1.9 years (interquartile range, 0.4-3.9) in All of Us, and 12.4 years (interquartile range, 11.7-13.1) in UK Biobank. Stroke events were identified and classified as ischemic or hemorrhagic using International Classification of Diseases codes. Subgroup analyses were conducted by driver gene, clone size, sex, and menopausal status. Genetically predicted levels of 27 cytokines were assessed for modification of CHIP-associated stroke risk.<br><br>RESULTS: CHIP was associated with increased risk of incident stroke in the meta-analysis (hazard ratio [HR], 1.20 [95% CI, 1.14-1.27]; P=1.92&#xd7;10[-10]). This association was observed for ischemic (HR, 1.18) and hemorrhagic (HR, 1.25) stroke subtypes. Gene-specific analyses showed strong associations for JAK2 (HR, 2.52) and TET2 (HR, 1.23). DNMT3A demonstrated weak but significant associations (HR, 1.13). CHIP was associated with stroke risk in both sexes; however, among women, the association was evident in postmenopausal (HR, 1.49 [95% CI, 1.16-1.92]; P=1.91&#xd7;10[-3]) but not in premenopausal participants (HR, 0.70 [95% CI, 0.36-1.43]; P=0.33). Among participants with CHIP, but not among participants without CHIP, genetically predicted levels of IL-1RAP (interleukin-1 receptor accessory protein) were predictive of risk for stroke, suggesting IL-1RAP as a modifier of the CHIP-associated risk for stroke.<br><br>CONCLUSIONS: Our large-scale, multicohort study establishes CHIP as a determinant of incident stroke risk and IL (interleukin)-1-mediated inflammation as a targetable pathway to reduce this risk.}, }
@article {pmid41948933, year = {2026}, author = {Konecny, AJ and Lim, FY and Domenjo-Vila, E and Lovas, E and Blazevic, RL and Kimball, LE and Boeckh, M and Waghmare, A and Prlic, M}, title = {An at-home blood collection device for remote immune monitoring by high-parameter flow cytometry.}, journal = {JCI insight}, volume = {11}, number = {7}, pages = {}, doi = {10.1172/jci.insight.201116}, pmid = {41948933}, issn = {2379-3708}, mesh = {Humans ; *Flow Cytometry/methods/instrumentation ; *Blood Specimen Collection/instrumentation/methods ; Male ; Female ; Monitoring, Immunologic/methods/instrumentation ; Middle Aged ; Adult ; Aged ; }, abstract = {At-home blood collection devices (ABCDs) can facilitate study participation for remote and rural cohorts. Previous studies used ABCDs to interrogate samples by proteomics and sequencing approaches. We wanted to address the question of whether this approach could be used to assess live immune cells with high-parameter flow cytometry to enable remote immune monitoring. We first compared blood from standard venipuncture with ABCD blood draws, followed by assessment of the impact of sample shipping on immune cell viability and phenotyping. We found that capillary blood collected with a Tasso+ device and concurrently drawn venipuncture blood samples had highly congruent immune cell composition and phenotype. Shipment of Tasso+ samples via the United States Postal Service altered the myeloid compartment, but T cell numbers, subsets, and phenotypes remained remarkably stable compared with non-shipped samples. Finally, we describe a flow cytometry analysis framework that allowed for direct sample comparison even when samples were stained and analyzed over a time period of 1.5 years. Overall, our data highlight the feasibility of using ABCDs combined with subsequent flow cytometry analysis for remote immune monitoring. Additionally, our study also identifies areas that could be improved to further promote the use of ABCDs for immune monitoring.}, }
@article {pmid41949764, year = {2026}, author = {Iancu, A and Gwin, W and Vinayak, S and Linden, HM and Specht, J and Symonds, L and Davidson, N and Hunter, N}, title = {Incidental discovery of second primary lung tumors in breast cancer patients: an institutional case series.}, journal = {The oncologist}, volume = {31}, number = {5}, pages = {}, pmid = {41949764}, issn = {1549-490X}, support = {P30CA15704//Fred Hutch Cancer Center/ ; }, mesh = {Humans ; Female ; *Lung Neoplasms/pathology/diagnosis ; *Breast Neoplasms/pathology/complications ; Middle Aged ; Aged ; *Neoplasms, Second Primary/diagnosis/pathology ; Incidental Findings ; }, abstract = {BACKGROUND: Guidelines recommend biopsy of first breast cancer recurrence. Our group recently showed that only half of patients in Washington diagnosed with metastatic breast cancer (MBC) between 2008 and 2017 underwent biopsy.<br><br>METHODS: Oncologists in our group identified patients in which a lung malignancy was diagnosed in patients with a breast cancer history.<br><br>RESULTS: We identified eight illustrative cases. Lung findings were typically identified on a CT obtained for staging or radiation planning. In five cases, patients were treated curatively for two early-stage malignancies. In two cases, patients with MBC were found to have early-stage lung adenocarcinomas. In one case, MBC and metastatic lung cancer were diagnosed synchronously.<br><br>CONCLUSIONS: While imaging can raise suspicion for breast cancer recurrence, relying on radiologic appearance to infer that a lesion (1) is malignant and (2) represents spread of the known primary risks treating both the primary tumor and the newly detected condition inappropriately.}, }
@article {pmid41950298, year = {2026}, author = {Demedis, J and Reedy, J and Chow, EJ and Peterson, PN and Dorsey, B and Studts, CR}, title = {Provider-Engaged Development of a Sexual Dysfunction Screening Approach for Adolescents and Young Adult Childhood Cancer Survivors: Iterative Co-Design Study.}, journal = {JMIR formative research}, volume = {10}, number = {}, pages = {e85905}, pmid = {41950298}, issn = {2561-326X}, mesh = {Humans ; *Cancer Survivors/psychology ; Adolescent ; Male ; Young Adult ; Female ; *Mass Screening/methods ; *Sexual Dysfunction, Physiological/diagnosis/etiology ; Adult ; *Neoplasms/complications ; Child ; }, abstract = {BACKGROUND: Sexual dysfunction (SD) is common among childhood cancer survivors, affecting approximately 20% to 50% of patients. National guidelines recommend discussions about sexuality throughout cancer care, and prior work demonstrates patient interest in SD conversations. Despite its prevalence and importance, SD is widely underrecognized and undertreated, creating gaps in comprehensive whole-person care.<br><br>OBJECTIVE: Our research aims to collaborate with provider partners to co-design an SD screening intervention prototype for implementation in a clinical oncology setting. This study outlines the co-design process to serve as a case study, highlighting challenges and strategies to achieve a consensus-driven intervention and implementation plan.<br><br>METHODS: We engaged pediatric cancer providers in a series of co-design sessions at a National Cancer Institute-designated cancer center within an academic children's hospital. For each co-design session, the research team created a template outlining considerations from formative work (eg, patient privacy) and key decisions to be made (eg, screening modality). Co-design session moderators facilitated discussion, guiding participants toward a consensus decision for each intervention component. A final process mapping session reviewed and outlined the entire SD prototype. We conducted a rapid qualitative analysis, compiling a templated summary synthesizing and organizing findings by discussion topic and decision point. Based on co-design discussions, the research team compiled a menu of options outlining key thematic findings, core screening intervention functions, and intervention form options to allow for future expansion and tailoring of the SD prototype.<br><br>RESULTS: Six provider participants, including attending physicians, advanced practice providers, and registered nurses representing multiple oncology subspecialty groups, engaged in a series of 5 co-design sessions. Participants assessed specific intervention component options, reached consensus on component decisions, and determined an intervention and implementation workflow for each. Throughout, providers needed to ensure workflows aligned with patient and provider priorities from foundational work and to ensure design feasibility, acceptability, and appropriateness. Key intervention and implementation decisions included target population, screening frequency, screening modality and workflow, management of screening results, clinic reminders and cues, and provider education and training. With several decisions being interconnected, there was often a cascade effect in which one decision influenced or limited future decisions and, in some cases, required revisiting prior decisions to ensure cohesive alignment into a single prototype. Co-design session moderators used several strategies (eg, reminders, redirection, providing information on feasibility, etc) to facilitate decision-making and implementation strategy selection.<br><br>CONCLUSIONS: Engaging provider partners in co-design sessions allowed for the collaborative development of a preliminary SD screening approach for adolescents and young adults with and surviving cancer. The dynamic co-design process and moderator strategies ensured that intervention and implementation decisions reflected the patient and provider priorities identified in prior work. Future work will test, adapt, and refine the prototype SD screening approach prior to effectiveness testing and eventual dissemination.}, }
@article {pmid41951456, year = {2026}, author = {Rathkopf, DE and Patel, MR and Choudhury, AD and Rasco, D and Lakhani, N and Hawley, JE and Srinivas, S and Aparicio, A and Narayan, V and Runcie, KD and Emamekhoo, H and Reichert, ZR and Nguyen, MH and Wells, AL and Kandimalla, R and Liu, C and Suryawanshi, S and Han, J and J Wu,  and Arora, VK and Pourdehnad, M and Armstrong, AJ}, title = {Corrigendum to "Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer": [Ann Oncol 36 (2025) 76-88].}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2026.01.016}, pmid = {41951456}, issn = {1569-8041}, }
@article {pmid41951840, year = {2026}, author = {Ramlal, R and Kim, J and Thompson, Z and Ochoa-Bayona, L and Mishra, A and Nishihori, T and Perez, L and Bejanyan, N and Castaneda Puglianini, O and Faramand, R and Mirza, S and Khimani, F and Lazaryan, A and Hansen, D and Locke, F and Artz, A and Sorror, M and Pidala, J}, title = {Single center evaluation of a composite risk assessment model to predict non-relapse mortality following allogeneic hematopoietic cell transplantation (HCT).}, journal = {Bone marrow transplantation}, volume = {}, number = {}, pages = {}, pmid = {41951840}, issn = {1476-5365}, }
@article {pmid41951860, year = {2026}, author = {Lin, X and Guan, W and Chen, L and Su, Y and Liang, Z and Xiao, C and Bai, Y and Lei, H and Lin, F and Huang, Z and Chow, ICL and Yang, B and Tsang, TK and Weng, Y and Bhandari, N and Varadarajan, R and Peiris, M and Cowling, B and Li, T and McGargill, M and Thomas, PG and Zhong, N and Webby, R and Yang, Z and Zanin, M and Wong, SS}, title = {Birth imprinting effects on the antibody responses of H7N9 patients from 2013-2018 in China.}, journal = {Communications medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43856-026-01554-1}, pmid = {41951860}, issn = {2730-664X}, support = {2019A1515012070//Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)/ ; 81761128014//National Natural Science Foundation of China (National Science Foundation of China)/ ; }, abstract = {BACKGROUND: There is an urgent need to understand the immune correlates of protection against avian influenza viruses (AIV), where pre-existing immunity may be limited.<br><br>METHODS: Here, we characterized the antibody response in 12 severely ill A(H7N9) patients and examined its association with early-life imprinting and clinical outcome.<br><br>RESULTS: We find that A(H7N9) patients imprinted with A(H2N2) during early life show minimal H7-IgM and a rapid IgG response across diverse hemagglutinin subtypes. They also have more high avidity H7-antibodies compared to older or younger patients. Early antibody titers against seasonal H1, H3, and conserved stalk domains trend negatively with clinical severity in A(H7N9) infection, while an inverse pattern is observed following severe A(H1N1) infection, potentially suggesting a different mechanism of immune regulation between seasonal and avian influenza virus infections.<br><br>CONCLUSIONS: These data provide direct serological evidence that birth imprinting profoundly shapes the humoral immune landscape during zoonotic influenza infection and may influence subsequent disease outcome.}, }
@article {pmid41952250, year = {2026}, author = {Hawwash, NK and Sperrin, M and Martin, GP and Sinha, R and Matthews, CE and Schulze, MB and Hiensch, A and Amiano, P and Neuhouser, ML and Joshu, CE and Platz, EA and Freisling, H and Gunter, MJ and Renehan, AG}, title = {Sensitive Period Analysis of Adulthood BMI and Cancer Risk: An Individual Participant Data Meta-Analysis of Over 720,000 Participants in the ABACus 2 Consortium.}, journal = {International journal of cancer}, volume = {}, number = {}, pages = {}, doi = {10.1002/ijc.70464}, pmid = {41952250}, issn = {1097-0215}, support = {C19941/A28707/CRUK_/Cancer Research UK/United Kingdom ; IS-BRC-1215-20007//Manchester Biomedical Research Centre/ ; /CA/NCI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; N01WH22110/HL/NHLBI NIH HHS/United States ; 24152/HL/NHLBI NIH HHS/United States ; 32100-2/HL/NHLBI NIH HHS/United States ; 32105-6/HL/NHLBI NIH HHS/United States ; 32108-9/HL/NHLBI NIH HHS/United States ; 32111-13/HL/NHLBI NIH HHS/United States ; 321115/HL/NHLBI NIH HHS/United States ; 32118-32119/HL/NHLBI NIH HHS/United States ; 32122/HL/NHLBI NIH HHS/United States ; 42107-26/HL/NHLBI NIH HHS/United States ; 42129-32/HL/NHLBI NIH HHS/United States ; 44221/HL/NHLBI NIH HHS/United States ; //Intramural Research Program of the National Cancer Institute/ ; //International Agency for Research on Cancer/ ; //Imperial College London/ ; //European Commission (DG-SANCO)/ ; //Danish Cancer Society/ ; //Ligue Contre le Cancer/ ; //Institut Gustave-Roussy/ ; //Mutuelle G&#xe9;n&#xe9;rale de l'Education Nationale/ ; //Institut National de la Sant&#xe9; et de la Recherche M&#xe9;dicale/ ; //Deutsche Krebshilfe/ ; //Deutsches Krebsfor- schungszentrum/ ; //German Federal Ministry of Education and Research/ ; //Hellenic Health Foundation/ ; //Associa- zione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council/ ; //Dutch Ministry of Public Health, Welfare, and Sports/ ; //Netherlands Cancer Registry/ ; //LK Research Funds/ ; //Dutch Prevention Funds/ ; //Dutch Zorg Onderzoek Nederland/ ; //World Cancer Research Fund/ ; //Statistics Netherlands/ ; //Health Research Fund/ ; //Instituto de Salud Carlos III/ ; //Catalan Institute of Oncology/ ; //Swedish Cancer Society/ ; //Swedish Scientific Council/ ; //Region Sk&#xe5;ne and Region V&#xe4;sterbotten/ ; MR/N003284/1/MRC_/Medical Research Council/United Kingdom ; MC-UU_12015/1/MRC_/Medical Research Council/United Kingdom ; MR/M012190/1/MRC_/Medical Research Council/United Kingdom ; }, abstract = {At least 13 cancers are linked to obesity. We analyse time-to-event data using Sensitive Period Analysis to explore whether associations between body mass index (BMI) and cancer incidence vary throughout adulthood to inform cancer prevention strategies, policy and weight management trials of optimal intervention ages. Using the European Prospective Investigation into Cancer and Nutrition cohort, Atherosclerosis Risk in Communities study, Women's Health Initiative, Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial, NIH-AARP Diet and Health, we predicted BMI throughout adulthood. We landmarked to predefined ages of interest (AOI), ages 30 to 65 (5-yearly). Super-landmarking and a two-stage IPD meta-analysis were used. A single stratified Cox proportional hazards model with interaction terms between BMI and AOIs was fitted to analyse associations between per 5 kg/m[2] BMI at AOIs and cancer incidence and identify sensitive age periods. 720,210 participants were followed up over 9.85 years in men and 10.80 years in women. Positive associations were found per 5 kg/m[2] BMI across ages 30-65 for obesity-related cancers. Some evidence suggests BMI in the 40s-50s raises cancer risk more than baseline. Interactions by age were found in women at ages 35 and 40 for obesity-related cancers with HRs per 5 kg/m[2] of 1.04 (95% CI: 1.01, 1.07, I[2]:0%) and 1.05 (95% CI: 1.01, 1.09, I[2]:50%), respectively, and at ages 35-65 for postmenopausal breast cancer. Higher BMI increased obesity-related cancer risk across ages 30-65. Similar associations across adulthood suggest adiposity at any age increases cancer risk. Policymakers should prevent excess adiposity accumulation in early life to minimise cancer risk.}, }
@article {pmid41952631, year = {2026}, author = {Gilbert, JS and Milano, F}, title = {Conditioning for acute myeloid leukemia: looking beyond intensity.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2026.300787}, pmid = {41952631}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid41952636, year = {2026}, author = {Olivieri, DJ and Gooley, T and Manjappa, S and Walter, RB and Keel, S and Flowers, M and Storb, R and Vo, P}, title = {Impact of horse anti-thymocyte globulin on graft-versus-host disease after human leukocyte antigen-matched related bone marrow transplantation for severe aplastic anemia.}, journal = {Haematologica}, volume = {}, number = {}, pages = {}, doi = {10.3324/haematol.2026.300746}, pmid = {41952636}, issn = {1592-8721}, abstract = {Not available.}, }
@article {pmid41954104, year = {2026}, author = {Shitole, SG and Chen, E and Naveed, M and Xue, X and Sharma, A and Hanna, DB and Anastos, K and Kaplan, RC and Levsky, JM and Tien, PC and Radparvar, AA and Bortnick, AE and Budoff, MJ and Kizer, JR}, title = {Brief Report: Association of HIV and HCV With Adverse Coronary Artery Phenotypes in Women: Findings From a Cross-Sectional Study.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {101}, number = {4}, pages = {399-404}, doi = {10.1097/QAI.0000000000003808}, pmid = {41954104}, issn = {1944-7884}, support = {U01 AI035004/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; Cross-Sectional Studies ; Middle Aged ; *HIV Infections/complications ; *Hepatitis C/complications ; *Coronary Artery Disease/complications ; Phenotype ; Adult ; *Coronary Vessels/pathology ; Computed Tomography Angiography ; Aged ; }, abstract = {BACKGROUND: HIV and hepatitis C virus (HCV) have each been associated with increased risk of coronary heart disease events. Coronary computed tomography angiography (CCTA) has linked HIV to noncalcified plaque, and HCV to both calcified and noncalcified plaque, but available data come mostly or exclusively from men.<br><br>METHODS: We performed a cross-sectional study of CCTA in women from the Bronx site of the Multicenter AIDS Cohort Study/Women's Interagency HIV Study Combined Cohort Study to investigate associations of HIV and HCV status with adverse coronary artery phenotypes, including total plaque, noncalcified plaque, and coronary artery calcium (CAC).<br><br>RESULTS: Of 79 participants (median age 56 years), 53 were women with HIV (WWHIV) and 16 were women with positive HCV status all but 1 of whom had cleared viremia). On multivariable adjustment, WWHIV had near-significantly higher noncalcified plaque volume extent [RR = 3.53 (0.98, 12.68), P = 0.053] compared with women without HIV, but there were no significant associations of HIV with other coronary phenotypes. Compared with HCV-negative women, HCV-positive women exhibited a significantly higher CAC score [RR = 4.77 (1.44, 15.85), P = 0.010] and near-significantly greater odds of noncalcified plaque [OR = 4.25 (0.97, 18.73), P = 0.055] and total plaque [OR = 4.26 (0.96, 18.87), P = 0.056].<br><br>CONCLUSIONS: The present findings support the association of HIV with higher-risk, noncalcified plaque in women, and with a more calcific plaque phenotype in HCV-positive women even after viremic clearance. Although these results require further investigation in larger samples, they underscore the importance of implementing recommended cardiovascular preventive and HCV screening efforts in this vulnerable population.}, }
@article {pmid41954617, year = {2026}, author = {Sorror, ML and Artz, AS and Olin, RL and Ramlal, R and Giralt, SA}, title = {Eligibility is not appropriateness: Reframing the role of age in allogeneic transplant decision-making.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026020278}, pmid = {41954617}, issn = {2473-9537}, }
@article {pmid41955253, year = {2026}, author = {Childers, CP and Sutherland, MJ and Selzer, DJ and Sheth, KR and Nepomnayshy, D and Tyler, KM and Senkowski, CK and Mabry, CD}, title = {Characteristics of Open and Conversion to Open Operations in a Minimally Invasive Era: Implications for the Physician Fee Schedule.}, journal = {Journal of the American College of Surgeons}, volume = {}, number = {}, pages = {}, doi = {10.1097/XCS.0000000000001940}, pmid = {41955253}, issn = {1879-1190}, abstract = {BACKGROUND: Current procedural terminology (CPT) valuation historically treated open and minimally invasive (MIS) abdominopelvic operations as interchangeable services performed on similar patients. As MIS has become the dominant approach, open surgery may now represent a distinct and more complex clinical scenario. This study characterized contemporary open operation for common abdominopelvic procedures.<br><br>STUDY DESIGN: The 2023 American College of Surgeons National Surgical Quality Improvement Program database was analyzed for appendectomy, cholecystectomy, right colectomy, low anterior resection, and Hartmann's procedure. Cases were categorized as MIS, straight-to-open, or conversion-to-open. Patient characteristics, operative time, length of stay, and 30-day complications were compared across approaches using binomial regression models.<br><br>RESULTS: Among 105,085 operations, MIS predominated for appendectomy (98%), cholecystectomy (98%), low anterior resection (84%), and right colectomy (72%), whereas Hartmann's procedures were primarily open (77%). Conversions represented approximately half of open appendectomies and cholecystectomies and had the longest operative times, exceeding MIS operations by 147% for appendectomy and 116% for cholecystectomy. Compared with MIS, straight-to-open appendectomy was associated with increased length of stay (IRR 2.92) and higher complication odds (OR 4.02), with conversion-to-open appendectomy showing further stepwise increases (IRR 4.85; OR 7.07). Similar stepwise patterns from MIS to straight-to-open to conversion-to-open were observed across procedures.<br><br>CONCLUSIONS: In contemporary practice, open abdominopelvic operations are uncommon and frequently represent conversion from MIS, identifying a subgroup with longer operations, longer hospitalization, and higher complication rates. Current CPT coding and work relative value units may not reflect the greater clinical complexity and effort associated with these cases, supporting reconsideration of open procedure valuation.}, }
@article {pmid41955632, year = {2026}, author = {Danilov, AV and Coombs, CC and Phillips, T and Allan, JN and Barrientos, JC and Barta, SK and Choi, MY and Cohen, JB and Hill, BT and Karmali, R and Patel, K and Rhodes, JM and Sauter, C and Strati, P and Wang, Y and Shadman, M}, title = {Clinical strategies for lymphoma management: Recommendations from the Bridging the Gaps in Leukemia, Lymphoma, and Multiple Myeloma Consensus Conference 2025.}, journal = {Cancer}, volume = {132}, number = {8}, pages = {e70389}, doi = {10.1002/cncr.70389}, pmid = {41955632}, issn = {1097-0142}, mesh = {Humans ; *Lymphoma, Mantle-Cell/therapy ; *Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; *Lymphoma, Large B-Cell, Diffuse/therapy ; *Multiple Myeloma/therapy ; Consensus ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; }, abstract = {The Bridging the Gaps (BTG) in Leukemia, Lymphoma and Multiple Myeloma Consensus Conference 2025 brought together a multidisciplinary group of oncology experts to address the complexities of lymphoma management, focusing on mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and diffuse large B-cell lymphoma (DLBCL). This article presents consensus recommendations developed through a modified Delphi process, which emphasize the need for tailored therapeutic strategies in light of recent advancements in treatment options. Key recommendations include the screening for high-risk features in MCL, use of the BOVen regimen (zanubrutinib, obinutuzumab, and venetoclax) for TP53-aberrant cases, and integration of chimeric antigen receptor T-cell therapy for patients with mantle cell lymphoma that is refractory to covalent Bruton tyrosine kinase inhibitors. For CLL, recommendations include consideration of time-limited therapies for younger patients and a "watch and wait" strategy for asymptomatic patients despite the improved activity and safety of current treatment regimens. For DLBCL, this article highlights the challenges in treatment sequencing and the role of circulating tumor DNA and minimal residual disease testing in monitoring disease progression. Overall, the conference describes the importance of ongoing research to refine management strategies and improve patient outcomes in lymphoma care, addressing the gaps in clinical practice where high-level evidence is lacking.}, }
@article {pmid41958647, year = {2026}, author = {Fiore-Gartland, A and Mayer-Blackwell, K and Stray, J and Neradilek, M and Lo, A and Hannah, A and Dong, T and Serebryannyy, L and Carroll, R and Lin, BC and Koup, RA and Garcia, NMG and Marcelin, JR and Pettifor, AE and Janes, H and Brown, ER and Yen, C and Andriesen, J and Corey, L and Stephenson, KE and Kublin, JG}, title = {Profiling of SARS-CoV-2 virus shedding, antibody neutralization, and T-cell receptor repertoires in a large, multi-center cohort of young adults with varied prior exposures.}, journal = {Frontiers in immunology}, volume = {17}, number = {}, pages = {1731974}, pmid = {41958647}, issn = {1664-3224}, mesh = {Humans ; *SARS-CoV-2/immunology/physiology ; *COVID-19/immunology/virology ; *Antibodies, Viral/immunology/blood ; *Antibodies, Neutralizing/immunology/blood ; Male ; Female ; Young Adult ; Adult ; *Virus Shedding/immunology ; *Receptors, Antigen, T-Cell/immunology/genetics ; COVID-19 Vaccines/immunology ; Cohort Studies ; Adolescent ; }, abstract = {BACKGROUND: The cellular and neutralizing antibody responses to SARS-CoV-2 infection are complex, particularly with multiple and heterogeneous exposures. We sought to understand the changes to the antibody and T-cell repertoire elicited by mildly symptomatic or asymptomatic infections in young adults, and how immune responses to prior vaccination may interact with new viral exposures in this population. Additionally, profiling both aspects of humoral and cellular immunity from a single vial of blood is experimentally challenging.<br><br>METHODS: We developed a protocol to recover T-cell receptor (TCR) repertoires from frozen blood clots, i.e., remnant material, retained after coagulation of whole blood for serum recovery and antibody analysis. The method was applied to a subset of participants in a COVID-19 vaccine trial (CoVPN 3006, n = 209 participants). We sequenced TCR repertoires and measured anti-SARS-CoV-2 antibody responses from pre-exposure, post-vaccination, and post-breakthrough blood samples.<br><br>RESULTS: Clot material provided suitable genomic DNA for TCR profiling, with vaccination and infection leading to expansions in T-cell responses. Consistent with prior studies, we found that hybrid immunological exposures (vaccination after infection) lead to the greatest antibody potency and spike TCR breadth. When the order of exposure was reversed, we observed evidence of attenuated disease severity (reduced shedding duration and lower peak nasal viral load) in post-vaccination versus primary infections.<br><br>DISCUSSION: The protocols described here for recovery of TCR repertoires from remnant coagulated material will facilitate more common estimation of cellular and neutralizing antibody immune responses as potential correlates of protection in large clinical trial cohorts where peripheral blood mononuclear cell (PBMC) acquisition or analysis is otherwise infeasible.}, }
@article {pmid41959656, year = {2025}, author = {King-Okoye, M and Fuller, H and Tan, K and Marlow, N and Fleuriot, J and Tzatzakis, C and Kanodia, S and Odoh, K and Dubbala, K and Alvarez, JA}, title = {Explainable and reproducible AI: culturally responsive AI for health equity in minoritized groups.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1683783}, pmid = {41959656}, issn = {2673-253X}, abstract = {Artificial intelligence (AI) is transforming healthcare by enabling advanced diagnostics, personalized treatments, and improved operational efficiencies. By identifying complex data patterns and correlations, AI could supplement clinical decision-making, enabling more rapid diagnoses and treatment decisions tailored to meet the unique needs of diverse communities. However, realizing these benefits requires that clinical AI models be consistent, reliable, and validated across diverse populations and clinical environments. In addition, as these data patterns and correlations may often be unexpected, AI models require more explainability compared to other medical technologies. This is especially true for complex models, where the processes driving a model to make a prediction are often unclear and uninterpretable to both model developers and medical professionals, resulting in AI models frequently being described as "black boxes". To address this fundamental challenge of interpretability, explainable AI (XAI) has emerged as a critical approach, providing insight (often in a post-hoc manner) into why models generate their given output. Studies have shown that most physicians prefer XAI to non-explainable AI. This commentary therefore explores key considerations needed to ensure that AI promotes health equity in marginalized communities, building on similar shifts toward anticipatory health action that have been explored in humanitarian and climate AI contexts (8, 9). We argue that equity in AI depends on embedding explainability and reproducibility within culturally responsive frameworks that address historical and structural bias.}, }
@article {pmid41960203, year = {2023}, author = {Gao, F and Xia, F and Chan, KCG}, title = {DEFINING AND ESTIMATING PRINCIPAL STRATUM SPECIFIC NATURAL MEDIATION EFFECTS WITH SEMI-COMPETING RISKS DATA.}, journal = {Statistica Sinica}, volume = {33}, number = {4}, pages = {2495-2517}, pmid = {41960203}, issn = {1017-0405}, support = {R01 HL122212/HL/NHLBI NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; }, abstract = {In many medical studies, an ultimate failure event, such as death, is likely to be affected by the occurrence and timing of other intermediate clinical events. Both event times are subject to censoring by loss-to-follow-up, but the nonterminal event may be further censored by the occurrence of the primary outcome, but not vice versa. To study the effect of an intervention on both events, the intermediate event may be viewed as a mediator. However, the conventional definitions of direct and indirect effects do not apply, because of the semi-competing risks data structure. We define three principal strata based on whether the potential intermediate event occurs before the potential failure event. This allows us to properly define direct and indirect effects in one stratum, and define total effects for all strata. We discuss the identification conditions for the stratum-specific effects, and propose a semiparametric estimator based on a multivariate logistic stratum membership model and within-stratum proportional hazards models for the event times. By treating the unobserved stratum membership as a latent variable, we propose an expectation-maximization algorithm for the computation. We study the asymptotic properties of the estimators using modern empirical process theory and examine the performance of the estimators in numerical studies.}, }
@article {pmid41961496, year = {2026}, author = {Williamson, MR and Whitsel, EA and Smith, RL and Collins, JM and Stewart, JD and Jung, SY and Harris, HR and Feiler, MO and Manson, JE and Qi, L and Schwartz, GG}, title = {Residential Radon Levels and Ovarian Cancer Among Postmenopausal Women.}, journal = {JAMA network open}, volume = {9}, number = {4}, pages = {e268641}, pmid = {41961496}, issn = {2574-3805}, support = {P20 GM155890/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/epidemiology/etiology ; *Radon/analysis/adverse effects ; Middle Aged ; Aged ; *Postmenopause ; Prospective Studies ; United States/epidemiology ; *Environmental Exposure/adverse effects/statistics &amp; numerical data ; Risk Factors ; Housing/statistics &amp; numerical data ; }, abstract = {IMPORTANCE: Few environmental risk factors for ovarian cancer have been discovered. Women exposed to ionizing radiation from the atomic bomb during World War II experienced an increased risk of ovarian cancer. Today, the largest source of ionizing radiation is radon gas in the home, but whether ionizing radiation is associated with increased risk of ovarian cancer more broadly is unknown.<br><br>OBJECTIVE: To evaluate whether higher home radon levels are associated with increased risk of ovarian cancer.<br><br>This prospective cohort study included 127&#x202f;547 women from the Women's Health Initiative, including 40 clinical centers across the US, with outcomes followed up for 31 years (1993-2024). Postmenopausal women aged 50 to 79 years were enrolled in an observational study or 1 or more randomized clinical trials. All cases of ovarian cancer were physician adjudicated.<br><br>EXPOSURE: Radon measurements from the 1993 US Geological Survey, classified into low (<2 pCi/L), medium (2-4 pCi/L), and high zones (>4 pCi/L), were linked with the geocoded home addresses of participants at baseline (1993-1998).<br><br>MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for ovarian cancer, adjusted for covariates with 95% CIs.<br><br>RESULTS: Among the 127&#x202f;547 women (mean [SD] age, 63.1 [7.2] years) with available radon zone values, 1645 incident ovarian cancers and 1048 ovarian cancer deaths were observed over a mean (SD) follow-up of 17.7 (8.4) years. After adjustment for covariates, the HR for all ovarian cancers for women living in the medium radon zone compared with women living in the low radon zone was not significantly higher (HR, 1.13 [95% CI, 1.00-1.29]). However, the HR was significantly higher for women living in the high radon zone compared with those living in the low radon zone (HR, 1.31 [95% CI, 1.11-1.54]). Similar findings were observed for the most common histologic type, serous ovarian cancer, for which the HR in the medium zone was 1.06 (95% CI, 0.88-1.27) and the HR in the high zone was 1.38 (95% CI, 1.09-1.74). Ovarian cancer mortality also was significantly higher in the high radon zone compared with the low radon zone (HR, 1.31 [95% CI, 1.07-1.60]). Sensitivity analyses using 3 alternate radon measures produced similar results.<br><br>CONCLUSIONS AND RELEVANCE: In this large, prospective cohort of postmenopausal women, the risks of ovarian cancer incidence and mortality were significantly higher for women living in homes in the high radon zone. Residential radon is a ubiquitous and modifiable risk factor. This is the first epidemiologic study of radon and ovarian cancer among postmenopausal women to date, and its findings suggest a potential target for mitigating cancer risk.}, }
@article {pmid41961500, year = {2026}, author = {Trivedi, MS and Unger, JM and Henry, NL and Darke, AK and Hertz, DL and Brannagan, TH and Reyes, SJ and Schneider, BP and Irvin, WJ and Hathaway, AR and Vander Woude, AC and Gudena, VK and Cabrera-Galeana, P and Orsted, M and LeBlanc, M and Fisch, MJ and Hershman, DL}, title = {Risk Prediction Model for Taxane-Induced Peripheral Neuropathy in Early-Stage Cancer.}, journal = {JAMA network open}, volume = {9}, number = {4}, pages = {e264901}, pmid = {41961500}, issn = {2574-3805}, mesh = {Humans ; *Peripheral Nervous System Diseases/chemically induced/epidemiology ; Female ; Middle Aged ; *Taxoids/adverse effects/therapeutic use ; Aged ; Prospective Studies ; Risk Assessment/methods ; Male ; *Neoplasms/drug therapy/pathology ; Adult ; *Bridged-Ring Compounds/adverse effects ; Quality of Life ; Docetaxel/adverse effects ; Paclitaxel/adverse effects ; Risk Factors ; *Antineoplastic Agents/adverse effects ; }, abstract = {IMPORTANCE: Taxane-induced peripheral neuropathy (TIPN) affects quality of life and ability to complete cancer treatment and has limited effective interventions for prevention and treatment.<br><br>OBJECTIVE: To develop and validate a TIPN risk prediction model.<br><br>SWOG S1714 was a prospective observational cohort study conducted at sites in the National Cancer Institute National Community Oncology Research Program between March 1, 2019, and November 15, 2021, with 3 years of follow-up. The study included evaluable participants 18 years or older with stage I to III lung, breast, or ovarian, fallopian tube, or primary peritoneal cancer who were starting taxane-based treatment. Statistical analysis was conducted from December 2023 to June 2024.<br><br>EXPOSURES: Taxane-based regimens including paclitaxel or docetaxel.<br><br>MAIN OUTCOMES AND MEASURES: The primary end point was occurrence of TIPN by 24 weeks. TIPN was assessed using the patient-reported European Organization of Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-item scale (CIPN-20) at baseline and weeks 4, 8, 12, and 24. Occurrence of TIPN was defined as an increase of 8 points or more over baseline in the CIPN-20 sensory subscale score. With a 60% random sample of evaluable participants, best-subset selection using logistic regression and k-fold cross-validation identified a best model based on demographic factors, baseline comorbid conditions, and treatment factors. Adverse risk factors were summed, generating a score, split at the median and tested in the remaining 40% of evaluable participants. The target difference was 12% between high-risk vs low-risk groups.<br><br>RESULTS: A total of 1336 participants enrolled in S1714. Of 1278 evaluable participants (median age, 55.0 years [range, 23.0-84.0 years]; 1264 women [98.9%]; 1164 with breast cancer [91.1%]), 804 (62.9%) experienced TIPN by week 24. Using the training set of 768 participants, a risk prediction model for TIPN was developed that included 5 adverse risk factors: receipt of paclitaxel; stage II or III disease; planned taxane duration of more than 12 weeks; diabetes, autoimmune disease, moderate kidney disease, or a neurologic condition; and self-identified race and ethnicity (Black, Hispanic, Native American, Pacific Islander, multiple races, or unknown race or ethnicity). In the test set of 510 participants, TIPN was more common in high-risk (235 of 345 [68.1%]) vs low-risk (84 of 165 [50.9%]) groups (absolute difference, 17.2%), exceeding the 12% target.<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of participants with early-stage cancer receiving a taxane regimen, a set of baseline risk factors stratified TIPN risk. A risk prediction model may guide treatment decision-making, symptom monitoring, and enrollment in interventional trials for TIPN prevention and treatment.}, }
@article {pmid41962175, year = {2026}, author = {Symonds, L and Swensen, SN and Nguyen, MH and Hippe, DS and Mullen, TD and Pang, S and Liu, A and Hunter, N and Vinayak, S and Calhoun, KE and Javid, SH and Gadi, VK and Linden, H and Specht, J and Gwin, W and Kim, JN}, title = {Concurrent Chemotherapy With Adjuvant Radiation for Patients With High-risk Locally Advanced Breast Cancer: Safety and Outcomes.}, journal = {Clinical breast cancer}, volume = {26}, number = {5}, pages = {63-70}, doi = {10.1016/j.clbc.2026.03.005}, pmid = {41962175}, issn = {1938-0666}, abstract = {BACKGROUND: Concurrent chemoradiation (chemoXRT) enhances the efficacy of adjuvant radiation by radiosensitizing microscopic residual disease and may improve locoregional control. We report our institutional experience using adjuvant chemoXRT for high-risk breast cancer patients.<br><br>METHODS: We conducted a retrospective study of patients with stage II-III invasive breast cancer treated with chemotherapy, surgery, and adjuvant chemoXRT between 2006 and 2019. The use of chemoXRT was based on provider discretion. Locoregional recurrence (LRR) was the primary outcome. Secondary outcomes included distant recurrence, disease free survival (DFS), overall survival (OS), and toxicity. LRR incidence was estimated with distant recurrence and death as competing risks. DFS and OS were estimated using the Kaplan-Meier method.<br><br>RESULTS: Forty-two patients met inclusion criteria; 35 (83%) patients received treatment at primary diagnosis and 7 (17%) for a LRR. In the primary setting, 91% had stage III disease. Of the patients who received neoadjuvant chemotherapy (71%), all had residual disease in the breast or lymph nodes. The majority received comprehensive regional nodal irradiation (40, 95%) with a median total dose of 57 Gy (range: 45-68 Gy). Concurrent chemotherapies included capecitabine, cisplatin, or paclitaxel. At median follow-up of 5 years, LRR risk was 7% (95% CI: 2%-21%). DFS was 47% (95% CI: 34%-65%) and OS was 56% (95% CI: 42%-74%). ChemoXRT was well tolerated with expected rates of dermatitis and no new toxicity signals.<br><br>CONCLUSIONS: Concurrent chemoXRT was safe and showed promise as a method to decrease risk of local recurrence in high-risk patients. Prospective evaluation is needed.}, }
@article {pmid41962590, year = {2026}, author = {Heller, KB and Mohamed, JS and Cherne, SL and Onono, M and Bukusi, EA and Njoroge, BW and Kimanthi, S and Hassan, RM and Rechkina, EA and McClelland, RS and Brown, ER and Mugo, NR and Barnabas, RV and , }, title = {High agreement of Seegene Anyplex[TM] HPV 28 and Allplex[TM] HPV 28 for High-Risk Vaccine-Type HPV Detection in the KEN SHE Study.}, journal = {Journal of virological methods}, volume = {}, number = {}, pages = {115395}, doi = {10.1016/j.jviromet.2026.115395}, pmid = {41962590}, issn = {1879-0984}, abstract = {BACKGROUND: The KEN SHE Study replaced Anyplex[TM] II HPV28 Detection multiplex real-time PCR kits (Anyplex) with Allplex[TM] HPV28 kits (Allplex) mid-study. Assay comparison is necessary for ongoing research.<br><br>OBJECTIVES: To estimate agreement between Allplex and Anyplex assays for vaccine type HPV DNA detection within the KEN SHE Study.<br><br>STUDY DESIGN: The KEN SHE Study is a randomized clinical trial of single-dose HPV vaccination. HPV DNA measured in cervical swab specimens collected every six months is used to ascertain the study endpoint of persistent positive HPV. Two hundred specimens previously tested using Anyplex were randomly selected for re-assay using Allplex. Prespecified selection criteria ensured high positivity for HPV 16/18/31/33/45/52/58 (70% positive per Anyplex). Cohen's Kappa coefficients were used to assess inter-assay agreement.<br><br>RESULTS: Agreement between Anyplex and Allplex was &#x3ba;=0.93 (95%CI: 0.88 - 0.99) for HPV 16, &#x3ba;=0.96 (0.91 -1.00) for HPV 18, &#x3ba;=0.90 (95% CI: 0.90 -1.00) for HPV 31, &#x3ba;=0.93 (0.80 - 1.00) for HPV 33, &#x3ba;=0.65 (0.37, 0.94) for HPV 45, &#x3ba;=0.88 (0.79 - 0.97) for HPV 52, and &#x3ba;=0.92 (0.92-1.00) for HPV 58. Inter-assay agreement for combined vaccine types HPV 16/18, HPV 31/33/45/52/58, and HPV 16/18/31/33/45/52/58 was also high. Most discordant results either had high cycle threshold (ct) values on Allplex (ct>35) or a single semiquantitative '+' on Anyplex.<br><br>CONCLUSIONS: The Allplex assay has excellent agreement with Anyplex for individual HPV types 16, 18, 31, 33, 52, and 58, as well as combined HPV 16/18, HPV 16/18/31/33/45/52/58 and HPV 31/33/45/52/58. These results support continued analysis with the Allplex assay.}, }
@article {pmid41962684, year = {2026}, author = {Zhuo, J and Tolomeo, C and Kurani, A and Burke, M and Wang, S and Feng, A and Zhang, Y and Dee, EC and Su, CT}, title = {Palliative Care for Immigrants with Cancer in the United States: A Roadmap to Equitable Care.}, journal = {Journal of pain and symptom management}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jpainsymman.2026.03.018}, pmid = {41962684}, issn = {1873-6513}, abstract = {Across the United States, immigrants with cancer, especially those who are undocumented or from low-income backgrounds, encounter significant barriers to accessing quality palliative care. Despite cancer comprising over one-third of global palliative care needs, immigrant patients are often excluded from essential services due to lack of insurance, immigration status, limited English proficiency, and culturally discordant care models. These challenges contribute to delayed diagnoses, inadequate symptom management, and lower quality of end-of-life care. This narrative review identifies both patient level and systemic barriers and offers a four-part roadmap to address them. First, care models that prioritize cultural humility and respectful curiosity should be implemented through targeted training programs and workforce diversification. Second, community-based palliative care programs should be expanded through partnerships with trusted local organizations, bringing services directly into immigrant communities. Third, successful state-level innovations can be scaled, like California's Senate Bill 1004 and Illinois' Health Benefits for Immigrant Adults and Seniors. Finally, the routine use of patient-reported symptom tracking can improve diagnosis and guide treatment decisions. Drawing on data from national surveys, state-level policy evaluations, and peer-reviewed research on palliative care disparities, this review presents actionable strategies to ensure that all patients receive high-quality palliative care, regardless of their immigration status.}, }
@article {pmid41962747, year = {2026}, author = {Erickson, DPJ and Shaver, BA and Grassberger, C and Morimoto, A and Seitz, Z and Cui, S and Cao, N and Saini, J and Wong, T and Mian, O and Ford, E and Rengan, R and Zeng, J and Schwarz, M}, title = {Split-Dose FLASH irradiation to investigate the clinical feasibility of multifield treatments.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2026.03.053}, pmid = {41962747}, issn = {1879-355X}, abstract = {PURPOSE: The "FLASH effect", a phenomenon in which radiation-induced toxicity is diminished in healthy tissues when treated at ultra-high dose rates, has been demonstrated in several experimental models. We aim to evaluate the impact of split doses, the time interval between splits, and the effect of dose rate variations below and above the 40 Gy/s threshold.<br><br>METHODS AND MATERIALS: Mice received 16 Gy pelvic radiation with a scattering beam or a scanning beam. The conventional dose rate (CONV) was set at 0.5-1 Gy/s, while the FLASH effect was observed at dose rates ranging from 20 to 120 Gy/s. The mice were irradiated with a single dose or with a split-dose regime (1 or 2 splits) with pauses between treatments of either 30 seconds or 2 minutes. The endpoint was survival.<br><br>RESULTS: The hazard ratio of a single irradiation in FLASH mode vs CONV was 0.31, confirming the presence of the FLASH effect. A split dose with a single 30-second or 2-minute pause reduced overall survival, with hazard ratios of 0.53 and 0.56, respectively. However, survival was still higher compared to CONV. Two 2-minute pauses were not significantly worse than one 2-minute pause. The lowest dose rate at which a FLASH effect was detected was 20 Gy/s; no benefit was observed for dose rates above 60 Gy/s. For the endpoint of 50% survival rate, the FLASH modification factor is 0.91 and 0.96 for irradiations without and with 1 or 2 pauses, respectively.<br><br>CONCLUSIONS: The FLASH effect is attenuated by the introduction of a split-dose regimen. In the clinical implementation of FLASH, the benefit of multiple fields should be weighed against a reduction of the FLASH effect. For our endpoint, the minimum dose rate for FLASH is 20 Gy/s, while an increase from 60 Gy/s to 120 Gy/s is not beneficial.}, }
@article {pmid41963322, year = {2026}, author = {Warmuth, L and Dötsch, S and Trebo, M and Bellucci, S and Engels, S and Valdivia Manrique, R and Moukarzel, K and Schütz, JM and Hammel, M and Straub, A and Wagner, S and Hochholzer, A and Salinno, C and Seigner, J and Zajc, CU and Schmidt, GP and Michael, J and Nerreter, T and Hudecek, M and Traxlmayr, MW and Casucci, M and Riddell, SR and Poltorak, MP and Busch, DH and D'Ippolito, E}, title = {Balancing the efficacy and safety of chimeric antigen receptor T-cell therapy by affinity combination.}, journal = {Nature communications}, volume = {17}, number = {1}, pages = {}, pmid = {41963322}, issn = {2041-1723}, support = {SFB-TRR 338/1 2021-452881907 (project A01)//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {*Receptors, Chimeric Antigen/immunology/metabolism/genetics ; Animals ; Humans ; *Immunotherapy, Adoptive/methods/adverse effects ; Mice ; *T-Lymphocytes/immunology/transplantation/metabolism ; *Receptors, Antigen, T-Cell/immunology/metabolism/genetics ; Lymphocyte Activation/immunology ; Xenograft Model Antitumor Assays ; Cytokine Release Syndrome/immunology ; Cytokines/metabolism ; Cell Line, Tumor ; Female ; *Neoplasms/therapy/immunology ; }, abstract = {Recent studies suggest that Chimeric Antigen Receptor (CAR) binding affinity to its ligand affects CAR-T-cell functionality. Affinity engineering towards lower binding strengths might mitigate therapeutic side effects arising from intense CAR-T-cell activation as well as tumor relapse due to antigen-escape or limited persistence of CAR-T cells during sustained activation via high-affinity receptors. Here we characterize a broad range of CARs with varying affinities to the same target epitope and leverage the insights we gain to design a combined high- and low-affinity CAR product. While CAR affinity impacts in vitro functionality minimally, it strongly correlates with tumor control in vivo. Low-affinity binders cause only mild cytokine release syndrome (CRS) in humanized mouse models at the expense of anti-tumour efficiency. In mixtures with low-affinity CARs, high-affinity CARs maintain strong functionality while showing reduced signs of exhaustion and monocyte-induced cytokine production, compared to high-affinity CAR-T cells alone. In long term in vitro and in vivo settings, low-affinity CAR-T cells dominate over time, proving more resilience to chronic antigen exposure. Overall, our findings demonstrate that affinity combination represents a promising strategy to generate more effective CAR-T-cell products with an improved therapeutic index, beyond affinity engineering alone.}, }
@article {pmid41964503, year = {2026}, author = {Waligorski, N and Ronsley, R and Stasi, SM and Stevens, J and Rudzinski, ER and Lockwood, CM and Leary, SES and Cole, BL and Ting, MA and Paulson, V}, title = {Evaluating the Utility of Paired Tumor and Germline Targeted DNA Sequencing for Pediatric Oncology Patients: A Single Institution Report.}, journal = {Pediatric blood &amp; cancer}, volume = {}, number = {}, pages = {e70326}, doi = {10.1002/1545-5017.70326}, pmid = {41964503}, issn = {1545-5017}, support = {//The Brotman Baty Institute/ ; }, abstract = {OBJECTIVE: To evaluate the diagnostic yield and utility of universal paired tumor-normal multigene panel sequencing in newly diagnosed pediatric solid and central nervous system (CNS) tumor patients and to compare the detection of germline pathogenic/likely pathogenic variants (PV/LPVs) against established clinical referral criteria for cancer predisposition assessment.<br><br>METHODS: From May 2021 to November 2022, all patients with newly diagnosed and previously untreated CNS and non-CNS solid tumors who had planned ongoing oncology care at Seattle Children's Hospital were offered paired tumor-normal targeted next-generation sequencing (NGS) using the UW-OncoPlex cancer gene panel, versions 6, 7, and 8. Known variant testing was offered to a subset of parents whose child was identified to carry a PV/LPV in a cancer susceptibility gene (CSG). Participant data was retrospectively reviewed based on the most utilized pediatric cancer predisposition screening tools to determine whether a patient met clinical criteria for referral for genetic assessment.<br><br>RESULTS: A total of 193 patients were eligible for sequencing. A number of 158/193 (82%) patients underwent paired tumor-normal sequencing. Twenty-eight (17.7%) patients tested positive for a PV/LPV in a CSG. Ten (6.3%) patients had a P/LPV in a CSG associated with adult-onset cancer risks. Four of 28 (14.2%) patients with a PV/LPV in a CSG would have been missed by phenotype or family history-based referral criteria.<br><br>CONCLUSIONS: Paired tumor-normal multigene panel testing of pediatric tumors remains an unbiased method of capturing patients with an underlying cancer predisposition syndrome that may otherwise go undetected with more selective screening tools.}, }
@article {pmid41964525, year = {2026}, author = {Miller, CA and Kumar, AM and Mendoza, JA and Barsell, JD and Diala, OR and Glasgow, TE and Dahman, B and Bradley, C and Resnicow, K and Leader, A and Briant, KJ and Poynter, JN and Winn, RA and Fuemmeler, BF}, title = {Cancer prevention in context: interplay of perceived discrimination, neighborhood deprivation, and cancer-related risk and protective factors.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag101}, pmid = {41964525}, issn = {1460-2105}, abstract = {BACKGROUND: Socio-environmental deprivation and discrimination are associated with poorer cancer outcomes, yet their combined impact remains understudied. This study examines the independent and combined impact of these factors on cancer-related outcomes.<br><br>METHODS: Survey data (2018 to 2020) from 7,977 participants across six NCI-designated cancer centers assessed perceived discrimination (PD), area-level deprivation, lifestyle factors (smoking and obesity), and self-reported breast and colorectal cancer screening behaviors. Multivariate and multilevel logistic regression models estimated associations and the interclass correlation (ICC) quantified variation attributable to area-level factors.<br><br>RESULTS: High PD was associated with 2.28 times higher odds of current smoking (95% CI: 1.71-3.05) and 1.33 times higher odds of obesity (95% CI: 1.03-1.72), compared to those with low PD. Living in socially deprived areas increased the odds of smoking by 1.51 (95% CI: 1.20-1.89), relative to socially privileged areas. ICC estimates that 4% of the variation in the association between high PD on smoking, and 2% of the variation between medium PD and obesity, were attributable to area-level factors. Neither PD nor neighborhood disadvantage were significantly associated with being up-to-date on cancer screenings.<br><br>CONCLUSIONS: PD and neighborhood deprivation independently increase risk of smoking and obesity, both cancer risk factors, but were not significantly associated with screening behaviors. Area-level factors explain modest variation in these associations.<br><br>IMPACT: Findings highlight the importance of integrating both social experience (PD) and structural conditions (neighborhood deprivation) in cancer prevention research. For practice and policy, results underscore the need for multilevel strategies and targeted prevention efforts to reduce behavioral cancer risk.}, }
@article {pmid41966988, year = {2026}, author = {Warrier, L and Saito, A and Graham, JB and Swarts, JL and Vick, SC and MacLean, F and Potchen, NB and Cruz Talavera, I and Tsegaye, AT and Thomas, KK and Chohan, BH and Ngure, K and Mugo, N and Lingappa, JR and Lund, JM}, title = {Initiation of oral pre-exposure prophylaxis associated with changes in genital tract T cell phenotypes in women exposed to HIV.}, journal = {The Journal of infectious diseases}, volume = {}, number = {}, pages = {}, doi = {10.1093/infdis/jiag204}, pmid = {41966988}, issn = {1537-6613}, abstract = {Oral tenofovir-based HIV-pre-exposure prophylaxis (PrEP), approved for use in preventing human immunodeficiency virus (HIV) infection, has been implicated in altering the immune landscape. We leveraged longitudinal samples from heterosexual couples with the male partner living with HIV and the female partner without HIV initiating PrEP after enrollment. Applying high parameter flow cytometry to cells from ectocervical and vaginal biopsies and peripheral blood samples, we found a decrease in activated ectocervical CD8+ and CD4+ T cell subsets after oral PrEP exposure. Our data expand the understanding of the immunological impact of oral PrEP and potential protective mechanisms of PrEP usage.}, }
@article {pmid41968745, year = {2026}, author = {Reimer Jensen, AM and Johansen, ND and Wolff, PS and Vaduganathan, M and Bhatt, AS and Modin, D and Skaarup, KG and Duus, LS and Chatur, S and Claggett, BL and Janstrup, KH and Hill, JA and Van Spall, HGC and Larsen, CS and Larsen, L and Wiese, L and Dalager-Pedersen, M and Køber, L and Solomon, SD and Sivapalan, P and Jensen, JUS and Martel, CJ and Krause, TG and Biering-Sørensen, T}, title = {Electronic Nudges to Increase Influenza Vaccination in Immunosuppressed Adults Across the Age Spectrum: A Pooled Analysis of Two Nationwide Randomized Trials.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {}, number = {}, pages = {}, doi = {10.1093/cid/ciag219}, pmid = {41968745}, issn = {1537-6591}, abstract = {BACKGROUND: Immunosuppressed individuals face higher risk of severe influenza complications, yet vaccination coverage remains low. We aimed to assess the effect of electronic letter-based nudges on influenza vaccination uptake by immunosuppression status.<br><br>METHODS: We performed a participant-level pooled analysis of two methodologically harmonized, nationwide, pragmatic randomized clinical trials (NUDGE-FLU-2 and NUDGE-FLU-CHRONIC) conducted during the 2023-2024 influenza season. Adults aged &#x2265;65 years (NUDGE-FLU-2) and adults aged 18-64 years with chronic conditions (NUDGE-FLU-CHRONIC) were included, with immunosuppression defined by an immunosuppressive diagnosis or a filled prescription for immunosuppressive therapy. Participants were randomized in a 2.45:1:1:1:1:1:1 ratio to usual care or one of six electronic letter interventions. The primary outcome was receipt of influenza vaccination by January 1, 2024, ascertained from nationwide administrative health registries. Effect modification by immunosuppression status was assessed using binomial regression.<br><br>RESULTS: Among 1,181,254 participants (mean age 67 years; 73,830 [6.3%] immunosuppressed), 66.1% were vaccinated. Any letter increased vaccine uptake compared with usual care (absolute difference, 2.79 percentage points; 95% CI, 2.60-2.98; p<0.001), with greater effect among immunosuppressed individuals (+4.12 vs +2.70 percentage points; pinteraction=0.002). In younger adults with chronic conditions, letter-based nudges increased vaccination rates by 11.7 percentage points overall and by 13.3 percentage points among those with immunosuppression (pinteraction=0.007). Among immunosuppressed individuals, nudging effects appeared greater for those with immunosuppressive conditions than for those receiving immunosuppressive treatment.<br><br>CONCLUSIONS: Electronic letter-based nudges increased influenza vaccination rates, with greater benefit among individuals with immunosuppression. These findings support implementation of low-cost, letter-based nudging strategies to improve vaccine uptake in this high-risk population.}, }
@article {pmid41971714, year = {2026}, author = {Ahn, JJ and Yu, TC and Dadonaite, B and Radford, CE and Bloom, JD}, title = {Influenza hemagglutinin subtypes have different sequence constraints despite sharing extremely similar structures.}, journal = {Virus evolution}, volume = {12}, number = {1}, pages = {veag018}, pmid = {41971714}, issn = {2057-1577}, abstract = {Hemagglutinins (HAs) from different influenza A virus subtypes share as little as ~40% amino acid identity, yet their protein structure and cell entry function are highly conserved. Here, we examine the extent that sequence constraints on HA differ across three subtypes. To do this, we first use pseudovirus deep mutational scanning to measure how all amino-acid mutations to an H7 HA affect its cell entry function. We then compare these new measurements to previously described measurements of how all mutations to H3 and H5 HAs affect cell entry function. We find that ~50% of HA sites display substantially diverged preferences for different amino acids across the HA subtypes. The sites with the most divergent amino-acid preferences tend to be buried and have biochemically distinct wildtype amino acids in the different HA subtypes. We provide an example of how rewiring the interactions among contacting residues has dramatically shifted which amino acids are tolerated at specific sites. Overall, our results show how proteins with the same structure and function can become subject to very different site-specific evolutionary constraints as their sequences diverge.}, }
@article {pmid41973829, year = {2026}, author = {Banerjee, R}, title = {Point: CAR-T therapy is the preferred option in relapsed/refractory multiple myeloma.}, journal = {Blood advances}, volume = {}, number = {}, pages = {}, doi = {10.1182/bloodadvances.2026019898}, pmid = {41973829}, issn = {2473-9537}, }
@article {pmid41973985, year = {2026}, author = {Walsh, C and Palazzo, L and Hansell, L and Louie, T and Long, S and Brown, M and Hippe, DS and Coronado, GD and DeCell, K and Leone, RJ and Lodhi, S and Wysham, N and Wernli, KJ and Triplette, M}, title = {Lung cancer screening care pathways in community settings: An examination of three healthcare systems.}, journal = {Annals of the American Thoracic Society}, volume = {}, number = {}, pages = {}, pmid = {41973985}, issn = {2325-6621}, support = {R01 CA284032/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) is recommended for individuals ages 50-80 with a high-risk tobacco history, but implementation of LCS in community settings remains a significant challenge. The benefits of LCS are tempered by both low uptake and low adherence to recommended follow-up, supporting the need for community-engaged research in this area.<br><br>OBJECTIVE: The objective of this study was to understand LCS workflows throughout the care continuum in representative community-care settings.<br><br>DESIGN: This is a case study informed by multi-method data collection to characterize three community-based LCS programs in Washington state who are participating in a hybrid effectiveness-implementation trial to enhance LCS program care coordination.<br><br>PARTICIPANTS: This research was conducted in collaboration with three community-based LCS referral programs. Participants included program partners who participated in formalized site visits and interviews.<br><br>APPROACH: To develop and refine LCS workflows, we triangulated data from rapid ethnographic assessment site visits (n&#x2009;=&#x2009;5), semi-structured interviews with care providers (n&#x2009;=&#x2009;15), and member checking with key programmatic partners from each site. Rapid Group Analysis Process was used to integrate findings and guide the development and visualization of LCS workflows.<br><br>KEY RESULTS: The three community-based programs provide LCS services for their regional primary care networks with various levels of centralized programmatic support. LCS workflows from each site demonstrate varied staff involvement and resources along the LCS care continuum. Provider interviews identified the need for patient education and outreach, provider support and resources, and attention to gaps in care along the LCS continuum.<br><br>CONCLUSIONS: The LCS system-level workflows demonstrate three approaches to LCS care in community settings. LCS workflows can enable the timely identification of barriers and facilitators to improving LCS implementation in community settings.}, }
@article {pmid41974306, year = {2026}, author = {Ellithi, M and Raj, S and Bromberg, M and Goldstein, I and Saldia, A and Papadopoulos, EB and Gyurkocza, B and Ponce, DM and Shaffer, BC and Tamari, R and Young, JW and Politikos, I and Shah, GL and Alhomoud, M and Raju, G and Hughes, CFM and Dahi, PB and Scordo, M and Giralt, SA and Perales, MA and Goldberg, AD and Berman, E and Wang, X and Stein, EM and Gonen, M and Jakubowski, AA and Lin, RJ}, title = {The Impact of Post-Transplant Interventions and Chronic GVHD on Survival in Myeloid Malignancies Harboring TP53 Alterations.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.03.039}, pmid = {41974306}, issn = {2666-6367}, abstract = {BACKGROUND: Myeloid malignancies with TP53 alterations are characterized by genomic instability, chemotherapy resistance, and very poor outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). Hypomethylating agents (HMAs), small molecule targeted therapies, and donor lymphocyte infusion (DLI) are often used post-transplant to mitigate relapse risk in high-risk myeloid malignancies, but their impact on survival in TP53-mutated disease remains uncertain.<br><br>OBJECTIVES: To evaluate the impact of post-transplant interventions and graft-versus-host disease (GVHD) on relapse and survival outcomes in patients with TP53-mutated or chromosomal 17p-deleted myeloid malignancies.<br><br>STUDY DESIGN: This is a single-center retrospective study of adult patients with TP53-mutated and/or chromosomal 17p-deleted myeloid malignancies who underwent first allo-HCT between 2014 and 2023. Survival outcomes were assessed using the Kaplan-Meier method. Univariable Cox proportional hazards regression was used to assess associations of baseline characteristics with outcomes. Analyses of post-HCT interventions (maintenance/preemptive HMAs, targeted therapies, and/or DLI) and the development of chronic GVHD (classic chronic or acute/chronic overlap) were landmarked at 60 and 180 days, respectively, and both exposures were treated as time-dependent covariates. Cause-specific multivariable Cox proportional hazards regression models adjusted for baseline covariates were fitted to assess associations of outcomes with the time-dependent exposures. Pre-specified subgroup analyses were performed for the ultra-high-risk group, defined as complex karyotype and/or &#x2265;2 TP53/17p alterations.<br><br>RESULTS: Among 158 patients (median age 65 years, IQR: 57- 70), acute myeloid leukemia (54%) and myelodysplastic syndromes (40%) were the most common myeloid malignancies. Complex karyotypes were present in 68%, and ultra-high-risk features were present in 73%. Reduced-intensity conditioning was used in 59%. Approximately 49% of patients received post-HCT interventions; 68% of these were administered before relapse (preemptively or as prophylaxis/maintenance). In a landmark analysis at day 60 post-HCT (N=145), pre-relapse HMA, targeted therapies, and/or DLI was not associated with improved overall survival (OS) (HR 0.95; 95% CI: 0.56, 1.62; p=0.80), progression free survival (PFS) (HR 0.95; 95% CI: 0.49, 1.30; p=0.40), or cumulative incidence of relapse (CIR) (HR 1.05; 95% CI: 0.60, 1.85; p=0.90) after adjusting for key baseline characteristics. Similarly, in a landmark analysis at day 180 post-HCT (N=100), the occurrence of chronic GVHD was not associated with OS (HR 0.78; 95% CI: 0.24, 2.61; p=0.70), PFS (HR 0.67; 95% CI: 0.20, 2.23; p=0.50), or CIR (HR 0.34; 95% CI: 0.05, 2.54; p=0.30). Findings were similar in the ultra-high-risk subgroup (N=115) where post-HCT interventions showed no association with OS (HR 0.81; 95% CI: 0.45, 1.45; p=0.50), PFS (HR 0.72; 95% CI: 0.42, 1.24; p=0.20), or CIR (HR 0.87; 95% CI: 0.46, 1.62; p=0.70).<br><br>CONCLUSIONS: In this single center study, preemptive or prophylactic post-HCT interventions did not significantly improve survival or reduce relapse risk in patients with TP53-altered myeloid malignancies, including those with ultra-high-risk features. While the study was limited by its small sample size and heterogeneous interventions, these findings highlight the urgent need to develop novel therapeutic strategies for this high-risk population.}, }
@article {pmid41974584, year = {2026}, author = {Law, AD and Lipton, JH}, title = {Allogeneic HSCT in Aplastic Anemia: Current Evidence, Controversies, and Practical Decision-Making.}, journal = {American journal of hematology}, volume = {}, number = {}, pages = {}, doi = {10.1002/ajh.70319}, pmid = {41974584}, issn = {1096-8652}, abstract = {Morbidity and mortality in bone marrow failure syndromes such as acquired aplastic anemia (AA) are driven by severe and prolonged cytopenia. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is potentially curative and offers a rapid route to hematopoietic reconstitution. In 2026, reduced-toxicity conditioning, improved supportive care, and novel graft versus host disease prevention through post-transplant cyclophosphamide (PTCy)-based platforms have brought alternative donor transplantation into the mainstream. This review examines contemporary evidence, particularly looking at the expanded role of transplant outside the widely accepted setting of younger patients with matched sibling donors and offers a pragmatic framework for context-adapted decision-making.}, }
@article {pmid41979606, year = {2026}, author = {Devall, MA and Taha, HM and Chen, M and Eaton, SD and Sun, X and Venkatesh, S and Ramirez, A and Habib, FZ and Ali, MW and Cooper, GS and Willis, J and Hu, G and Ebrahim, S and Schmit, SL and Peters, U and Powell, SM and Yoshida, C and Li, L}, title = {Interrogating the mechanistic link between neighborhood deprivation and colorectal cancer risk through transcriptomic analysis of normal colorectal biopsies.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1158/1055-9965.EPI-25-1685}, pmid = {41979606}, issn = {1538-7755}, abstract = {BACKGROUND: Greater neighborhood deprivation, as defined by the Neighborhood Deprivation Index (NDI), has been associated with increased colorectal cancer (CRC) risk. However, the biological mechanisms underlying this association remain unclear.<br><br>METHODS: Normal colorectal biopsies (matched right and left colon, and rectum) from African Americans (AA; (n = 34)) and European Americans (EA; (n = 23)) adults undergoing colonoscopy were collected for a cross-sectional study in Cleveland, Ohio. NDI-associated differentially expressed genes (DEGs) were identified from RNA-sequencing (RNA-seq) using limma. Normal colon organoid lines were derived from biopsies of AA (n = 4) and EA (n = 6) individuals in Charlottesville, Virginia, treated daily with metformin for 72-hours, and metformin-DEGs were identified in limma.<br><br>RESULTS: A total of 237 DEGs were found to be commonly associated with NDI in AA and EA populations across individual-matched biopsy triplets (right and left colon, and rectum). Of the 237 NDI-associated DEGs, 82 overlapped with CRC tumor DEGs from a publicly available dataset (P=2.21E&#x207b;05), and nine were prioritized as therapeutic targets, including MYC overexpression (Benjamani Hochberg (BH)=2.48E-12). Metformin exposure in colon organoids also altered the expression of 28 of these genes, with ~79% showing opposite direction, including reduced MYC expression (BH=0.095).<br><br>CONCLUSIONS: NDI is associated with CRC-related transcriptional differences. The observed reversal of gene expression by metformin, including at MYC, suggests a potential role for metformin in reducing CRC risk by modifying NDI-high related gene expression.<br><br>IMPACT: NDI-associated CRC risk genes provide novel opportunity for future biomarkers or early therapeutic targets in at-risk populations.}, }
@article {pmid41980093, year = {2026}, author = {Romero, EV and Clyde, AE and Giorgi, EE and Westfall, DH and Azam, W and Taylor, ML and Caskey, M and Feder, AF and Cohn, LB}, title = {Recurrent mutations drive rapid HIV escape from two broadly neutralizing antibodies in vivo.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {123}, number = {16}, pages = {e2524021123}, doi = {10.1073/pnas.2524021123}, pmid = {41980093}, issn = {1091-6490}, support = {UM1AI64565//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01AI169385//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; Research Scholars//Pew Charitable Trusts (Pew)/ ; 1DP2CA280623-01//HHS | NIH | National Cancer Institute (NCI)/ ; Research Scholars//Gilead Sciences (Gilead)/ ; }, mesh = {Humans ; *HIV Infections/immunology/virology/drug therapy ; *Mutation ; *Antibodies, Neutralizing/immunology/genetics/therapeutic use ; *HIV Antibodies/immunology/genetics ; *HIV-1/genetics/immunology ; env Gene Products, Human Immunodeficiency Virus/genetics/immunology ; *Immune Evasion/genetics ; Broadly Neutralizing Antibodies/immunology ; }, abstract = {Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding in vivo viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full-length HIV envelope (env) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify in vivo routes and parallelism underlying HIV escape from each bNAb, providing insight into this evolutionary process. We find that 10-1074 escape is restricted to a small number of previously documented pathways seen across participants, but these escape mutations 1) emerge via extensively recurrent mutation, 2) are not equally preferred, and 3) can preexist at low frequency in intrahost viral populations before therapy, although their detection does not predict rebound timing. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one intrahost population rarely emerge or spread in other populations, except among highly related viruses. Despite this, 3BNC117 escape mutations can still emerge recurrently within their host. Our findings map longitudinal in vivo antibody escape across 20 diverse clade B HIV intrahost populations and reveal clinically relevant resistance dynamics that highlight how combination bNAb therapies will need to contend with extensively recurring escape mutations and dependence on genetic background.}, }
@article {pmid41980929, year = {2026}, author = {Hansen, DK and Dima, D and Mian, H and Devos, J and Brazauskas, R and Oloyede, T and Afrough, A and Ahmed, N and Anderson, L and Banerjee, R and Berdeja, JG and Bidikian, A and Dhakal, B and Dias, A and Efebera, Y and Faisal, MS and Gowda, L and Hashmi, H and Mirza, AS and Mohan, M and Narra, R and Rosko, AE and Schroeder, M and Nishihori, T and Landau, H and Usmani, S and Pasquini, MC and Akhtar, OS and Sidana, S and Patel, KK}, title = {Safety and efficacy of ciltacabtagene autoleucel for relapsed/refractory multiple myeloma: a CIBMTR study.}, journal = {Blood cancer journal}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41408-026-01496-w}, pmid = {41980929}, issn = {2044-5385}, support = {U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; U24CA076518//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; 75R60222C00011//U.S. Department of Health &amp; Human Services | Health Resources and Services Administration (Health Resources &amp; Services Administration)/ ; 75R60222C00011//U.S. Department of Health &amp; Human Services | Health Resources and Services Administration (Health Resources &amp; Services Administration)/ ; 75R60222C00011//U.S. Department of Health &amp; Human Services | Health Resources and Services Administration (Health Resources &amp; Services Administration)/ ; 75R60222C00011//U.S. Department of Health &amp; Human Services | Health Resources and Services Administration (Health Resources &amp; Services Administration)/ ; N00014-25-1-2146//United States Department of Defense | United States Navy | Office of Naval Research (ONR)/ ; N00014-25-1-2146//United States Department of Defense | United States Navy | Office of Naval Research (ONR)/ ; N00014-25-1-2146//United States Department of Defense | United States Navy | Office of Naval Research (ONR)/ ; N00014-25-1-2146//United States Department of Defense | United States Navy | Office of Naval Research (ONR)/ ; }, abstract = {Ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy, was approved in 2022 for heavily pretreated relapsed/refractory multiple myeloma (RRMM). This study evaluates the safety and efficacy of cilta-cel in RRMM patients reported to the Center for International Blood and Marrow Transplant Research registry between March 2022 and December 2023 who met commercial release specifications. Among 595 patients, median age was 64 years, 57% were male, and 70% had ≥1 comorbidity. Extramedullary disease and marrow plasma cell burden ≥ 50% were present in 13% and 14% of patients, respectively. The median number of prior lines of therapy was 7 and 8% had received prior BCMA-directed therapy. Median follow-up was 12 months (range, 1-25 months). Cytokine release syndrome occurred in 80% (≥ grade 3: 4%) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 22% (≥ grade 3: 4%). Non-ICANS neurotoxicity was seen in 5% (n = 31), including Parkinsonism in 2.7% (n = 16) and cranial nerve palsies in 2.5% (n = 15), primarily cranial nerve VII (n = 12/15). Infections occurred in 47% and treatment-related mortality was 5%. The best overall response rate was 87%, with ≥ very good partial response rate in 75%, and ≥ complete response rate in 35%. Estimated 12-month progression-free and overall survival were 73% (95% CI: 68-77%) and 85% (95% CI: 81-88%), respectively. This represents the largest standard-of-care (SOC) study of cilta-cel in RRMM patients to date. Despite advanced disease and high comorbidity burden, cilta-cel demonstrated favorable safety and efficacy, supporting its use in clinical practice.}, }
@article {pmid41981308, year = {2026}, author = {Mahalingam, D and Shroff, RT and Carneiro, BA and Ji, Y and Coveler, AL and Cervantes, A and Sahai, V and Ploquin, A and Hiret, S and LoConte, NK and Percent, IJ and Lopez, CD and Pernot, S and Kavan, P and Mulcahy, M and Carr, R and Giles, FJ and Seifarth, C and Ugolkov, A and Weiskittel, T and Fine, G and Jaros, M and Mazar, AP and Bekaii-Saab, TS}, title = {Elraglusib and chemotherapy in metastatic pancreatic ductal adenocarcinoma: a randomized controlled phase 2 trial.}, journal = {Nature medicine}, volume = {}, number = {}, pages = {}, pmid = {41981308}, issn = {1546-170X}, abstract = {Metastatic pancreatic ductal adenocarcinoma (mPDAC) is one of the leading causes of cancer-related mortality, but advances in therapeutic treatments remain limited. Elraglusib (9-ING-41), an inhibitor of GSK-3β, exhibits a multimodal mechanism of action based on antitumor activity in preclinical models of cancer, including pancreatic. The efficacy and safety of elraglusib with gemcitabine plus nab-paclitaxel (GnP) were assessed in patients with previously untreated mPDAC. In an open-label, international, multicenter, phase 2 study, patients were randomized 2:1 to weekly elraglusib/GnP or GnP alone. Primary endpoints were median overall survival (OS) and 1-year survival rate. The prespecified modified intention-to-treat population included 155 patients on elraglusib/GnP and 78 on GnP. As of the data cutoff of 27 April 2025, elraglusib/GnP improved median OS by 2.9 months and decreased the risk of death by 38% versus GnP (median OS 10.1 months versus 7.2 months, respectively (hazard ratio 0.62; 95% confidence interval 0.46 to 0.84; P = 0.01)). The 1-year survival rates were 44.1% versus 22.3%, respectively. The safety profile of elraglusib/GnP was manageable. The most common grade 3 or higher treatment-emergent adverse events (TEAEs) with elraglusib/GnP versus GnP alone were neutropenia (52.3% versus 30.8%), anemia (25.2% versus 29.5%) and fatigue (16.8% versus 5.1%). Explorative correlative analyses demonstrated that baseline circulating immune-related factors (that is, CXCL2 and TRAIL ligands) were associated with improved survival in the elraglusib/GnP arm. Treatment was accompanied by increases in intratumoral cytotoxic immune cell populations. Together, these findings support the clinical activity of elraglusib/GnP as first-line treatment in mPDAC and provide a biological context for the observed survival benefit. Based on the results of this phase 2 trial, a phase 3 trial is being planned. ClinicalTrials.gov registration: NCT03678883.}, }
@article {pmid41981715, year = {2026}, author = {Braun, LW and Pedroso, CM and Cotter, HM and Dean, D and Prado-Ribeiro, AC and Martins, MD and Sollecito, TP and DeLisser, HM and Santos-Silva, AR}, title = {Spirituality and Religiosity in Adults With Head and Neck Cancer: A Scoping Review of Concepts, Measures, and Outcomes.}, journal = {Oral diseases}, volume = {}, number = {}, pages = {}, doi = {10.1111/odi.70335}, pmid = {41981715}, issn = {1601-0825}, abstract = {OBJECTIVE: To synthesize evidence on spirituality in patients with head and neck cancer (HNC), focusing on its dimensions, assessment strategies, and impact on health outcomes.<br><br>METHODS: A comprehensive search of PubMed, Embase, LILACS, Web of Science, Scopus, and gray literature identified qualitative and quantitative studies explicitly addressing spirituality in HNC. Eligible sources were narratively synthesized.<br><br>RESULTS: Twenty-one studies met inclusion criteria. Core spiritual dimensions included the search for meaning, inner peace, religious faith, and a positive outlook. Six studies reported associations between spirituality and improved quality of life (QoL), while three described enhanced coping capacity and emotional resilience. Religious faith, irrespective of denomination, was associated with better pain management, fewer treatment-related side effects, lower existential distress, and, in some studies, improved survival outcomes. The Functional Assessment of Chronic Illness Therapy-Spiritual Well-being Scale was the most frequently applied instrument, assessing beliefs, meaning, and inner peace.<br><br>CONCLUSION: Spirituality was frequently associated with coping capacity, psychological adjustment, and QoL in patients with HNC. Integrating spiritual care into holistic oncology practice may enhance treatment adherence, resilience, and patient well-being.}, }
@article {pmid41981957, year = {2026}, author = {Karaba, A and Lewis, H and Boonyaratanakornkit, J}, title = {Antibodies as Therapy: A Coming of Age in Transplantation.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {}, number = {}, pages = {e70215}, doi = {10.1111/tid.70215}, pmid = {41981957}, issn = {1399-3062}, }
@article {pmid41982242, year = {2026}, author = {Moon, J and Choi, M and Kim, Y and Rhee, H and Park, SJ and Kim, JS and Lee, IJ}, title = {Deep learning-based auto-segmentation and RECIST evaluation after concurrent chemoradiotherapy in locally advanced hepatocellular carcinoma patients.}, journal = {Frontiers in oncology}, volume = {16}, number = {}, pages = {1775269}, pmid = {41982242}, issn = {2234-943X}, abstract = {BACKGROUND AND PURPOSE: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality, and intrahepatic progression after following treatment is common. Accurate tumor evaluation is essential for treatment decisions but remains challenging due to tumor heterogeneity, the background of cirrhotic liver, and treatment-related artifacts. This study investigated the feasibility of a deep learning-based auto-segmentation approach for response evaluation in locally advanced HCC treated with concurrent chemoradiotherapy (CCRT).<br><br>METHODS: We retrospectively analyzed 83 treatment-na&#xef;ve patients with locally advanced HCC who underwent definitive CCRT between 2016 and 2021. Tumor contours were manually delineated on pre-treatment (CTpre) and first post-treatment CT (CTpost). A fully convolutional DenseNet (FCD) and an intentional deep overfit learning (IDOL) framework were trained and validated. Performance was assessed using the Dice similarity coefficient (DSC), and RECIST-based diameters were compared between manual and predicted contours.<br><br>RESULTS: In the full cohort, the FCD model achieved mean DSCs of 0.53 for CTpre and 0.33 for CTpost, while the IDOL model improved CTpost DSCs to 0.49. In the RECIST cohort (n = 63), mean DSCs were 0.61 for CTpre and 0.53 for CTpost using FCD, versus 0.63 for IDOL. For the RECIST cohort (n = 14 validation cases), predicted diameters differed by a mean of 9.2 mm from manual values (p = 0.032), showing a tendency toward overestimation in peritumoral inflammatory areas. However, RECIST-based response showed high concordance in 13 of 14 cases.<br><br>CONCLUSIONS: The patient-specific IDOL framework improved auto-segmentation accuracy compared with conventional models and provided reliable data for RECIST-based response assessment. Despite limitations and lack of external validation, this study demonstrates the preliminary feasibility of auto-segmentation to support response evaluation in treated HCC.}, }
@article {pmid41984442, year = {2026}, author = {Childers, CP and Selzer, DJ}, title = {Recalibrating Productivity Benchmarks.}, journal = {JAMA surgery}, volume = {}, number = {}, pages = {}, doi = {10.1001/jamasurg.2026.0889}, pmid = {41984442}, issn = {2168-6262}, }
@article {pmid41984598, year = {2026}, author = {Mishra, R and Song, S and Choradia, D and Rudoy, D and Wladyka, CL and Hoang, P and Kim, JY and Coleman, IM and Arora, S and Dobersch, S and Orellana, AE and Lin, C and Gafken, PR and Corey, E and Nelson, PS and Kugel, S and Li, H and Sengupta, A and Hsieh, AC}, title = {Therapeutic targeting of the eIF4E cap-binding domain reveals control of lineage fate in prostate cancer.}, journal = {The Journal of clinical investigation}, volume = {}, number = {}, pages = {}, doi = {10.1172/JCI199838}, pmid = {41984598}, issn = {1558-8238}, abstract = {Lineage plasticity underscores the resilience of cancer cells in the context of drug treatment. However, lineage fates can also be therapeutically directed. We demonstrate that the eukaryotic initiation factor 4E (eIF4E) cap-binding domain is a critical regulator of lineage plasticity in prostate cancer. Using a first-in-class cap-binding domain inhibitor, we found that plasticity is driven by translational repression of basal keratins through a shared cis-regulatory element enciphered in their 5' untranslated regions (UTRs). Simultaneously this stabilized the androgen receptor (AR) through translational upregulation of the deubiquitinases BAP1 and OTUD3. This lineage program is essential for cell survival and drives a druggable vulnerability. Notably, tumors resistant to AR blockade regained sensitivity upon eIF4E cap-binding domain inhibition, which reprogrammed them toward a luminal state. In castration-resistant prostate cancer (CRPC) patients, elevated eIF4E expression was associated with a basal phenotype, reduced luminal differentiation and accelerated resistance to AR pathway inhibitors (ARPIs). These discoveries uncover a role for the eIF4E cap-binding domain in lineage plasticity and highlight that targeting this domain offers a promising strategy to overcome treatment resistance in prostate cancer.}, }
@article {pmid41985129, year = {2026}, author = {Heymach, JV and Yamamoto, N and Girard, N and Ruiter, G and Smit, EF and Planchard, D and Nadal, E and Wu, YL and Zugazagoitia, J and Tu, HY and Baik, CS and Yoh, K and Soo, RA and Zhao, Y and Sabari, JK and Wermke, M and Scheffler, M and Ahn, MJ and Fernamberg, K and Schroeter, L and Sadrolhefazi, B and Thamer, C and Eigenbrod-Giese, S and Popat, S and , }, title = {First-Line Zongertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer.}, journal = {The New England journal of medicine}, volume = {}, number = {}, pages = {}, doi = {10.1056/NEJMoa2516969}, pmid = {41985129}, issn = {1533-4406}, abstract = {BACKGROUND: Until recently, no first-line targeted treatment options were available for patients with human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxic effects.<br><br>METHODS: We conducted a phase 1a-1b, multicohort trial to assess zongertinib in patients with advanced or metastatic nonsquamous HER2-mutant NSCLC. Here, we evaluated zongertinib at a dose of 120 mg once daily in patients who had not previously received treatment (cohort 2). The primary end point was objective response as assessed by blinded independent central review. Secondary end points included duration of response and progression-free survival. In addition, zongertinib was evaluated in patients with active brain metastases (exploratory cohort 4).<br><br>RESULTS: In cohort 2, a total of 74 previously untreated patients received zongertinib at a dose of 120 mg. As of August 21, 2025, the percentage of patients with a confirmed objective response was 76% (95% confidence interval [CI], 65 to 84); the median duration of response was 15.2 months (95% CI, 9.8 to not evaluable), and the median progression-free survival was 14.4 months (95% CI, 11.1 to not evaluable). Adverse events of any grade occurred in 73 patients (99%), including events of grade 3 or higher in 33 patients (45%). Treatment-related adverse events occurred in 67 patients (91%), including events of grade 3 or higher in 14 patients (19%). In cohort 4, a total of 30 patients with active brain metastases received zongertinib at a dose of 120 mg; of these, 47% (95% CI, 30 to 64) had a confirmed intracranial objective response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. In this cohort, treatment-related adverse events of grade 3 or higher occurred in 5 patients (17%).<br><br>CONCLUSIONS: Zongertinib showed sustained efficacy in previously untreated patients with advanced or metastatic HER2-mutant NSCLC. Treatment-related adverse events were predominantly low-grade. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).}, }
@article {pmid41986233, year = {2026}, author = {Hamm, DC and O'Donnell, AB and Bennett, SR and Lemmers, RJLF and van der Vliet, PJ and van der Maarel, SM and Tapscott, SJ}, title = {KLF18 is a necessary component of the DUX4-initiated transcriptional network and a candidate locus for phenotypic diversity.}, journal = {Genes &amp; development}, volume = {}, number = {}, pages = {}, doi = {10.1101/gad.353253.125}, pmid = {41986233}, issn = {1549-5477}, abstract = {DUX4 initiates the first wave of zygotic genome activation (ZGA) in the human embryo, and its misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). However, other factors that help regulate ZGA-like transcription in human development and disease are still not fully understood. Here we identify Krüppel-like factor 18 (KLF18) as a component of a DUX4 feed-forward network that is necessary for expression of KLF17 and a subset of DUX4-regulated totipotency-associated genes. We mapped the genome-wide binding profile of KLF18 downstream from DUX4 and showed that its activity is influenced by DUX4 and chromatin accessibility. We found that in contrast to the rodent ortholog, human KLF18 has a predicted β-solenoid structure composed of a variable number of tandem repeats (VNTR) with multiple different structural variants in the human population. Expression of different KLF18 variants in combination with DUX4 showed similar transcriptional activity, whereas assessment of KLF18 structural variants in individuals with FSHD1 showed inconsistent association with disease severity that requires further study as a modifier locus. Together, these findings establish the polymorphic transcription factor KLF18 as a critical component of a DUX4-initiated feed-forward network and a candidate locus for human diversity.}, }
@article {pmid41986366, year = {2026}, author = {Schmidt, SD and Subramanian, R and Basappa, M and Carroll, R and Rexhepaj, M and Posavad, CM and Liao, JA and Bohl, JA and Chowdhury, A and Spaulding, AB and Lin, BC and Castro, M and Koup, RA and Serebryannyy, LA and Douek, DC}, title = {SARS-CoV-2 vaccination and infection elicit cross-neutralizing responses against clade 3 and 4 sarbecoviruses.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71662-y}, pmid = {41986366}, issn = {2041-1723}, abstract = {Two sarbecoviruses, SARS-CoV-1 and SARS-CoV-2 that engage ACE2 through their receptor-binding domains, have caused major human outbreaks. The pandemic potential of sarbecoviruses has prompted the discovery and classification of bat and other zoonotic sarbecoviruses that are also able to use human ACE2 or ACE2 ortholog receptors for infection. However, the current human immunological landscape reactive to these SARS-CoV-2-related viruses is not well profiled. Using a panel of pseudotyped lentiviruses expressing only spike proteins, we assess serum neutralization activity against clade 3 and 4 (also designated as clade 1c) receptor binding domain classified sarbecoviruses in a cohort who received a primary series of COVID-19 mRNA vaccines as well as individuals before and after infection with BA.5 or XBB.1.5 variants. Detectable neutralizing responses against clade 3 and 4 sarbecoviruses are observed in both vaccinees and convalescents and are comparable in magnitude to titers against SARS-CoV-2 variants. Infection with XBB.1.5 increases neutralization titers against SARS-CoV-2 variants as well as against clade 3 and 4 sarbecoviruses. Collectively, our findings suggest that the current immunologic landscape of vaccination and infection may confer some level of immunity against a variety of clade 3 and 4 sarbecoviruses, which should inform future pandemic response and pan-sarbecovirus countermeasure efforts.}, }
@article {pmid41986623, year = {2026}, author = {Mehta, RS and Kanakry, CG and Nawas, M and Lazaryan, A and Kanakry, JA and Holtan, S and Al-Juhaishi, T and Rimando, JC and Singh, A and Saultz, J and Mccurdy, SR and Milano, F}, title = {Haploidentical versus matched unrelated donor transplantation with post-transplant cyclophosphamide: a platform-dependent machine learning analysis of donor age.}, journal = {Leukemia}, volume = {}, number = {}, pages = {}, pmid = {41986623}, issn = {1476-5551}, abstract = {In allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy), clinicians frequently face a critical choice between a readily available, often younger, haploidentical and a fully matched unrelated donor (MUD). The platform-specific influence of donor age on survival is a critical, unquantified factor that complicates clinical decision-making. We retrospectively analyzed 4258 adult patients with acute leukemia who underwent first allogeneic HCT with PTCy (2017-2021). We employed machine learning (Random Survival Forests and DeepSurv) alongside robust regression models, including Inverse Probability of Treatment Weighting, 1:1 Propensity Score Matching, and Elastic-Net penalized Cox regression. Machine learning models revealed a divergent association of donor age with survival depending on donor type. The MUD-PTCy platform proved remarkably resilient; a 1% absolute increase in mortality risk (equivalent to Number-Needed-to-Harm of 100) did not emerge in donors up to age 50. In stark contrast, the age-sensitive Haploidentical cohort reached this same risk threshold at a donor age of just 38 years. MUD-PTCy was independently associated with a significant overall survival advantage (Adjusted Hazard Ratio 0.85; 95% confidence interval, 0.75-0.97; P = 0.01). This analysis provides a quantitative framework to guide the trade-off between HLA matching and donor age, supporting individualized decision-making and a rationale to reconsider restrictive donor age policies.}, }
@article {pmid41988904, year = {2026}, author = {Osazuwa-Peters, N and Hunter, AE and Salas, J and Chrusciel, T and Kahmke, RR and Bates, NE and Scherrer, JF}, title = {Cumulative Incidence and Risk of Depression After Opioid Use in Head and Neck Cancer Patients.}, journal = {Head &amp; neck}, volume = {}, number = {}, pages = {}, doi = {10.1002/hed.70254}, pmid = {41988904}, issn = {1097-0347}, support = {K01 DE030916/DE/NIDCR NIH HHS/United States ; R01 DE032216/DE/NIDCR NIH HHS/United States ; }, abstract = {BACKGROUND: This study examined the relationship between postoperative opioid duration and new-onset depression following head and neck cancer (HNC) surgery.<br><br>METHODS: We conducted a retrospective review of opioid-na&#xef;ve patients undergoing HNC surgery from 2007 to 2020, using national Veterans Health Administration claims data. Postoperative opioid duration was categorized as 1-30&#x2009;days, 31-90&#x2009;days, or >&#x2009;90&#x2009;days (long-term opioid therapy [LTOT]). The primary outcome was new-onset depression within 24&#x2009;months. Competing risk survival models with entropy balancing evaluated associations.<br><br>RESULTS: Among 9148 patients, 24.3% received LTOT. Rates of new-onset depression per 1000 person-years were 46.8 (1-30&#x2009;days), 70.2 (31-90&#x2009;days), and 88.4 (LTOT). LTOT was associated with a 20% increased risk of depression compared with 1-30&#x2009;days of use. LTOT was associated with higher rates of comorbidities, non-cancer pain, anxiety, substance use, and preoperative benzodiazepine use.<br><br>CONCLUSION: LTOT was independently associated with higher risk of depression after HNC surgery.}, }
@article {pmid41989584, year = {2026}, author = {Elhaw, AT and Tang, PW and Cheng, YY and Kamlapurkar, S and Javed, Z and Al-Saad, S and White, SR and Abdelnaby, AE and Khan, H and Choi, AS and Mattheyses, AL and Cole, AR and Kim, YS and Atiya, HI and Trebak, M and Zervantonakis, IK and Buckanovich, RJ and Aird, KM and Coffman, LG and Mythreye, K and Hempel, N}, title = {RHOV is a Detachment-Responsive Rho GTPase Necessary for Ovarian Cancer Peritoneal Metastasis.}, journal = {Cancer research}, volume = {}, number = {}, pages = {}, pmid = {41989584}, issn = {1538-7445}, support = {R01 CA230628/CA/NCI NIH HHS/United States ; P50 CA272218/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R01 CA242021/CA/NCI NIH HHS/United States ; T32 HL110849/HL/NHLBI NIH HHS/United States ; }, abstract = {A defining feature of epithelial ovarian cancer, irrespective of histologic subtype, is its predominant spread through transcoelomic metastasis, where tumor cells disseminate into the peritoneal fluid, resist anoikis, and form multicellular aggregates that invade the peritoneum. This tumor progression represents the main driver of mortality for ovarian cancer patients. Identification of the earliest adaptations necessary for metastasizing ovarian cancer cells to survive matrix detachment could help develop strategies to prevent the initiation of transcoelomic metastasis. In this study, we identified a conserved detachment-sensitive gene signature activated shortly after matrix-detachment across multiple ascites-derived ovarian cancer cell lines. Within this signature, RHOV, an atypical and fast-cycling Rho GTPase, emerged as a top transcript that was confirmed to be highly induced in patient-ascites derived cells. Loss of RHOV impaired anoikis resistance, multicellular aggregate compaction, migration, and invasion in vitro, and it completely abolished metastasis in vivo. Mechanistically, RHOV enhanced c-Jun signaling and cytoskeletal remodeling to support pro-metastatic signaling. Rescue experiments showed that both GTP-binding and membrane localization were required for the pro-metastatic function of RHOV. Together, these findings define RHOV as a unique detachment-sensitive Rho GTPase and establish RHOV as a critical and necessary mediator of early adaptations that prime ovarian cancer cells for peritoneal metastatic progression. This work provides key insights into the molecular vulnerabilities of disseminating tumor cells, establishes the targeting of early molecular adaptations following matrix detachment as a potential therapeutic strategy for metastatic disease, and uncovers functions of an understudied member of the Rho GTPase family.}, }
@article {pmid41990179, year = {2026}, author = {Hartweger, H and Ruprecht, C and Yao, KH and Laffont, P and Lima Dos Reis, G and Zhou, P and Hägglöf, T and Binet, L and Loewe, M and Hong, JP and Xiao, T and Sefik, E and Hernandez, B and Gazumyan, A and Jankovic, M and Seaman, MS and Costa, G and Nelson, SA and Clark, J and Kanatani, S and Wilson, PC and Krammer, F and Levashina, EA and Julien, JP and Wardemann, H and Sinnis, P and Stamatatos, L and Flavell, RA and Nussenzweig, MC}, title = {B lymphocyte protein factories produced by hematopoietic stem cell gene editing.}, journal = {Science (New York, N.Y.)}, volume = {392}, number = {6795}, pages = {eadz8994}, doi = {10.1126/science.adz8994}, pmid = {41990179}, issn = {1095-9203}, mesh = {Animals ; Mice ; *B-Lymphocytes/immunology ; Broadly Neutralizing Antibodies/immunology ; CRISPR-Cas Systems ; *Gene Editing/methods ; Hematopoietic Stem Cell Transplantation ; *Hematopoietic Stem Cells/immunology ; HIV Antibodies/blood/immunology/biosynthesis ; HIV-1/immunology ; Malaria/prevention &amp; control/immunology/therapy ; Mice, Inbred C57BL ; Orthomyxoviridae Infections/prevention &amp; control/immunology ; Plasma Cells/immunology ; Precursor Cells, B-Lymphoid/immunology ; Antibodies, Protozoan/biosynthesis/blood/immunology ; }, abstract = {Long-term in vivo production of therapeutic proteins and development of vaccines that elicit protective levels of broadly neutralizing antibodies (bNAbs) against major pathogens face challenges. In this study, we report on an alternative gene editing approach using small numbers of hematopoietic stem and progenitor cells (HSPCs) to direct long-term, high-level expression of antibodies or cargo proteins. In mice, edited B lymphocytes derived from transplanted HSPCs were activated by cognate antigen, underwent clonal expansion, and developed into specific antibody-synthesizing or cargo protein-synthesizing plasma cells. These cells produced long-lasting, therapeutic levels of serum antibody against HIV-1, malaria, or an anti-influenza virus bNAb that mediated universal protection from heterologous lethal challenge. Our data provide a paradigm for cell therapy approaches to prevent or treat disease using self-amplifying B cell protein factories.}, }
@article {pmid41992009, year = {2026}, author = {Moosavi, D and Lim, U and Hullar, MA and Rettenmeier, C and Kwee, SA and Monroe, KR and Ernst, T and Randolph, T and Wilkens, LR and Le Marchand, L and Lampe, JW and Park, SY}, title = {Association between plant-based diet quality and metabolic dysfunction-associated steatotic liver disease (MASLD) among multiethnic adults.}, journal = {European journal of clinical nutrition}, volume = {}, number = {}, pages = {}, pmid = {41992009}, issn = {1476-5640}, support = {(U01 CA164973//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R01 MD018265-03S2//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01 MD018265/MD/NIMHD NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; P01 CA168530/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly non-alcoholic fatty liver disease (NAFLD), is a growing public health concern with limited effective treatments. Diet quality may influence MASLD risk, yet the role of plant-based dietary patterns in diverse populations remains unclear.<br><br>OBJECTIVE: To evaluate the associations of plant-based dietary patterns with liver fat content or MASLD prevalence in multiethnic older adults.<br><br>METHODS: We analyzed cross-sectional data on 1598 participants of five racial and ethnic groups in the Adiposity Phenotype Study, nested within the Multiethnic Cohort Study. Participants' adherence to three established plant-based diet indices was estimated from their food frequency questionnaire responses: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). Magnetic resonance imaging was used to quantify liver fat and identify MASLD cases. Multivariable-adjusted linear regression of liver fat and logistic models of MASLD were performed to determine their associations with the plant-based diet indices, adjusting for demographic, lifestyle, and anthropometric covariates.<br><br>RESULTS: Higher hPDI scores were associated with lower liver fat content (adjusted mean liver fat for 4th (5.39%) vs. 1st quartile (6.52%) of hPDI) and reduced likelihood of MASLD (OR for 4th vs. 1st quartile = 0.58 (95% CI: 0.41-0.81)). The hPDI-MASLD association varied by race and ethnicity (p-heterogeneity = 0.001), with stronger inverse associations observed among Latino and White participants than among African American, Japanese American, or Native Hawaiian participants. No consistent associations were observed for PDI or uPDI. Among hPDI components, higher nut and lower animal fat intakes were associated with lower hepatic adiposity.<br><br>CONCLUSIONS: Greater adherence to a healthful plant-based diet is associated with lower liver fat and MASLD prevalence, with some racial and ethnic variation. These findings underscore the importance of plant-food quality and may inform dietary strategies for MASLD prevention in heterogeneous populations.}, }
@article {pmid41993886, year = {2026}, author = {Tan, J and Wu, Y and Barve, R and Lalmansingh, J and Li, F and Payne, P and Kong, N and Jin, SC and Shan, Y and Zhou, R and Ge, X and Li, JJ and Head, R and Sun, Y}, title = {SnakeAltPromoter Facilitates Differential Alternative Promoter Analysis.}, journal = {Computational and structural biotechnology journal}, volume = {35}, number = {1}, pages = {0033}, pmid = {41993886}, issn = {2001-0370}, abstract = {Background: Alternative promoter usage contributes to isoform diversity and gene regulation in mammals but remains difficult to study at scale. Cap Analysis of Gene Expression precisely maps transcription start sites, but its cost limits large-scale application. Alternatively, ProActiv, Salmon, and DEXSeq can be utilized with widely available RNA sequencing (RNA-seq) data to infer promoter activity. However, there is currently no framework available to automate the generation of reproducible results for these methods. Results: SnakeAltPromoter, a scalable end-to-end Snakemake workflow, has been developed to automate alternative promoter analysis from raw RNA-seq data. The workflow performs quality control, alignment, and promoter quantification using 3 complementary RNA-seq analysis methods (junction-based, transcript-based, and first-exon-based), followed by promoter classification and differential activity or usage analysis. SnakeAltPromoter supports both command-line and graphical user interface usage and utilizes standardized modules to enhance reproducibility. A built-in benchmarking module compares promoter activities inferred from RNA-seq data to matched Cap Analysis of Gene Expression data to evaluate quantification performance. Our analyses revealed robust and complementary performance profiles among the evaluated methods across tissues and cell types, highlighting the value of a unified framework for promoter analysis. Conclusions: To our knowledge, SnakeAltPromoter is the first unified and reproducible framework that combines scalable execution and guided method selection for RNA-seq-based promoter analysis. By standardizing and integrating existing RNA-seq-based promoter analysis tools, it provides researchers with a robust and accessible platform to investigate promoter-level regulation and alternative promoter activity and will enhance the research value of large, public RNA-seq repositories. Code is freely available at https://github.com/YidanSunResearchLab/SnakeAltPromoter.git.}, }
@article {pmid41995270, year = {2026}, author = {Chae, YK and Czeskleba, J and Patel, SP and Mentor, A and Robinson, W and Jones, NL and Rampurwala, M and Naing, A and Beck, JM and Moloney-Lineen, C and Chung, LI and McLeod, CM and Chen, HX and Sharon, E and Threlkel, S and Othus, M and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609: vaginal cancer sub cohort results.}, journal = {Journal of gynecologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.3802/jgo.2026.37.e92}, pmid = {41995270}, issn = {2005-0399}, support = {U10CA180888//National Institutes of Health/National Cancer Institute/United States of America ; U10CA180819//National Institutes of Health/National Cancer Institute/United States of America ; U10CA180821//National Institutes of Health/National Cancer Institute/United States of America ; U10CA180868//National Institutes of Health/National Cancer Institute/United States of America ; UG1CA233198//National Institutes of Health/National Cancer Institute/United States of America ; UG1CA233320//National Institutes of Health/National Cancer Institute/United States of America ; UG1CA233327//National Institutes of Health/National Cancer Institute/United States of America ; //Bristol Myers Squibb Company/United States of America ; 5U01CA180888-08/CA/NCI NIH HHS/United States ; 5UG1CA233198-05/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: The SWOG S1609 Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors (DART) trial is the first basket study to include a sub-cohort assessing ipilimumab and nivolumab in patients with primary vaginal cancers with differing histology.<br><br>METHODS: DART is a prospective, open-label, multicenter, multi-cohort phase II clinical trial of ipilimumab (1 mg/kg intravenously) 6 weekly plus nivolumab (240 mg intravenously) 2 weekly across multiple rare tumor cohorts, with the vagina cohort (any vaginal histology) reported here. The primary endpoint was objective response rate (ORR) per RECISTv1.1; progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease [SD] &#x2265;6 months), and toxicity are secondary endpoints.<br><br>RESULTS: Seven evaluable patients (median age, 60 years; performance status 0-1; no prior exposure to immunotherapy) were analyzed, of whom 3 had adenocarcinoma, 2 had squamous cell carcinoma (SCC), one had small-cell carcinoma and one had undifferentiated histology. The ORR was 29%, with 1 patient (14%) with undifferentiated histology achieving complete response (lasting 14.8 months) and 1 patient with SCC histology (14%) attaining a partial response (lasting 45.2 months). The CBR was 43%. The 6-month PFS rate was 43% and the median OS was 11.7 months. Five patients (71.4%) experienced an adverse event (AE) with 4 (57.1%) having grade 3-4 AE's.<br><br>CONCLUSION: Ipilimumab plus nivolumab showed efficacy (ORR was 29% and CBR of 43%) and durability (one patient with prolonged SD >6 months) in a sub cohort of patients with vaginal cancer of differing histology without new safety signals.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02834013.}, }
@article {pmid41995339, year = {2026}, author = {Ayalew, M and Hoffman, AM and Fuller, K and Kerr, J and Lee, A and Lee, J and Martinez, ES and Ulbricht, K and Xie, X}, title = {Microbiome education at under-resourced institutions: current status, barriers, and approaches to successful implementation.}, journal = {Journal of microbiology &amp; biology education}, volume = {}, number = {}, pages = {e0028825}, doi = {10.1128/jmbe.00288-25}, pmid = {41995339}, issn = {1935-7877}, abstract = {Microbiome research offers significant promise for advancing public health, medicine, environmental science, and industry. The topic also lends itself well to engaging students and teaching a "new biology" that integrates several disciplines, including computational biology. However, access to microbiome education remains limited, particularly at under-resourced institutions. We conducted a poll showing that over 90% of faculty expressed strong interest in microbiomes; however, only 48% reported that their institutions offer related courses or modules. The most commonly cited barrier was a lack of time and/or funding for design or implementation. A secondary barrier was limited access to professional development or a supportive community of practice. Through case vignettes and reflective analysis, we explore successful efforts to incorporate microbiome education at under-resourced institutions, highlighting the role of faculty development, collaboration, curriculum design, and external funding. These cases demonstrate that implementation is possible with varying levels of investment. We conclude by emphasizing the need for innovative and collaborative strategies, along with sustained resources, to support microbiome education and empower the next generation of genomic data scientists from diverse educational backgrounds.}, }
@article {pmid41995349, year = {2026}, author = {Schiffer, JT and Reeves, DB and Mayer, B and Rodriguez, LR and Duke, ER and Haddock, B and Avila-Ponce de Leon, U and Iwami, S and Owens, K and Esmaeili-Wellman, S}, title = {Clinical trial simulation of antiviral drugs.}, journal = {Journal of virology}, volume = {}, number = {}, pages = {e0181424}, doi = {10.1128/jvi.01814-24}, pmid = {41995349}, issn = {1098-5514}, abstract = {Antiviral clinical trial simulation (CTS) is a type of mathematical modeling that couples viral- immune dynamics (VID) unique to each human viral pathogen, with mechanistic, pharmacokinetic (PK), and pharmacodynamic (PD) drug characteristics. Validation is achieved by matching model output to detailed viral load trajectories from trials. Antiviral CTS can be applied at all stages of drug development to viruses with distinct shedding patterns. Models can capture the activity of small molecules, neutralizing antibodies, and cellular therapies, as well as combination strategies to enhance potency and avoid drug resistance. Several principles are observed across antiviral CTS models. First, PK and PD models that recapitulate drug levels and concentration-dependent antiviral activity are often necessary, but never sufficient to predict trial results. VID equations are also required to guide optimal treatment timing because expanding immune responses synergistically eliminate infection but are deleterious if too sustained or intense. Therefore, equivalent antiviral doses may have different efficacy if given during different infection stages. Second, antiviral CTS models identify effective plasma drug concentrations in humans, which are often poorly predicted by in vitro assays. Finally, models that do not consider drug mechanisms lead to incorrect efficacy estimates. Data-validated CTS is increasingly used to inform drug dose and dosing interval, treatment timing and duration, virologic endpoint selection, and sample size, particularly when applied to detailed phase 1 and 2 trial data. Given the high expense of antiviral licensure trials, CTS models are vital to optimize trial efficacy and de-risk the drug development process.}, }
@article {pmid41996472, year = {2026}, author = {Attalla, SA and Isaac, KJ and Pfeffer, M and Hockaday, JR and Weatherly, R and Asselin, MB and Lewis, AK and Rai, V and Huff, WA and Long, MH and Placide, T and Pearce, KR and Nkengbeza, LN and Thurman, AK and Cox, AL and Diaz, GD and Carter, J and Stein, N and Fischer, S and Ellis, BL}, title = {Mass drug administration approved and candidate anthelmintics beginning on larval stage 1 Caenorhabditis elegans are generally potent, suggesting a novel, pre-infective control for helminths.}, journal = {PloS one}, volume = {21}, number = {4}, pages = {e0346795}, pmid = {41996472}, issn = {1932-6203}, mesh = {Animals ; *Caenorhabditis elegans/drug effects/growth &amp; development ; Larva/drug effects ; *Anthelmintics/pharmacology/administration &amp; dosage ; *Mass Drug Administration ; }, abstract = {About 1.5 billion people are infected with at least one of three soil-transmitted helminths (STHs) - roundworm, hookworm, and whipworm- which have devastating outcomes for growth, nutrition, cognition, and school attendance, trapping them in poverty. The WHO currently approves only two anthelmintics with only one mechanism of action for mass drug administration (MDA), and resistance has been documented. This calls for new drugs and new strategies to reduce worm burden. Previous research, beginning with larval stage 4 (L4) C. elegans as a model, used a health-rating system to score individual worms in varying concentrations of anthelmintics. We hypothesized that younger worms would be more susceptible to drugs. We tested beginning at larval stage 1 (L1) C. elegans, using the health-rating system, with the same drugs, and additionally tested mebendazole, from both the L1 and L4 stages, allowing comparison at different stages. We found that L1 worms are susceptible to all anthelmintics tested, including the MDA drug of choice, albendazole, but surprisingly showed significantly lower efficacy with pyrantel and nitazoxanide at the L1 stage, as measured by motility and fraction alive, compared to L4. Furthermore, mortality and inhibition tended to begin earlier in the L4 stages. Finally, we found that ivermectin was the most potent anthelmintic against L1, as previously shown for L4. Beyond providing systematic drug-to-drug and stage-to-stage comparisons that can guide therapeutic development for larval-stage helminth infections, our findings suggest, for the first time, the possibility of spraying the environment with anthelmintics to reduce hookworm populations before people become infected. As hookworm is not infective until the L3 stage from soil, targeting L1-L3 larvae presents a strategic intervention window. Because previous work on C. elegans showed lower benzimidazole drug susceptibility than helminths, our L1 results may represent conservative estimates of efficacy against STH larvae in vitro and in environmental applications.}, }
@article {pmid41996694, year = {2026}, author = {Scoville, C and Gati Mirembe, B and Voldal, E and Maena, J and Etima, J and Harris-Wisecarver, J and Rukundo, I and Ssemere, H and Kemigisha, D and Nakyanzi, T and Nakalega, R and Conserve, DF and Albano, M and Dyer, M and Piwowar-Manning, E and Spiegel, H and Nakabiito, C and Mujugira, A and Donnell, D and Lukyamuzi, Z}, title = {Feasibility and Acceptability of Barbershop-Based HIV Prevention Among Heterosexual Men in Kalangala Islands, Uganda: Protocol for a Cluster Randomized Trial (HPTN 111).}, journal = {JMIR research protocols}, volume = {15}, number = {}, pages = {e87612}, doi = {10.2196/87612}, pmid = {41996694}, issn = {1929-0748}, mesh = {Humans ; Male ; *HIV Infections/prevention &amp; control ; *Heterosexuality/psychology ; Uganda/epidemiology ; Feasibility Studies ; Adult ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; *Barbering/methods ; Randomized Controlled Trials as Topic ; Young Adult ; HIV Testing ; }, abstract = {BACKGROUND: Globally, successful strategies to engage high-risk heterosexual men in HIV prevention are scarce, resulting in limited access and uptake. Barbershops offer a potential venue for HIV prevention.<br><br>OBJECTIVE: The primary objective was to evaluate the feasibility and acceptability of a barbershop-based HIV prevention initiative. The secondary objectives were to compare completion of self-initiated HIV testing between intervention and control groups, evaluate the preliminary effectiveness of the intervention on change in behaviors associated with HIV acquisition, compare interest in or use of HIV prevention services between intervention and control groups, and assess interest in long-acting preexposure prophylaxis among all participants and by study arm. The exploratory objective was to evaluate the preliminary effectiveness of the intervention on incident sexually transmitted infections.<br><br>METHODS: HIV Prevention Trials Network 111 (HPTN 111; Testing a Barbershop-based HIV Prevention Initiative Among Men [TRIM]) is a cluster randomized trial conducted in Kalangala district, Uganda, among barbershop-going men. Approximately 250 men were assigned to either an intervention barbershop (n=12) or a control barbershop to receive the standard of care (n=6). Participants assigned to intervention barbershops received an intervention package that included HIV-status neutral education, distribution of HIV self-test kits, and barber-led peer group sessions. Feasibility and acceptability of the intervention were assessed from participants in the intervention group at week 26 and week 52. The study will also assess the effectiveness of the intervention on changes in HIV testing and use of prevention services. Self-reported sexual behaviors associated with HIV incidence and sexually transmitted infection incidence rates will also be compared to the standard of care.<br><br>RESULTS: Data collection began in March 2024 and concluded in June 2025. Participants were followed for 12 months. Data analysis has been completed. The primary manuscript is expected to be submitted for publication by March 30, 2026.<br><br>CONCLUSIONS: The results of this study will provide crucial information about the feasibility and acceptability of novel interventions, such as barbershops, to impact behavior change, as well as about the engagement of heterosexual men in high HIV transmission settings in HIV prevention and treatment trials in the future.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT06148584; https://clinicaltrials.gov/study/NCT06148584.<br><br>RR1-10.2196/87612.}, }
@article {pmid41997295, year = {2026}, author = {Patel, SP and Othus, M and Chae, YK and Azenkot, T and Alviz, C and Threlkel, S and Haymaker, C and Streicher, HZ and Magner, CM and Chen, HX and Sharon, E and Ryan, CW and Blanke, CD and Kurzrock, R}, title = {DART (NCI/SWOG S1609): Comprehensive Final Results from Dual Checkpoint Inhibition with CTLA-4 and PD-1 Blockade in Rare Cancers.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.annonc.2026.04.004}, pmid = {41997295}, issn = {1569-8041}, abstract = {BACKGROUND: We summarize final results of the NCI/SWOG S1609 trial, whose objective was to evaluate efficacy signals across 53 refractory rare cancer cohorts treated with dual CTLA-4 and PD-1 inhibition.<br><br>PATIENTS AND METHODS: A prospective, open-label, multicenter phase 2 trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks) was conducted (N=53 cohorts). A statistical framework was established to evaluate each cohort in a two-stage design. The primary end point was objective response rate (ORR), with progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR, ORR plus stable disease >6 months), i-outcomes, and toxicity as secondary and exploratory endpoints.<br><br>RESULTS: Overall, 798 previously treated patients were enrolled onto S1609/DART; 727 eligible patients received treatment; 1083 national (USA) sites opened the trial. Twenty-four of 53 cohorts (45%) demonstrated clinical activity, defined as &#x2265;2 patients with confirmed response. Median (range) ORR was 12% (0-75%); CBR, 27% (0-75%). Median (range) 2-year PFS was 10% (0-75%); 3-year OS was 23% (0-100%). PFS at 6 months was moderately correlated with 1- and 3-year OS. Patients who attained an iOR versus OR had similar OS. Altogether, 82 patients (11% of the 727 enrolled patients) had an iPFS of &#x2265;2 years. Immune-related toxicity rates were comparable to prior studies. Adverse events (AEs) led to treatment discontinuation in 102 patients (14%). The most common AEs were fever, diarrhea, and rash/pruritis. Patients alive at 6 months who discontinued treatment due to immune-related toxicity had longer OS than those who discontinued treatment for other reasons.<br><br>CONCLUSION: Patients with multiple refractory rare cancer types derived meaningful response to ipilimumab plus nivolumab treatment. More robust characterization of biologically defined subsets is underway to optimize therapeutic selection.}, }
@article {pmid41997298, year = {2026}, author = {Switzer, GE and Bruce, JG and Shaw, BE and Kuniyil, V and Varni, JW and Butler, BJ and Erickson, C and Mussetter, A and Neutzling, A and Abdel-Azim, H and Aguayo-Hiraldo, P and Anderson, EJ and Aquino, VM and Boone, K and Boulad, F and Chewning, JH and Cooper, J and Dahlberg, A and Dvorak, CC and Galvez-Silva, J and Haight, AE and Hoag, JA and Hudspeth, M and Jacobsohn, D and Kasow, KA and Kitko, CL and Krishnamurti, L and Madden, L and Miller, HK and Morales, E and Olson, TS and Pawlowska, AB and Prasad, VK and Quigg, TC and Scaradavou, A and Shah, NC and Shenoy, S and Terwilliger, NB and Wiener, L and Yanik, GA and Yu, LC and Pulsipher, MA}, title = {Factors associated with pre-donation health-related quality-of-life among pediatric sibling hematopoietic cell donors; A DonorKids QL study.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2026.04.012}, pmid = {41997298}, issn = {2666-6367}, abstract = {BACKGROUND: Due to limited published data assessing pediatric hematopoietic cell donor experiences, we previously conducted one of the largest quantitative investigations of pediatric donor experiences and health-related quality-of-life (HRQoL) at the time (RDSafe). Findings from RDSafe demonstrated that a subset of pediatric HC donors experienced very poor HRQoL; unfortunately, that dataset addressed only a limited number of factors, and key associations explaining this poor HRQoL were not found.<br><br>OBJECTIVES: In this study, our goal was to address that deficit by describing pre-donation donor HRQoL in detail and identifying factors across five key domains that were associated with donor HRQoL.<br><br>STUDY DESIGN: We conducted a prospective study involving 29 centers in the US (31 enrolled, 29 contributed data). After consent at the local center, data were collected via telephone interviews with donors, recipients, other siblings, and parents, and via a web-based survey from transplant centers. Family data (donors, recipients, sibling, parents) were collected before donation and at four weeks, six months, and one-year post-donation. Domains assessed included sociodemographics, general and donation-related psychosocial, clinical, and transplant center characteristics. Data presented here are from the 133 donor-parent pairs who completed the pre-donation interview, 64 recipients, 59 non-donor/non-recipient siblings in these related donor families, and 78 comparison siblings of patients receiving unrelated marrow, PBSC, or cord blood transplantation.<br><br>RESULTS: Important percentages of pediatric donors reported very poor psychosocial (20%) and overall (13%) HRQoL and parents overestimated their donor child's HRQoL. Donors had significantly better HRQoL than recipients and worse HRQoL than parent proxy reports. Multiple donor, recipient, parent and transplant center characteristics were associated with HRQoL in bivariate analyses. Multivariable analyses by donor age group suggested that donor HRQoL was significantly negatively associated with donor self-reported anxiety, depression and parental education and significantly positively associated with family cohesion, understanding of donation and proxy reports of donor HRQoL.<br><br>CONCLUSIONS: The link between donor HRQoL and recipient and parent health and well-being suggests that variations in donor HRQoL do not occur in isolation but affect and/or are affected by the overall functioning and well-being of other family members and the family as a whole. Particularly striking is the association of donor HRQoL with perceived understanding of the donation process - improved donor education is a potential pathway to improving donor HRQoL. Assessment of - and Interventions to mitigate - risks to donors should involve the functioning of the family as a whole and not just the donor.}, }
@article {pmid41997451, year = {2026}, author = {Lee, C and Mille, MM and Griffin, KT and Rigsby, C and Popescu, A and Gopalakrishnan, M and Leisenring, W and Peterson, S and Dome, JS and Laurie, F and Fitzgerald, TJ and Bentzen, S and Jung, JW and Lee, C and Kalapurakal, JA}, title = {Estimation of detailed cardiac doses for pediatric radiotherapy patients in National Wilms Tumor Study.}, journal = {International journal of radiation oncology, biology, physics}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.ijrobp.2026.04.006}, pmid = {41997451}, issn = {1879-355X}, abstract = {PURPOSE: Substructure-level heart dosimetry may improve the evaluation of long-term cardiac toxicity in childhood cancer survivors, but detailed pediatric heart models are limited. We developed age-specific heart models (1, 5, 10, and 15 years) using high-resolution imaging and integrated them into computational phantoms to estimate cardiac substructure doses in patients treated on the National Wilms Tumor Study (NWTS) protocols and evaluate the impact of anatomical detail on radiotherapy dose estimates.<br><br>MATERIALS AND METHODS: Heart models with detailed substructures including chambers, myocardium, arteries, valves, and conduction nodes were developed from pediatric MR and adult CT images. These were incorporated into a size-dependent phantom library representing a wide range of pediatric body sizes. Patient-specific radiotherapy plans were reconstructed using the Pinnacle treatment planning system, and heart doses were calculated using both treatment planning system (TPS) and Monte Carlo (MC) methods.<br><br>RESULTS: The developed heart models closely matched ICRP reference masses (within 2%). TPS and MC dose calculations showed strong agreement (median difference <2%) so that MC-based doses were used for further analysis. Among 4,716 NWTS patients treated with radiotherapy, the median whole-heart dose was 4.2 Gy. Cardiac and substructure doses varied by treatment region with the right atrium and left ventricular myocardium receiving higher doses (up to 5.1 and 4.5 Gy), while coronary arteries and valves received lower doses (<1 Gy). In non-chest fields, substructure doses differed significantly from whole-heart doses (p < 0.001), reflecting steep intra-cardiac dose gradients. Chest fields alone resulted in uniformly high cardiac doses with minimal variation.<br><br>CONCLUSION: Our results demonstrate that relying solely on whole heart dose may obscure clinically relevant exposure to critical substructures. Detailed heart models enable more accurate dosimetry and support improved risk assessment and safer pediatric radiotherapy planning to reduce long-term cardiac toxicity.}, }
@article {pmid41997993, year = {2026}, author = {Paredes, MI and Liang, C and Suen, SC and Holloway, IW and Garrigues, JM and Green, NM and Bedford, T and Müller, NF and Osmundson, J}, title = {Viral introductions and return to baseline sexual behaviors maintain low-level mpox incidence in Los Angeles.}, journal = {Nature communications}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41467-026-71993-w}, pmid = {41997993}, issn = {2041-1723}, support = {2237959//National Science Foundation (NSF)/ ; R35 GM119774/GM/NIGMS NIH HHS/United States ; }, abstract = {In 2022, mpox clade IIb disseminated around the world, causing outbreaks in more than 117 countries. Despite the decay of the 2022 epidemic and the increased immunity within sexual networks, mpox continues to persist in North America without extinction, raising concerns of future outbreaks. We combined phylodyamic inference and microsimulation modeling to understand the heterogeneous dynamics governing local mpox persistence in Los Angeles County (LAC) from 2023 to 2024. Our Bayesian phylodynamic analysis revealed a time-varying pattern of viral importations into the county, which seeded mpox outbreak clusters that display "stuttering chains" dynamics. Our phylodynamics-informed microsimulation model demonstrated that the mpox cases in LAC can be explained by a combination of waves of viral introductions, a median effective reproductive rate below one, and a return to near-baseline sexual behaviors after the 2022 epidemic. Our counterfactual scenario modeling showed that frequent public health interventions that either promote increased isolation of infectious individuals or enact behavior-modifying campaigns during the periods with the highest viral importation intensity are actionable and effective at curbing mpox cases. Our work highlights the factors that maintain present-day mpox dynamics in a large, urban US county and describes how to leverage these results into community-centered public health interventions.}, }
@article {pmid41998406, year = {2026}, author = {Hahn, WO and Fisher, LH and Ward, A and Grant, S and Yen, C and Randhawa, AK and Li, X and Ramirez, S and Espy, N and Hural, J and Hanke, J and Roychoudhury, P and Kelley, CF and Rouphael, N and Cantos, VD and Pinto, J and Cahn, PE and Manentsa, M and Makhema, J and Samaneka, W and Bhondai-Mhuri, M and Stranix-Chibanda, L and Losso, MH and Garcia, EAR and Innes, C and Chinula, L and Lama, JR and Gallardo-Cartagena, JA and Kabengele, C and Chilengi, R and Nchabeleng, M and Tieu, HV and Hoagland, B and Grinsztejn, B and Brumskine, WL and Ahmed, K and Wallis, CL and Greninger, AL and Corey, L and Hyrien, O}, title = {Viral variant but not host factors associate with SARS-CoV-2 viral kinetics.}, journal = {Communications medicine}, volume = {}, number = {}, pages = {}, doi = {10.1038/s43856-026-01588-5}, pmid = {41998406}, issn = {2730-664X}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: It is challenging to assess SARS-CoV-2 viral kinetics amidst viral variant evolution and changes in population-level immunity. However, understanding the relationship between host factors and viral replication deepens our understanding of viral fitness.<br><br>METHODS: In CoVPN 5001, we enrolled N&#x2009;=&#x2009;953 adults diagnosed with acute SARS-CoV-2 from July 2020 to July 2022 across 51 sites. We confirmed SARS-CoV-2 infection by RT-PCR and identified the variant via viral genome sequencing. Using multivariable linear regression and median regression, we studied the association between host factors and either observed peak viral load (VL) or clinical viral shedding, respectively, accounting for viral variant effects in a demographically and clinically diverse longitudinal cohort.<br><br>RESULTS: In this observational study, we determine that while host factors, including age, BMI, sex, medical comorbidities, and HIV, have no significant associations with either observed peak VL or clinical viral shedding in the nasopharynx, viral variant is significantly associated with observed peak VL and clinical viral shedding. We show that neither observed peak VL nor shedding duration predict evolutionary success since the dominant variants in the SARS-CoV-2 pandemic did not all align with the variants with the highest peak and longest shedding duration.<br><br>CONCLUSIONS: Altogether, our work shows that observed peak VL and shedding duration should be cautiously interpreted as predictors of viral fitness.}, }
@article {pmid41999375, year = {2026}, author = {Ahn, J and Ahsan, H and Anderson, GL and Aschebrook-Kilfoy, B and Beery, D and Carrick, W and Celedón, JC and Chan, KCG and Chen, Y and Ðoàn, LN and Fang, CY and Floyd, JS and Hayes, RB and Henderson, V and Hong, Y and Hsing, AW and Hsu, L and Hu, FB and Jin, JL and John, EM and Kanaya, AM and Kaplan, RC and Kibriya, MG and Kim, K and Kushida, C and Lampe, JW and Li, S and Lu, Y and Ma, GX and Mau, MKLM and Maunakea, AK and Mendoza, JA and Neuhouser, ML and Newman, JD and Odden, MC and Palaniappan, L and Park, SL and Randal, F and Rhew, IC and Santos, S and Soliman, EZ and Thyagarajan, B and Hsin-Chun Tsai, J and VoPham, T and Wang, P and Wion, E and Yan, Y and Yi, SS and Zhu, L and , }, title = {Design of MOSAAIC (Multi-Ethnic Observational Study in American Asian and Pacific Islander Communities).}, journal = {JACC. Asia}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jacasi.2026.02.027}, pmid = {41999375}, issn = {2772-3747}, abstract = {BACKGROUND: Asian American (AsA) and Native Hawaiian and Pacific Islander (NHPI) populations are underrepresented in U.S. health studies.<br><br>OBJECTIVES: The MOSAAIC (Multi-ethnic Observational Study in American Asian and Pacific Islander Communities) is a cohort study designed to improve understanding of disparities in cardiovascular disease and other health conditions affecting AsA and NHPI groups.<br><br>METHODS: Through broad eligibility criteria and outreach tailored to each study community, MOSAAIC will include 11,500 adults aged 18+ years living in 5 field center regions: New York, Philadelphia, Chicago, San Francisco Bay Area, and Honolulu. The protocol specifies sample-size targets to allow valid comparisons among persons having personal or family origins in 4 geographically defined regions, including East Asia (the largest groups being Chinese and Korean), South Asia (Indian), Southeast Asia (Vietnamese and Filipino) and Oceania (NHPI). Measurements to be obtained at an in-person examination include clinical laboratory tests, medical history, medication use, spirometry, cognitive and physical function, anthropometry, and electrocardiogram. Surveys in multiple languages to assess medical, behavioral, lifestyle, social and environmental influences on health were developed by a multistep process to ensure equivalency between translations and cultural appropriateness. Biospecimens are stored for future studies. Long-term follow-up will be conducted to ascertain and adjudicate major health events including myocardial infarction, stroke, heart failure, and mortality.<br><br>CONCLUSIONS: The National Institutes of Health established MOSAAIC as a resource for wide-ranging epidemiologic investigation of factors related to cardiometabolic, pulmonary, or mental health in persons of diverse AsA and NHPI background.}, }
@article {pmid41999663, year = {2026}, author = {Kader, T and Chen, YA and Hug, CB and Lin, JR and Muhlich, JL and Coy, S and Jung, E and Schwartz, LE and Fazio, T and Chiu, C and Ryall, ST and Drescher, CW and Sorger, PK and Drapkin, R and Santagata, S}, title = {Spatial integration of protein and chromosomal states reveals early copy number changes and genotype-associated immune neighborhoods in serous ovarian cancer evolution.}, journal = {Cancer discovery}, volume = {}, number = {}, pages = {}, doi = {10.1158/2159-8290.CD-26-0171}, pmid = {41999663}, issn = {2159-8290}, abstract = {Detecting chromosomal copy-number alterations together with protein-defined cell states in intact tissue is critical for understanding early clonal evolution and microenvironmental interactions in cancer. We developed ORION-FISH, which integrates high-plex tissue imaging with a morphology-preserving DNA-FISH workflow and single-cell registration, yielding measurements concordant with clinical FISH. In High Grade Serous Ovarian Carcinoma (HGSOC), ORION-FISH recapitulated known chromosomal changes while revealing subclonal heterogeneity missed by targeted sequencing. Applied to serous tubal intraepithelial carcinomas (STICs), precursors of HGSOC, ORION-FISH identified intermixed epithelial cells with MYC or CCNE1 copy-number gains, as well as concurrent alterations associated with distinct immune microenvironments. In addition, epithelial cells with MYC and CCNE1 copy-number gains were detected in morphologically normal fallopian tube epithelium, along with rare MDM4 increases across epithelial lineages. Together, ORION-FISH provides a framework linking chromosomal copy number states to protein-defined phenotypes within preserved tissue architecture, enabling context-aware interrogation of early copy-number diversification at single-cell resolution.}, }
@article {pmid42000378, year = {2026}, author = {Bashi, A and Penvose, KN and Wright, JD and Blank, SV and Albright, BB and Hazelton, WD and Rossi, E and Myers, ER and Secord, AA and Havrilesky, LJ}, title = {Cost and efficiency of universal versus selective next generation sequencing for advanced stage endometrial cancer.}, journal = {Gynecologic oncology}, volume = {207S}, number = {}, pages = {67-73}, doi = {10.1016/j.ygyno.2026.02.009}, pmid = {42000378}, issn = {1095-6859}, mesh = {Humans ; Female ; *Endometrial Neoplasms/genetics/pathology/economics/diagnosis ; *High-Throughput Nucleotide Sequencing/economics/methods ; Neoplasm Staging ; Cost-Benefit Analysis ; Tumor Suppressor Protein p53/genetics ; DNA Mismatch Repair ; Decision Trees ; Erb-b2 Receptor Tyrosine Kinases/genetics ; Immunohistochemistry/economics ; Mutation ; Neoplasm Recurrence, Local/genetics ; }, abstract = {OBJECTIVE: We sought to identify efficient tumor molecular profiling strategies for patients with newly diagnosed stage III-IVA endometrial cancer.<br><br>METHODS: We constructed a decision tree model to compare molecular profiling strategies. We considered testing options of mismatch repair (MMR), p53, and HER2 immunohistochemistry (IHC), and next generation sequencing (NGS, assessing for MMR protein, TP53 and POLE mutations). Strategies included (1) MMR/p53: MMR/p53 IHC at diagnosis, with HER2 IHC if p53 abnormal and NGS reserved for first progression/recurrence; (2) Selective NGS: MMR/p53 IHC at diagnosis, with immediate NGS and HER2 IHC if p53 abnormal, otherwise NGS at recurrence; (3) Universal NGS: NGS and HER2 IHC at diagnosis for all. Molecular subtype prevalence and six-year recurrence-free survival by subtype were derived from the GOG-0258 randomized trial. Outcomes included costs (2024 US$), timely NGS results (results available at recurrence/progression), and unnecessary NGS (NGS performed in patients who remained recurrence-free).<br><br>RESULTS: Universal NGS resulted in unnecessary NGS in 57% of patients who remained recurrence-free, compared with 7% under the Selective NGS strategy and 0% with MMR/p53. MMR/p53 was the least costly strategy (mean cost $3772), followed by Selective NGS ($4186) and Universal NGS ($6250). Compared with MMR/p53, Selective NGS cost $2571 per additional timely NGS result, while Universal NGS cost $7600 per additional timely NGS result compared with Selective NGS.<br><br>CONCLUSIONS: Selective molecular profiling of newly diagnosed stage III-IVA endometrial cancers using MMR and p53 IHC with reflex to NGS for p53-abnormal tumors improves testing efficiency and reduces unnecessary NGS compared with universal upfront NGS testing.}, }
@article {pmid42000737, year = {2026}, author = {Janes, H and Fong, Y and Huang, Y and Benkeser, D and Kelly, EJ and Hirsch, I and Stanley, AM and Villafana, T and Petropoulos, CJ and Leith, A and Haugaard, D and Webb, B and Lu, Y and Yu, C and Borate, B and van der Laan, LWP and Hejazi, NS and Randhawa, AK and Andrasik, MP and Kublin, JG and Isaacs, MB and Makhene, M and Tong, T and Robb, ML and Corey, L and Neuzil, KM and Follmann, D and Falsey, AR and Sobieszczyk, ME and Koup, RA and Gilbert, PB and ,  and ,  and , }, title = {Correlates of severe and delta COVID-19 in a phase 3 trial of the AZD1222 vaccine.}, journal = {NPJ vaccines}, volume = {}, number = {}, pages = {}, doi = {10.1038/s41541-026-01411-1}, pmid = {42000737}, issn = {2059-0105}, support = {UM1 AI68614//National Institute of Allergy and Infectious Diseases/ ; UM1 AI68635//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {In the phase 3 AZD1222 COVID-19 vaccine trial, anti-Spike (vaccine-matched and Delta) binding IgG antibody concentration and neutralizing antibody (nAb) titer (vaccine-matched+D614G and Delta), measured four weeks post-dose two (D57), were assessed as correlates of risk of severe COVID-19 and Delta COVID-19 over ~4 to ~13 months (severe) or ~11 months (Delta) post-D57. Using a case-control design, antibodies were measured in baseline SARS-CoV-2-negative per-protocol ChAdOx1 nCoV-19 recipients (19 severe COVID-19 cases, 57 Delta COVID-19 cases, 111 controls). The hazard ratio (HR) of severe COVID-19 per 10-fold vaccine-matched D57 marker increase was 0.16 (95% CI: 0.05, 0.54; p = 0.004) for Spike IgG and 0.13 (0.03, 0.59; p = 0.009) for nAb titer. D57 Delta antibodies were weak correlates of Delta COVID-19: HR per 10-fold increase 0.70 (0.14, 3.47; p = 0.66) for Delta Spike IgG; 0.46 (0.14, 1.47; p = 0.19) for Delta nAb titer. Binding and nAb levels strongly predicted severe COVID-19, even with antibody waning.}, }
@article {pmid42001218, year = {2026}, author = {Wu, X and Kim, A and Breeze, CE and O'Mara, TA and Ramachandran, D and Dörk, T and Koutros, S and Rothman, N and Prokunina-Olsson, L and Mancuso, N and Lindström, S and Kraft, P}, title = {Prioritizing context-specific genetic risk mechanisms in 11 solid cancers.}, journal = {Journal of the National Cancer Institute}, volume = {}, number = {}, pages = {}, doi = {10.1093/jnci/djag073}, pmid = {42001218}, issn = {1460-2105}, abstract = {BACKGROUND: While genome-wide association studies (GWAS) have identified hundreds of cancer-associated genetic variants, the specific biological contexts where these variants exert their effects remain largely unknown. We aimed to prioritize context-specific genetic risk mechanisms for 11 solid cancers at both genome-wide and single-variant resolutions.<br><br>METHODS: We integrated cancer GWAS summary statistics from European ancestry samples (avg. n cases&#x2009;=&#x2009;47,856) with 1,473 context-specific annotations representing candidate cis-regulatory elements. For genome-wide analysis, we applied CT-FM, a method that jointly models heritability enrichments across annotations to select likely disease-relevant biological contexts. Following functionally informed fine-mapping to identify high-confidence (PIP&#x2009;&#x2265;&#x2009;0.5) causal SNPs, we used CT-FM-SNP to identify relevant contexts for individual variants. A combined SNP-to-gene framework was applied to construct putative {regulatory SNP-context-gene-cancer} quadruplets.<br><br>RESULTS: Stratified LD score regression analysis identified 141 annotations showing significant heritability enrichment (FDR q&#x2009;&#x2264;&#x2009;0.05). CT-FM prioritized four high-confidence (PIP&#x2009;&#x2265;&#x2009;0.5) biological contexts mammary luminal epithelial cells for overall and estrogen receptor (ER)-positive breast cancer, a prostate cancer epithelial cell line (VCaP) for prostate cancer, and bulk tumor tissue contexts for colorectal and renal cancers. Variant-level analysis of hundreds of putatively causal SNPs aligned with these findings and identified additional high-confidence contexts for ER-negative breast, endometrial, lung, and bladder cancers. A total of 489 putative regulatory quadruplets were constructed, proposing specific molecular hypotheses underlying the observed GWAS signals.<br><br>CONCLUSION: These findings advance our understanding of genetic susceptibility to different cancers. Future work in larger, more diverse GWAS, coupled with more comprehensive annotation atlases, is essential to expand upon and validate our results.}, }
@article {pmid40350587, year = {2025}, author = {Sala, M and Roos, CR and Kober, H and Bricker, JB and Stern, CM and Plutchik, J and John, M and Haeny, AM and Feldman, JM and Aslan, M and Hay, JL and Forman, EM}, title = {Combining Cognitive-Behaviour Therapy With Mindfulness Training in a Digital Intervention for Binge Eating Disorder: A Single-Session Pilot Trial.}, journal = {European eating disorders review : the journal of the Eating Disorders Association}, volume = {33}, number = {5}, pages = {1051-1060}, pmid = {40350587}, issn = {1099-0968}, support = {K23 AT012126/AT/NCCIH NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; K23AT012126/AT/NCCIH NIH HHS/United States ; K23AT012126/AT/NCCIH NIH HHS/United States ; }, mesh = {Humans ; *Mindfulness/methods ; *Cognitive Behavioral Therapy/methods ; *Binge-Eating Disorder/therapy ; Pilot Projects ; Female ; Adult ; Male ; Middle Aged ; Treatment Outcome ; Patient Satisfaction ; Young Adult ; }, abstract = {OBJECTIVE: Delivering a single-session treatment digitally can offer increased accessibility. We developed and tested a single-session digital intervention for binge-eating disorder (BED) combining cognitive behavioural therapy (CBT) and mindfulness training.<br><br>METHOD: English-speaking adults who met criteria for BED were recruited nationally. Participants completed a 60-min digital single-session intervention for BED. Our primary outcome was to evaluate initial acceptability (usability, overall satisfaction, engagement, visual appeal of content, understandability of programme material, desire to continue the programme, and overall helpfulness) and feasibility (intervention completion). We also evaluated changes in binge eating episodes, assessed via the Eating Disorder Examination Questionnaire (EDE-Q) objective binge eating episodes question, and eating disorder symptoms, assessed via the EDE-Q and Binge Eating Scale (BES). Acceptability measures were administered immediately after the completion of the digital module, while the BES and EDE-Q were administered at pre-treatment and at 1-month follow-up.<br><br>RESULTS: All participants (N&#xa0;=&#xa0;21) completed the intervention. Ratings for acceptability were excellent, with averages above a four on a five-point Likert scale on ratings for all dimensions. Participants reported large and significant decreases in binge eating episodes (d&#xa0;=&#xa0;0.86) and BES scores (d&#xa0;=&#xa0;0.91) as well as medium and significant decreases in global eating disorder symptoms at 1-month follow-up (d&#xa0;=&#xa0;0.55).<br><br>DISCUSSION: Results from this pilot suggest promising acceptability and feasibility for a single session of Mindful Courage for BED. This single session also appears to be preliminarily efficacious in reducing binge eating.}, }
@article {pmid40355027, year = {2025}, author = {Phelan, R and Rotz, S and Dandoy, CE and Auletta, JJ and Badia, P and Bhatt, NS and Ballard, SA and Blacken, R and Daraiseh, NM and Desmond, C and Dunseath, C and Epling, P and Flesch, L and Huber, J and Jenssen, K and Kapadia, M and Kent, G and Klunk, A and Kusnier, K and Lehmann, L and Liberio, N and Maier, S and Myers, KC and O'Connor, G and Pai, A and Tarquini, S and Fitch, TJ and Hartley, D}, title = {Multicenter Study on Caregiver Experiences in Pediatric Hematopoietic Stem Cell Transplantation: Part II. Treatment Challenges, Communication Barriers, and Caregiver-Driven Approaches to Mitigation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {8}, pages = {590.e1-590.e16}, doi = {10.1016/j.jtct.2025.04.012}, pmid = {40355027}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology/adverse effects ; *Caregivers/psychology ; Female ; Male ; Child ; Prospective Studies ; Longitudinal Studies ; *COVID-19/epidemiology ; Adult ; Adolescent ; Child, Preschool ; *Communication Barriers ; Qualitative Research ; SARS-CoV-2 ; Adaptation, Psychological ; Middle Aged ; Infant ; }, abstract = {Hematopoietic stem cell transplantation (HSCT) is a life-saving yet complex treatment for pediatric patients that introduces significant physical, emotional, and logistical challenges for caregivers. This multicenter, prospective qualitative longitudinal study explored caregiver experiences across 4 time points: pre-transplant (n = 47), 30 d post-transplant (n = 43), 100 d post-transplant (n=34), and 6 months post-transplant (n=26). Forty-nine caregivers participated in semi-structured interviews, which were transcribed and thematically analyzed. This manuscript encompasses the following themes that emerged from the interviews: treatment-related side effects and complications, communication gaps, and the impact of the COVID-19 pandemic. Caregiver priorities evolved over time, shifting from managing acute complications such as pain, infections, mucositis, and medication administration to addressing longer-term concerns like developmental delays, nutritional rehabilitation, and psychosocial adaptation. Caregivers reported challenges such as information overload, inconsistent messaging, and limited preparation for transitions in care. They employed various strategies to cope, including advocacy, peer support, and the use of healthcare team resources. These findings highlight the importance of stage-specific, tailored interventions to support caregivers throughout the HSCT journey. Clear communication, accessible education, and coordinated multidisciplinary care are essential to fostering caregiver resilience and improving patient and family-centered outcomes.}, }
@article {pmid40357217, year = {2025}, author = {Kuczmarski, TM and Lynch, RC}, title = {Optimizing therapy for relapsed/refractory classic Hodgkin lymphoma in the era of PD-1 blockade.}, journal = {HemaSphere}, volume = {9}, number = {5}, pages = {e70110}, pmid = {40357217}, issn = {2572-9241}, }
@article {pmid40357548, year = {2025}, author = {Blair, KM and Bohinc, DJ and Bane, KL and Warnock, M and Abuaita, B and Gura, C and Grinsztejn, E and Marshall, SH and Wilson, BM and Bonomo, RA and Tambralli, A and Knight, JS and O'Riordan, MX and Lawrence, DA and Stavrou, EX and Sandkvist, M}, title = {Acinetobacter Baumannii Secreted Protease CpaA Inhibits Factor XII-Mediated Bradykinin Generation and Neutrophil Activation.}, journal = {Circulation research}, volume = {137}, number = {1}, pages = {e1-e15}, pmid = {40357548}, issn = {1524-4571}, support = {U2C DK129440/DK/NIDDK NIH HHS/United States ; R01 AI137085/AI/NIAID NIH HHS/United States ; R01 HL055374/HL/NHLBI NIH HHS/United States ; R01 HL163870/HL/NHLBI NIH HHS/United States ; I01 BX003851/BX/BLRD VA/United States ; P30 CA043703/CA/NCI NIH HHS/United States ; R01 AI072219/AI/NIAID NIH HHS/United States ; R01 HL137695/HL/NHLBI NIH HHS/United States ; }, mesh = {*Bradykinin/metabolism/biosynthesis ; Humans ; *Neutrophil Activation ; *Acinetobacter baumannii/enzymology ; *Factor XII/metabolism ; *Neutrophils/metabolism/immunology ; Factor XIIa/metabolism ; *Bacterial Proteins/metabolism/genetics ; Animals ; Prekallikrein/metabolism ; Mice ; Kallikrein-Kinin System ; }, abstract = {BACKGROUND: FXII (coagulation factor XII) is best known for its roles in the contact and kallikrein-kinin pathways. FXII is converted to FXIIa (activated factor XII) by PKa (plasma kallikrein) or its unique ability to autoactivate on bacterial or other biologic surfaces. In vivo, FXIIa initiates the intrinsic coagulation pathway and promotes inflammation by reciprocal activation of prekallikrein, which cleaves HK (high-molecular-weight kininogen) to liberate bradykinin. CpaA (coagulation targeting metallo-endopeptidase of A baumannii) is a secreted metalloprotease identified in a human clinical isolate of Acinetobacter baumannii that cleaves FXII at O-linked glycosylated sites, inhibiting contact activation. While CpaA facilitates a modest in vivo fitness advantage in mice, the role of CpaA in human infection remains unclear. As such, the objectives of this study were to characterize the structural details of the interaction between CpaA, FXII, and the KKS (kallikrein-kinin system) and to determine the downstream consequences on thromboinflammatory responses.<br><br>METHODS: The effect of purified CpaA on the coagulant activity of FXII and the generation of bradykinin was characterized. Neutrophil signaling, flow cytometry, and functional assays were performed to define how CpaA-mediated cleavage of FXII affects innate immune functions. Bacterial killing by human neutrophils was performed with wild-type and mutant A baumannii strains lacking CpaA.<br><br>RESULTS: We found that CpaA cleaves both FXII zymogen and FXIIa but not beta Factor XII. However, cleavage of FXIIa by CpaA does not significantly inhibit its clotting activity, demonstrating that CpaA does not inactivate FXIIa, but rather prevents activation of zymogen FXII. CpaA also cleaves HK, resulting in reduced kallikrein activation and bradykinin generation. We previously identified that zymogen FXII interacts with the urokinase receptor on neutrophils and upregulates neutrophil activation. Here, we demonstrate that CpaA cleaves neutrophil FXII, resulting in reduced Akt2 phosphorylation, chemotaxis, oxidative burst, and neutrophil extracellular trap formation. Importantly, CpaA decreases the human neutrophil killing efficiency of A baumannii in culture.<br><br>CONCLUSIONS: These data identify a role for FXII in responding to bacterial infection and suggest that by inhibiting the contact and kallikrein-kinin pathways and impairing neutrophil activation, CpaA may blunt the innate immune response and help prevent the elimination of A baumannii from the human host.}, }
@article {pmid40358803, year = {2025}, author = {Krisch, JM and Ermoian, RP and Indelicato, DJ and Lee, JY and Perentesis, JP and Perkins, SM and Laack, NN and Chang, JH and MacEwan, IJ and Wolden, SL and Wang, D and Yock, TI and Aridgides, PD}, title = {Outcomes following radiation therapy for embryonal tumor with multilayered rosettes (ETMR): results from the Pediatric Proton/Photon Consortium Registry (PPCR).}, journal = {Journal of neuro-oncology}, volume = {174}, number = {2}, pages = {369-380}, pmid = {40358803}, issn = {1573-7373}, mesh = {Humans ; Child ; Female ; Male ; *Proton Therapy/mortality ; Child, Preschool ; Registries ; Infant ; *Neoplasms, Germ Cell and Embryonal/radiotherapy/pathology/mortality ; Follow-Up Studies ; *Brain Neoplasms/radiotherapy/pathology/mortality ; Survival Rate ; Treatment Outcome ; Prognosis ; }, abstract = {PURPOSE: Embryonal tumor with multilayered rosettes (ETMR) is a rare pediatric CNS embryonal tumor with poor survival. The Pediatric Proton/Photon Consortium Registry (PPCR) was queried for outcomes data from prospectively consenting pediatric patients with ETMR treated with proton radiation therapy (RT).<br><br>METHODS: 20 patients (2013-2021) at 9 institutions had ETMR; 2 with prior RT were excluded from statistical analyses (PPCR ETMR, N&#x2009;=&#x2009;18). Overall Survival (OS) and Event Free Survival (EFS) analyses were performed using the Kaplan-Meier method and log-rank values. Median follow-up was calculated using the reverse Kaplan-Meier method.<br><br>RESULTS: Median age at RT was 3.0 years (1.7-12.2); median follow-up was 55.5 months (2.6-119.4). 8 patients (44%) expired and 6 patients (33%) are surviving&#x2009;&#x2265;&#x2009;55 months. 11 (61%) patients received systemic therapy with stem cell support. The majority (89%) had focal RT (median dose 54&#xa0;Gy), while 2 patients received craniospinal irradiation (CSI, 30.6-36&#xa0;Gy). 4-year OS and EFS were 59.6% and 54.2%, respectively. Local control (LC) at 4 years was 81%. No differences in OS or EFS were observed for receipt of systemic therapy with stem cell support (p&#x2009;=&#x2009;0.361, p&#x2009;=&#x2009;0.57), progression prior to RT (p&#x2009;=&#x2009;0.127, p&#x2009;=&#x2009;0.18), or surgery to RT&#x2009;&#x2265;&#x2009;200 days (p&#x2009;=&#x2009;0.35, p&#x2009;=&#x2009;0.254). Symptomatic radionecrosis was not reported.<br><br>CONCLUSION: Focal proton RT provided effective local control as part of multimodality therapy for ETMR, with encouraging survival for this rare and often infant age tumor. Outcomes for CSI were limited to 2 patients treated upfront, and 1 patient receiving salvage CSI for disseminated relapse after focal RT who is surviving&#x2009;>&#x2009;1 year.<br><br>TRIAL REGISTRATION: DFCI protocol 12-103, clinicaltrials.gov NCT01696721, date of registration 9/27/2012.}, }
@article {pmid40358923, year = {2025}, author = {Yorke, AA and Schandorf, MT and Quaye, ANM and Twum, PT and Sengupta, B and Nkansah-Poku, K and Kplorfia, JA and Fagestrom, J}, title = {Empowering young minds through STEM education: Engaging high schoolers in Ghana through medical physics.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {6}, pages = {e70126}, pmid = {40358923}, issn = {1526-9914}, mesh = {Humans ; Ghana ; Female ; Adolescent ; *Health Physics/education ; *Students/psychology ; *Mathematics/education ; *Engineering/education ; *Career Choice ; *Science/education ; *Radiation Oncology/education ; *Empowerment ; *Technology/education ; Schools ; Surveys and Questionnaires ; }, abstract = {PURPOSE: To promote diversity in Science, Technology, Engineering, and Mathematics (STEM), an educational presentation and hands-on session was organised to raise awareness of STEM career opportunities among high school girls to introduce the students to the field of medical physics.<br><br>MATERIALS AND METHODS: The study involved 65 first-year Senior High School girls, aged 13-16, pursuing general science in Accra, Ghana. This initiative, organised by the Girls Excellence Movement (GEM) in collaboration with a United States (US) institution, implemented the "heroes in radiation oncology" program, which included a relatable presentation and hands-on experience in simulation to treatment planning activities. The program's effectiveness was assessed through pre-and post-assessment surveys, and a thematic analysis of student feedback.<br><br>RESULTS: Participants' awareness of career fields showed an interest in traditional healthcare professions (92%) and engineering (73.8%), with minimal medical physics awareness (12.3%). Post-presentation survey showed a significant change in participants' perception of medical physics 87.3%. Thematic analysis revealed increased awareness, understanding, and interest, dispelled misconceptions about radiation safety, and highlighted the interdisciplinary nature and career opportunities. The presentation was successful in inspiring participants and expanding their perspectives on medical physics.<br><br>CONCLUSION: The program raised awareness of medical physics among participants, many of whom were previously unfamiliar with the field. Participants reported a newfound understanding of the interdisciplinary nature of medical physics, its connections to biology, mathematics, and engineering.This program can easily be reproduced in community and school outreaches.}, }
@article {pmid40359110, year = {2025}, author = {Gen, R and Addetia, A and Asarnow, D and Park, YJ and Quispe, J and Chan, MC and Brown, JT and Lee, J and Campbell, MG and Lapointe, CP and Veesler, D}, title = {SARS-CoV-2 nsp1 mediates broad inhibition of translation in mammals.}, journal = {Cell reports}, volume = {44}, number = {5}, pages = {115696}, doi = {10.1016/j.celrep.2025.115696}, pmid = {40359110}, issn = {2211-1247}, mesh = {*Viral Nonstructural Proteins/metabolism/chemistry/genetics ; Animals ; *SARS-CoV-2/metabolism ; Humans ; Chiroptera/virology ; *Protein Biosynthesis ; Cryoelectron Microscopy ; COVID-19/virology ; Mammals ; Ribosome Subunits, Small, Eukaryotic/metabolism ; HEK293 Cells ; }, abstract = {Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) non-structural protein 1 (nsp1) promotes innate immune evasion by inhibiting host translation in human cells. However, the role of nsp1 in other host species remains elusive, especially in bats-natural reservoirs of sarbecoviruses with a markedly different innate immune system than humans. We reveal that nsp1 potently inhibits translation in Rhinolophus lepidus bat cells, which belong to the same genus as known sarbecovirus reservoir hosts. We determined a cryoelectron microscopy structure of nsp1 bound to the R. lepidus 40S ribosomal subunit, showing that it blocks the mRNA entry channel by targeting a highly conserved site among mammals. Accordingly, we found that nsp1 blocked protein translation in mammalian cells from several species, underscoring its broadly inhibitory activity and conserved role in numerous SARS-CoV-2 hosts. Our findings illuminate the arms race between coronaviruses and mammalian host immunity, providing a foundation for understanding the determinants of viral maintenance in bat hosts and spillover.}, }
@article {pmid40359708, year = {2025}, author = {Gouda, MA and Voss, MH and Tawbi, H and Gordon, M and Tykodi, SS and Lam, ET and Vaishampayan, U and Tannir, NM and Chaves, J and Nikolinakos, P and Fan, A and Lee, R and McDermott, D and Shapiro, GI and Gandhi, L and Bhatia, S and Katragadda, V and Meric-Bernstam, F}, title = {A phase I/II study of the safety and efficacy of telaglenastat (CB-839) in combination with nivolumab in patients with metastatic melanoma, renal cell carcinoma, and non-small-cell lung cancer.}, journal = {ESMO open}, volume = {10}, number = {5}, pages = {104536}, pmid = {40359708}, issn = {2059-7029}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Nivolumab/administration &amp; dosage/therapeutic use/adverse effects/pharmacology ; Male ; Female ; Middle Aged ; Aged ; *Melanoma/drug therapy/pathology ; *Lung Neoplasms/drug therapy/pathology ; *Carcinoma, Non-Small-Cell Lung/drug therapy/pathology ; *Carcinoma, Renal Cell/drug therapy/pathology ; *Kidney Neoplasms/drug therapy/pathology ; Adult ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Aged, 80 and over ; Treatment Outcome ; }, abstract = {BACKGROUND: Telaglenastat (CB-839) is a glutaminase 1 inhibitor that targets the dysregulation in glutamine metabolism in cancer cells and the tumor microenvironment. Preclinical data suggested that the combination of telaglenastat with programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) antibodies can lead to enhanced immune response against cancer.<br><br>PATIENTS AND METHODS: We designed a phase I/II trial to investigate the safety and efficacy of telaglenastat combined with nivolumab in patients with advanced solid tumors. Dose escalation was carried out using a 3 + 3 design with two dose levels for telaglenastat (600 mg and 800 mg twice daily). Nivolumab was given at a fixed dose of 240 mg by intravenous infusion on days 1 and 15 of a 28-day cycle in all patients. Expansion in phase II was planned using Simon's two-stage design in disease- and prior therapy-specific cohorts.<br><br>RESULTS: We included a total of 118 patients across different cohorts. The most frequently reported adverse events were fatigue (42.4%; n = 50), nausea (39%; n = 46), and photophobia (32.2%; n = 38). In the response-assessable analysis set (including 107 patients in dose expansion and recommended phase II dose of dose escalation), the overall response rate (ORR) was 8.4% (n = 9). The ORR was 24% in 25 patients with clear-cell renal cell carcinoma (ccRCC) who were checkpoint inhibitor-na&#xef;ve, 5.9% in 17 patients with ccRCC after nivolumab, 0% in 9 patients with ccRCC after other prior anti-PD-1/PD-L1, 5.4% in 37 patients with melanoma after anti-PD-1/PD-L1, and 0% in 19 patients with non-small-cell lung cancer after anti-PD-1/PD-L1.<br><br>CONCLUSIONS: Telaglenastat in combination with nivolumab was generally well tolerated. The combination did not show a pattern of efficacy across different study cohorts.}, }
@article {pmid40360879, year = {2025}, author = {Wang'ondu, RW and Ashcraft, E and Chang, TC and Roberts, KG and Brady, SW and Fan, Y and Evans, W and Relling, MV and Crews, KR and Yang, J and Yang, W and Pounds, S and Wu, G and Devidas, M and Maloney, K and Mattano, L and Schore, RJ and Angiolillo, A and Larsen, E and Salzer, W and Burke, MJ and Loh, ML and Jeha, S and Pui, CH and Inaba, H and Cheng, C and Mullighan, CG}, title = {Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia.}, journal = {Leukemia}, volume = {39}, number = {7}, pages = {1595-1606}, pmid = {40360879}, issn = {1476-5551}, support = {U24 CA196173/CA/NCI NIH HHS/United States ; U10 CA98543, U10 CA180886, U10 CA98413, U10 CA180899, U24 CA114766, U24-CA196173//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA197695/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; American Society of Hematology Minority Hematology Fellow award//American Society of Hematology (ASH)/ ; U10 CA098413/CA/NCI NIH HHS/United States ; P30 CA021765 and R35 CA197695//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U24 CA114766/CA/NCI NIH HHS/United States ; CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U10 CA180899/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Ikaros Transcription Factor/genetics ; Child ; Female ; Male ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology/mortality ; Child, Preschool ; Adolescent ; Prognosis ; Infant ; Recurrence ; *Neoplasm Recurrence, Local/genetics/pathology ; *Biomarkers, Tumor/genetics ; Genomics ; Polymorphism, Single Nucleotide ; }, abstract = {Genomic alterations of IKZF1 are common and associated with adverse clinical features in B-progenitor acute lymphoblastic leukemia (B-ALL). The relationship between the type of IKZF1 alteration, B-ALL genomic subtype and outcome are incompletely understood. B-ALL subtype and genomic alterations were determined using transcriptome and genomic sequencing, and SNP microarray analysis in 688 pediatric patients with B-ALL in the St. Jude Total Therapy XV and 16 studies. IKZF1 alterations were identified in 115 (16.7%) patients, most commonly in BCR::ABL1 (78%) and CRLF2-rearranged, BCR::ABL1-like B-ALL (70%). These alterations were associated with 5-year cumulative incidence of relapse (CIR) of 14.8 ± 3.3% compared to 5.0 ± 0.9% for patients without any IKZF1 alteration (P < 0.0001). In separate multivariable analyses adjusting for genetic subtype groups and other factors, IKZF1 deletions of exons 4-7 (P = 0.0002), genomic IKZF1[plus] with any IKZF1 deletion (P = 0.006) or with focal IKZF1 deletion (P = 0.0007), and unfavorable genomic subtypes (P < 0.005) were independently adverse prognostic factors. Associations of genomic IKZF1[plus] and exon 4-7 deletions with adverse outcomes were confirmed in an independent cohort. The type of IKZF1 alteration, together with the subtype, are informative for risk stratification and to predict response in patients with B-ALL.}, }
@article {pmid40364846, year = {2025}, author = {Battisti, P and Ykema, MR and Kasal, DN and Jennewein, MF and Beaver, S and Weight, AE and Hanson, D and Singh, J and Bakken, J and Cross, N and Fusco, P and Archer, J and Reed, S and Gerhardt, A and Julander, JG and Casper, C and Voigt, EA}, title = {A bivalent self-amplifying RNA vaccine against yellow fever and Zika viruses.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1569454}, pmid = {40364846}, issn = {1664-3224}, support = {75N93019C00059/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; *Zika Virus/immunology ; *Zika Virus Infection/prevention &amp; control/immunology ; Antibodies, Neutralizing/immunology/blood ; Mice ; *Yellow fever virus/immunology ; Antibodies, Viral/immunology/blood ; *Yellow Fever/prevention &amp; control/immunology ; Mice, Inbred C57BL ; Cricetinae ; *Viral Vaccines/immunology ; Female ; Mesocricetus ; CD8-Positive T-Lymphocytes/immunology ; *Yellow Fever Vaccine/immunology ; Immunogenicity, Vaccine ; }, abstract = {INTRODUCTION: Yellow fever (YFV) and Zika (ZIKV) viruses cause significant morbidity and mortality, despite the existence of an approved YFV vaccine and the development of multiple ZIKV vaccine candidates to date. New technologies may improve access to vaccines against these pathogens. We previously described a nanostructured lipid carrier (NLC)-delivered self-amplifying RNA (saRNA) vaccine platform with excellent thermostability and immunogenicity, appropriate for prevention of tropical infectious diseases.<br><br>METHODS: YFV and ZIKV prM-E antigen-expressing saRNA constructs were created using a TC-83 strain Venezuelan equine encephalitis virus-based replicon and complexed with NLC by simple mixing. Monovalent and bivalent vaccine formulations were injected intramuscularly into C57BL/6 mice and Syrian golden hamsters, and the magnitude, durability, and protective efficacy of the resulting immune responses were then characterized.<br><br>RESULTS AND DISCUSSION: Monovalent vaccines established durable neutralizing antibody responses to their respective flaviviral targets, with little evidence of cross-neutralization. Both vaccines additionally elicited robust antigen-reactive CD4[+] and CD8[+] T cell populations. Notably, humoral responses to YFV saRNA-NLC vaccination were comparable to those in YF-17D-vaccinated animals. Bivalent formulations established humoral and cellular responses against both viral targets, commensurate to those established by monovalent vaccines, without evidence of saRNA interference or immune competition. Finally, both monovalent and bivalent vaccines completely protected mice and hamsters against lethal ZIKV and YFV challenge. We present a bivalent saRNA-NLC vaccine against YFV and ZIKV capable of inducing robust and efficacious neutralizing antibody and cellular immune responses against both viruses. These data support the development of other multivalent saRNA-based vaccines against infectious diseases.}, }
@article {pmid40364850, year = {2025}, author = {Rubinstein, S and Mohsin, A and Banerjee, R and Ma, W and Mishra, S and Kwok, M and Yang, P and Warner, JL and Cowan, AJ}, title = {Summarizing clinical evidence utilizing large language models for cancer treatments: a blinded comparative analysis.}, journal = {Frontiers in digital health}, volume = {7}, number = {}, pages = {1569554}, pmid = {40364850}, issn = {2673-253X}, support = {U24 CA265879/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Concise synopses of clinical evidence support treatment decision-making but are time-consuming to curate. Large language models (LLMs) offer potential but they may provide inaccurate information. We objectively assessed the abilities of four commercially available LLMs to generate synopses for six treatment regimens in multiple myeloma and amyloid light chain (AL) amyloidosis.<br><br>METHODS: We compared the performance of four LLMs: Claude 3.5, ChatGPT 4.0; Gemini 1.0 and Llama-3.1. Each LLM was prompted to write synopses for six regimens. Two hematologists independently assessed accuracy, completeness, relevance, clarity, coherence, and hallucinations using Likert scales. Mean scores with 95% confidence intervals (CI) were calculated across all domains and inter-rater reliability was evaluated using Cohen's quadratic weighted kappa.<br><br>RESULTS: Claude demonstrated the highest performance in all domains, outperforming the other LLMs in accuracy: mean Likert score 3.92 (95% CI 3.54-4.29); ChatGPT 3.25 (2.76-3.74); Gemini 3.17 (2.54-3.80); Llama 1.92 (1.41-2.43);completeness: mean Likert score 4.00 (3.66-4.34); GPT 2.58 (2.02-3.15); Gemini 2.58 (2.02-3.15); Llama 1.67 (1.39-1.95); and extentofhallucinations: mean Likert score 4.00 (4.00-4.00); ChatGPT 2.75 (2.06-3.44); Gemini 3.25 (2.65-3.85); Llama 1.92 (1.26-2.57). Llama performed considerably poorer across all the studied domains. ChatGPT and Gemini had intermediate performance. Notably, none of the LLMs registered perfect accuracy, completeness, or relevance.<br><br>CONCLUSION: Claude performed at a consistently higher level than other LLMs, all tested LLMs required careful editing from a domain expert to become usable. More time will be needed to determine the suitability of LLMsto independently generate clinical synopses.}, }
@article {pmid40364978, year = {2025}, author = {Alavattam, KG and Dickson, BM and Hirano, R and Dell, R and Tsukiyama, T}, title = {ChIP-seq Data Processing and Relative and Quantitative Signal Normalization for Saccharomyces cerevisiae.}, journal = {Bio-protocol}, volume = {15}, number = {9}, pages = {e5299}, pmid = {40364978}, issn = {2331-8325}, support = {R35 GM139429/GM/NIGMS NIH HHS/United States ; }, abstract = {Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) is a widely used technique for genome-wide analyses of protein-DNA interactions. This protocol provides a guide to ChIP-seq data processing in Saccharomyces cerevisiae, with a focus on signal normalization to address data biases and enable meaningful comparisons within and between samples. Designed for researchers with minimal bioinformatics experience, it includes practical overviews and refers to scripting examples for key tasks, such as configuring computational environments, trimming and aligning reads, processing alignments, and visualizing signals. This protocol employs the sans-spike-in method for quantitative ChIP-seq (siQ-ChIP) and normalized coverage for absolute and relative comparisons of ChIP-seq data, respectively. While spike-in normalization, which is semiquantitative, is addressed for context, siQ-ChIP and normalized coverage are recommended as mathematically rigorous and reliable alternatives. Key features • ChIP-seq data processing workflow for Linux and macOS integrating data acquisition, trimming, alignment, processing, and multiple forms of signal computation, with a focus on reproducibility. • ChIP-seq signal generation using siQ-ChIP to quantify absolute IP efficiency-providing a rigorous alternative to spike-in normalization-and normalized coverage for relative comparisons. • Broad applicability demonstrated with Saccharomyces cerevisiae (experimental) and Schizosaccharomyces pombe (spike-in) data but suitable for ChIP-seq in any species. • In-depth notes and troubleshooting guide users through setup challenges and key concepts in basic bioinformatics, data processing, and signal computation. Graphical overview Flowchart depicting ChIP-seq data processing steps covered in this protocol.}, }
@article {pmid40365115, year = {2025}, author = {Restar, AJ and Lucas, R and Nfn, S and Alpert, AB and Phipps, A and Wang, G and Operario, D and Radix, A and van der Merwe, LA and Lindström, S and Everhart, A and Gamarel, KE and Streed, CG}, title = {Underinvested, Under-Referred, and Underserved: Applying a Gender Equity Continuum Framework in Cancer Control Continuum Programs and Policies to Expand to Transgender and Nonbinary Populations.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {e2400023}, pmid = {40365115}, issn = {2994-9750}, abstract = {Gender-inclusive and gender-specific approaches are critically needed in cancer control continuum services to recognize and meet the needs of transgender and nonbinary (trans) populations. Current research, programs, and policies largely cater to cisgender populations and subscribe to a binary, gendered cisnormative ideology, both within health care systems and insurance policies, leaving trans people's cancer prevention and treatment needs neglected. Such disparities can be attributed to the significant gap in funding and research to address trans cancer prevention and treatment. We discuss the research, program, and policy implications of cisnormative practices and provide recommendations for promoting gender-inclusive and specific services across the cancer control continuum with the goal of eliminating cancer disparities and improving cancer outcomes for people of all gender groups, including trans populations.}, }
@article {pmid40365909, year = {2025}, author = {Levy, JA and Kazemian, E and Ramin, C and Loroña, NC and Nadri, M and Gasho, JO and Silos, KD and Nikolova, AP and Dey, D and Siegel, EM and Gigic, B and Hardikar, S and Byrd, DA and Toriola, AT and Ose, J and Li, CI and Shibata, D and Ulrich, CM and Tamarappoo, BK and Atkins, KM and Figueiredo, JC}, title = {Subclinical Atherosclerosis and Cardiovascular Events Among Patients With Colorectal Cancer.}, journal = {Cancer medicine}, volume = {14}, number = {10}, pages = {e70938}, pmid = {40365909}, issn = {2045-7634}, support = {R01CA189184//National Cancer Institute of the National Institutes of Health/ ; U01CA206110//National Cancer Institute of the National Institutes of Health/ ; R01CA207371//National Cancer Institute of the National Institutes of Health/ ; P30CA042014//National Cancer Institute of the National Institutes of Health/ ; R01CA160684//National Cancer Institute of the National Institutes of Health/ ; R01 CA254108/CA/NCI NIH HHS/United States ; R03CA270473//National Cancer Institute of the National Institutes of Health/ ; R01CA254108//National Cancer Institute of the National Institutes of Health/ ; R01CA215134//National Cancer Institute of the National Institutes of Health/ ; U01CA246659//National Cancer Institute of the National Institutes of Health/ ; }, mesh = {Humans ; Male ; Female ; *Colorectal Neoplasms/complications/epidemiology/therapy ; Middle Aged ; Aged ; Prospective Studies ; *Atherosclerosis/epidemiology/etiology ; *Cardiovascular Diseases/epidemiology/etiology ; Risk Factors ; Positron Emission Tomography Computed Tomography ; Coronary Vessels/diagnostic imaging ; }, abstract = {BACKGROUND: Prior studies have documented that patients with colorectal cancer (CRC) are at an increased risk of cardiovascular disease (CVD).<br><br>OBJECTIVES: To examine coronary artery calcium (CAC) as a marker of subclinical atherosclerosis and its association with major adverse cardiovascular events (MACE) in patients with CRC across the cancer treatment trajectory.<br><br>METHODS: Adults with newly diagnosed CRC were enrolled in the prospective ColoCare study from 2017 to 2024. CAC was measured from routine diagnostic computed tomography (CT) and positron emission tomography-CT scans at CRC diagnosis until 5&#x2009;years post-diagnosis. Atherosclerosis was defined as the presence of CAC. We used multivariable-adjusted Fine and Gray models to assess the association between CAC and MACE risk, accounting for competing risks.<br><br>RESULTS: Among 300 CRC patients, the most common CVD risk factors at cancer diagnosis were hypertension (37%), hyperlipidemia (24%), and diabetes (14%). During follow-up (median&#x2009;=&#x2009;5.3&#x2009;years), 75 (25%) individuals experienced MACE: stroke (3%), new/worsening HF (9%), HF exacerbation requiring hospitalization (2%), coronary revascularization (3%), and death (19%). Among individuals with imaging at baseline (n&#x2009;=&#x2009;101), 37 (36.6%) had CAC, and statins were not prescribed in 11 (55.0%) patients with moderate/high CAC. For those with serial imaging (n&#x2009;=&#x2009;61), 31.1% showed worsening CAC and 3% developed new CAC. Baseline CAC conferred a higher risk of MACE (HR&#x2009;=&#x2009;4.79; 95% CI: 1.05-21.75, p&#x2009;=&#x2009;0.04) after accounting for cancer-related deaths as a competing risk.<br><br>CONCLUSIONS: Subclinical atherosclerosis and MACE are common among patients with CRC. Integrating CAC from routine cancer imaging can identify patients who may benefit from cardio-preventive treatment.}, }
@article {pmid40366394, year = {2025}, author = {Hardy, S and Chhan, CB and Davis, AR and McGuire, AT}, title = {Viral Entry.}, journal = {Current topics in microbiology and immunology}, volume = {}, number = {}, pages = {}, doi = {10.1007/82_2025_300}, pmid = {40366394}, issn = {0070-217X}, abstract = {Epstein-Barr virus chiefly infects B cells and epithelial cells but is capable of infecting other cell types in the human host. Host cell entry is a complex process mediated by several viral glycoproteins that define tropism and mediate membrane fusion. This chapter will review what is known about the function of viral glycoproteins in the entry process, explore the nature of interactions between viral glycoproteins and host cell receptors, and highlight gaps in knowledge about the entry process that remain to be filled.}, }
@article {pmid40367160, year = {2025}, author = {Stepanov, I and Gottshall, NR and Ahmadianyazdi, A and Sinha, D and Lockhart, EJ and Nguyen, TNH and Hassan, S and Horowitz, LF and Yeung, RS and Gujral, TS and Folch, A}, title = {Low-cost robotic manipulation of live microtissues for cancer drug testing.}, journal = {Science advances}, volume = {11}, number = {20}, pages = {eads1631}, pmid = {40367160}, issn = {2375-2548}, support = {R01 CA181445/CA/NCI NIH HHS/United States ; R01 CA272677/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Robotics/economics/instrumentation ; Drug Screening Assays, Antitumor/methods/economics/instrumentation ; *Antineoplastic Agents/pharmacology ; *Neoplasms/drug therapy/pathology ; Lab-On-A-Chip Devices ; }, abstract = {The scarcity of human biopsies available for drug testing is a paramount challenge for developing therapeutics, disease models, and personalized treatments. Microtechnologies that combine the microscale manipulation of tissues and fluids offer the exciting possibility of miniaturizing both disease models and drug testing workflows on scarce human biopsies. Unfortunately, these technologies presently require microfluidic devices or robotic dispensers that are not widely accessible. We have rapidly prototyped an inexpensive platform based on an off-the-shelf robot that can microfluidically manipulate live microtissues into/out of culture plates without using complicated accessories such as microscopes or pneumatic controllers. The robot integrates complex functions with a simple, cost-effective, and compact construction, allowing placement inside a tissue culture hood for sterile workflows. We demonstrated a proof-of-concept cancer drug evaluation workflow of potential clinical utility using patient tumor biopsies with multiple drugs on 384-well plates. Our user-friendly, low-cost platform promises to make drug testing of microtissues broadly accessible to pharmaceutical, clinical, and biological laboratories.}, }
@article {pmid40368025, year = {2025}, author = {Park, ER and Kirchhoff, AC and Mitchell, CO and Durieux, N and Foor, A and Kuhlthau, K and Perez, GK and Ards, L and Alston, S and Armstrong, GT and Vaca Lopez, PL and McDonald, A and Nolan, VG and Levy, DE and Leisenring, WM and Galbraith, AA and Nathan, PC and Vukadinovich, C and Cooper, CL and Donelan, K}, title = {Assessing the effect of virtual navigation interventions to improve health insurance literacy and decrease financial burden in cancer survivors: The HINT II study protocol.}, journal = {Contemporary clinical trials}, volume = {154}, number = {}, pages = {107952}, pmid = {40368025}, issn = {1559-2030}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA271380/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors ; *Health Literacy/organization &amp; administration/methods ; *Insurance, Health ; *Patient Navigation/organization &amp; administration ; Health Expenditures/statistics &amp; numerical data ; Randomized Controlled Trials as Topic ; *Neoplasms/economics/therapy ; Adult ; Patient Acceptance of Health Care/statistics &amp; numerical data ; Cost of Illness ; Male ; }, abstract = {BACKGROUND: Childhood cancer survivors often face high healthcare costs to monitor and manage new or lasting effects of their treatment. Enhancing survivors' health insurance literacy (HIL) - the knowledge, ability, and confidence in enrolling in and navigating health plans - is vital for minimizing financial burden. Few studies have assessed the effect of a health insurance navigation program on improving HIL among survivors. We present the protocol for an ongoing randomized controlled trial (RCT) assessing the effectiveness of two health insurance navigation programs (HINT-S and HINT-A) on improving HIL, financial burden, out-of-pocket costs, and healthcare utilization for adult survivors of childhood cancer.<br><br>METHODS: This three-arm RCT assesses the effectiveness of two digitally delivered health insurance navigation interventions and enhanced usual care (EUC) on improving HIL at six and 12&#xa0;months in a national cohort of childhood cancer survivors. While HINT-S is composed of five synchronous, navigator-led sessions, HINT-A is an asynchronous, prerecorded set of five videos. EUC participants receive only a health insurance informational booklet. Financial burden, medical out-of-pocket costs, and healthcare utilization (receipt of preventive care, recommended screenings/vaccinations, and acute care) are assessed at 12&#xa0;months. Moderators to the interventions' effectiveness will be investigated, as well as implementation outcomes (feasibility, acceptability, appropriateness, fidelity, and cost-effectiveness).<br><br>CONCLUSIONS: There is a strong need for interventions to improve cancer survivors' HIL, helping them navigate the complexity of the U.S. healthcare system. This trial will elucidate the potential effectiveness and implementation of health insurance navigation programs that may benefit many cancer survivors.<br><br>TRIAL REGISTRATION: NCT05527392.}, }
@article {pmid40368142, year = {2025}, author = {Friedman, RK and Heath, AS and Huffman, JE and Baker, JT and Hasbani, NR and Gagliano Taliun, SA and Chen, MH and Howard, TE and Lewis, JP and Pankratz, N and Patil, S and Reiner, AP and Thibord, F and Yanek, LR and Yao, J and Chen, HH and Curran, JE and Faraday, N and Guo, X and Wheeler, MM and Ryan, KA and Zhou, X and Cho, K and Almasy, L and Auer, PL and Becker, LC and Wilson, PWF and Boerwinkle, E and O'Connell, JR and Rich, SS and Samuels, DC and ,  and ,  and ,  and Blangero, J and Fornage, M and Kooperberg, C and Mathias, RA and Mitchell, BD and Rotter, JI and Johnson, AD and Smith, NL and Coban-Akdemir, ZH and Below, JE and Morrison, AC and Johnsen, JM and de Vries, PS}, title = {Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {23}, number = {8}, pages = {2410-2421}, doi = {10.1016/j.jtha.2025.04.029}, pmid = {40368142}, issn = {1538-7836}, support = {R01 EB015611/EB/NIBIB NIH HHS/United States ; R01 HL139553/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *von Willebrand Factor/genetics/analysis ; *von Willebrand Diseases/genetics/blood/diagnosis ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Female ; Male ; Case-Control Studies ; *Hemorrhage/genetics/blood/diagnosis ; Phenotype ; Middle Aged ; ABO Blood-Group System/genetics ; Risk Factors ; Adult ; Risk Assessment ; Polymorphism, Single Nucleotide ; }, abstract = {BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored.<br><br>OBJECTIVES: To identify genetic variants influencing VWF:Ag levels &#x2264; 50 IU/dL.<br><br>METHODS: We performed a genome-wide association study in 926 cases with VWF:Ag levels &#x2264; 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen.<br><br>RESULTS: Variants at 2 loci were associated (P < 5 &#xd7; 10[-9]) with VWF:Ag levels &#x2264; 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels &#x2264; 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54).<br><br>CONCLUSIONS: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels &#x2264; 50 IU/dL, bleeding, and VWD.}, }
@article {pmid40369385, year = {2025}, author = {Manohar, PM and Peterson, LM and Jenkins, IC and Wu, QV and Kurland, BF and Novakova-Jiresova, A and Muzi, M and Chen, DL and Specht, JM and Dintzis, S and Kinahan, PE and Mankoff, DA and Linden, HM}, title = {[18 F]-Fluoroestradiol PET (FES-PET) and [18 F] Flurodeoxyglucose PET (FDG-PET) Imaging May Aid in Managing Therapy in Patients with Metastatic Lobular Breast Cancer.}, journal = {Molecular imaging and biology}, volume = {27}, number = {3}, pages = {410-420}, pmid = {40369385}, issn = {1860-2002}, support = {R50 CA211270/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Fluorodeoxyglucose F18/chemistry ; Female ; *Breast Neoplasms/diagnostic imaging/pathology/therapy ; Middle Aged ; *Positron-Emission Tomography/methods ; Aged ; Adult ; *Estradiol/analogs &amp; derivatives/chemistry ; Neoplasm Metastasis ; *Carcinoma, Lobular/diagnostic imaging/therapy/pathology ; Retrospective Studies ; Aged, 80 and over ; }, abstract = {AIM: This study examines the combination of FES-PET and FDG-PET as complementary imaging for detection of metastatic ILC.<br><br>METHODS: We retrospectively evaluated FES and FDG uptake in patients with metastatic ILC from an estrogen receptor (ER) positive primary tumor. We classified lesions into three categories (FES high/FDG low, FES high/FDG high, FES low/FDG low) using SUVmax cut-off values of 1.5 for FES and 5.0 for FDG. Qualitative evaluation included examination of the difference in the extent of disease between FES and FDG.<br><br>RESULTS: Of the 38 patients, 82% had FES uptake in all tumor sites identified by FDG, with 18% lacking FES uptake in at least one lesion. Mean (range)&#xa0;SUVmax&#xa0;for FES and FDG was 4.0 (0.67-10.6) and 4.6 (1.3-12.5), respectively.&#xa0;The majority of ILC patients (25/38), had lesions with FES high/FDG low uptake, consistent with the strongly ER&#x2009;+&#x2009;indolent nature of ILC. Patients with disease classified as FES high/FDG low had longer median overall survival (OS) (3.2&#xa0;years) and progression-free survival (PFS) (1.5&#xa0;years) than FES high/FDG high (OS&#x2009;=&#x2009;2.1&#xa0;years and PFS&#x2009;=&#x2009;0.46&#xa0;years). The median overall OS for all patients was 3.0&#xa0;years (95% CI 2.5, 4.8) and PFS of 1.3&#xa0;years (95% CI 0.6, 2.5). 8 patients (21%) had qualitatively more extensive disease by FES-PET.<br><br>CONCLUSIONS: Our findings suggest that both FES-PET and FDG-PET can identify metastatic ILC and be useful in detecting the pattern and extent of disease. The imaging combination provides additional information for prognosis and clinical decision making, balancing suitability for endocrine therapy and aggressiveness/indolence of disease.}, }
@article {pmid40371912, year = {2025}, author = {Wesselink, E and Thomas, CE and Takashima, Y and Mizuno, H and Buchanan, DD and Qu, C and Hsu, L and Dias Costa, A and Ugai, S and Zhong, Y and Huyghe, JR and Thomas, S and Gallinger, S and Grant, RC and Le Marchand, L and Masugi, Y and van Duijnhoven, FJB and Ugai, T and Ogino, S and Nowak, JA and Peters, U and Phipps, AI}, title = {Associations between Calcium Intake and T-cell Infiltration in Colorectal Tumors.}, journal = {Cancer prevention research (Philadelphia, Pa.)}, volume = {18}, number = {9}, pages = {561-571}, pmid = {40371912}, issn = {1940-6215}, support = {S10OD028685//Office of Research Infrastructure Programs (ORIP)/ ; R01 CA273198/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; CRP-24-1185864-01-PROF//American Cancer Society (ACS)/ ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; 112746//Canadian Institutes of Health Research (CIHR)/ ; UM1 CA167551/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; C10674/A27140//Cancer Research UK (CRUK)/ ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U24 CA074783/CA/NCI NIH HHS/United States ; R01 CA206279/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; R50 CA274122/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; GNT1194896//National Health and Medical Research Council (NHMRC)/ ; R21 CA191312/CA/NCI NIH HHS/United States ; P20 CA252733/CA/NCI NIH HHS/United States ; R01 CA244588/CA/NCI NIH HHS/United States ; R01 CA488857//National Cancer Institute (NCI)/ ; T32 CA009168/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; HHSN268201700006I//National Institutes of Health (NIH)/ ; GL201-043//Ontario Research Foundation (ORF)/ ; UM1 CA186107/CA/NCI NIH HHS/United States ; L70 CA284301/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/immunology/pathology ; *Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Female ; Tumor Microenvironment/immunology ; Middle Aged ; *Calcium, Dietary/administration &amp; dosage ; Aged ; Prognosis ; *T-Lymphocyte Subsets/immunology ; Cohort Studies ; }, abstract = {UNLABELLED: Higher T-cell infiltration in colorectal tumors has been associated with better prognosis. Evidence indicates that calcium signaling is essential for T-cell functioning. However, as it is unknown whether calcium intake influences T-cell infiltration, we investigated the association of calcium intake with T-cell subsets in the tumor microenvironment of colorectal cancer. In total, 943 participants from three cohort studies, for which data on tumor-infiltrating T cells and calcium intake were available, were included for these analyses. Immune cell infiltration was quantified by digital image analyses with machine learning algorithms using a customized 9-plex multispectral immunofluorescence assay (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3, KRT, MKI67, and di-(4-amidinophenyl)-1H-indole-6-carboxamidine). Associations between prediagnostic calcium intake and densities of nonoverlapping subsets of epithelial and stromal tissue area T cells were assessed using multivariable binary or ordinal logistic regression analyses. A higher dietary calcium intake was positively associated with CD3+CD4-CD8- double-negative T-cell density in the epithelial (OR, 1.57; 95% confidence interval, 1.13-2.24) and stromal (OR, 1.24; 95% confidence interval, 1.06-1.45) tumor tissue areas. No other statistically significant associations were observed after correcting for multiple testing. In conclusion, dietary calcium intake was associated with a higher density of CD4-CD8- double-negative T cells in the epithelial and stromal tumor tissue areas but not with the infiltration of CD4+ or CD8+ T cells. More research is needed to further unravel the role of calcium in tumor-immune profiles and associations with clinical outcomes. Our findings offer a promising basis for further research.<br><br>PREVENTION RELEVANCE: Our research contributes to the understanding of how diet could influence immune cell infiltration in and around the tumor. Understanding which factors influence antitumor immune responses is of importance in the prevention of cancer recurrence and/or progression.}, }
@article {pmid40372237, year = {2025}, author = {Hullar, MAJ and Kahsai, OJ and Hill, C and Levy, L and Malen, RC and Curtis, KR and Ammar, H and Sillah, A and Reedy, AM and Lampe, JW and Ogino, S and Potter, JD and Newcomb, PA and Phipps, AI}, title = {Highly Sensitive DNA Testing of Fusobacterium nucleatum in Colorectal Tumors.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {8}, pages = {1377-1385}, pmid = {40372237}, issn = {1538-7755}, support = {R01CA076366//National Cancer Institute (NCI)/ ; P30CA015704//National Cancer Institute (NCI)/ ; P50 CA285275/CA/NCI NIH HHS/United States ; P20 CA252733/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; CRP-24-1185864-01-PROF//American Cancer Society (ACS)/ ; U01CA74794//National Cancer Institute (NCI)/ ; UK C10674/A27140//Cancer Research UK (CRUK)/ ; R01 CA217970/CA/NCI NIH HHS/United States ; U01CA167551//National Cancer Institute (NCI)/ ; R35CA197735//National Cancer Institute (NCI)/ ; T32 CA094880/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; R01 CA248857/CA/NCI NIH HHS/United States ; R01CA217970//National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Fusobacterium nucleatum/genetics/isolation &amp; purification ; Female ; Male ; *Colorectal Neoplasms/microbiology/genetics/pathology ; Middle Aged ; Aged ; *DNA, Bacterial/genetics/analysis ; *Fusobacterium Infections/microbiology/diagnosis ; Polymerase Chain Reaction/methods ; }, abstract = {BACKGROUND: Fusobacterium nucleatum (Fn) has been associated with the risk of colorectal cancer, poor colorectal cancer survival, and tumor attributes. Accurate and sensitive detection of Fn in tumor tissue is critical for evaluating their role in colorectal cancer.<br><br>METHODS: We developed a droplet digital PCR (ddPCR) assay for detecting Fn using the transcription termination/antitermination gene (nusG) normalized for host tissue (solute carrier organic anion transporter family member 2A1). We assayed Fn(nusG) in matched tumor and normal tissues for 613 participants in the Seattle site of the Colon Cancer Family Registry. We used logistic regression to determine the odds of Fn enrichment in tumor tissue according to the tumor site and stage, adjusting for age, sex, and body mass index.<br><br>RESULTS: The limit of quantitation for Fn(nusG) was 4.1 copies/10 ng host tissue. Detection of Fn was quenched and poor at low levels in formalin-fixed, paraffin-embedded tissues using qPCR. There was a low agreement between qPCR and ddPCR (Cohen's kappa = 0.46). Fn(nusG) was detected in tumor (21%) and normal (10%) tissues and was enriched in 19% of tumors. Individuals with tumors enriched in Fn were more likely to be female (59% vs. 48%, respectively; P = 0.04) with proximal colon tumors (57% vs. 43%; P = 0.026). In multivariable-adjusted analyses, proximal colon tumors were significantly associated with Fn enrichment (OR vs. rectal tumors: 1.86; 95% confidence interval, 1.11-3.24).<br><br>CONCLUSIONS: We established a sensitive and specific method to detect Fn enrichment in human tissues.<br><br>IMPACT: ddPCR enhanced detection of Fn(nusG) for studies targeting tumor-associated bacteria.}, }
@article {pmid40372253, year = {2025}, author = {Elkholi, IE and Robert, A and Malouf, C and Wu, JL and Kuasne, H and Drapela, S and Macleod, G and Hébert, S and Pacis, A and Calderon, V and Kleinman, CL and Gomes, AP and Alvarez, JV and Aguirre-Ghiso, JA and Park, M and Angers, S and Côté, JF}, title = {Targeting the Dependence on PIK3C3-mTORC1 Signaling in Dormancy-Prone Breast Cancer Cells Blunts Metastasis Initiation.}, journal = {Cancer research}, volume = {85}, number = {12}, pages = {2179-2198}, pmid = {40372253}, issn = {1538-7445}, support = {//U.S. Department of Defense (DOD)/ ; P30CA013330//National Cancer Institute (NCI)/ ; //Miles for Moffit/ ; R01 CA292658/CA/NCI NIH HHS/United States ; R01 CA109182/CA/NCI NIH HHS/United States ; //The Gurwin Foundation/ ; //Melanoma Research Alliance (MRA)/ ; //Quebec Breast Cancer Foundation/ ; //Samuel Waxman Cancer Research Foundation (SWCRF)/ ; CA253977//National Cancer Institute (NCI)/ ; //Diane and Sal Guerrera Chair in Cancer Genetics/ ; U01 CA284085/CA/NCI NIH HHS/United States ; RSG-22-164-01-MM//American Cancer Society (ACS)/ ; //Institut de Recherche Clinique De Montr&#xe9;al Foundation/ ; //Calcul Quebec/ ; CA284085//National Cancer Institute (NCI)/ ; FDN-143281//Canadian Institutes of Health Research (CIHR)/ ; //Fonds de Recherche du Qu&#xe9;bec - Sant&#xe9; (FRQS)/ ; CA109182//National Cancer Institute (NCI)/ ; //Compute Canada (Calcul Canada)/ ; PJT-156086//Canadian Institutes of Health Research (CIHR)/ ; //Canada Research Chairs (Chaires de recherche du Canada)/ ; 25244//Cancer Research Society (CRS)/ ; R01CA292658//National Cancer Institute (NCI)/ ; //Peter Quinlan Postdoctoral research Fellowship in Oncology/ ; R01 CA253977/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; //The Mark Foundation Aspire Program/ ; //Rose C. Falkenstein Chair in Cancer Research/ ; //Canadian Cancer Society (CCS)/ ; }, mesh = {*Mechanistic Target of Rapamycin Complex 1/metabolism/antagonists &amp; inhibitors/genetics ; Animals ; Humans ; Female ; *Breast Neoplasms/pathology/metabolism/genetics/drug therapy ; Mice ; Signal Transduction/drug effects ; *Class III Phosphatidylinositol 3-Kinases/metabolism/antagonists &amp; inhibitors/genetics ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Neoplasm Metastasis ; Mice, Inbred BALB C ; }, abstract = {UNLABELLED: Halting breast cancer metastatic relapse following primary tumor removal remains challenging due to a lack of specific vulnerabilities to target during the clinical dormancy phase. To identify such vulnerabilities, we conducted genome-wide CRISPR screens on two breast cancer cell lines with distinct dormancy properties: 4T1 (short-term dormancy) and 4T07 (prolonged dormancy). The dormancy-prone 4T07 cells displayed a unique dependency on class III PI3K (PIK3C3). Unexpectedly, 4T07 cells exhibited higher mechanistic target of rapamycin complex 1 (mTORC1) activity than 4T1 cells due to lysosome-dependent signaling occurring at the cell periphery. Pharmacologic inhibition of PIK3C3 suppressed this phenotype in the 4T1-4T07 models as well as in human breast cancer cell lines and a breast cancer patient-derived xenograft. Furthermore, inhibiting PIK3C3 selectively reduced metastasis burden in the 4T07 model and eliminated dormant cells in a HER2-dependent murine breast cancer dormancy model. These findings suggest that PIK3C3-peripheral lysosomal signaling to mTORC1 may represent a targetable axis for preventing dormant cancer cell-initiated metastasis in patients with breast cancer.<br><br>SIGNIFICANCE: Dormancy-prone breast cancer cells depend on the class III PI3K to mediate peripheral lysosomal positioning and mTORC1 hyperactivity, which can be targeted to blunt breast cancer metastasis.}, }
@article {pmid40372917, year = {2025}, author = {Alassaf, M and Madan, A and Ranganathan, S and Marschall, S and Wong, JJ and Goldberg, ZH and Brent, AE and Rajan, A}, title = {Adipocyte metabolic state regulates glial phagocytic function.}, journal = {Cell reports}, volume = {44}, number = {5}, pages = {115704}, pmid = {40372917}, issn = {2211-1247}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; R35 GM124593/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; }, mesh = {Animals ; *Neuroglia/metabolism ; *Adipocytes/metabolism ; *Phagocytosis ; Drosophila Proteins/metabolism ; Drosophila melanogaster/metabolism ; Mitochondria/metabolism ; Glycolysis ; Apolipoproteins B/metabolism ; Lipid Metabolism ; Brain/metabolism ; Membrane Proteins/metabolism ; }, abstract = {Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions.}, }
@article {pmid40373112, year = {2025}, author = {Willis, JR and Prabhakaran, M and Muthui, M and Naidoo, A and Sincomb, T and Wu, W and Cottrell, CA and Landais, E and deCamp, AC and Keshavarzi, NR and Kalyuzhniy, O and Lee, JH and Murungi, LM and Ogonda, WA and Yates, NL and Corcoran, MM and Phulera, S and Musando, J and Tsai, A and Lemire, G and Sein, Y and Muteti, M and Alamuri, P and Bohl, JA and Holman, D and Himansu, S and Leav, B and Reuter, C and Lin, LA and Ding, B and He, C and Straus, WL and MacPhee, KJ and Regadas, I and Nyabundi, DV and Chirchir, R and Anzala, O and Kimotho, JN and Kibet, C and Greene, K and Gao, H and Beatman, E and Benson, K and Laddy, D and Brown, DM and Bronson, R and Jean-Baptiste, J and Gajjala, S and Rikhtegaran-Tehrani, Z and Benner, A and Ramaswami, M and Lu, D and Alavi, N and Amirzehni, S and Kubitz, M and Tingle, R and Georgeson, E and Phelps, N and Adachi, Y and Liguori, A and Flynn, C and McKenney, K and Zhou, X and Owuor, DC and Owuor, SA and Kim, SY and Duff, M and Kim, JY and Gibson, G and Baboo, S and Diedrich, J and Schiffner, T and Shields, M and Matsoso, M and Santos, J and Syvertsen, K and Kennedy, A and Schroeter, M and Vekemans, J and Yates, JR and Paulson, JC and Hyrien, O and McDermott, AB and Maenetje, P and Nyombayire, J and Karita, E and Ingabire, R and Edward, V and Muturi-Kioi, V and Maenza, J and Shapiro, AE and McElrath, MJ and Edupuganti, S and Taylor, BS and Diemert, D and Ozorowski, G and Koup, RA and Montefiori, D and Ward, AB and Karlsson Hedestam, GB and Tomaras, G and Hunt, DJ and Muema, D and Sok, D and Laufer, DS and Andrews, SF and Nduati, EW and Schief, WR}, title = {Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6759}, pages = {eadr8382}, doi = {10.1126/science.adr8382}, pmid = {40373112}, issn = {1095-9203}, support = {UM1 AI100663/AI/NIAID NIH HHS/United States ; UM1 AI144462/AI/NIAID NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Young Adult ; *AIDS Vaccines/immunology/adverse effects/administration &amp; dosage ; *Broadly Neutralizing Antibodies/blood/immunology ; *HIV Antibodies/immunology/blood ; *HIV Infections/prevention &amp; control/immunology ; *HIV-1/immunology ; Immunization, Secondary ; Immunogenicity, Vaccine ; *mRNA Vaccines/administration &amp; dosage/immunology ; *Nanovaccines/administration &amp; dosage/immunology ; Rwanda ; Somatic Hypermutation, Immunoglobulin ; South Africa ; Vaccination ; }, abstract = {A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI G002 in the United States and IAVI G003 in Rwanda and South Africa (IAVI, International Aids Vaccine Initiative), we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI G002). The vaccines were generally safe and well tolerated, except that 18% of IAVI G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM; heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development; and elicited antibodies exhibited precise bnAb structural mimicry. The results establish clinical proof of concept that heterologous boosting can advance bnAb precursor maturation and demonstrate bnAb priming in Africa, where the HIV burden is highest.}, }
@article {pmid40373114, year = {2025}, author = {Caniels, TG and Prabhakaran, M and Ozorowski, G and MacPhee, KJ and Wu, W and van der Straten, K and Agrawal, S and Derking, R and Reiss, EIMM and Millard, K and Turroja, M and Desrosiers, A and Bethony, J and Malkin, E and Liesdek, MH and van der Veen, A and Klouwens, M and Snitselaar, JL and Bouhuijs, JH and Bronson, R and Jean-Baptiste, J and Gajjala, S and Rikhtegaran Tehrani, Z and Benner, A and Ramaswami, M and Duff, MO and Liu, YW and Sato, AH and Kim, JY and Baken, IJL and Mendes Silva, C and Bijl, TPL and van Rijswijk, J and Burger, JA and Cupo, A and Yasmeen, A and Phulera, S and Lee, WH and Randall, KN and Zhang, S and Corcoran, MM and Regadas, I and Sullivan, AC and Brown, DM and Bohl, JA and Greene, KM and Gao, H and Yates, NL and Sawant, S and Prins, JM and Kootstra, NA and Kaminsky, SM and Barin, B and Rahaman, F and Meller, M and Philiponis, V and Laufer, DS and Lombardo, A and Mwoga, L and Shotorbani, S and Holman, D and Koup, RA and Klasse, PJ and Karlsson Hedestam, GB and Tomaras, GD and van Gils, MJ and Montefiori, DC and McDermott, AB and Hyrien, O and Moore, JP and Wilson, IA and Ward, AB and Diemert, DJ and de Bree, GJ and Andrews, SF and Caskey, M and Sanders, RW}, title = {Precise targeting of HIV broadly neutralizing antibody precursors in humans.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6759}, pages = {eadv5572}, pmid = {40373114}, issn = {1095-9203}, support = {INV-008352/GATES/Gates Foundation/United States ; INV-007371/GATES/Gates Foundation/United States ; INV-036842/GATES/Gates Foundation/United States ; INV-008017/GATES/Gates Foundation/United States ; INV-002916/GATES/Gates Foundation/United States ; INV-029691/GATES/Gates Foundation/United States ; INV-007368/GATES/Gates Foundation/United States ; INV-032929/GATES/Gates Foundation/United States ; INV-002202/GATES/Gates Foundation/United States ; P30 AI036214/AI/NIAID NIH HHS/United States ; P01 AI110657/AI/NIAID NIH HHS/United States ; INV-008818/GATES/Gates Foundation/United States ; R01 AI036082/AI/NIAID NIH HHS/United States ; INV-007375/GATES/Gates Foundation/United States ; }, mesh = {Humans ; Adjuvants, Immunologic/administration &amp; dosage ; *AIDS Vaccines/immunology ; *Antibodies, Monoclonal/immunology/chemistry/genetics ; B-Lymphocytes/immunology ; *Broadly Neutralizing Antibodies/chemistry/genetics/immunology ; CD4 Antigens/immunology ; Double-Blind Method ; *env Gene Products, Human Immunodeficiency Virus/immunology ; *HIV Antibodies/immunology/chemistry/genetics ; *HIV Infections/immunology/prevention &amp; control ; *HIV-1/immunology ; Somatic Hypermutation, Immunoglobulin ; }, abstract = {A protective HIV vaccine will need to induce broadly neutralizing antibodies (bnAbs) in humans, but priming rare bnAb precursor B cells has been challenging. In a double-blinded, placebo-controlled phase 1 human clinical trial, the recombinant, germline-targeting envelope glycoprotein (Env) trimer BG505 SOSIP.v4.1-GT1.1, adjuvanted with AS01B, induced bnAb precursors of the VRC01-class at a high frequency in the majority of vaccine recipients. These bnAb precursors, which target the CD4 receptor binding site, had undergone somatic hypermutation characteristic of the VRC01-class. A subset of isolated VRC01-class monoclonal antibodies neutralized wild-type pseudoviruses and was structurally extremely similar to bnAb VRC01. These results further support germline-targeting approaches for human HIV vaccine design and demonstrate atomic-level manipulation of B cell responses with rational vaccine design.}, }
@article {pmid40373198, year = {2026}, author = {Davis, MR and Kufel, JE and Kufel, WD and McCreary, EK and Oleksiuk, LM and Ours, R and Pham, CU and Ross, JK and Smith, EA and Trisler, MJ and Tverdek, F}, title = {You've Got a Friend in Me: Curbside Questions Infectious Diseases Clinicians Ask Infectious Diseases Pharmacists.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {82}, number = {1}, pages = {58-61}, doi = {10.1093/cid/ciaf250}, pmid = {40373198}, issn = {1537-6591}, mesh = {Humans ; *Pharmacists ; *Communicable Diseases/diagnosis ; *Referral and Consultation ; }, abstract = {This multicenter study highlights the critical role of infectious diseases (ID) pharmacists in supporting ID consult services, with 89% of 1518 curbside inquiries from ID clinicians resulting in clinical management changes as recommended by the pharmacist. These findings emphasize the necessity of ID pharmacists in optimizing multidisciplinary patient care.}, }
@article {pmid40373748, year = {2025}, author = {Kublin, JG}, title = {Antibiotics fire up inflammation to cool vaccine responsiveness.}, journal = {Cell host &amp; microbe}, volume = {33}, number = {5}, pages = {618-620}, doi = {10.1016/j.chom.2025.04.015}, pmid = {40373748}, issn = {1934-6069}, mesh = {Humans ; *Anti-Bacterial Agents/adverse effects ; *Inflammation/chemically induced/immunology ; *Rabies Vaccines/immunology/administration &amp; dosage ; *Gastrointestinal Microbiome/drug effects/immunology ; Vaccination ; Animals ; }, abstract = {In this issue of Cell Host &amp; Microbe, Feng et al. find that broad-spectrum antibiotics perturbed the ecology of the gut microbiome in individuals receiving a rabies vaccine, resulting in systemic inflammatory responses. Such inflammation is hypothesized to alter immune homeostasis with consequences for immunological responsiveness to vaccination.}, }
@article {pmid40373766, year = {2025}, author = {Sajadi, MM and Abbasi, A and Tehrani, ZR and Siska, C and Clark, R and Chi, W and Seaman, MS and Mielke, D and Wagh, K and Liu, Q and Jumpa, T and Ketchem, RR and Nguyen, DN and Tolbert, WD and Pierce, BG and Atkinson, B and Deming, D and Sprague, M and Asakawa, A and Ferrer, D and Dunn, Y and Calvillo, S and Yin, R and Guest, JD and Korber, B and Mayer, BT and Sato, AH and Ouyang, X and Foulke, S and Habibzadeh, P and Karimi, M and Aslanabadi, A and Hojabri, M and Saadat, S and Zareidoodeji, R and Kędzior, M and Pozharski, E and Heredia, A and Chen, H and Montefiori, D and Ferrari, G and Pazgier, M and Lewis, GK and Jardine, JG and Lusso, P and DeVico, A}, title = {A comprehensive engineering strategy improves potency and manufacturability of a near pan-neutralizing antibody against HIV.}, journal = {Structure (London, England : 1993)}, volume = {33}, number = {7}, pages = {1150-1164.e8}, pmid = {40373766}, issn = {1878-4186}, support = {I01 BX004525/BX/BLRD VA/United States ; INV-036842/GATES/Gates Foundation/United States ; R01 AI155150/AI/NIAID NIH HHS/United States ; P01 AI131251/AI/NIAID NIH HHS/United States ; R01 AI147870/AI/NIAID NIH HHS/United States ; P01 AI162242/AI/NIAID NIH HHS/United States ; R35 GM144083/GM/NIGMS NIH HHS/United States ; R01 AI174908/AI/NIAID NIH HHS/United States ; INV-005284/GATES/Gates Foundation/United States ; }, mesh = {Humans ; *HIV Antibodies/chemistry/immunology/genetics/pharmacology ; *Antibodies, Neutralizing/chemistry/immunology/genetics/pharmacology ; *Protein Engineering ; *HIV-1/immunology ; HIV Infections/immunology ; CD4 Antigens/immunology/metabolism ; Animals ; Broadly Neutralizing Antibodies/chemistry ; }, abstract = {Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential to prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials with "first-generation" bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of "enhanced" antibodies will be required for optimal clinical utility, while preserving or enhancing Current Good Manufacturing Practices (cGMP) manufacturing capability. Here, we report the engineering of an anti-CD4-binding site (CD4bs) bnAb, N49P9.3. Through a series of rational modifications, we produced a variant, N49P9.6-FR-LS, that demonstrates enhanced potency, superior antiviral activity in combination with other bnAbs, low polyreactivity, and longer circulating half-life. Additional engineering for manufacturing produced a final variant, eN49P9, with properties conducive to cGMP production. Overall, these efforts demonstrate the feasibility of developing enhanced anti-CD4bs bnAbs with greatly improved antiviral properties as well as potential translational value.}, }
@article {pmid40374764, year = {2025}, author = {Kwak, JW and Houghton, AM}, title = {Targeting neutrophils for cancer therapy.}, journal = {Nature reviews. Drug discovery}, volume = {24}, number = {9}, pages = {666-684}, pmid = {40374764}, issn = {1474-1784}, mesh = {Humans ; *Neutrophils/immunology/drug effects ; *Neoplasms/immunology/drug therapy/pathology ; Tumor Microenvironment/immunology/drug effects ; Animals ; *Antineoplastic Agents/pharmacology/therapeutic use ; }, abstract = {Neutrophils are among the most abundant immune cell types in the tumour microenvironment and have been associated with poor outcomes across multiple cancer types. Yet despite mounting evidence of their role in tumour progression, therapeutic strategies targeting neutrophils have only recently gained attention and remain limited in scope. This is probably due to the increasing number of distinct neutrophil subtypes identified in cancer and the limited understanding of the mechanisms by which these subsets influence tumour progression and immune evasion. In this Review, we discuss the spectrum of neutrophil subtypes - including those with antitumour activity - and their potential to polarize towards tumour-suppressive phenotypes. We explore the molecular pathways and effector functions by which neutrophils modulate cancer progression, with an emphasis on identifying tractable therapeutic targets. Finally, we examine emerging clinical trials aimed at modulating neutrophil lineages and consider their implications for patient outcomes.}, }
@article {pmid40376501, year = {2025}, author = {Wang, S and Ding, W and Lu, S and Li, L and Qian, F and Chen, C and Liu, L and Cai, Y and Liu, X and Perez, S and Frutos, R and Yao, H and Zhou, Y and Ye, C and Wu, D and Li, S and Kwete, XJ and Sui, Y and Wang, D}, title = {China's Malaria R&amp;D Innovations: A Scoping Review from 2013-2023.}, journal = {China CDC weekly}, volume = {7}, number = {18}, pages = {635-643}, pmid = {40376501}, issn = {2096-7071}, abstract = {Malaria remains a major global health challenge. Understanding the research progress of the potential innovative tools is important for malaria elimination. This scoping review aims to explore China's research and development (R&amp;D) advances from 2013-2023 in addressing the current challenges and contributing to global malaria elimination. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), this review searched the English and Simplified Chinese data sources from five databases. A total of 11,112 English articles and 2,944 Chinese articles were retrieved. After screening, 44 English and 13 Chinese articles were included. Key advancements were identified in three domains: vector control, pathogen screening and diagnosis, and prevention and treatment. Innovations in vector control include studies such as the use of Serratia strains and symbiont-mediated RNAi approaches to block malaria transmission. Advances in pathogen screening and diagnosis feature biosensor development, AI monitoring technologies, and novel amplification gene and nucleic acid detection technologies. In prevention and treatment, artemisinin-based combination therapies (ACTs) remain a cornerstone, with additional progress in industrial pharmaceuticals and technologies already in field and semi-field-testing stages. This review underscores the importance of leveraging China's R&amp;D capacity to meet global challenges. To maximize impact, we call for global attention to strengthening international collaboration with China in malaria R&amp;D to accelerate the commercialization, regulatory approval, and large-scale deployment of innovations.}, }
@article {pmid40376505, year = {2025}, author = {Li, Y and Zheng, J and Mlacha, YP and Lu, S and Abdulla, S and Li, Q and Yan, G and Zhou, X and Xiao, N and Githu, V and Gavana, T and Chaki, P and Bi, P and Sui, Y and Wang, Y and Wang, D}, title = {Impact of Implementation Interruptions of 1,7-Malaria Reactive Community-Based Testing and Response Approach on Malaria Control Efforts - Southern Tanzania.}, journal = {China CDC weekly}, volume = {7}, number = {18}, pages = {628-634}, pmid = {40376505}, issn = {2096-7071}, abstract = {INTRODUCTION: Surveys from the China-Tanzania Malaria Control Project demonstrated that the 1,7-malaria Reactive Community-Based Testing and Response (1,7-mRCTR) approach significantly reduced malaria incidence rates. However, implementation was disrupted by security concerns, infectious disease outbreaks, and supply shortages. This study evaluates how these interruptions affected intervention effectiveness to inform future malaria control strategies.<br><br>METHODS: The study employed a two-phased design: Phase I (2016-2018) and Phase II (2019-2021). Weekly malaria incidence rates per 100 people were calculated from cases reported by local health facilities in the intervention areas during both phases. Seasonal and trend decomposition using loess (STL) and interrupted time series modeling with piecewise linear regression were used to evaluate the impact of disruptions on 1,7-mRCTR implementation effectiveness.<br><br>RESULTS: In Tanzania's 1,7-mRCTR areas, malaria incidence peaked during November-December and June-July. Phase I's 8-month interruption reversed the weekly trend from a 0.17% decline to a 0.58% increase (P=0.001). After resumption, incidence dropped 8.96% (P=0.039) and maintained a 0.39% long-term decline (P=0.003). Even with seasonal adjustment, the interruption slowed the weekly decline from 0.08% to 0.07% (P=0.003). Phase II showed a similar pattern: a one-week interruption caused a 0.70% drop (P=0.007) but shifted the trend from a 0.02% decline to a 0.08% increase (P=0.001). After resumption, interventions stabilized the decline at 0.11% weekly (P=0.001).<br><br>CONCLUSIONS: This research demonstrates that Tanzania's malaria incidence is closely linked to seasonal patterns and consistent intervention efforts. Phase I's 8-month security-related interruption reduced 1,7-mRCTR effectiveness by 12.5%, while Phase II's 3-month pandemic-induced interruption caused only short-term fluctuations with minimal long-term impact. Rapid resumption of interventions after disruptions allowed for prompt recovery, highlighting the importance of adaptive strategies to maintain progress toward malaria control goals.}, }
@article {pmid40377211, year = {2025}, author = {Dadafarin, S and Alvi, MA and Massa, ST and Veatch, J and Rizvi, ZH}, title = {Survival Correlates With Adjuvant Choice in Sentinel Node Positive Head and Neck Cutaneous Melanoma.}, journal = {The Laryngoscope}, volume = {135}, number = {10}, pages = {3670-3679}, doi = {10.1002/lary.32269}, pmid = {40377211}, issn = {1531-4995}, support = {R25 DC021791/DC/NIDCD NIH HHS/United States ; 1R25DC021791-01/DC/NIDCD NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/mortality/therapy/pathology ; Female ; Male ; *Skin Neoplasms/mortality/therapy/pathology ; *Head and Neck Neoplasms/mortality/therapy/pathology ; Middle Aged ; *Sentinel Lymph Node Biopsy/statistics &amp; numerical data ; Aged ; *Lymph Node Excision/statistics &amp; numerical data ; *Immunotherapy/statistics &amp; numerical data/methods ; Retrospective Studies ; Cutaneous Malignant Melanoma ; Adult ; Prognosis ; }, abstract = {OBJECTIVE(S): The objective of this study is to evaluate the utilization and outcomes of completion lymph node dissection (CLND) and immunotherapy for sentinel lymph node biopsy (SLNB) positive head and neck cutaneous melanoma (HNCM).<br><br>METHODS: Patients with primary HNCM and positive SLNB in the 2020 National Cancer Database (NCDB) Melanoma file were reviewed. The frequency of CLND and immunotherapy was tracked from 2012 to 2019. Clinicodemographic features of patients were evaluated with respect to their post-SLNB treatment choice. Overall survival (OS) was calculated from the time of diagnosis, and the association of therapy choice with survival was determined using a multivariate Cox regression analysis.<br><br>RESULTS: The rates of CLND declined from 66% to 18% while adjuvant immunotherapy increased to a peak of approximately 40%, with an inflection point occurring in 2016. Multivariate survival analysis indicated that immunotherapy use alone, though not CLND, was associated with improved prognosis (hazard ratio 0.65, 95% confidence interval 0.45-0.93). Patient characteristics associated with immunotherapy administration included age (p&#x2009;<&#x2009;0.01), insurance type (p&#x2009;=&#x2009;0.002), income (p&#x2009;<&#x2009;0.001), and healthcare facility type (p&#x2009;=&#x2009;0.005).<br><br>CONCLUSION: In this retrospective NCDB-based study, we find that the modern management of SLNB-positive patients has shifted towards greater use of adjuvant immunotherapy and a decline in CLND; the use of immunotherapy is associated with improved OS. Patients treated with immunotherapy were more likely to be younger, of higher income, and with private health insurance.}, }
@article {pmid40377378, year = {2025}, author = {Subramanian, NG and Guffey, D and Avery, J and Garcia, D and Basom, R and Lee, SJ and Klein, K and Kebriaei, P and Rondon, G and Shpall, E and Jin, S and Young, E and Rojas Hernandez, CM and Li, A}, title = {Clinical Factors Associated With Catheter-Related VTE in Patients Undergoing Hematopoietic Cell Transplantation: A Multi-Center Study.}, journal = {American journal of hematology}, volume = {100}, number = {8}, pages = {1463-1466}, pmid = {40377378}, issn = {1096-8652}, support = {//American Society of Hematology/ ; K23 HL159271/HL/NHLBI NIH HHS/United States ; RR190104//Cancer Prevention and Research Institute of Texas/ ; 3OT2OD032581-01S1//Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity/ ; OT2 OD032581/OD/NIH HHS/United States ; //Conquer Cancer Foundation/ ; }, }
@article {pmid40378559, year = {2025}, author = {Bakaloudi, DR and Talukder, R and Enright, T and Leary, JB and Makrakis, D and Diamantopoulos, LN and Hobeika, C and Thomas, VM and Swami, U and Zakopoulou, R and Bamias, A and Brown, JR and Pinato, DJ and Latchford, C and Jindal, T and Koshkin, VS and Murgić, J and Miletić, M and Frobe, A and Johnson, J and Zakharia, Y and Alva, A and Nguyen, CB and Hui, G and Drakaki, A and Rodriguez-Vida, A and Rey-Cárdenas, M and Castellano, D and Buznego, LA and Duran, I and Barrera, RM and Marmolejo, D and McKay, RR and Stewart, TF and Barata, P and Epstein, IB and Bellmunt, J and Yu, EY and Raychaudhuri, R and Nadal, R and Vakar-Lopez, F and Gupta, S and Wright, JL and Khaki, AR and Grivas, P}, title = {Response and Survival With Immune Checkpoint Inhibitor in Patients With Advanced Urothelial Carcinoma and Histology Subtypes.}, journal = {Clinical genitourinary cancer}, volume = {23}, number = {4}, pages = {102356}, doi = {10.1016/j.clgc.2025.102356}, pmid = {40378559}, issn = {1938-0682}, mesh = {Humans ; *Immune Checkpoint Inhibitors/therapeutic use ; Male ; Female ; Aged ; Middle Aged ; *Carcinoma, Transitional Cell/drug therapy/pathology/mortality ; Antibodies, Monoclonal, Humanized/therapeutic use ; Aged, 80 and over ; Progression-Free Survival ; Retrospective Studies ; *Urinary Bladder Neoplasms/drug therapy/pathology/mortality ; Treatment Outcome ; *Urologic Neoplasms/drug therapy/pathology/mortality ; }, abstract = {BACKGROUND: Immune Checkpoint Inhibitors (ICIs) are used for advanced urothelial carcinoma (aUC) in different settings. Most patients have pure UC (PUC) but about one-third have UC mixed with histology subtypes (HS). We examined outcomes in patients with HS aUC treated with ICI.<br><br>MATERIALS AND METHODS: We included patients from 26 centers with PUC and any HS treated with ICI as 1st line (1L) upfront, maintenance avelumab (mAV), and &#x2265;2nd line [2+L] therapy. We calculated overall and progression-free survival (OS, PFS) and observed response rate (ORR) from ICI start.<br><br>RESULTS: We included 1511 patients; 752 1L, 609 2+L, 150 mAV. 1L: median OS was 15 (95% CI, 12-17) months for patients with PUC (n = 518), 15 (95% CI, 8-23) months for squamous UC (n = 85) (HR = 1.2, [95% CI, 0.8-1.6]), 11 (95% CI, 6-17) months for micropapillary UC (n = 46) (HR = 1.2, [95% 0.8-1.8]), and 21 (95% CI, 12-30) months in patients with UC mixed with &#x2265;2 HS (n = 30), (HR = 0.9, [95% CI, 0.5-1.4]). 2+L: median OS was 9 (95% CI, 8-10) months for patients with PUC (n = 441), 9 (95% CI, 1-12) months for squamous UC (n = 60) (HR = 1.1, (95% CI, 0.8-1.6]), 6 (95% CI, 1-11) months for micropapillary UC (n = 37) (HR = 1.1, [95% 0.7-1.6]), and 7 (95% CI, 4-10) months in patients with UC mixed with &#x2265;2 HS (n = 17), (HR = 1.6, [95% CI, 0.9-3.1]).<br><br>CONCLUSION: We found no significant OS difference between PUC and HS in patients with aUC treated with ICI monotherapy. Limitations include retrospective design, small sample size in several subsets, lack of randomization, no central imaging or pathology review, selection and confounding biases. Results are hypothesis-generating and need prospective validation.}, }
@article {pmid40378608, year = {2025}, author = {Ahmad, K and Henikoff, S}, title = {Profiling regulatory elements in vivo by genome-wide methods.}, journal = {Current opinion in structural biology}, volume = {92}, number = {}, pages = {103064}, doi = {10.1016/j.sbi.2025.103064}, pmid = {40378608}, issn = {1879-033X}, mesh = {Chromatin/metabolism/genetics ; Humans ; Animals ; *Regulatory Sequences, Nucleic Acid/genetics ; *Genome ; DNA/metabolism/genetics ; *Genomics/methods ; }, abstract = {The biology of gene regulation in eukaryotic genomes is a mature field. The biochemical principles of factor binding to DNA are well-known from in vitro studies, as are the structural interactions in which specific domains of these proteins interface across a short stretch of DNA to confer sequence-specific recognition. Whereas the basic principles of binding and dissociation defined in vitro apply in vivo, the living nucleus is a dynamic compartment crowded with molecules, including motors that drive chromatin movements critical for the regulation of gene expression. Understanding these dynamics in vivo has spurred the development of cutting-edge technologies to observe factor-DNA interactions. The biological significance of chromatin dynamics is now revealed by a wide variety of high-resolution chromatin profiling methods.}, }
@article {pmid40378930, year = {2025}, author = {Jreij, G and Canton, G and Hippe, DS and Balu, N and Yuan, C and Cebral, J and Crone, C and Sikdar, S and Hatsukami, T and Gray, V and Desikan, S and Beach, K and Lal, BK}, title = {Systematic review of biomechanical forces associated with carotid plaque disruption and stroke.}, journal = {Journal of vascular surgery}, volume = {82}, number = {3}, pages = {1113-1124.e7}, doi = {10.1016/j.jvs.2025.05.014}, pmid = {40378930}, issn = {1097-6809}, support = {IK2 RX003798/RX/RRD VA/United States ; I01 CX001621/CX/CSRD VA/United States ; I01 RX000995/RX/RRD VA/United States ; U01 NS080168/NS/NINDS NIH HHS/United States ; R01 NS097876/NS/NINDS NIH HHS/United States ; Z01 AG000513/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Plaque, Atherosclerotic ; *Carotid Stenosis/complications/physiopathology/diagnostic imaging/pathology ; Biomechanical Phenomena ; *Stroke/etiology/physiopathology ; Stress, Mechanical ; Rupture, Spontaneous ; Risk Factors ; *Carotid Arteries/physiopathology/diagnostic imaging/pathology ; Models, Cardiovascular ; Risk Assessment ; Prognosis ; Patient-Specific Modeling ; }, abstract = {OBJECTIVE: Carotid plaque disruption with release of atheroembolic debris and consequent brain infarction is the primary mechanism for brain injury in patients with carotid stenosis. Disease severity is quantified traditionally by the degree of stenosis, although it is not an accurate marker of stroke risk. It has been proposed that biomechanical forces acting on a carotid plaque may render it vulnerable to rupture by causing adverse remodeling of its morphology or by direct disruption. We conducted a systematic review to assess the forces acting on carotid plaques and their relationship to adverse plaque outcomes.<br><br>METHODS: A literature search for studies reporting measurements of flow-related biomechanical forces acting on carotid atherosclerotic plaques was conducted using PubMed, Embase, and Web of Science. Studies were included if they reported on human carotid plaques, used patient-specific geometry, measured forces on or in the atherosclerotic lesions, and reported on carotid plaque-related adverse outcomes.<br><br>RESULTS: Of 5635 articles screened, 154 met eligibility criteria. Forces were computed using patient-specific arterial geometry derived from multiple imaging modalities, mainly magnetic resonance imaging (58.4%) and ultrasound examination (25.3%). Methodologies used to quantify the forces included computational fluid dynamics (31.8%), finite element analysis (10.4%), fluid-structure interaction models (27.3%), in vivo measurements (29.9%), and in vitro assessments (0.6%). Wall shear stress (WSS) and plaque wall stress (PWS) were the most frequently measured forces, in 72.1% and 45.5% of studies, respectively. Principal PWS (n = 15 studies) and WSS (n = 21 studies) were elevated in patients with adverse outcomes. PWS levels of >160 kPa had a sensitivity of >80% and specificity of >75% in identifying patients with adverse events. Increasing PWS was associated with subsequent ischemic cerebrovascular events (HR=hazard ratio, 12.98 per 1 kPa increase; P = .02). WSS levels of >50 dyn/cm[2] had a sensitivity of 100% and specificity of 67% in differentiating patients with adverse events (plaque rupture, cerebral infarction, stroke, or transient ischemic attack) compared with those without.<br><br>CONCLUSIONS: There is heterogeneity in sample size, study design, imaging protocols, image processing methodology, forces assessed, and adverse carotid plaque-related outcomes measured in the literature. Despite these limitations, increasing PWS and WSS were associated with adverse plaque outcomes consistently and predicted adverse outcomes with moderate to high degrees of sensitivity and specificity. Because the information available is heterogenous, these relationships need to be confirmed in larger prospective studies.}, }
@article {pmid40379030, year = {2025}, author = {Verwimp, S and Wagoner, J and Arenas, EG and De Coninck, L and Abdelnabi, R and Hyde, JL and Schiffer, JT and White, JM and Matthijnssens, J and Neyts, J and Polyak, SJ and Delang, L}, title = {Combinations of approved oral nucleoside analogues confer potent suppression of alphaviruses in vitro and in vivo.}, journal = {Antiviral research}, volume = {239}, number = {}, pages = {106186}, doi = {10.1016/j.antiviral.2025.106186}, pmid = {40379030}, issn = {1872-9096}, mesh = {Animals ; *Antiviral Agents/pharmacology/administration &amp; dosage/therapeutic use ; Mice ; Humans ; *Alphavirus/drug effects ; Sofosbuvir/pharmacology/administration &amp; dosage/therapeutic use ; Chikungunya virus/drug effects ; *Alphavirus Infections/drug therapy/virology ; Amides/pharmacology/administration &amp; dosage/therapeutic use ; Pyrazines/pharmacology/administration &amp; dosage/therapeutic use ; Disease Models, Animal ; Administration, Oral ; Chikungunya Fever/drug therapy/virology ; Encephalitis Virus, Venezuelan Equine/drug effects ; Sindbis Virus/drug effects ; *Nucleosides/pharmacology/administration &amp; dosage ; Semliki forest virus/drug effects ; Drug Synergism ; Drug Therapy, Combination ; Cytidine/analogs &amp; derivatives/pharmacology/administration &amp; dosage ; Fibroblasts/virology/drug effects ; Cell Line ; Hydroxylamines ; }, abstract = {Alphaviruses, including chikungunya virus (CHIKV), pose a significant global health threat, yet specific antiviral therapies remain unavailable. We evaluated combinations of three oral directly acting antiviral drugs (sofosbuvir (SOF), molnupiravir (MPV), and favipiravir (FAV)), which are approved for other indications, against CHIKV, Semliki Forest virus (SFV), Sindbis virus (SINV), and Venezuelan Equine Encephalitis virus (VEEV) in vitro and in vivo. We assessed antiviral efficacy in human skin fibroblasts and liver cells, as well as in a mouse model of CHIKV-induced arthritis. In human skin fibroblasts, synergistic antiviral effects were observed for combinations of MPV + SOF and FAV + SOF against CHIKV, and for FAV + SOF against SFV. In human liver cells, FAV + MPV conferred additive to synergistic activity against VEEV and SINV, while SOF synergized with FAV against SINV. In mice, MPV improved CHIKV-induced foot swelling and reduced systemic infectious virus titres. Combination treatment with MPV and SOF significantly reduced swelling and infectious titres compared to monotherapies of each drug. Sequencing of CHIKV RNA from joint tissue revealed that MPV caused dose-dependent increases in mutations in the CHIKV genome. Upon combination therapy of MPV with SOF, the number of mutations was significantly lower compared to monotherapy with several higher doses of MPV. Combining these approved oral nucleoside analogues confers potent suppression of multiple alphaviruses in vitro and in vivo with enhanced control of viral genetic evolution in face of antiviral pressure. These drug combinations may ultimately lead to the development of potent combinations of pan-family alphavirus inhibitors.}, }
@article {pmid40379049, year = {2025}, author = {Mehta, RS and Aljawai, YM and Al-Juhaishi, T and Saultz, J and Milano, F and Kanakry, JA and Kanakry, CG and Lazaryan, A}, title = {Role of Donor Cytomegalovirus Serostatus in Cytomegalovirus-Seronegative Recipients of Unrelated Donor Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide Prophylaxis.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {672.e1-672.e9}, pmid = {40379049}, issn = {2666-6367}, support = {U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Female ; Male ; *Cyclophosphamide/therapeutic use/pharmacology ; Adult ; *Cytomegalovirus Infections/prevention &amp; control/virology ; Middle Aged ; Retrospective Studies ; *Cytomegalovirus/immunology ; *Unrelated Donors ; *Leukemia, Myeloid, Acute/therapy/mortality ; Graft vs Host Disease/prevention &amp; control ; }, abstract = {While donor age significantly impacts allogeneic hematopoietic cell transplantation (HCT) outcomes, the effect of donor cytomegalovirus (CMV) serostatus, particularly in CMV-seronegative recipients, remains a critical consideration. Donor CMV seropositivity is linked to increased CMV viremia and non-relapse mortality (NRM) in these recipients. Given the limited scope of novel antiviral prophylaxis drugs, eg, letermovir solely for CMV-seropositive recipients and the association of post-transplant cyclophosphamide (PTCy) with increased CMV reactivation, this study investigates the impact of donor CMV serostatus on outcomes in CMV-seronegative acute myeloid leukemia (AML) patients undergoing HLA-matched or mismatched unrelated donor HCT with PTCy. We retrospectively analyzed data from the Center for International Blood and Marrow Transplant Research, including adult CMV-seronegative AML patients who underwent unrelated donor HCT with PTCy between 2017 and 2021. Primary outcome was overall survival (OS). Secondary outcomes included relapse, NRM, and acute/chronic graft-versus-host disease. Donor age was dichotomized at ≤32 and >32 years. Multivariable Cox proportional hazards models, stratified by donor age, and Restricted Mean Survival Time (RMST) and Restricted Mean Time Lost (RMTL) analyses were performed. Of 408 CMV-seronegative recipients, 127 received transplants from CMV-seropositive donors. Baseline characteristics were well-balanced between groups. Multivariable analysis demonstrated that recipients of CMV-seropositive donors had a significantly higher hazard of mortality (hazard ratios [HR] 1.51, 95% confidence interval [CI] 1.07 to 2.14, P = .019). Donor age and donor type did not significantly impact OS in this CMV seronegative patient population. RMST analysis showed that recipients with CMV-seronegative donors lived on average 2.95 months longer (P = .045), while RMTL ratio was 1.34 (P = .037), indicating that recipients of CMV-seropositive donors experienced a 34% higher risk of loss of survival time. The difference in OS was primarily driven by a trend toward increased relapse risk in the CMV-seropositive donor group (HR 1.42, 95% CI: 0.95 to 2.08, P = .06) rather than NRM (HR 1.19, 95% CI: 0.66 to 2.13, P = .56). In CMV-seronegative adult AML patients undergoing unrelated donor HCT with PTCy, CMV-seropositive donors are associated with worse OS than CMV-seronegative donors, likely linked to higher relapse risk. These findings underscore the importance of considering donor CMV serostatus in donor selection for CMV-seronegative recipients undergoing HCT with PTCy. Further investigation is necessary to optimize donor selection strategies and improve outcomes in this patient population.}, }
@article {pmid40379905, year = {2025}, author = {Krakow, EF and Lee, N and Jenkins, I and Sala-Torra, O and Beppu, L and Radich, JP and Fukuda, B and Sandmaier, BM and Yeung, CC and Bozic, I}, title = {A clinical solution for tracking clonal evolution of acute myeloid leukemia after allogeneic transplantation using bulk next generation sequencing.}, journal = {Bone marrow transplantation}, volume = {60}, number = {8}, pages = {1083-1091}, pmid = {40379905}, issn = {1476-5365}, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/therapy/pathology ; *High-Throughput Nucleotide Sequencing/methods ; *Clonal Evolution/genetics ; Transplantation, Homologous/methods ; Male ; Female ; Adult ; Middle Aged ; *Hematopoietic Stem Cell Transplantation/methods ; Polymorphism, Single Nucleotide ; Neoplasm, Residual ; Software ; }, abstract = {Clinical next generation sequencing (NGS) typically relies on limited gene panels run on bulk marrow or blood. Current computational tools for inferring clonal relationships is generally limited by the use of a small panel of pathogenic mutations to define clones. We developed an online software (CloneTracker) that uses 'incidentally-sequenced' single nucleotide polymorphisms (SNPs) in the regions of recurrent somatic mutations in addition to conventional mutation data from bulk NGS gene panels to provide detailed visualizations of clonal evolution during cancer treatment, alongside clinical data. Tested on 29 patients who underwent non-myeloablative transplantation for AML, CloneTracker successfully reconstructed the evolutionary dynamics of donor engraftment from bulk NGS and rendered intuitive visualizations of residual patient-derived hematopoiesis and relapsing malignant clones. The software does not require sequencing donor samples, as donor-derived clones are identifiable from post-HCT SNP data. This manuscript aims to introduce CloneTracker to the BMT community and make it available for those who would ascertain its clinical utility, e.g, in BMT trials leveraging molecular minimal residual disease (MRD) monitoring and targeted interventions to pre-empt relapse.}, }
@article {pmid40381914, year = {2025}, author = {Yeung, CCS and Narava, SK and Chang, TC and Saeed, M and Aicher, L and Beppu, LW and Majano, MS and Taylor, EM and Camalier, CE and Sandhuria, P and Sala-Torra, O and Li, J and Yee, LM and McShane, LM and Karlovich, C and Little, RF and Harris, L and Doroshow, JH and Williams, PM and Radich, JP and Jiwani, S}, title = {Analytical Performance of the NCI-myeloMATCH Assay: A Rapid Turnaround Genomic Profiling Assay for Myeloid Disorders.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {27}, number = {8}, pages = {783-795}, pmid = {40381914}, issn = {1943-7811}, mesh = {Humans ; *Myelodysplastic Syndromes/genetics/diagnosis ; Reproducibility of Results ; *Leukemia, Myeloid, Acute/genetics/diagnosis ; Mutation ; Sensitivity and Specificity ; *Genomics/methods ; National Cancer Institute (U.S.) ; United States ; High-Throughput Nucleotide Sequencing/methods ; Precision Medicine/methods ; Biomarkers, Tumor/genetics ; }, abstract = {myeloMATCH is a National Cancer Institute (NCI) precision medicine clinical trial initiative to evaluate treatments for acute myeloid leukemia and myelodysplastic syndrome based on a leukemia's diagnostic molecular-genetic profile. The NCI myeloid assay version 2 (NMAv2) uses the Genexus System, an automated platform with <48-hour turnaround from specimen receipt to reporting, to provide harmonized regulatory-compliant use for myeloMATCH across two independent clinical laboratories. Using clinical specimens, cell lines, and contrived reference materials, NMAv2 exhibited 99% sensitivity for 291 known mutations and 100% specificity. High reproducibility detecting all reportable variants was observed, with >98% mean positive percentage agreement and 100% negative percent agreement across six reproducibility assessments. Reproducibility experiments of companion diagnostic biomarkers (1 to 1.5× clinical limit of reporting) showed 100% positive percentage agreement and negative percent agreement. The limit of detection was 0.06% for hotspot single-nucleotide variants, 0.16% for non-hotspot single-nucleotide variants, 0.51% for hotspot insertion/deletions, approximately 1% for non-hotspot insertion/deletions, 0.23% for FLT3-internal tandem duplications, and ≤40 reads at 0.1% tumor content for fusions. Concordance of 99.39% was observed in orthogonal assays testing 76 blinded myeloid specimens in the sensitivity study, and 100% concordance was observed in testing 54 FLT3-internal tandem duplication specimens. The results show that NMAv2 has high specificity, sensitivity, accuracy, and reproducibility, and can rapidly characterize genomic alterations in acute myeloid leukemia and myelodysplastic syndrome.}, }
@article {pmid40382524, year = {2025}, author = {Yap, TA and LoRusso, P and Miller, RE and Kristeleit, R and Paulovich, AG and McMorn, S and Oplustil O'Connor, L and Lombardi, B and Marco-Casanova, P and Gangl, ET and Patel, B and O'Connor, MJ and Dean, E and Zviezdin, R and Plummer, R}, title = {The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study.}, journal = {British journal of cancer}, volume = {133}, number = {2}, pages = {168-177}, pmid = {40382524}, issn = {1532-1827}, support = {R01 CA235575/CA/NCI NIH HHS/United States ; R50 CA211499/CA/NCI NIH HHS/United States ; U01 CA271407/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Doxorubicin/analogs &amp; derivatives/administration &amp; dosage/adverse effects ; Polyethylene Glycols/administration &amp; dosage/adverse effects ; Aged ; *Neoplasms/drug therapy/pathology ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use/administration &amp; dosage ; Adult ; Maximum Tolerated Dose ; }, abstract = {BACKGROUND: Upregulation of DNA-dependent protein kinase (DNA-PK) is associated with poor prognosis and decreased response to DNA-damaging agents across cancer types. A Phase I/IIa study (NCT03907969) investigated the highly potent, selective DNA-PK inhibitor AZD7648 as monotherapy or combined with pegylated liposomal doxorubicin (PLD) in patients with advanced cancer.<br><br>METHODS: Thirty patients received escalating doses of AZD7648 as monotherapy (n&#x2009;=&#x2009;14), starting at 5&#x2009;mg QD, or with PLD 40&#x2009;mg/m[2] (n&#x2009;=&#x2009;16). The primary objective was safety and tolerability.<br><br>RESULTS: AZD7648 monotherapy was administered at 5-160&#x2009;mg BID. The most frequent class of adverse events was gastrointestinal disorders (9/14 patients, 64.3%); one patient (160&#x2009;mg BID) experienced dose-limiting toxicities (DLTs). No responses to AZD7648 monotherapy were observed. The maximum dose of combination therapy was AZD7648 40&#x2009;mg QD days 1-7&#x2009;+&#x2009;PLD every 28 days. 13/16 patients (81.3%) experienced gastrointestinal disorders and 11/16 (68.8%) patients had anaemia. Three patients experienced DLTs (two at AZD7648 20&#x2009;mg QD 7 days + PLD; one at AZD7648 30&#x2009;mg QD 7 days + PLD). Limited efficacy was observed, with one RECIST partial response.<br><br>DISCUSSION: Toxicity of AZD7648&#x2009;+&#x2009;PLD was greater than expected and antitumour activity was limited, leading to early study termination.}, }
@article {pmid40383698, year = {2025}, author = {Hill, M and Garcia, LR and Nguyen, E and Korolkova, A and Cohn, L and Rodriguez, A and Hoh, R and Deeks, SG and Peluso, MJ and Sauceda, JA and Dubé, K}, title = {Corrigendum to 'Evaluating the psychosocial experiences of participants in HIV cure research before, during, and after analytical treatment interruptions: A longitudinal qualitative study in the United States' [Soc. Sci. Med. Volume 366, February 2025, 117644].}, journal = {Social science &amp; medicine (1982)}, volume = {381}, number = {}, pages = {118161}, doi = {10.1016/j.socscimed.2025.118161}, pmid = {40383698}, issn = {1873-5347}, }
@article {pmid40383778, year = {2025}, author = {Kim, S and Radford, CE and Xu, D and Zhong, J and Do, J and Pham, DM and Travisano, KA and Filsinger Interrante, MV and Bruun, TUJ and Rezek, V and Wilder, B and Palomares, M and Seaman, MS and Kitchen, SG and Bloom, JD and Kim, PS}, title = {A broad antibody with enhanced HIV-1 neutralization via bispecific antibody-mediated prepositioning.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4617}, pmid = {40383778}, issn = {2041-1723}, support = {DP1 AI158125/AI/NIAID NIH HHS/United States ; P30 AI152501/AI/NIAID NIH HHS/United States ; 5DP1AI158125//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {*HIV-1/immunology/genetics/drug effects ; *Antibodies, Bispecific/immunology/pharmacology/genetics ; Humans ; Animals ; *HIV Infections/immunology/virology ; Mice ; Male ; *Antibodies, Neutralizing/immunology ; *HIV Antibodies/immunology ; HIV Envelope Protein gp41/immunology/genetics ; Viral Load/drug effects ; HEK293 Cells ; Receptors, IgG/genetics/immunology/metabolism ; Neutralization Tests ; CD4 Antigens/immunology ; Broadly Neutralizing Antibodies/immunology ; }, abstract = {Antibodies targeting the highly conserved prehairpin intermediate (PHI) of class I viral membrane-fusion proteins are generally weakly neutralizing and are not considered viable therapeutic agents. We previously demonstrated that antibodies targeting the gp41 N-heptad repeat (NHR), which is transiently exposed in the HIV-1 PHI, exhibit enhanced broad neutralization in cells expressing the Fc receptor, FcγRI. To enhance neutralization in cells lacking FcγRI, we here develop a bispecific antibody (bsAb) by fusing an NHR-targeting antibody to an antibody against CD4, the HIV-1 receptor on T cells. The bsAb provides a 5000-fold neutralization enhancement and shows unprecedented neutralization breadth compared to existing broadly neutralizing antibodies. Importantly, the bsAb reduces viral load in HIV-1-infected humanized male mice, and viral envelope sequencing under bsAb pressure revealed an NHR mutation that potentially impairs viral fitness. These findings validate the NHR as a potential HIV-1 therapeutic target, setting the stage for a new class of broadly neutralizing antibodies.}, }
@article {pmid40383922, year = {2025}, author = {Dashevsky, BZ and Fish, LJ and Breit, S and Waheed, U and Coffey, K and Parikh, JR and Mullen, LA and Reig, B and Dontchos, BN and Dodelzon, K and Grimm, LJ}, title = {Contrast-Enhanced Mammography Implementation: Early Struggles and Successes.}, journal = {Journal of breast imaging}, volume = {7}, number = {3}, pages = {345-354}, doi = {10.1093/jbi/wbaf018}, pmid = {40383922}, issn = {2631-6129}, mesh = {Humans ; *Mammography/methods/economics ; *Contrast Media ; Female ; *Breast Neoplasms/diagnostic imaging ; United States ; Workflow ; Focus Groups ; Patient Selection ; *Practice Patterns, Physicians'/statistics &amp; numerical data ; }, abstract = {We used focus groups of radiologists who led the implementation of contrast-enhanced mammography (CEM) in their practice to identify barriers and strategies for adoption. Members of the Society of Breast Imaging in the United States who served as lead on CEM implementation were invited to participate in 2 separate focus groups. Ten breast imaging radiologists with varied geographic and practice type (60% academic, 30% private, and 10% community practice) participated. There were 4 major themes identified: patient selection, workflow, contrast, and billing. Patient selection varied widely among practices, with some limiting CEM to patients unable to obtain MRI and others routinely using CEM for diagnostic workup. Lack of Food and Drug Administration approval limited screening applications in some practices. Workflow challenges were numerous, and site-specific solutions were developed for ordering, scheduling, staffing, and intravenous access. There were universal concerns regarding contrast, including safe administration, response to reactions, and biopsy planning for findings only visible on CEM. Contrast reaction training, including conducting mock codes at some practices, helped alleviate concerns of the radiologists and technologists. Finally, billing was an administrative hurdle that influenced patient selection. Ample preparation is needed to successfully start a CEM program with particular attention to patient selection, workflow, contrast administration/reactions, and billing.}, }
@article {pmid40384398, year = {2025}, author = {Moore, M and Glidden, D and Anderson, P and Hendrix, C and Dimitrov, D}, title = {Dosing forgiveness of oral PrEP for cisgender women remains uncertain.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {5}, pages = {e26496}, pmid = {40384398}, issn = {1758-2652}, support = {R01AI170298//National Institute of Allergy and Infectious Diseases/ ; 5UM1AI068617-20/DA/NIDA NIH HHS/United States ; R01 AI179417/AI/NIAID NIH HHS/United States ; 1R01AI179417-01A1//National Institute of Allergy and Infectious Diseases/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; 5UM1AI068617-20//National Institute of Allergy and Infectious Diseases/ ; R01 AI143357/AI/NIAID NIH HHS/United States ; }, }
@article {pmid40384469, year = {2025}, author = {Bell-Brown, A and Tawfik, B and Segarra-Vazquez, B and Hopkins, T and Watabayashi, K and O'Kane, P and Carlos, RC and Langer, SL and Unger, JM and Darke, AK and Hershman, DL and Ramsey, SD and Shankaran, V}, title = {Addressing Challenges in Research Aimed at Reducing Financial Toxicity Among Cancer Patients and Caregivers: An Example From the CREDIT Study (SWOG S1912CD).}, journal = {Cancer control : journal of the Moffitt Cancer Center}, volume = {32}, number = {}, pages = {10732748251344469}, pmid = {40384469}, issn = {1526-2359}, support = {R01 CA248656/CA/NCI NIH HHS/United States ; UG1 CA189856/CA/NCI NIH HHS/United States ; UG1 CA189974/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Caregivers/economics/psychology ; *Neoplasms/economics/therapy ; *Financial Stress/prevention &amp; control ; Female ; Male ; }, abstract = {IntroductionCancer-related financial hardship is pervasive, impacting both patients and caregivers, making it crucial to address financial hardship at the household level. The CREDIT (S1912CD) study was designed to enroll and randomize cancer patients and spousal caregivers as dyads to proactive financial navigation compared to usual care. The study faced several challenges to recruitment. This paper discusses the changes made to successfully complete the study.MethodsThe study took place among NCI Community Oncology Research Program (NCORP) sites and allowed several venues for protocol feedback, including SWOG group meetings, NCORP administrator meetings, and individual calls with recruiting sites. A patient advocate worked with the study team to review and update documents to ensure the study was relevant and accessible to potential participants.ResultsSeveral barriers were identified including sites facing challenges in enrolling patient-spouse dyads, multiple financial navigation partners causing confusion and delays in delivery of the intervention, eligibility criteria concerns, and participant discomfort with providing social security numbers. Several modifications were made to address these obstacles during a study restructure, including making caregiver participation optional, streamlining intervention delivery, and modifying eligibility criteria to allow more time between diagnosis and enrollment. Changes from the restructure resulted, on average, in a 9.5 patient per month increase in accrual (4.1 to 13.6) and has enabled the study to reach overall accrual within the study timeline. Importantly, the study maintained diverse accrual and continued to accrue willing caregivers to enable exploratory analysis of caregiver outcomes.ConclusionInterventions examining how to mitigate financial hardship for cancer patients and those affected by cancer, must be pragmatic in order to be translated into sustainable programs in real world settings. Providing recruiting sites an avenue for feedback ensured that the study team could adjust the protocol to meet site needs and successfully complete this financial navigation study.}, }
@article {pmid40384751, year = {2025}, author = {Sanchez-Youngman, S and Jacquez, B and Adsul, P and Dickson, E and Akintobi, TH and Hoffman, L and Rosas, LG and Gay, S and Mendoza, JA and Mapes, D and Oetzel, J and Nease, D and Wallerstein, N}, title = {Engage for equity plus: Transforming academic health centers to sustain patient/community engaged research structures, policies, and practices.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e80}, pmid = {40384751}, issn = {2059-8661}, support = {P30 DK111024/DK/NIDDK NIH HHS/United States ; U48 DP006802/DP/NCCDPHP CDC HHS/United States ; }, abstract = {INTRODUCTION: Community-based participatory research (CBPR) and patient/ community engaged research (P/CEnR) are shown to be effective approaches that improve health inequities, particularly among disadvantaged populations. While the science of CBPR demonstrates promising partnering practices that lead to effective interventions, there are institutional and structural barriers to creating and sustaining patient/community research within academic health centers (AHCs). As the field matures, there is a growing need to enhance patient/community leadership so that communities can set their own research agendas and priorities.<br><br>METHODS: Engage for Equity PLUS sought to address these challenges by implementing an engagement intervention aimed at transforming AHCs through supporting champion teams of academic, community, and patient partners to strengthen research infrastructures for P/CEnR. This paper uses a qualitative, case study analysis to describe how E2PLUS enabled champion teams at Stanford School of Medicine, Fred Hutchinson/University of Washington Cancer Consortium, and Morehouse School of Medicine to pursue institutional change strategies through coaching, workshops, contextual data analysis, and a community of practice.<br><br>RESULTS: This paper describes key themes of how E2Plus helped identify targets of change by a) using institutional data collection as core to generating critical consciousness of contextual conditions; b) implementing feasible E2PLUS strategies to leverage conditions for catalyzing a champion team for advocacy and achievable actions; c) identifying the critical role of patients/community members in stimulating change; and d) the role of continual collective reflection.<br><br>CONCLUSION: We discuss the overall implications for E2 PLUS for other AHCs working toward sustainable community/patient engaged research policies and practices.}, }
@article {pmid40384944, year = {2025}, author = {Halloran, ME}, title = {Designs for Vaccine Studies.}, journal = {Annual review of statistics and its application}, volume = {12}, number = {}, pages = {1-18}, pmid = {40384944}, issn = {2326-8298}, support = {R01 AI085073/AI/NIAID NIH HHS/United States ; }, abstract = {Due to dependent happenings, vaccines can have different effects in populations. In addition to direct protective effects in the vaccinated, vaccination in a population can have indirect effects in the unvaccinated individuals. Vaccination can also reduce person-to-person transmission to vaccinated individuals or from vaccinated individuals compared with unvaccinated individuals. Design of vaccine studies has a history extending back over a century. Emerging infectious diseases, such as the SARS-CoV-2 pandemic and the Ebola outbreak in West Africa, have stimulated new interest in vaccine studies. We focus on some recent developments, such as target trial emulation, test-negative design, and regression discontinuity design. Methods for evaluating durability of vaccine effects were developed in the context of both blinded and unblinded placebo crossover studies. The case-ascertained design is used to assess the transmission effects of vaccines. The novel ring vaccination trial design was first used in the Ebola outbreak in West Africa.}, }
@article {pmid40386555, year = {2025}, author = {Alabi, A and Ainsworth, V and Lawal, A and Kizub, D and Chin, J and Woodmark, C and Omidiji, O and Adegboyega, B and Sowunmi, A and Ogunyemi, A and Swanson, W and Joseph, A and Ngwa, W}, title = {Key stakeholders' experiences, knowledge and perspectives regarding care quality for breast cancer in South-West Nigeria.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1418649}, pmid = {40386555}, issn = {2234-943X}, support = {R01 CA239042/CA/NCI NIH HHS/United States ; }, abstract = {The landscape of breast cancer care in Nigeria is complex, with various structural and individual barriers impacting patient care. Breast cancer (BC) is the most common cancer and a leading cause of cancer deaths among women worldwide. In Africa, the cancer burden is expected to rise significantly, with projections estimating an increase of 50% by 2050. Rising incidence rates and barriers to care contribute to a healthcare crisis, leading to late-stage presentation and high mortality rates for women with breast cancer in Nigeria. Quality healthcare must be patient-centered, involving stakeholders - patients, clinical and community partners, and other healthcare stakeholders to achieve a desired outcome. Understanding the cancer journey from different perspectives allows for targeted approaches for increasing access to quality healthcare as well as reducing morbidity and mortality rates. To address this, healthcare provider perspectives about breast cancer care were compared with the lived experiences of breast cancer patients to emphasize the need to increase access and quality of care. A mixed method study was conducted in 2 phases: Phase I: 3 Focus group discussions (FGDs) with breast cancer patients and their care givers were conducted at the NSIA-LUTH Cancer Centre in Lagos, Nigeria. Phase II: A pre and post-survey of a continuing medical education course focused on breast cancer was delivered to healthcare providers in southwest Nigeria. Survey responses regarding causes for delays and barriers to care indicated financial strain, fear, and alternative treatments as the largest hurdles, coinciding with patient testimony from the FGD. Fear of mastectomy was a perceived barrier to care for 90% of healthcare providers while 87% and 86% of providers perceived seeking spiritual and herbal treatments as the largest delays of care. Despite this, a significant number of focus group participants (39%) presented within the first month of noticing a breast symptom to a proper healthcare provider. Data from our study reports that 70% of patients receive help from family to fund treatment highlighting why cancer can be a poverty trap for families and the need for universal health insurance. Half of the focus group participants had a positive interaction with their doctors, with the rest reporting neutral (19%) or even negative (31%) interactions. Our study also reports 42% of healthcare providers feeling only "somewhat" qualified to deal with breast cancer, highlighting the significant need for more education, with a further 14% feeling neutral or negative about their qualification, a potential contributing factor in negative interactions recalled by patients. Knowledge increase was consistent for best practice diagnostic modalities among healthcare providers (p < 0.05). At the same time, items related to symptoms and risks of breast cancer had inconsistent knowledge increases, indicating why further courses like these should be pursued. With the success of the course and the inspiration of breast cancer survivors, a proposed expansion into community awareness is discussed along with enlisting local practitioners in the fight against breast cancer in hopes of lowering the barriers to and delays of care in Nigeria.}, }
@article {pmid40388716, year = {2025}, author = {Ashford, NK and Rane, S and Farris, KM and Miglani, J and Chu, B and Hippe, DS and Gandhi, T and Hanson, AJ}, title = {Acute cerebral blood flow response to heavy cream ingestion in older adults: A non-randomized pilot study.}, journal = {Journal of Alzheimer's disease : JAD}, volume = {106}, number = {1}, pages = {331-341}, pmid = {40388716}, issn = {1875-8908}, support = {R01 AG067563/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Aged ; Pilot Projects ; *Cerebrovascular Circulation/physiology ; Magnetic Resonance Imaging ; Middle Aged ; *Brain/diagnostic imaging/blood supply ; Blood Pressure/physiology ; Spin Labels ; }, abstract = {BackgroundHypertension and the APOE4 allele are known risk factors for Alzheimer's disease (AD) and E4 carriers show different blood pressure (BP) and cognitive responses to high fat feeding.ObjectiveWe investigated the influence of these factors on global cerebral blood flow (CBF) and four regions of interest (ROIs) (angular gyrus, hippocampus, posterior cingulate, temporal lobe) using arterial spin labeling (ASL) MRI in fasting state and after ingestion of heavy cream in older adults.Methods29 adults (age in years 66.8 ± 4.1) underwent baseline and 1, 2, 3-h ASL MRI after ingestion of 100 mL heavy cream. We used pCASL MRI with background suppression to measure CBF in ml/100 g/min. Statistical analyses included mixed-effects modeling and Pearson correlation to ascertain whether CBF changed over time and how variables influenced results.ResultsGlobal CBF decreased at 1-, 2-, and 3-h post-heavy cream, compared to time 0 (overall change 7.11%, p < 0.01); recapitulated in 3 of 4 ROIs. Mean arterial pressure emerged as a predictive variable for both baseline and post-heavy cream CBF (β = -0.25, 95% CI = -0.39, -0.10, p = 0.002). Individuals with higher BP demonstrated reduced CBF, particularly in posterior cingulate and temporal lobe (β = -5.50, 95% CI = -9.9, -1.09; β = -6.28, 95% CI = -12.35, -0.21, respectively, both p < 0.05). Examination of correlations with BP and change scores revealed that this relationship was driven largely by E4 carriers.ConclusionsCBF decreased after ingestion of heavy cream, globally and in regions known to be important in AD, and this finding was driven by E4 carriers with higher BP.}, }
@article {pmid40389082, year = {2025}, author = {Yang, H and Wang, Y and Luo, K and Mossavar-Rahmani, Y and Cordero, C and Ostfeld, RJ and Martinez, C and Maldonado, L and Pirzada, A and Daviglus, M and Yu, B and Hu, FB and Kaplan, RC and Qi, Q}, title = {Dietary patterns, serum metabolites, and risk of cardiovascular disease in United States Hispanic/Latino adults: a prospective analysis of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {The American journal of clinical nutrition}, volume = {122}, number = {1}, pages = {92-100}, pmid = {40389082}, issn = {1938-3207}, support = {R01 DK126698/DK/NIDDK NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; R01 HL170904/HL/NHLBI NIH HHS/United States ; R01 DK134672/DK/NIDDK NIH HHS/United States ; R01 AG085320/AG/NIA NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; R01 HL060712/HL/NHLBI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Cardiovascular Diseases/epidemiology/blood/ethnology ; *Diet ; *Hispanic or Latino ; Prospective Studies ; Risk Factors ; United States/epidemiology ; }, abstract = {BACKGROUND: Healthy dietary patterns are recommended to prevent cardiovascular disease (CVD), yet the relationships among healthy dietary patterns, blood metabolite profile, and incident CVD are not well understood.<br><br>OBJECTIVES: This study aimed to assess the associations of healthy dietary patterns and related serum metabolite profiles with incident CVD in United States Hispanic/Latino adults.<br><br>METHODS: The study included 13,922 participants aged 18-74 y from the Hispanic Community Health Study/Study of Latinos. Dietary pattern scores, including Healthy Eating Index (HEI)-2020, healthful Plant-based Diet Index (hPDI), and alternate Mediterranean diet score (aMED), were constructed at baseline (2008-2011) based on 2 24-h dietary recalls. The primary outcome was incident CVD, encompassing myocardial infarction, heart failure, and stroke. Dietary-pattern-associated metabolites were identified in a subsample of participants free of diabetes at baseline (n = 4096). Associations of dietary pattern scores, individual metabolites, and metabolite scores with incident CVD were evaluated using multivariable Cox regression.<br><br>RESULTS: During a median 9.7-y follow-up period, 260 CVD events occurred among 13,922 participants. After adjusting for demographic, socioeconomic and behavioral factors, higher dietary pattern scores were associated with lower risk of CVD [hazard ratios (HRs) = 0.53 (95% confidence interval: 0.30, 0.92), 0.50 (0.27, 0.91) and 0.62 (0.36, 1.07) for HEI-2020, hPDI, and aMED, respectively, by comparing the highest tertile to the lowest tertile]. A total of 60 metabolites were identified to be associated with all 3 dietary pattern scores, including 45 metabolites positively and 15 metabolites negatively associated with dietary pattern scores. A total metabolite score based on these 60 dietary-pattern-associated metabolites was negatively associated with the risk of CVD after multivariable adjustment [HR = 0.57 (0.35, 0.92) by comparing the highest tertile to the lowest tertile].<br><br>CONCLUSIONS: Healthier diet patterns and related serum metabolite profiles are associated with a lower risk of CVD in United States Hispanic/Latino adults.}, }
@article {pmid40389573, year = {2025}, author = {Khyzha, N}, title = {SLAM-RT&amp;Tag: spatiotemporal profiling of RNA within nuclear compartments in situ.}, journal = {Nature reviews. Genetics}, volume = {26}, number = {7}, pages = {439}, pmid = {40389573}, issn = {1471-0064}, }
@article {pmid40390365, year = {2025}, author = {Arimura, Y and Konishi, HA and Funabiki, H}, title = {MagIC-Cryo-EM, structural determination on magnetic beads for scarce macromolecules in heterogeneous samples.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40390365}, issn = {2050-084X}, support = {Scholarship for Study Abroad//Osamu Hayaishi Memorial Scholarship/ ; Overseas Research Fellowships//Japan Society for the Promotion of Science/ ; R35 GM132111/GM/NIGMS NIH HHS/United States ; SNF Institute for Global Infectious Disease Research//Stavros Niarchos Foundation/ ; R35GM132111/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Histones/chemistry ; Nucleosomes/ultrastructure/chemistry ; *Cryoelectron Microscopy/methods ; Xenopus laevis ; *Macromolecular Substances/chemistry ; Nucleoplasmins/chemistry ; Nucleophosmin ; }, abstract = {Cryo-EM single-particle analyses typically require target macromolecule concentration at 0.05~5.0 mg/ml, which is often difficult to achieve. Here, we devise Magnetic Isolation and Concentration (MagIC)-cryo-EM, a technique enabling direct structural analysis of targets captured on magnetic beads, thereby reducing the targets' concentration requirement to <0.0005 mg/mL. Adapting MagIC-cryo-EM to a Chromatin Immunoprecipitation protocol, we characterized structural variations of the linker histone H1.8-associated nucleosomes that were isolated from interphase and metaphase chromosomes in Xenopus egg extract. Combining Duplicated Selection To Exclude Rubbish particles (DuSTER), a particle curation method that excludes low signal-to-noise ratio particles, we also resolved the 3D cryo-EM structures of nucleoplasmin NPM2 co-isolated with the linker histone H1.8 and revealed distinct open and closed structural variants. Our study demonstrates the utility of MagIC-cryo-EM for structural analysis of scarce macromolecules in heterogeneous samples and provides structural insights into the cell cycle-regulation of H1.8 association to nucleosomes.}, }
@article {pmid40392206, year = {2025}, author = {Hery, CM and Zhang, X and McLaughlin, E and Von Ah, D and Anderson, GL and Harris, HR and VoPham, T and Garcia, L and Shadyab, AH and Follis, S and Paskett, ED}, title = {Association of Cancer History with COVID-19 Risk and Outcomes among Older Postmenopausal Women: Results from the Women's Health Initiative.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {8}, pages = {1286-1294}, pmid = {40392206}, issn = {1538-7755}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; K00 CA253745/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *COVID-19/epidemiology/virology ; Aged ; *Postmenopause ; Middle Aged ; Risk Factors ; *Neoplasms/epidemiology ; Women's Health ; Prospective Studies ; SARS-CoV-2/isolation &amp; purification ; United States/epidemiology ; }, abstract = {BACKGROUND: Several studies early in the COVID-19 pandemic suggested that those with a cancer history had a higher risk of COVID-19 infections and complications. However, few prospective studies evaluated the association of cancer with COVID-19 in older women. We aimed to examine the association of cancer history with the risk of COVID-19 and various COVID-19 outcomes among older women.<br><br>METHODS: The Women's Health Initiative is an ongoing cohort study that recruited 161,808 postmenopausal women of 50 to 79 years of age from 1993 to 1998. Those who completed the COVID-19 survey (2021-2022) were included (n = 35,623). Multivariable linear and logistic regressions were used to examine COVID-19 positivity, symptom severity, long COVID, and COVID concerns/anxiety outcomes.<br><br>RESULTS: Twenty-eight percent (n = 9,901) of participants had a history of cancer. Cancer history was not significantly associated with COVID-19 positivity [OR = 0.94; 95% confidence interval (CI), 0.81-1.08], COVID-19 hospitalization (OR = 1.21; 95% CI, 0.85-1.72), number of symptoms (least squares mean = 0.33; 95% CI, -0.20 to 0.85), and long COVID (OR = 1.18; 95% CI, 0.88-1.58).<br><br>CONCLUSIONS: A history of cancer was not associated with most COVID-19 outcomes. Future studies should continue to examine physiologic mechanisms contributing to differences among cancer survivors and prioritize the inclusion of underserved populations to identify strategies to address the impact of COVID-19.<br><br>IMPACT: These findings may assure cancer survivors that their diagnosis alone does not increase their risk of COVID-19 and suggest that older women with a history of cancer may have similar risks of COVID-19 outcomes compared with their noncancer counterparts.}, }
@article {pmid40392851, year = {2025}, author = {Zhu, L and Beichman, A and Harris, K}, title = {Population size interacts with reproductive longevity to shape the germline mutation rate.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {21}, pages = {e2423311122}, pmid = {40392851}, issn = {1091-6490}, support = {T32 AG066574/AG/NIA NIH HHS/United States ; R35GM133428//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; Career Award at the Scientific Interface//Burroughs Wellcome Fund (BWF)/ ; Discovery Center for Cell Lineage Tracing//Allen Foundation (The Allen Foundation)/ ; R35 GM133428/GM/NIGMS NIH HHS/United States ; Pew Scholarship//Pew Charitable Trusts (PEW)/ ; }, mesh = {*Mutation Rate ; *Germ-Line Mutation/genetics ; Animals ; Population Density ; Male ; *Reproduction/genetics ; Female ; *Longevity/genetics ; DNA Repair ; Germ Cells ; Spermatogonia ; DNA Damage ; }, abstract = {Mutation rates vary across the tree of life by many orders of magnitude, with fewer mutations occurring each generation in species that reproduce quickly and maintain large effective population sizes. A compelling explanation is that large effective population sizes facilitate selection against weakly deleterious "mutator alleles" such as variants that modulate cell division or interfere with the molecular efficacy of DNA repair. However, while the fidelity of a single cell division largely determines microorganisms' mutation rates, the relationship of the mutation rate to the molecular determinants of DNA damage and repair is more complex in multicellular species with long generation times. Since long generations leave more time for mutations to accrue each generation, we posit that a long generation time likely amplifies the fitness consequences of any damage agent or DNA repair defect that creates extra mutations in the spermatogonia or oocytes. This leads to the counterintuitive prediction that the species with the highest germline mutation rates per generation are also the species with most effective mechanisms for avoiding and repairing mutations in their reproductive cells. Consistent with this, we show that mutation rates in the reproductive cells are inversely correlated with generation time; in contrast, the number of germline mutations that occur during prepuberty development trends weakly upward as generation time increases. Our results parallel recent findings that the longest-lived species have the lowest mutation rates in adult somatic tissues, potentially due to selection to keep the lifetime mutation load below a harmful threshold.}, }
@article {pmid40392909, year = {2025}, author = {Naudin, S and Wang, M and Dimou, N and Ebrahimi, E and Genkinger, J and Adami, HO and Albanes, D and Babic, A and Barnett, M and Bogumil, D and Cai, H and Chen, C and Eliassen, AH and Freudenheim, JL and Gierach, G and Giovannucci, EL and Gunter, MJ and Håkansson, N and Hirabayashi, M and Hou, T and Huang, BZ and Huang, WY and Jayasekara, H and Jones, ME and Katzke, VA and Koh, WP and Lacey, JV and Lagerros, YT and Larsson, SC and Liao, LM and Lo, K and Loftfield, E and MacInnis, RJ and Männistö, S and McCullough, ML and Miller, A and Milne, RL and Moore, SC and Mucci, LA and Neuhouser, ML and Patel, AV and Platz, EA and Prizment, A and Robien, K and Rohan, TE and Sacerdote, C and Sandin, S and Sawada, N and Schoemaker, M and Shu, XO and Sinha, R and Snetselaar, L and Stampfer, MJ and Stolzenberg-Solomon, R and Thomson, CA and Tjønneland, A and Um, CY and van den Brandt, PA and Visvanathan, K and Wang, SS and Wang, R and Weiderpass, E and Weinstein, SJ and White, E and Willett, W and Woslk, A and Wolpin, BM and Yaun, SS and Yuan, C and Yuan, JM and Zheng, W and Brennan, P and Smith-Warner, SA and Ferrari, P}, title = {Alcohol intake and pancreatic cancer risk: An analysis from 30 prospective studies across Asia, Australia, Europe, and North America.}, journal = {PLoS medicine}, volume = {22}, number = {5}, pages = {e1004590}, pmid = {40392909}, issn = {1549-1676}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; UM1 CA173640/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 AA024770/AA/NIAAA NIH HHS/United States ; R01 CA039742/CA/NCI NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; U01 CA199277/CA/NCI NIH HHS/United States ; UM1 CA164917/CA/NCI NIH HHS/United States ; U01 CA210171/CA/NCI NIH HHS/United States ; U01 HL145386/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 CA063673/CA/NCI NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA144034/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; R01 CA077398/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; U01 CA164973/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/epidemiology/etiology ; Female ; Male ; Middle Aged ; *Alcohol Drinking/adverse effects/epidemiology ; North America/epidemiology ; Europe/epidemiology ; Prospective Studies ; Australia/epidemiology ; Risk Factors ; Asia/epidemiology ; Aged ; Adult ; Incidence ; Proportional Hazards Models ; }, abstract = {BACKGROUND: Alcohol is a known carcinogen, yet the evidence for an association with pancreatic cancer risk is considered as limited or inconclusive by international expert panels. We examined the association between alcohol intake and pancreatic cancer risk in a large consortium of prospective studies.<br><br>METHODS AND FINDINGS: Population-based individual-level data was pooled from 30 cohorts across four continents, including Asia, Australia, Europe, and North America. A total of 2,494,432 participants without cancer at baseline (62% women, 84% European ancestries, 70% alcohol drinkers [alcohol intake&#xa0;&#x2265;&#xa0;0.1&#xa0;g/day], 47% never smokers) were recruited between 1980 and 2013 at the median age of 57 years and 10,067 incident pancreatic cancer cases were recorded. In age- and sex-stratified Cox proportional hazards models adjusted for smoking history, diabetes status, body mass index, height, education, race and ethnicity, and physical activity, pancreatic cancer hazard ratios (HR) and 95% confidence intervals (CI) were estimated for categories of alcohol intake and in continuous for a 10&#xa0;g/day increase. Potential heterogeneity by sex, smoking status, geographic regions, and type of alcoholic beverage was investigated. Alcohol intake was positively associated with pancreatic cancer risk, with HR30-to-<60&#xa0;g/day and HR&#x2265;60&#xa0;g/day equal to 1.12 (95% CI [1.03,1.21]) and 1.32 (95% CI [1.18,1.47]), respectively, compared to intake of 0.1 to&#x2009;<5&#xa0;g/day. A 10&#xa0;g/day increment of alcohol intake was associated with a 3% increased pancreatic cancer risk overall (HR: 1.03; 95% CI [1.02,1.04]; pvalue&#xa0;<&#xa0;0.001) and among never smokers (HR: 1.03; 95% CI [1.01,1.06]; pvalue&#xa0;=&#xa0;0.006), with no evidence of heterogeneity by sex (pheterogeneity&#xa0;=&#xa0;0.274) or smoking status (pheterogeneity&#xa0;=&#xa0;0.624). Associations were consistent in Europe-Australia (HR10&#xa0;g/day&#xa0;=&#xa0;1.03, 95% CI [1.00,1.05]; pvalue&#xa0;=&#xa0;0.042) and North America (HR10&#xa0;g/day&#xa0;=&#xa0;1.03, 95% CI [1.02,1.05]; pvalue&#xa0;<&#xa0;0.001), while no association was observed in cohorts from Asia (HR10&#xa0;g/day&#xa0;=&#xa0;1.00, 95% CI [0.96,1.03]; pvalue&#xa0;=&#xa0;0.800; pheterogeneity&#xa0;=&#xa0;0.003). Positive associations with pancreatic cancer risk were found for alcohol intake from beer (HR10&#xa0;g/day&#xa0;=&#xa0;1.02, 95% CI [1.00,1.04]; pvalue&#xa0;=&#xa0;0.015) and spirits/liquor (HR10&#xa0;g/day&#xa0;=&#xa0;1.04, 95% CI [1.03,1.06]; pvalue&#xa0;<&#xa0;0.001), but not wine (HR10&#xa0;g/day&#xa0;=&#xa0;1.00, 95% CI [0.98,1.03]; pvalue&#xa0;=&#xa0;0.827). The differential associations across geographic regions and types of alcoholic beverages might reflect differences in drinking habits and deserve more investigations.<br><br>CONCLUSIONS: Findings from this large-scale pooled analysis support a modest positive association between alcohol intake and pancreatic cancer risk, irrespective of sex and smoking status. Associations were particularly evident for baseline alcohol intake of at least 15&#xa0;g/day in women and 30&#xa0;g/day in men.}, }
@article {pmid40394326, year = {2025}, author = {Flanagan, MR and van den Bruele, AMB and Downs-Canner, SM and Thomas, SM and Gallagher, KK and Jakub, JW and Tevis, SEA and Verdial, FC and Zhang, JQ and Elmore, LC and Mukhtar, RA and Brennan, M and Lillie, M and Gibson, TC and Verosky, A and Plichta, JK and Rosenberger, LH}, title = {A Multi-Institutional Analysis of Contralateral Axillary Metastases: Advanced Local-Regional Disease Divergent from Stage IV Breast Cancer.}, journal = {Annals of surgical oncology}, volume = {32}, number = {8}, pages = {5551-5562}, pmid = {40394326}, issn = {1534-4681}, support = {P30CA014236//Duke Cancer Institute/ ; }, mesh = {Humans ; Female ; *Breast Neoplasms/pathology/therapy/mortality ; Middle Aged ; Retrospective Studies ; Axilla ; Aged ; Survival Rate ; Neoplasm Staging ; Lymphatic Metastasis ; Follow-Up Studies ; Prognosis ; *Lymph Node Excision/mortality ; Neoadjuvant Therapy/mortality ; *Carcinoma, Ductal, Breast/secondary/therapy ; *Neoplasm Recurrence, Local/pathology ; }, abstract = {BACKGROUND: Contralateral axillary metastasis (CAM) is a rare event and is considered stage IV disease. We sought to evaluate outcomes in a CAM cohort treated with curative intent and contemporary systemic and locoregional therapy.<br><br>PATIENTS AND METHODS: A retrospective multi-institutional review was conducted from 2016 to 2022 of patients with CAM who underwent axillary surgery. Survival outcomes were compared with those with locally advanced breast cancer (LABC) and metastatic breast cancer (MBC).<br><br>RESULTS: In total, 754 patients were included in the study (63 CAM, 188 LABC, and 503 MBC). The median age at CAM diagnosis was 62 years [(interquartile range (IQR) 49.2-69.3)], and the majority demonstrated invasive ductal histology (74.6%). Over half of the patients with CAM received neoadjuvant chemotherapy (55.6%) followed by axillary dissection (82.5%) and adjuvant radiation (74.6%) in most cases. On unadjusted analysis, the LABC cohort demonstrated the highest 3-year unadjusted overall survival (OS) (89.4%), followed by CAM (79.7%) and MBC (53%) (p < 0.001). On multivariable analysis adjusting for age, race/ethnicity, insurance, and hormone receptor status, patients with MBC had inferior survival compared with LABC [hazard ratio (HR) 6.59, 95% confidence interval (CI) 4.22-10.28, p < 0.001], while CAM had similar survival to that seen in LABC (HR 2.13, 95% CI 0.82-5.52, p = 0.12).<br><br>CONCLUSIONS: Survival was higher for patients with CAM compared with MBC and was similar to patients with LABC. Though the LABC group demonstrated better recurrence-free survival than the CAM group, these numbers were comparable within the first 2 years of follow-up. Our data provides additional support for the consideration of curative intent management for patients with CAM.}, }
@article {pmid40394536, year = {2025}, author = {Hamoud, J and Devkota, J and Regan, T and Luken, A and Waring, J and Han, JJ and Naughton, F and Vilardaga, R and Bricker, J and Latkin, C and Moran, M and Thrul, J}, title = {Smoking cessation message testing to inform app-based interventions for young adults - an online experiment.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {1852}, pmid = {40394536}, issn = {1471-2458}, support = {NIDA; T32 DA007292/DA/NIDA NIH HHS/United States ; T32 DA007292/DA/NIDA NIH HHS/United States ; R01 CA246590/CA/NCI NIH HHS/United States ; K02 DA054304/DA/NIDA NIH HHS/United States ; NCI; R01 CA246590/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation/methods/psychology ; Male ; Female ; Adult ; Young Adult ; *Mobile Applications ; Cognitive Behavioral Therapy ; Acceptance and Commitment Therapy ; Motivation ; }, abstract = {BACKGROUND: To improve the efficacy of digital smoking cessation interventions for young adults, intervention messages need to be acceptable and appropriate for this population. The current study compared ratings of smoking cessation and urge reduction messages based on Cognitive Behavioral Therapy (distraction themed) and Acceptance and Commitment Therapy (acceptance themed) in young adults who smoke.<br><br>METHODS: A total of 124 intervention messages were rated by an online Qualtrics panel of N&#x2009;=&#x2009;301 diverse young adults who currently smoked tobacco cigarettes (Age M&#x2009;=&#x2009;26.6 years; 54.8% male; 51.5% racial/ethnic minority; 16.9% sexual or gender minority (SGM); 62.5% daily smoking). Each participant rated 10 randomly selected messages (3,010 total message ratings; 24.3 ratings per message) on 5-point scales (higher scores representing more favorable ratings) evaluating quality of content, quality of design, perceived support for coping with smoking urges, and perceived support for quitting smoking. Mixed models examined associations between message category (distraction vs. acceptance), participant level predictors (sociodemographic variables, readiness and motivation to quit, daily smoking, psychological flexibility), and message ratings.<br><br>RESULTS: Overall ratings ranged from M&#x2009;=&#x2009;3.61 (SD&#x2009;=&#x2009;1.25) on support for coping with urges to M&#x2009;=&#x2009;3.90 (SD&#x2009;=&#x2009;1.03) on content, with no differences between distraction and acceptance messages. Male participants gave more favorable ratings on the dimensions of support for coping (p&#x2009;<&#x2009;0.01) and support for quitting (p&#x2009;<&#x2009;0.01). Participants identifying as SGM gave lower ratings for message design (p&#x2009;<&#x2009;0.05). Participants with a graduate degree gave higher ratings on support for coping with urges and support for quitting (both p&#x2009;<&#x2009;0.05). Higher motivation to quit was associated with more favorable scores across all dimensions (all p&#x2009;<&#x2009;0.01). Those smoking daily rated messages as less helpful for coping with urges (p&#x2009;<&#x2009;0.01) and quitting smoking (p&#x2009;<&#x2009;0.05) compared to those smoking non-daily. Few interactions were found between message category distraction vs. acceptance and participant characteristics.<br><br>CONCLUSIONS: Distraction and acceptance messages received similar ratings among young adults who smoke cigarettes. Message revisions may be needed to increase appeal to women, SGM, those with lower education, and those less motivated to quit. Messages will be refined and used in an ongoing micro-randomized trial to investigate their real-time impact on smoking urges and behaviors.}, }
@article {pmid40394759, year = {2025}, author = {Christofferson, RC and Giovanni, JE and Koumans, EH and Ategbole, M and Clark, SD and Godfred-Cato, S and Menon, MP and Sastalla, I and Schweitzer, BK and Uyeki, TM}, title = {A Systematic Review of Prolonged SARS-CoV-2 Shedding in Immunocompromised Persons.}, journal = {Influenza and other respiratory viruses}, volume = {19}, number = {5}, pages = {e70121}, pmid = {40394759}, issn = {1750-2659}, mesh = {Humans ; *Immunocompromised Host ; *COVID-19/virology/immunology ; *SARS-CoV-2/physiology/isolation &amp; purification/genetics ; *Virus Shedding ; RNA, Viral ; }, abstract = {BACKGROUND: Although reports have documented prolonged SARS-CoV-2 RNA detection in immunocompromised patients, few studies have systematically analyzed data on duration of SARS-CoV-2 in respiratory specimens of immunocompromised patients.<br><br>METHODS: A systematic review was undertaken to describe SARS-CoV-2 RNA and infectious virus detection in immunocompromised patients from published data between January 1, 2020 and July 1, 2022. Patients were included if there was &#x2265;&#x2009;1 positive SARS-CoV-2 RNA result in respiratory specimens collected > 20&#x2009;days since symptom onset or first positive SARS-CoV-2 RT-PCR result.<br><br>RESULTS: Of the 183 patients, 175 were symptomatic with 83 (47.4%) that experienced intermittent relapsing symptoms, while pneumonia was reported in 122 (66.7%). Immunocompromising conditions represented were hematologic malignancy treatment (89, 48.6%), solid organ transplant (47, 25.7%), autoimmune disease treatment (14, 7.7%), solid tumor treatment (3, 1.6%), HIV infection (15, 8.2%), and primary immunodeficiency (15, 8.2%). Median duration from the first to the last positive SARS-CoV-2 RT-PCR result was 56&#x2009;days in upper respiratory and 60&#x2009;days in lower respiratory tract specimens. Significant differences in median duration of SARS-CoV-2 RNA detection were observed between patients with and without pneumonia and for patients with hematologic malignancies compared to solid organ transplant patients. Among patients with viral culture performed, median duration of replication-competent SARS-CoV-2 was 60.5&#x2009;days from symptom onset (maximum 238&#x2009;days) and 59&#x2009;days from first RT-PCR positive result (maximum 268&#x2009;days).<br><br>CONCLUSIONS: Immunocompromised persons can have replication-competent SARS-CoV-2 in respiratory tissues for months, including while asymptomatic. Serial SARS-CoV-2 testing can inform the duration of isolation for immunocompromised patients with SARS-CoV-2 infection.}, }
@article {pmid40394810, year = {2025}, author = {Marks, DI and Cassaday, RD and Ribera, JM and Schuh, AC and Park, JH and Chiaretti, S and Stelljes, M}, title = {Identifying people with acute lymphoblastic leukemia who are most suitable for treatment with inotuzumab ozogamicin: a plain language summary.}, journal = {Expert review of hematology}, volume = {18}, number = {5}, pages = {345-349}, doi = {10.1080/17474086.2025.2493325}, pmid = {40394810}, issn = {1747-4094}, }
@article {pmid40394842, year = {2025}, author = {Ghodsi, A and Demirci, RA and Chen, DL and Nelson, PS and Schweizer, MT and Yu, EY and Iravani, A}, title = {The Role of SPECT/CT in 177 Lu-PSMA-617 Theranostics: Case-based Review of Response and Progression Patterns.}, journal = {Clinical nuclear medicine}, volume = {50}, number = {8}, pages = {e453-e460}, doi = {10.1097/RLU.0000000000005986}, pmid = {40394842}, issn = {1536-0229}, mesh = {Humans ; Male ; *Dipeptides/therapeutic use ; *Disease Progression ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; *Lutetium/therapeutic use ; Prostatic Neoplasms, Castration-Resistant/diagnostic imaging/radiotherapy/pathology ; *Radioisotopes/therapeutic use ; *Single Photon Emission Computed Tomography Computed Tomography ; *Theranostic Nanomedicine ; Treatment Outcome ; Prostate-Specific Antigen ; }, abstract = {Lutetium-177 prostate-specific membrane antigen-617 (Lu-PSMA) has demonstrated efficacy in improving progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). Post-treatment single photon emission tomography/computed tomography (SPECT/CT) imaging is an emerging tool for monitoring treatment response, enabling the tracking of functional changes during therapy. While quantitative SPECT analysis can predict patient outcomes, qualitative assessments are more practical and time-efficient in clinical settings. This case-based review examines treatment responses based on post-treatment SPECT/CT imaging, categorizing them into favorable response, progression, and mixed response patterns to improve interpretation and guide therapeutic adjustments, aiming to optimize management of mCRPC with Lu-PSMA therapy.}, }
@article {pmid40397323, year = {2025}, author = {Wadden, E and Yogeswaran, V and Ray, RM and Vasbinder, A and Shadyab, AH and Xiao, Q and Richey, PA and Saquib, N and Sun, Y and Jung, SY and Pichardo, MS and Manson, JE and Anderson, G and Simon, M and Stefanick, ML and Reding, K and Barac, A and Cheng, RK}, title = {Social determinants of cardiovascular disease in women with and without breast cancer.}, journal = {Breast cancer research and treatment}, volume = {212}, number = {2}, pages = {371-386}, pmid = {40397323}, issn = {1573-7217}, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/complications ; Middle Aged ; *Social Determinants of Health ; *Cardiovascular Diseases/epidemiology/etiology ; Aged ; Socioeconomic Factors ; Risk Factors ; Proportional Hazards Models ; Women's Health ; }, abstract = {PURPOSE: Social determinants of health (SDOH) may impact cardiovascular (CV) risk in women with and without breast cancer (BC).<br><br>METHODS: In 153,401 participants without prevalent CV disease from the Women's Health initiative (WHI), we assessed key SDOH factors: geographic region, rurality, insurance status, and household income. Multivariable Cox proportional hazards models were used to assess associations between SDOH factors and a composite CV outcome, which included incident myocardial infarction, incident stroke, hospitalization for heart failure, or CV death.<br><br>RESULTS: In the final cohort, 10,954 (mean&#x2009;&#xb1;&#x2009;standard deviation [SD] age 62&#x2009;&#xb1;&#x2009;7&#xa0;years) women developed BC, and 142,144 (mean age 63&#x2009;&#xb1;&#x2009;7&#xa0;years) women remained free of BC. During a median follow-up time of 13&#xa0;years, 18,148 women experienced the composite CV outcome. Rurality, low household income, and non-private insurance were associated with an increased risk of the composite CV outcome and CV death, both in women with and without BC.<br><br>CONCLUSIONS: SDOH factors are associated with an increased risk of CV events among women, irrespective of BC status. These associations highlight the importance of socioeconomic factors across cardiovascular health outcomes.}, }
@article {pmid40397817, year = {2025}, author = {Watling, CZ and Petrick, JL and Graubard, BI and Zhang, X and Barnett, MJ and Buring, JE and Chen, Y and Eliassen, AH and Gaziano, M and Kang, JH and Koshiol, J and Huang, WY and Lee, IM and Moore, SC and Mucci, LA and Neuhouser, ML and Newton, CC and Palmer, JR and Rosenberg, L and Sesso, HD and Shrubsole, M and Tinker, L and Triplette, M and Um, CY and Visvanathan, K and Wactawski-Wende, J and Willett, W and Wu, F and Zheng, W and Hofmann, J and Purdue, MP and Campbell, PT and Barupal, D and McGlynn, KA}, title = {Circulating per- and polyfluoroalkyl substances and liver cancer risk: a nested case-control analysis of individual participant data from 12 prospective cohorts.}, journal = {Environmental health perspectives}, volume = {}, number = {}, pages = {}, pmid = {40397817}, issn = {1552-9924}, support = {Z01 CP010158/ImNIH/Intramural NIH HHS/United States ; }, abstract = {BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) have been associated with numerous deleterious health outcomes including liver damage. However, whether exposure to PFAS is associated with liver cancer risk remains unclear.<br><br>METHODS: We conducted a matched nested case-control study among 12 prospective cohort studies located in the United States. Pre-diagnostic PFAS, namely perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS), were measured from blood samples among 853 individuals who developed liver cancer and 853 matched control participants. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable-adjusted conditional logistic regression for liver cancer risk by study-specific quartiles of concentrations and per 90[th] vs. 10[th] percentile incremental increase.<br><br>RESULTS: In the main multivariable-adjusted model, circulating PFOS, PFOA, and PFHxS levels were not associated with liver cancer risk (OR per 90[th] vs. 10[th] percentile increase: 1.00, 95% CI: 0.79-1.28; 0.92, 0.73-1.15; and 0.95, 0.75-1.21, respectively). However, when analyses were stratified by sex, PFOA concentrations were positively associated with liver cancer risk in males (OR per 90[th] vs. 10[th] percentile increase: 1.62 95% CI:1.07-2.45), whereas an inverse association was observed amongst females (OR per 90[th] vs. 10[th] percentile increase:0.68, 0.50-0.92; p-interaction=0.005). Analyses separating liver cancer subtypes, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma, showed no evidence of heterogeneity, although associations were stronger but not significant for HCC. No evidence of interaction was observed by time to diagnosis, time period of blood draw, body mass index, alcohol intake, ethnicity, or diabetes status.<br><br>CONCLUSIONS: In the largest study to date, none of the measured circulating PFAS were associated with liver cancer risk; however, PFOA associations appeared to differ by sex and further research is needed to explore these apparent differences by sex. https://doi.org/10.1289/EHP16980.}, }
@article {pmid40397836, year = {2025}, author = {Ramsey, SD and Sun, Q and Fedorenko, CR and Li, L and Panattoni, LE and Kreizenbeck, KL and Shankaran, V}, title = {Telehealth and Emergency Department Use Among Commercially Insured, Medicaid, and Medicare Patients Receiving Systemic Cancer Therapy in Washington State After COVID-19.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2400217}, doi = {10.1200/CCI-24-00217}, pmid = {40397836}, issn = {2473-4276}, mesh = {Humans ; *COVID-19/epidemiology/virology/prevention &amp; control ; *Telemedicine/statistics &amp; numerical data ; *Medicaid/statistics &amp; numerical data ; *Medicare/statistics &amp; numerical data ; Washington/epidemiology ; *Emergency Service, Hospital/statistics &amp; numerical data ; Male ; Female ; *Neoplasms/therapy/epidemiology ; United States/epidemiology ; Aged ; Middle Aged ; SARS-CoV-2 ; Insurance, Health/statistics &amp; numerical data ; Adult ; SEER Program ; }, abstract = {PURPOSE: In oncology, telehealth services were adopted as a means of mitigating the risk of COVID-19 transmission. We hypothesized that Medicaid enrollees would have less access to telehealth than commercially insured or Medicare enrollees during the pandemic, resulting in higher rates of emergency department (ED) visits during systemic cancer treatment.<br><br>METHODS: Linking Washington State SEER records with commercial, Medicaid, and Medicare records, we evaluated adults with new solid tumor malignancies who received initial systemic treatment before the COVID-19 pandemic (January 1, 2017-December 31, 2019) and after the pandemic (March 1, 2020-November 30, 2021). Poisson and logistic regressions were used to evaluate differences in the number of office visits, telehealth visits, and ED visits in the 3 months after starting systemic anticancer treatment between insurance groups before versus after the pandemic.<br><br>RESULTS: Among 2,936 commercial, 2,039 Medicaid, and 7,333 Medicare enrollees who met inclusion criteria, office-based visits fell substantially for all groups during the COVID-19 period. Medicare enrollees had fewer telehealth visits while Medicaid had more telehealth visits, compared with commercial enrollees. ED visits declined for all patients, but there were no differences between insurance groups.<br><br>CONCLUSION: In Washington State, COVID-19 resulted in a substantial decrease in office-based visits, with an accompanying increase in telehealth visits partially offsetting the difference in overall access to care. ED visit rates fell substantially, without differences between insurance groups.}, }
@article {pmid40398416, year = {2025}, author = {Aditham, AK and Radford, CE and Carr, CR and Jasti, N and King, NP and Bloom, JD}, title = {Deep mutational scanning of rabies glycoprotein defines mutational constraint and antibody-escape mutations.}, journal = {Cell host &amp; microbe}, volume = {33}, number = {6}, pages = {988-1003.e10}, pmid = {40398416}, issn = {1934-6069}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; }, mesh = {*Rabies virus/immunology/genetics ; *Antibodies, Viral/immunology ; *Glycoproteins/genetics/immunology ; *Viral Envelope Proteins/genetics/immunology ; *Antigens, Viral/genetics/immunology ; Humans ; Antibodies, Monoclonal/immunology ; Antibodies, Neutralizing/immunology ; Animals ; Rabies/immunology/virology ; *Immune Evasion ; Mutation ; Epitopes/immunology/genetics ; }, abstract = {Rabies virus causes nearly 60,000 human deaths annually. Antibodies that target the rabies glycoprotein (G) are being developed as post-exposure prophylactics, but mutations in G can render such antibodies ineffective. Here, we use pseudovirus deep mutational scanning to measure how all single-amino-acid mutations to G affect cell entry and neutralization by a panel of antibodies. These measurements identify sites critical for G function and define constrained regions that are attractive epitopes for clinical antibodies, including at the apex and base of the protein. We provide complete maps of escape mutations for eight monoclonal antibodies, including some in clinical use or development. Escape mutations for most antibodies are present in some natural rabies strains. Overall, this work provides comprehensive information on the functional and antigenic effects of G mutations that can inform development of stabilized vaccine antigens and antibodies that are resilient to rabies genetic variation.}, }
@article {pmid40398620, year = {2025}, author = {Burleigh, K and Stratton, KG and Smith, JL and Jensen, MC and Turtle, CJ and Keenan, C and Annesley, C and Summers, C and Webb-Robertson, BJ and Hirayama, AV and Gardner, RA and Gustafson, HH}, title = {Low Peripheral Blood Counts and Elevated Proinflammatory Cytokines Signal a Poor CD19 Chimeric Antigen Receptor T-cell Response in Acute Lymphoblastic Leukemia.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {8}, pages = {551-564}, pmid = {40398620}, issn = {2666-6367}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R37 CA266777/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cytokines/blood ; Male ; Female ; *Antigens, CD19/immunology ; Adult ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy/blood/immunology ; Child ; *Immunotherapy, Adoptive/methods/adverse effects ; Adolescent ; Middle Aged ; *Receptors, Chimeric Antigen/immunology ; Young Adult ; Child, Preschool ; *Receptors, Antigen, T-Cell ; }, abstract = {CD19 chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, approximately 20% of patients fail to achieve a complete remission (CR), and some develop severe, life-threatening toxicities. Understanding the biological mechanisms underlying both dysfunctional responses and severe toxicity is essential for optimizing patient management and improving therapeutic efficacy. This study aimed to (1) characterize cytokine profiles associated with dysfunctional responses and severe toxicity following CAR-T infusion, (2) examine the timing and trajectory of cytokine changes in relation to treatment outcomes, and evaluate potential strategies for mitigating toxicity and treatment failure. We conducted a comprehensive analysis of serum cytokine profiles in 86 adult and pediatric patients undergoing autologous CD19 CAR-T therapy for B-ALL. Patients were categorized into three groups: (1) Dysfunctional response-Patients who failed to achieve a minimal residual disease-negative CR (MRD-CR) by Day 63 or who experienced recurrence of CD19+ disease in the setting ongoing CAR-T cell detection before Day 63. (2) Functional response with severe cytokine release syndrome (CRS) and/or neurotoxicity (NTX)-Patients with best response of MRD-CR by Day 63 who experienced grade 3 or higher CRS or NTX. (3) Functional response without severe CRS or NTX-Patients with best response of MRD-CR by Day 63 who did not experience grade ≥3 CRS or NTX. Cytokine levels were measured during the first-week postinfusion and correlated with treatment efficacy, toxicity outcomes, complete blood counts, and CAR-T expansion dynamics. This analysis aimed to better understand how cytokine profiles relate to patient outcomes and immune responses in CAR-T therapy. Patients with dysfunctional response exhibited decreased neutrophils, platelets, and levels of granulocytic cytokines (suggestive of low bone marrow reserve) alongside elevated pro-inflammatory cytokines by Day 1. Functional response with severe toxicity patients showed a progressive rise in proinflammatory cytokines, reaching similar levels to dysfunctional response patients by Day 7. We observed that high cytokines at both the Day 1 and Day 7 time points were associated with poor survival. These findings remained significant when adjusting for high disease burden, a known predictor of severe inflammatory toxicity and lack of response. Early post-CAR-T infusion inflammation is associated with both dysfunctional response and severe toxicity-even after adjusting for disease burden. This suggests that inflammation, in addition to disease burden, plays a role in determining patient outcome. Therefore, strategies aimed at reducing the pro-inflammatory state prior to or early after CAR-T cell infusion may improve outcomes for R/R B-ALL patients.}, }
@article {pmid40398621, year = {2025}, author = {Spellman, SR and Xu, K and Oloyede, T and Ahn, KW and Akhtar, O and Bolon, YT and Broglie, L and Bloomquist, J and Bupp, C and Chen, M and Devine, SM and El-Jurdi, N and Hamadani, M and Hengen, M and Huppler, AH and Jaglowski, S and Kuxhausen, M and Lee, SJ and Moskop, A and Page, KM and Pasquini, MC and Perez, W and Phelan, R and Rizzo, D and Saber, W and Stefanski, HE and Steinert, P and Tuschl, E and Visotcky, A and Vogel, R and Auletta, JJ and Shaw, BE and Allbee-Johnson, M}, title = {Current Activity Trends and Outcomes in Hematopoietic Cell Transplantation and Cellular Therapy - A Report from the CIBMTR.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {8}, pages = {505-532}, pmid = {40398621}, issn = {2666-6367}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/trends/methods/adverse effects ; Middle Aged ; Aged ; Adult ; Male ; Graft vs Host Disease/prevention &amp; control ; Female ; Adolescent ; COVID-19/epidemiology ; Child ; United States/epidemiology ; Young Adult ; Transplantation, Homologous ; Child, Preschool ; Treatment Outcome ; Myelodysplastic Syndromes/therapy ; *Cell- and Tissue-Based Therapy/trends ; SARS-CoV-2 ; Infant ; Transplantation, Autologous ; Unrelated Donors ; Leukemia, Myeloid, Acute/therapy ; }, abstract = {The Center for International Blood and Marrow Transplant Research (CIBMTR) compiles annual summary slides describing trends in hematopoietic cell transplantation (HCT) and cellular therapy (CT) practice and outcomes. This year's report includes all patients receiving their first autologous and/or allogeneic HCT/CT in the United States between 2013 and 2023 or chimeric antigen receptor T-cell (CAR-T) therapy from 2016 and 2023, reported to the CIBMTR. A relative proportion of allogeneic and autologous HCT/CT was generated as percentage of total for donor type and for patient age, disease indication, graft-versus-host disease (GVHD) prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival. New for this year, disease risk stratification reflects the European LeukemiaNet cytogenetic risk score for acute myeloid leukemia (AML) and the Revised International Prognostic Scoring System for myelodysplastic syndromes (MDS). Use of allogeneic HCT increased substantially in 2023, recovering from a decline in activity during the COVID-19 pandemic, with growth predominately in the 65- to 74-year-old age group. Overall, matched unrelated donors (MUDs) continue to be the most common allogeneic donor source (45%) followed by haploidentical related donors (Haplo; 21%), matched related donors (MRDs; 18%), mismatched unrelated donors (MMUDs; (12%), and cord blood (Cord; 3%). These trends hold in the adult patient population, with a notable doubling of MMUD utilization since 2020 driven by the rapid shift to post-transplantation cyclophosphamide-based GVHD prophylaxis (PTCy) in this setting. In the pediatric setting, Haplo was the most common donor source, surpassing MRD use in 2023 followed by MUD, Cord, and MMUD use. Autologous HCT continued to decline slightly, whereas use of CAR-T therapy has rapidly increased since commercial approval in 2017, with lymphoma and multiple myeloma reaching 45% and 16%, respectively, in 2023. Significant recent changes in GVHD prophylaxis in the adult allogeneic HCT setting have occurred. PTCy is most common in Haplo HCT with >90% since 2016. Among other donor sources, the most rapid adoption is in MMUD HCT at 82% in 2023. In MRDs and MUDs, PTCy use differs by conditioning intensity, with non-myeloablative/reduced-intensity conditioning (NMA/RIC) higher (58% and 64%, respectively), reflecting the standard of care established by BMT CTN 1703, compared with myeloablative (MAC; 43% and 46%, respectively). In pediatrics, calcineurin inhibitor ± others remains the most common GVHD prevention strategy for use of MRDs (88%) and MUDs (68%). Although common in the pediatric Haplo HCT setting at 68% in 2023, use of PTCy is less common across other mismatched donor types in which use of abatacept or ex-vivo T-cell depletion/CD34 selection accounts for 28% and 17% in MMUDs, respectively. Three-year overall survival continues to significantly improve among patients receiving allogeneic (62.1% vs. 55.8%) and autologous (82.6% vs. 79.6%) HCT when comparing HCT from 2017 to 2022 versus 2012 to 2016 (P < .001), respectively. In both the adult and pediatric settings, primary cause of mortality after 100 days post-HCT remains primary disease in both allogeneic (47% and 45%, respectively) and autologous (60% and 79%, respectively). HCT/CT and CAR-T use continues to grow. Relapse remains the primary cause of death in the malignant setting, supporting further efforts to mitigate risk.}, }
@article {pmid40399555, year = {2025}, author = {Lammi, V and Nakanishi, T and Jones, SE and Andrews, SJ and Karjalainen, J and Cortés, B and O'Brien, HE and Ochoa-Guzman, A and Fulton-Howard, BE and Broberg, M and Haapaniemi, HH and Kanai, M and Pirinen, M and Schmidt, A and Mitchell, RE and Mousas, A and Mangino, M and Huerta-Chagoya, A and Sinnott-Armstrong, N and Cirulli, ET and Vaudel, M and Kwong, ASF and Maiti, AK and Marttila, MM and Posner, DC and Rodriguez, AA and Batini, C and Minnai, F and Dearman, AR and Warmerdam, CAR and Sequeros, CB and Winkler, TW and Jordan, DM and Rešcenko, R and Miano, L and Lane, JM and Chung, RK and Guillen-Guio, B and Leavy, OC and Carvajal-Silva, L and Aguilar-Valdés, K and Frangione, E and Guare, L and Vergasova, E and Marouli, E and Striano, P and Zainulabid, UA and Kumar, A and Ahmad, HF and Edahiro, R and Azekawa, S and ,  and ,  and ,  and ,  and ,  and ,  and ,  and ,  and ,  and Luoh, SW and Erikstrup, C and Pedersen, OBV and Lerner-Ellis, J and Colombo, A and Grzymski, JJ and Ishii, M and Okada, Y and Beckmann, ND and Kumari, M and Wagner, R and Heid, IM and John, C and Short, PJ and Magnus, P and Ansone, L and Valenti, LVC and Lee, SA and Wain, LV and Verdugo, RA and Banasik, K and Geller, F and Franke, LH and Rakitko, A and Duncan, EL and Renieri, A and Tsilidis, KK and de Cid, R and Niavarani, A and Abner, E and Tusié-Luna, T and Verma, SS and Smith, GD and Timpson, NJ and Madduri, RK and Cho, K and Daly, MJ and Ganna, A and Schulte, EC and Richards, JB and Ludwig, KU and Marks-Hultström, M and Zeberg, H and Ollila, HM}, title = {Genome-wide association study of long COVID.}, journal = {Nature genetics}, volume = {57}, number = {6}, pages = {1402-1417}, pmid = {40399555}, issn = {1546-1718}, support = {R00 AG070109/AG/NIA NIH HHS/United States ; S10 OD026880/OD/NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R01 AI159260/AI/NIAID NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; R01 AI170850/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Genome-Wide Association Study ; *COVID-19/genetics ; SARS-CoV-2 ; *Forkhead Transcription Factors/genetics ; Polymorphism, Single Nucleotide ; Male ; Female ; Genetic Predisposition to Disease ; Case-Control Studies ; Pandemics ; Middle Aged ; *Pneumonia, Viral/genetics ; Post-Acute COVID-19 Syndrome ; }, abstract = {Infections can lead to persistent symptoms and diseases such as shingles after varicella zoster or rheumatic fever after streptococcal infections. Similarly, severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection can result in long coronavirus disease (COVID), typically manifesting as fatigue, pulmonary symptoms and cognitive dysfunction. The biological mechanisms behind long COVID remain unclear. We performed a genome-wide association study for long COVID including up to 6,450 long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We discovered an association of FOXP4 with long COVID, independent of its previously identified association with severe COVID-19. The signal was replicated in 9,500 long COVID cases and 798,835 population controls. Given the transcription factor FOXP4's role in lung physiology and pathology, our findings highlight the importance of lung function in the pathophysiology of long COVID.}, }
@article {pmid40399683, year = {2025}, author = {Rademaker, G and Hernandez, GA and Seo, Y and Dahal, S and Miller-Phillips, L and Li, AL and Peng, XL and Luan, C and Qiu, L and Liegeois, MA and Wang, B and Wen, KW and Kim, GE and Collisson, EA and Kruger, SF and Boeck, S and Ormanns, S and Guenther, M and Heinemann, V and Haas, M and Looney, MR and Yeh, JJ and Zoncu, R and Perera, RM}, title = {PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer.}, journal = {Nature}, volume = {643}, number = {8074}, pages = {1381-1390}, pmid = {40399683}, issn = {1476-4687}, support = {P30 DK026743/DK/NIDDK NIH HHS/United States ; P50 CA257911/CA/NCI NIH HHS/United States ; R01 CA240603/CA/NCI NIH HHS/United States ; }, mesh = {*Proprotein Convertase 9/metabolism/genetics/deficiency ; Animals ; Mice ; Humans ; *Pancreatic Neoplasms/pathology/metabolism/enzymology/genetics ; Cell Line, Tumor ; *Carcinoma, Pancreatic Ductal/pathology/metabolism/enzymology/secondary/genetics ; Lung Neoplasms/secondary/metabolism/enzymology ; Female ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Liver Neoplasms/secondary/metabolism/enzymology ; Cholesterol, LDL/metabolism ; Male ; Lysosomes/metabolism ; *Neoplasm Metastasis ; Cholesterol/biosynthesis/metabolism ; Liver/metabolism/pathology ; Tumor Microenvironment ; *Sterols/metabolism ; }, abstract = {To grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs[1]. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there remain undefined. Here we identified PCSK9 as predictive of liver versus lung colonization by integrating metastatic tropism data of human PDAC cell lines[2], in vivo metastasis modelling in mice and gene expression correlation analysis. PCSK9 negatively regulates low density lipoprotein (LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells preferentially colonize LDL-rich liver tissue. LDL-cholesterol taken up by liver-avid PCSK9-low cells supports activation of pro-growth mTORC1 activation at the lysosome, and through conversion into the signalling oxysterol, 24(S)-hydroxycholesterol, reprogrammes the microenvironment to release nutrients from neighbouring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates-7-dehydrocholesterol and 7-dehydrodesmosterol-with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing the amount of PCSK9 redirected liver-avid cells to the lung whereas ablating PCSK9 drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC.}, }
@article {pmid40402042, year = {2025}, author = {Moosavi, D and Curtis, KR and Randolph, TW and Kahsai, OJ and Ammar, H and Lim, U and Cheng, I and Wilkens, LR and Le Marchand, L and Lampe, JW and Hullar, MAJ}, title = {Stability and Variability of the Human Fecal Microbiome over 2 Years in the Multiethnic Cohort Study: A Metagenomic Analysis.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {8}, pages = {1386-1394}, pmid = {40402042}, issn = {1538-7755}, support = {P01 CA168530/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; P01 CA168530/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; 3U01 CA164973-09S2//National Cancer Institute (NCI)/ ; T32 CA0924080//National Cancer Institute (NCI)/ ; //Fred Hutchinson Cancer Center (FHCRC)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Feces/microbiology ; Male ; Female ; *Gastrointestinal Microbiome/genetics ; Aged ; *Metagenomics/methods ; Middle Aged ; Cohort Studies ; }, abstract = {BACKGROUND: Understanding the longitudinal variability of the gut microbiome is essential for advancing microbiome-based measurements and designing robust sampling protocols in observational and intervention studies of cancer and other health outcomes. The aim of this study was to explore the temporal variability and stability of the fecal microbiome over a 2-year period using intraclass correlation (ICC) analysis of metagenomic sequencing data.<br><br>METHODS: We studied 25 older adults from the Multiethnic Cohort Adiposity Phenotype Study (2013-2016). Stool samples were collected every 6 months over a 2-year period (five samples) and analyzed using metagenomic sequencing. The temporal stability was evaluated using ICCs across taxonomic levels, diversity, and functional genes and pathways.<br><br>RESULTS: The microbial community showed stability in &#x3b1; diversity and overall structure, with no significant changes observed across time points (Shannon diversity, P = 0.95). Taxonomic composition showed strong reliability over time, with median ICCs of 0.7 at the genus level and 0.75 at the species level. Functional genes also demonstrated good stability (median ICC = 0.68). However, microbial pathways were more variable with a fair median ICC of 0.49.<br><br>CONCLUSIONS: Although the fecal microbiome was generally stable, some taxa and functions were more dynamic and responsive to external influences.<br><br>IMPACT: Findings highlight the need for reliable microbiome measurements and sampling strategies to reduce bias in studies of the microbiome and cancer.}, }
@article {pmid40402477, year = {2025}, author = {Li, T and Su, YR and Lee, JM and O'Meara, ES and Miglioretti, DL and Kerlikowske, K and Henderson, L and Houssami, N}, title = {Tomosynthesis vs Digital Mammography Screening in Women with a Family History of Breast Cancer.}, journal = {JAMA oncology}, volume = {11}, number = {7}, pages = {742-752}, pmid = {40402477}, issn = {2374-2445}, support = {P01 CA154292/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging/genetics/pathology ; Middle Aged ; *Mammography/methods ; *Early Detection of Cancer/methods ; Adult ; Aged ; Cohort Studies ; Breast Density ; }, abstract = {IMPORTANCE: Evidence on screening outcomes with digital breast tomosynthesis (DBT) vs digital mammography (DM) in women with a family history of breast cancer is limited.<br><br>OBJECTIVE: To compare the performance of DBT and DM screening in women with a family history of breast cancer overall and subdivided by breast cancer family history category, breast density, age group, screening interval, and screening round, and to describe characteristics of cancers detected on screening vs interval cancers.<br><br>In this comparative cohort study at imaging facilities affiliated with the Breast Cancer Surveillance Consortium, adult women 18 years and older with a self-reported family history of breast cancer who underwent DBT or DM from 2011 to 2018 were included, with a 1-year follow-up for breast carcinoma. Data analysis was performed between November 2023 and August 2024.<br><br>EXPOSURES: DBT or DM.<br><br>MAIN OUTCOMES AND MEASURES: The main outcomes were absolute risk difference (ARD) between DBT and DM for recall rate, cancer detection rate, interval cancer rate, advanced cancer rate, biopsy rate, positive predictive values, sensitivity, and specificity, with inverse probability of treatment weighting.<br><br>RESULTS: A total of 208&#x202f;945 women with a family history of breast cancer undergoing 502&#x202f;357 screening examinations were included in the sample. Median (IQR) age was 58 (50-66) and 57 (49-66) years for the DBT and DM groups, respectively. Adjusted ARDs (DBT vs DM) were significant for recall rate (-1.51%; 95% CI, -2.42% to -0.59%) and specificity (1.56%; 95% CI, 0.65%-2.46%) in the overall cohort of 121&#x202f;698 DBT and 380&#x202f;561 DM examinations and among women with 1 first-degree relative (recall rate ARD, -1.72%; 95% CI, -2.70% to -0.74%; specificity ARD, 1.75%; 95% CI, 0.81%-2.69%). Among those with only second-degree relatives, the biopsy rate for DBT was significantly higher (ARD, 0.39%; 95% CI, 0.18%-0.61%). Significant ARDs were observed for the ductal carcinoma in situ detection rate (-0.71 per 1000 examinations; 95% CI, -1.03 to -0.38 per 1000 examinations) in women with almost entirely fatty breasts; recall rate (-1.90%; 95% CI, -2.88% to -0.92%) and specificity (1.93%; 95% CI, 0.97%-2.89%) in women with scattered fibroglandular densities. Significant ARDs were also observed for the positive predictive value for recall (1.75%; 95% CI, 0.84%-2.67%) in heterogeneously dense breasts, as well as the biopsy rate (0.48%; 95% CI, 0.16%-0.80%) and advanced cancer rate (-0.61 per 1000 examinations; 95% CI, -1.02 to -0.20 per 1000 examinations) in extremely dense breasts. DBT screening had a higher proportion than DM of screen-detected early-stage, invasive cancers with favorable prognostic characteristics.<br><br>CONCLUSIONS AND RELEVANCE: In this cohort study of women with a family history of breast cancer, DBT screening reduced recall rates and increased specificity compared to DM, particularly in women with 1 first-degree relative with breast cancer and those with scattered fibroglandular breast density, and reduced advanced cancer rates in women with extremely dense breasts.}, }
@article {pmid40403387, year = {2025}, author = {Mahalingam, D and Saeed, A and Powell, SF and Huerta, M and Sahai, V and Coveler, AL and Davis, EJ and Steeghs, N and Mulcahy, M and Raufi, AG and Cavalcante, L and Cervantes, A and Berlin, J and Weisskittel, T and Ugolkov, A and Mazar, AP and Mikrut, W and Smith, S and Giles, FJ and Carneiro, BA}, title = {Phase II study of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine plus nab-paclitaxel in previously untreated metastatic pancreatic cancer.}, journal = {ESMO open}, volume = {10}, number = {6}, pages = {105122}, pmid = {40403387}, issn = {2059-7029}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Albumins/administration &amp; dosage ; *Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage ; *Carcinoma, Pancreatic Ductal/drug therapy ; *Deoxycytidine/administration &amp; dosage/analogs &amp; derivatives ; Gemcitabine ; *Glycogen Synthase Kinase 3 beta/antagonists &amp; inhibitors ; Neoplasm Metastasis ; *Paclitaxel/administration &amp; dosage ; *Pancreatic Neoplasms/drug therapy/pathology/mortality ; }, abstract = {INTRODUCTION: The purpose of this study was to assess the efficacy and safety of elraglusib (9-ING-41), a GSK-3β inhibitor, in combination with gemcitabine/nab-paclitaxel (GnP) in previously untreated metastatic pancreatic ductal adenocarcinoma (mPDAC).<br><br>MATERIAL AND METHODS: In a nonrandomized, Simon's two-stage, phase II study, patients with mPDAC received elraglusib 15 mg/kg on days 1 and 4 each week and GnP on days 1, 8, and 15 in a 28-day cycle. The primary endpoint was disease control rate (DCR); secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-emergent adverse events (TEAEs).<br><br>RESULTS: A total of 42 patients, who were enrolled and treated, had a median age of 67 years and were 57.1% male. Overall, 38 patients received elraglusib at 15 mg/kg and 4 at 9.3 mg/kg with GnP. DCR was 35.7% [95% confidence interval (CI) 21.6% to 52.0%], and ORR was 26.2%. The median PFS and OS were 5.4 months (95% CI 4.4-9.2 months) and 11.9 months (95% CI 7.8-16.5 months), respectively. Most common TEAEs were visual impairment (83.3%), fatigue (69%), and nausea (66.7%). Grade &#x2265;3 TEAEs occurred in 85.7% of patients and included neutropenia (52.4%), leukopenia (42.9%), and fatigue (21.4%). The dose of elraglusib was reduced to 9.3 mg/kg due to increased exacerbation of GnP-related toxicities and frequent dose interruptions and reductions of elraglusib.<br><br>CONCLUSIONS: Elraglusib/GnP showed preliminary clinical activity. In terms of safety, elraglusib resulted in a modest exacerbation of GnP-related toxicities, leading to a dose reduction of elraglusib to 9.3 mg/kg twice a week. Based on the initial efficacy and safety data, the study was amended to a randomized phase II study that will evaluate the 9.3 mg/kg dose.}, }
@article {pmid40404528, year = {2025}, author = {Lee, W and Chung, JY and Baidoo, KE and Nambiar, D and Basuli, F and Coleman, I and Bakht, M and Li, C and Shin, J and Jeong, SU and Cho, YM and Beltran, H and Nelson, PS and Sowalsky, AG and Choyke, PL and Escorcia, FE}, title = {Glypican-3 as a Radiotheranostic Target for Neuroendocrine Prostate Cancer.}, journal = {European urology}, volume = {88}, number = {3}, pages = {301-303}, pmid = {40404528}, issn = {1873-7560}, support = {R37 CA241486/CA/NCI NIH HHS/United States ; }, }
@article {pmid40404994, year = {2025}, author = {Jones, DC and Elz, AE and Hadadianpour, A and Ryu, H and Glass, DR and Newell, EW}, title = {Cell simulation as cell segmentation.}, journal = {Nature methods}, volume = {22}, number = {6}, pages = {1331-1342}, pmid = {40404994}, issn = {1548-7105}, support = {U19AI128914//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; R01 CA264646/CA/NCI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; Computer Simulation ; CD8-Positive T-Lymphocytes/metabolism ; Carcinoma, Renal Cell/pathology/immunology/genetics ; Lymphocytes, Tumor-Infiltrating ; Kidney Neoplasms/pathology/genetics/immunology ; Algorithms ; Tumor Microenvironment ; Gene Expression Profiling/methods ; Chemokine CXCL13/metabolism ; Computational Biology/methods ; Transcriptome ; Neutrophils ; }, abstract = {Single-cell spatial transcriptomics promises a highly detailed view of a cell's transcriptional state and microenvironment, yet inaccurate cell segmentation can render these data murky by misattributing large numbers of transcripts to nearby cells or conjuring nonexistent cells. We adopt methods from ab initio cell simulation, in a method called Proseg (probabilistic segmentation), to rapidly infer morphologically plausible cell boundaries. Benchmarking applied to datasets generated by three commercial platforms shows superior performance and computational efficiency of Proseg when compared to existing methods. We show that improved accuracy in cell segmentation aids greatly in detection of difficult-to-segment tumor-infiltrating immune cells such as neutrophils and T cells. Last, through improvements in our ability to delineate subsets of tumor-infiltrating T cells, we show that CXCL13-expressing CD8[+] T cells tend to be more closely associated with tumor cells than their CXCL13-negative counterparts in data generated from samples from patients with renal cell carcinoma.}, }
@article {pmid40405591, year = {2025}, author = {Feng, E and Feng, E and Berg, T and Nguyen, IS and Nguyen, LG and Chen, W and Zhang, M and Quigley, D and Sharifi, M and Li, H and Coleman, I and Nelson, PS and Sjöström, M and Zhao, SG}, title = {Identifying prognostic targets in metastatic prostate cancer beyond AR.}, journal = {FEBS open bio}, volume = {15}, number = {11}, pages = {1827-1840}, pmid = {40405591}, issn = {2211-5463}, support = {PC230420//DoD/ ; P50 CA097186/CA/NCI NIH HHS/United States ; R50 CA274336/CA/NCI NIH HHS/United States ; PC200334//DoD/ ; R50CA274336/GF/NIH HHS/United States ; P50CA097186/GF/NIH HHS/United States ; PC210122//DoD/ ; DP2 CA271832/CA/NCI NIH HHS/United States ; //Institute for Prostate Cancer Research/ ; //Prostate Cancer Foundation/ ; //Swedish Cancer Society (Cancerfonden)/ ; 1DP2CA271832-01/GF/NIH HHS/United States ; //Swedish Prostate Cancer Foundation (Prostatacancerf&#xf6;rbundet)/ ; //Hjelms Stiftelse f&#xf6;r Medicinsk Forskning/ ; PC190039//DoD/ ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/pathology/metabolism/diagnosis/drug therapy ; Prognosis ; Cell Line, Tumor ; *Receptors, Androgen/metabolism/genetics ; Gene Expression Regulation, Neoplastic ; Neoplasm Metastasis ; Biomarkers, Tumor/genetics ; }, abstract = {Genome-wide screens using CRISPR/RNAi can identify new therapeutic vulnerabilities in prostate cancer. In this study, we combine DepMap functional screen data with a large gene expression database (N = 1012) and clinical outcomes to identify potentially druggable targets. Eight genes (CYC, CYP51A1, DHFR, EBP, KIF15, PPM1D, SQLE, and UMPS) demonstrated strong dependency in cell lines and were also associated with worse prognosis clinically, representing potential therapeutic targets in metastatic prostate cancer. Four of these (DHFR, EBP, KIF15, and PPM1D) demonstrated higher expression in neuroendocrine prostate cancer. Furthermore, all but one (KIF15) were not significantly decreased from pretreatment to posttreatment, suggesting that they may remain targetable postabiraterone therapy. All eight genes showed evidence of protein expression in prostate cancers or cell lines. These potentially druggable targets associated with prostate cancer cell line dependency and worse clinical outcomes have also demonstrated literature support as potential targets, supporting further research into their potential clinical relevance as therapeutic targets in prostate cancer.}, }
@article {pmid40406922, year = {2025}, author = {,  and Rautalin, I and Volovici, V and Stark, BA and Johnson, CO and Kaprio, J and Korja, M and Krishnamurthi, RV and Nair, BS and Ranta, A and Rinkel, GJE and Vergouwen, MDI and Abate, YH and Abbastabar, H and Abd-Allah, F and Abdelkader, A and Abdi, P and Abdollahi, A and Abdullahi, A and Abiodun, OO and Aboagye, RG and Abouzid, M and Abtahi, D and Abu Rumeileh, S and Abualhasan, A and Abualruz, H and Abukhadijah, HJ and Abu-Zaid, A and Adamu, LH and Addo, IY and Adedoyin, RA and Adegboye, OA and Adra, S and Adzigbli, LA and Agyemang-Duah, W and Ahinkorah, BO and Ahmad, A and Ahmad, D and Ahmadzade, AM and Ahmed, A and Ahmed, H and Ahmed, SA and Aji, B and Akkaif, MA and Al-Ajlouni, Y and Al-Aly, Z and Albashtawy, M and Ali, MU and Alif, SM and Alimohamadi, Y and Aljunid, SM and Alomari, MA and Alrawashdeh, A and Alsabri, MA and Salman, RA and Altaf, A and Al-Tammemi, AB and Alvis-Guzman, N and Alwafi, H and Al-Wardat, M and Al-Worafi, YM and Aly, H and Alyahya, MSI and Alzoubi, KH and Amani, R and Amin, TT and Amindarolzarbi, A and Amusa, GA and Anderlini, D and Angappan, D and Anil, A and Anuoluwa, BS and Anwar, S and Anyasodor, AE and Apostol, GLC and Arabloo, J and Areda, D and Ärnlöv, J and Artamonov, AA and Artanti, KD and Arumugam, A and Aryan, Z and Asghari-Jafarabadi, M and Ashemo, MY and Ashraf, T and Athar, M and Athari, SS and Aujayeb, A and Awotidebe, AW and Azadnajafabad, S and Aziz, S and Azzam, AY and Babu, GR and Bagheri, N and Bahrami Taghanaki, P and Bahramian, S and Bai, R and Baig, AA and Bako, AT and Baltatu, OC and Bam, K and Banach, M and Bandyopadhyay, S and Banik, B and Bardhan, M and Barker-Collo, SL and Bärnighausen, TW and Barqawi, HJ and Barua, L and Bastan, MM and Basu, S and Bell, SL and Bensenor, IM and Berhie, AY and Beyene, KA and Bhagavathula, AS and Bhaskar, S and Bhat, AN and Bhat, V and Bhatti, GK and Bhatti, JS and Bijani, A and Bikbov, B and Birhan, MM and Birhanu, MM and Bitra, VR and Boloor, A and Borhany, H and Breitner, S and Brenner, H and Bugiardini, R and Bulamu, NB and Butt, ZA and Cabral, LS and Caetano Dos Santos, FL and Calina, D and Cámera, LA and Campos, LA and Campos-Nonato, I and Capodici, A and Carvalho, F and Castañeda-Orjuela, CA and Catapano, AL and Cegolon, L and Chadwick, J and Chakraborty, C and Chakraborty, PA and Chakraborty, S and Chandika, RM and Chanie, GS and Chattu, VK and Chaudhary, AA and Chi, G and Chichagi, F and Ching, PR and Chopra, H and Choudhari, SG and Chowdhury, EK and Chu, DT and Chung, SC and Columbus, A and Criqui, MH and da Silva, AG and Dabbagh Ohadi, MA and Dadras, O and Dai, X and Dalal, K and Dalli, LL and D'Amico, E and Dashti, M and Davletov, K and De la Cruz-Góngora, V and Debopadhaya, S and Delgado-Enciso, I and Derviševic, E and Devanbu, VGC and Dewan, SMR and Dhane, AS and Dibas, M and Do, TC and Do, THP and Dohare, S and Doheim, MF and Dokova, KG and Dongarwar, D and D'Oria, M and Doshi, OP and Doshi, RP and Dowou, RK and Dsouza, HL and Dutta, S and Dziedzic, AM and E'mar, AR and Edvardsson, D and Efendi, D and Efendi, F and El Nahas, N and Elgendy, IY and Elhadi, M and Eltaha, C and Eltahir, ME and Emeto, TI and Fabin, N and Fagbamigbe, AF and Fahim, A and Fakhradiyev, IR and Fares, J and Faris, PS and Fauk, NK and Fazylov, T and Fekadu, G and Ferreira, N and Fetensa, G and Fischer, F and Foschi, M and Fridayani, NKY and Gaipov, A and Gajjar, AA and Gandhi, AP and Ganesan, B and Garg, RK and Gebregergis, MW and Gebrehiwot, M and Gebremeskel, TG and Getie, M and Ghadimi, DJ and Ghadirian, F and Ghahramani, S and Ghasemzadeh, A and Ghazy, RM and Gholamalizadeh, M and Ghozy, S and Gil, AU and Gilani, JA and Gnedovskaya, EV and Goleij, P and Goulart, AC and Goulart, BNG and Guan, SY and Gupta, S and Habibzadeh, F and Hadei, M and Hadi, NR and Hamidi, S and Hanifi, N and Hankey, GJ and Harlianto, NI and Haro, JM and Hasan, F and Hasani, H and Hasnain, MS and Hassan Zadeh Tabatabaei, MS and Haubold, J and Havmoeller, RJ and Hay, SI and Hbid, Y and Heidari, G and Heidari, M and Hemmati, M and Hiraike, Y and Hoan, NQ and Holla, R and Hosseinzadeh, M and Hostiuc, S and Huang, J and Huynh, HH and Hwang, BF and Ibitoye, SE and Ikeda, N and Ikiroma, A and Ilaghi, M and Ilesanmi, OS and Ilic, IM and Ilic, MD and Islam, MR and Ismail, NE and Iso, H and Isola, G and Iwagami, M and Jacob, L and Jafarzadeh, A and Jain, A and Jairoun, AA and Jakovljevic, M and Jatau, AI and Jawaid, T and Jayapal, SK and Jonas, JB and Joseph, N and Jürisson, M and Kadashetti, V and Kalani, R and Kamal, VK and Kamireddy, A and Kanchan, T and Kandel, H and Karami, J and Karaye, IM and Karimi, Y and Karimi Behnagh, A and Kashoo, FZ and Kayode, GA and Kazemi, F and Kesse-Guyot, E and Khader, YS and Khaing, IK and Khan, F and Khan, MJ and Khatatbeh, H and Khatatbeh, MM and Khayat Kashani, HR and Kheirallah, KA and Khidri, FF and Khormali, M and Khosla, AA and Kim, K and Kim, YJ and Kisa, A and Kisa, S and Kivimäki, M and Kolahi, AA and Kompani, F and Korzh, O and Kostev, K and Kothari, N and Krishan, K and Krishna, V and Krishnamoorthy, V and Kuddus, M and Kulimbet, M and Kunutsor, SK and Kurniasari, MD and Kusuma, D and Kytö, V and La Vecchia, C and Lahariya, C and Lai, DTC and Lai, H and Laksono, T and Lallukka, T and Latief, K and Latifinaibin, K and Le, NHH and Le, TTT and Lee, M and Lee, SW and Lee, WC and Lee, YH and Lenzi, J and Leonardi, M and Li, MC and Li, X and Lim, SS and Lin, J and Liu, X and Lohner, V and Lorenzovici, L and Lotufo, PA and Lucchetti, G and Lusk, JB and Lutzky Saute, R and M Amin, HI and Malhotra, AK and Malhotra, K and Malik, AA and Malta, DC and Mansournia, MA and Mantovani, LG and Manu, E and Marateb, HR and Marino, M and Maroufi, SF and Martinez-Piedra, R and Martini, S and Martorell, M and Marzo, RR and Mathangasinghe, Y and Mathews, E and Maugeri, A and McPhail, SM and Mehmood, A and Mehndiratta, MM and Mehrabani-Zeinabad, K and Menezes, RG and Meo, SA and Meretoja, A and Mestrovic, T and Mettananda, CDK and Miazgowski, T and Micheletti Gomide Nogueira de Sá, AC and Minervini, G and Minh, LHN and Mirica, A and Mirrakhimov, EM and Mirza-Aghazadeh-Attari, M and Mishra, AK and Mithra, P and Mohamed, AZ and Mohamed, AI and Mohammad, AM and Mohammadi, S and Mohammadian-Hafshejani, A and Mohammed, S and Mokdad, AH and Molinaro, S and Momani, S and Moni, MA and Moodi Ghalibaf, A and Moradi, M and Moradi, Y and Moraga, P and Morawska, L and Msherghi, A and Munjal, K and Murray, CJL and Nagarajan, AJ and Naik, GR and Najdaghi, S and Nakhostin Ansari, N and Nargus, S and Davani, DN and Natto, ZS and Nauman, J and Nayak, VC and Nazri-Panjaki, A and Negoi, RI and Nematollahi, S and Newton, CRJ and Nguyen, DH and Nguyen, HTH and Nguyen, HQ and Nguyen, PT and Nguyen, VT and Niazi, RK and Nigatu, YT and Nikoobar, A and Nogueira de Sá, AT and Nomura, S and Noubiap, JJ and Nugen, F and Nzoputam, CI and Oancea, B and Oduro, MS and Ojo-Akosile, TR and Okati-Aliabad, H and Okeke, SR and Okekunle, AP and Olagunju, AT and Olaiya, MT and Oliveira, AB and Oliveira, GMM and Olorukooba, AA and Olufadewa, II and Ornello, R and Ortiz-Prado, E and Osuagwu, UL and Ouyahia, A and Owolabi, MO and Ozair, A and P A, MP and Padron-Monedero, A and Padubidri, JR and Panagiotakos, D and Panos, GD and Panos, LD and Pantazopoulos, I and Parikh, RR and Park, S and Patel, J and Patel, UK and Patoulias, D and Pedersini, P and Peprah, EK and Pereira, G and Perianayagam, A and Perico, N and Perna, S and Petermann-Rocha, FE and Philip, AK and Piradov, MA and Plotnikov, E and Polibin, RV and Postma, MJ and Pradhan, J and Prasad, M and Puvvula, J and Qasim, NH and Qian, G and Raggi, A and Rahim, F and Rahimi-Movaghar, V and Rahman, M and Rahman, MA and Rahmani, AM and Rahmanian, M and Rajaa, S and Rajabpour Sanati, A and Rajpoot, PL and Rajput, P and Ramadan, MM and Ramasamy, SK and Ramazanu, S and Rane, A and Rashedi, S and Rashidi, MM and Rathish, D and Rawaf, S and Razo, C and Reddy, MMRK and Redwan, E and Remuzzi, G and Rezaei, N and Rezaei, N and Rezaeian, M and Rocha, HAL and Rodriguez, JAB and Roever, L and Romoli, M and Romozzi, M and Ross, AG and Rout, HS and Roy, N and Roy, P and Saad, AMA and Saadatian, Z and Sabour, S and Sacco, S and Saddik, BA and Sadeghi, E and Saeed, U and Saheb Sharif-Askari, F and Sahebkar, A and Sahoo, PM and Sajib, MRUZ and Salaroli, LB and Saleh, MA and Samodra, YL and Samuel, VP and Samy, AM and Santric-Milicevic, MM and Saravanan, A and Sarkar, T and Sarode, GS and Sarode, SC and Sartorius, B and Satpathy, M and Schlaich, MP and Schneider, IJC and Schuermans, A and Selvaraj, S and Senthilkumaran, S and Sepanlou, SG and Sethi, Y and Seylani, A and Shaaban, AN and Shafie, M and Shahwan, MJ and Shaikh, MA and Shaikh, SZ and Shamim, MA and Shamsi, A and Shamsutdinova, A and Shanawaz, M and Shannawaz, M and Sharifan, A and Sharifi Rad, J and Sharma, V and Shashamo, BB and Shetty, M and Shetty, PK and Shigematsu, M and Shittu, A and Shiue, I and Shlobin, NA and Shorofi, SA and Siddig, EE and Singh, B and Singh, P and Singh, P and Singh, S and Sobia, F and Solanki, R and Solanki, S and Soraneh, S and Spartalis, M and Srinivasamurthy, SK and Stanaway, JD and Stanikzai, MH and Starodubova, AV and Sun, J and Sun, Z and Swain, CK and Szarpak, L and Tabaee Damavandi, P and Tabatabaei, SM and Tabatabaeizadeh, SA and Tabche, C and Taiba, J and Talaat, IM and Tamuzi, JL and Tan, KK and Temsah, MH and Teramoto, M and Thakur, R and Thankappan, KR and Thayakaran, R and Thirunavukkarasu, S and Ticoalu, JHV and Tiwari, K and Tonelli, M and Topor-Madry, R and Tovani-Palone, MR and Tran, AT and Tran, JT and Tran, TH and Tran Minh Duc, N and Truelsen, TC and Truyen, TTTT and Tsai, DH and Ullah, A and Unim, B and Unnikrishnan, B and Unsworth, CA and Usman, JS and Vahdati, S and Vaithinathan, AG and Valizadeh, R and Van den Eynde, J and Varghese, J and Vasankari, TJ and Venketasubramanian, N and Vervoort, D and Villafañe, JH and Vinayak, M and Vladimirov, SK and Wafa, HA and Waheed, Y and Wahood, W and Walde, MT and Wang, Y and Wickramasinghe, ND and Willeit, P and Wolde, AA and Wolfe, CDA and Wubie, YM and Xiao, H and Xu, S and Xu, X and Yamagishi, K and Yano, Y and Yarahmadi, A and Yaribeygi, H and Yaya, S and Ye, P and Yon, DK and Yonemoto, N and Yu, C and Zanghì, A and Zare, I and Zastrozhin, M and Zhang, C and Zhang, Y and Zhang, ZJ and Zhang, Z and Zhao, H and Zhou, SC and Zhumagaliuly, A and Zia, H and Zielinska, M and Zyoud, SH and Roth, GA and Feigin, VL}, title = {Global, Regional, and National Burden of Nontraumatic Subarachnoid Hemorrhage: The Global Burden of Disease Study 2021.}, journal = {JAMA neurology}, volume = {82}, number = {8}, pages = {765-787}, pmid = {40406922}, issn = {2168-6157}, support = {001/WHO_/World Health Organization/International ; }, abstract = {IMPORTANCE: Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure.<br><br>OBJECTIVE: To estimate the worldwide burden of SAH.<br><br>Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021.<br><br>EXPOSURES: SAH and 14 modifiable risk factors.<br><br>MAIN OUTCOMES AND MEASURES: Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor-specific population attributable fractions (PAFs).<br><br>RESULTS: In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100&#x202f;000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF]&#x2009;=&#x2009;51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF&#x2009;=&#x2009;14.4%; 95% UI, 12.4%-16.5%) had the highest attribution.<br><br>CONCLUSIONS AND RELEVANCE: Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.}, }
@article {pmid40407323, year = {2025}, author = {Landazuri Vinueza, J and Salisbury, NJH and Dye, KN and Roman, A and Galloway, DA}, title = {Delta-catenin is required for cell proliferation in virus-positive Merkel cell carcinoma cell lines but not in human fibroblasts.}, journal = {mBio}, volume = {16}, number = {6}, pages = {e0083225}, pmid = {40407323}, issn = {2150-7511}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA209979/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; T32 AI083203/NH/NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/virology/genetics/pathology ; *Fibroblasts/virology/metabolism ; *Merkel cell polyomavirus/physiology/genetics ; *Cell Proliferation ; Cell Line, Tumor ; *Catenins/metabolism/genetics ; *Skin Neoplasms/virology ; Tumor Virus Infections/virology ; Virus Replication ; }, abstract = {Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer often driven by the integration of Merkel cell polyomavirus (MCPyV) into the host genome and the persistent expression of its viral oncoproteins, small tumor (ST) antigen, and truncated large tumor (t-LT) antigen. While human fibroblasts support MCPyV replication, the cell of origin for MCC remains unknown. We hypothesized that MCPyV initially replicates in fibroblasts but, in rare cases, infects Merkel cell progenitors, contributing to MCC development. Using TurboID mass spectrometry, we identified δ-catenin as a novel ST interactor in fibroblasts. However, while ST binds δ-catenin in fibroblasts, this interaction is absent in virus-positive (VP)-MCC cell lines. Despite this, δ-catenin is essential for VP-MCC, but not for fibroblast cell proliferation. We found that fibroblasts predominantly express δ-catenin isoform 1, whereas VP-MCC cells mainly express isoform 3. Overexpression of isoform 1 in VP-MCC failed to restore ST binding. δ-Catenin promotes VP-MCC proliferation by regulating cell cycle gene expression through its interaction with Kaiso, a transcriptional repressor. Additionally, we found that lysine-specific histone demethylase 1 (LSD1, also known as KDM1A) regulates δ-catenin isoform 3 expression by modulating ESRP1, a δ-catenin splicing factor. Our findings reveal novel host factors involved in MCPyV infection and MCC tumorigenesis, suggesting that the host cell supporting viral replication and the MCC cell of origin may be distinct cell types.IMPORTANCEMerkel cell polyomavirus (MCPyV), the only known human oncogenic polyomavirus, is the primary cause of Merkel cell carcinoma (MCC), a rare and aggressive type of skin cancer. MCC is driven by two viral proteins: small T (ST) and large T (LT). While the virus can replicate in skin fibroblasts, it is still unknown which type of skin cell becomes cancerous. We found that ST binds to a host protein, δ-catenin in fibroblasts, potentially playing a role in the virus lifecycle, but this interaction is missing in the cancer cells. Our study provides evidence that the cells in which the virus replicates and causes cancer are different.}, }
@article {pmid40408282, year = {2025}, author = {Marsh, TL and Johnston, JM and Homan, C and Townshend-Bulson, LJ and Kim, NJ and VoPham, T and Li, X and He, Q and McMahon, BJ and Ioannou, GN and Feng, Z}, title = {HCC surveillance in hepatitis C: A longitudinal algorithm improves alpha-fetoprotein screening.}, journal = {Hepatology communications}, volume = {9}, number = {6}, pages = {}, pmid = {40408282}, issn = {2471-254X}, support = {P20 CA252732/CA/NCI NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; R01 CA223498/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *alpha-Fetoproteins/analysis/metabolism ; *Carcinoma, Hepatocellular/diagnosis/blood/virology ; *Algorithms ; *Liver Neoplasms/diagnosis/blood/virology ; Male ; Female ; Middle Aged ; *Hepatitis C/complications ; Bayes Theorem ; Sensitivity and Specificity ; Aged ; *Early Detection of Cancer/methods ; Alaska/epidemiology ; Liver Cirrhosis/blood ; Longitudinal Studies ; Adult ; *Hepatitis C, Chronic/complications/blood ; }, abstract = {BACKGROUND: Surveillance for HCC remains important after hepatitis C cure. Improved sensitivity of screening with alpha-fetoprotein (AFP) by using a parametric empirical Bayes (PEB) algorithm, which incorporates an individual patient's longitudinal AFP measurements, was previously demonstrated in a retrospective analysis of clinical trial data prior to widespread hepatitis C cure.<br><br>METHODS: We analyzed de-identified data extracted from the medical records of participants in the Alaska Hepatitis C Study, which aims to enroll all Alaska Native persons living in Alaska with a history of hepatitis C.&#xfeff;We compared the performance characteristics of AFP as a screening test using the PEB method versus a fixed cutoff (FC) method in an observational setting, separately for HCC surveillance in active and cured hepatitis C.<br><br>RESULTS: The PEB and FC methods were applied to AFP levels from participants with F3/F4 fibrosis who had active hepatitis C (173 no HCC, 14 HCC) or after they achieved hepatitis C cure (162 no HCC, 12 HCC). Compared to a fixed 20&#xa0;ng/mL cutoff, demonstrating 91.2% specificity in active hepatitis C, PEB increased sensitivity from 64.3% to 71.4%. After cure, a fixed 7.2&#xa0;ng/mL cutoff demonstrated 91.2% specificity, and PEB increased sensitivity from 58.3% to 91.7%.<br><br>CONCLUSIONS: The PEB algorithm can increase sensitivity and lead to earlier detection of HCC among patients with F3/F4 fibrosis, both in active and even more so in cured hepatitis C. Lower AFP levels after cure indicate that for either PEB or FC methods, screening parameters, such as cutoffs for a target specificity, should be specified separately by hepatitis C treatment status for HCC surveillance.}, }
@article {pmid40409326, year = {2025}, author = {Wu, RL and Houser, KV and Gaudinski, MR and Widge, AT and Awan, SF and Carter, CA and Holman, LA and Saunders, J and Hendel, CS and Eshun, A and Whalen, WR and Wang, X and Arthur, A and Cunningham, JE and Beck, A and Casazza, JP and Yamshchikov, GV and Rothwell, RS and Strom, L and Dittakavi, T and Happe, M and Hickman, SP and Conan-Cibotti, M and Carlton, K and Zhang, L and Huang, Y and Capparelli, EV and Castro, M and Lin, BC and O'Connell, S and Flach, BS and Bailer, RT and Narpala, SR and Serebryannyy, L and McDermott, AB and Arnold, FJ and Gall, JG and Vazquez, S and Berkowitz, NM and Gordon, IJ and Chen, GL and Kwong, PD and Huang, J and Pierson, TC and Connors, M and Mascola, JR and Zhou, T and Doria-Rose, NA and Koup, RA and Dropulic, LK and , }, title = {Safety and pharmacokinetics of N6LS, a broadly neutralising monoclonal antibody for HIV: a phase 1, open-label, dose-escalation study in healthy adults.}, journal = {The lancet. HIV}, volume = {12}, number = {7}, pages = {e485-e495}, pmid = {40409326}, issn = {2352-3018}, support = {Z99 AI999999/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; Adult ; Male ; Female ; Young Adult ; *HIV Infections/drug therapy/immunology/prevention &amp; control ; Healthy Volunteers ; *HIV Antibodies/administration &amp; dosage/adverse effects/immunology ; *HIV-1/immunology ; Middle Aged ; Adolescent ; *Broadly Neutralizing Antibodies/administration &amp; dosage/adverse effects ; *Antibodies, Neutralizing/administration &amp; dosage/adverse effects/immunology ; *Antibodies, Monoclonal/administration &amp; dosage/pharmacokinetics/adverse effects ; Injections, Subcutaneous ; }, abstract = {BACKGROUND: Broadly neutralising antibodies (bNAbs) have shown promise as both prevention and treatment strategies against HIV-1. The clinical effectiveness of bNAbs depends on enhancing their neutralisation breadth and extending their serum half-lives. In this study, we aimed to assess the safety, tolerability, pharmacokinetic profile, and neutralisation activity in serum of N6LS, a HIV-1 bNAb.<br><br>METHODS: In this first-in-human, dose-escalation, open-label, phase 1 trial, healthy adult participants (aged 18-50 years) who were HIV-1 negative were recruited to the National Institutes of Health Clinical Center (Bethesda, MD, USA). Three groups received one intravenous administration of N6LS at 5 mg/kg (n=3), 20 mg/kg (n=3), or 40 mg/kg (n=3); one group received one subcutaneous administration of 5 mg/kg N6LS (n=3); two groups received three administrations of either 5 mg/kg subcutaneous (n=5) or 20 mg/kg intravenous (n=5) N6LS every 12 weeks; and two groups received one subcutaneous administration of either 5 mg/kg (n=5) or 20 mg/kg (n=5) N6LS with ENHANZE drug product (EDP), recombinant human hyaluronidase PH20. The primary objectives were the safety and tolerability of N6LS with and without EDP. All participants who received N6LS were included in the primary safety analyses. This trial is registered at ClinicalTrials.gov, NCT03538626, and is complete.<br><br>FINDINGS: Between June 18, 2018, and April 11, 2022, we enrolled 33 healthy adults (19 female individuals and 14 male individuals). One participant did not receive N6LS and one participant was lost to follow-up after 8 weeks. N6LS had an encouraging safety profile similar to other HIV-1 bNAbs, with no serious adverse events. Local reactogenicity was observed after administration of N6LS, with the most common symptom being mild to moderate injection site pain or tenderness in subcutaneous groups, reported in six of eight participants. All ten participants who received N6LS with EDP had mild to severe injection site erythema, which, despite being graded as severe in size, was generally not noticed by participants or deemed bothersome, and resolved without intervention. Systemic reactogenicity was mild in all groups. N6LS had an overall mean serum half-life of 48&#xb7;6 days and retained its broad and potent neutralisation characteristics in serum. EDP administration increased N6LS bioavailability. No functional anti-drug antibodies to N6LS were detected following administration.<br><br>INTERPRETATION: N6LS showed a promising safety and pharmacokinetics profile while retaining its potent neutralisation characteristics in serum, making it a promising candidate for inclusion in HIV-1 prevention and therapeutic combination strategies. The addition of EDP can enable safe subcutaneous administration of higher doses and larger volumes of N6LS, supporting additional methods for prophylactic and therapeutic bNAb administration.<br><br>FUNDING: US National Institute of Allergy and Infectious Diseases Intramural Research Program, National Institutes of Health.}, }
@article {pmid40409689, year = {2025}, author = {Kampouri, E and Handley, G and Phan, TL and Lee, YJ and Shaw, R and Carpenter, PA and Dadwal, SS and Chemaly, RF and Papanicolaou, GA and Ogata, M and Boeckh, M and Zerr, DM and Hill, JA}, title = {American Society for Transplantation and Cellular Therapy Series #9: Management of Human Herpesvirus 6B After Hematopoietic Cell Transplantation and Chimeric Antigen Receptor-T-Cell Therapy.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {8}, pages = {480-493}, pmid = {40409689}, issn = {2666-6367}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Herpesvirus 6, Human ; *Roseolovirus Infections/therapy/diagnosis/etiology/prevention &amp; control ; *Receptors, Chimeric Antigen/immunology ; *Cell- and Tissue-Based Therapy ; *Immunotherapy, Adoptive/adverse effects ; Risk Factors ; }, abstract = {The Practice Guidelines Committee and the Transplant Infectious Disease Special Interest Group of the American Society for Transplantation and Cellular Therapy developed guidelines focusing on human herpesvirus 6B (HHV-6B). A compendium-style approach was used to address a series of standalone frequently asked questions (FAQs), supported by tables and figures to spotlight key concepts. Adult and pediatric infectious disease and hematopoietic cell transplantation (HCT) content experts developed these FAQs and finalized recommendations after consensus was reached. This ninth topic in the series focuses on the relevant risk factors, diagnostic considerations, prophylaxis, and treatment approaches relevant to HHV-6B infections after HCT and chimeric antigen receptor-T-cell therapy.}, }
@article {pmid40409691, year = {2025}, author = {Lee, SJ and Williams, KM and Sarantopoulos, S and Kitko, CL and Cutler, C and Pidala, J and Hill, GR and DeFilipp, Z and Greinix, HT and Wolff, D and Paczesny, S and Cuvelier, GDE and Schultz, KR and Pavletic, SZ}, title = {NIH Chronic Graft-Versus-Host Disease Consensus Conference 2025 Update.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {678.e1-678.e16}, pmid = {40409691}, issn = {2666-6367}, support = {R01 CA118953/CA/NCI NIH HHS/United States ; U01 CA236229/CA/NCI NIH HHS/United States ; }, mesh = {*Graft vs Host Disease/therapy/prevention &amp; control ; Humans ; Chronic Disease ; United States ; National Institutes of Health (U.S.) ; *Hematopoietic Stem Cell Transplantation/adverse effects ; }, abstract = {In 2020, the third NIH Consensus Development Project on Criteria for Chronic Graft-versus-Host Disease (GVHD) Clinical Trials was held with the goals of identifying gaps in understanding, prevention and treatment of chronic graft-versus-host disease (GVHD) and making actionable recommendations that would advance the field. An interim meeting was held in October 2024 to review progress on the 2020 recommendations. Each group was charged with reviewing their previous recommendations, assessing whether the field is on track to eventually achieve the goals, and considering whether recommendations should be modified in light of new data or insufficient progress. This manuscript summarizes the Working Groups' reports and helps define the research agenda for future studies in chronic GVHD. Overall, modest progress has been made on most initiatives. Some studies in progress will address key recommendations and results are eagerly anticipated.}, }
@article {pmid40409951, year = {2025}, author = {Thomas, AB and Van Son, CR and Nelson, LA and Fergadiotis, G and Barbosa-Leiker, C}, title = {A Principle-Based Concept Analysis of Supported Conversation for Adults With Aphasia.}, journal = {Research and theory for nursing practice}, volume = {}, number = {}, pages = {}, doi = {10.1891/RTNP-2024-0094}, pmid = {40409951}, issn = {1541-6577}, abstract = {Background and Purpose: Supported Conversation for Adults with Aphasia (SCA[™]), an evidence-based framework to improve communicative access, is a unique concept to nursing with theoretical and technical components. Effective communication is essential in all patient interactions, and SCA™ could aid health care professionals in meeting the needs of people with aphasia. Methods: A principle-based concept analysis was conducted using a systematic and conceptually driven literature search. A review of literature from 1998 to 2024 contained in CINAHL, PubMed, and PsycINFO databases was performed on the concept of SCA[™] The concept was explored for (a) definitional clarity (epistemological principle), (b) relevance to nursing (pragmatic principle), (c) consistency in meaning (linguistic principle), and (d) differentiation from related concepts (logical principle). Results: The final dataset consisted of 49 articles. Findings revealed that (a) SCA[™] is composed of theoretical and technical components used to acknowledge and reveal the competence of a person with aphasia, but there is a vague use and a lack of definitional clarity; (b) the philosophical framework and techniques outlined by the concept are relevant and useful for nursing; (c) there is variability in the use, nomenclature, and conceptualization of SCA[™]; and (d) the concept is poorly differentiated from other similar concepts. Implications for Practice: Nurses working with people diagnosed with aphasia and other communication disorders should consider SCA[™] and its application in nursing practice. Findings from this concept analysis stress the importance of an interdisciplinary approach to future SCA[™] studies, as nursing can lend its distinct viewpoint to integrate SCA[™] techniques into practice.}, }
@article {pmid40410231, year = {2025}, author = {Dhodapkar, KM and Castellino, S and Kapadia, S and Azeem, MI and Horvat, A and Lawrence, T and DeRyckere, D and Dhodapkar, MV}, title = {Immune-aging at diagnosis determines T-cell recovery in childhood leukemia survivors.}, journal = {npj aging}, volume = {11}, number = {1}, pages = {39}, pmid = {40410231}, issn = {2731-6068}, support = {R01 AR077926/AR/NIAMS NIH HHS/United States ; NIH CA238471/GF/NIH HHS/United States ; P30 CA138292/CA/NCI NIH HHS/United States ; R35CA197603/GF/NIH HHS/United States ; SCOR//Leukemia and Lymphoma Society/ ; R35 CA197603/CA/NCI NIH HHS/United States ; R01 CA238471/CA/NCI NIH HHS/United States ; }, abstract = {We show that T cells in survivors of childhood leukemia exhibit distinct profiles dominated by aging-associated changes and consistent with premature immune aging. Immune profiles during survivorship in biospecimens (n = 251) from uniformly-treated children with B-acute lymphoblastic leukemia recapitulate heterogeneity at diagnosis in individual patients and correlate with genetic-risk subtypes. These data suggest that pre-therapy immune aging may determine variance in immune status during survivorship.}, }
@article {pmid40411791, year = {2025}, author = {Heffner, JL and Baker, K and Georgiou, K and Graham, AL and Kelly, MM and Konstantinou, P and Lamprou, E and Lele, C and Lok, KZ and Orzechowski, M and Ruiz, RA and Serfozo, E and Karekla, M}, title = {ACT on Vaping: Pilot Randomized Controlled Trial of a Novel Digital Health App with Text Messaging for Young Adult Vaping Cessation.}, journal = {Nicotine &amp; tobacco research : official journal of the Society for Research on Nicotine and Tobacco}, volume = {}, number = {}, pages = {}, doi = {10.1093/ntr/ntaf112}, pmid = {40411791}, issn = {1469-994X}, support = {UG3 DA057032/DA/NIDA NIH HHS/United States ; }, abstract = {BACKGROUND: There is no published evidence to support the efficacy of any digital vaping cessation program for young adults (YAs) at differing levels of readiness to quit. In this pilot randomized controlled trial, we evaluated the preliminary acceptability and efficacy of a program for vaping cessation based on acceptance and commitment therapy (ACT on Vaping), delivered via a smartphone app and text messaging.<br><br>METHODS: YAs age 18-30 (n=61) were randomized 1:1 to ACT on Vaping (n=31) or incentivized text message control (n=30). Outcome data were collected at 3 months post-randomization. Results were compared against a priori benchmarks for acceptability (satisfaction of &#x2265; 3.5 on 5-point scale) and efficacy relative to control (meeting at least one of three): &#x2265; 1-point difference in Contemplation Ladder change scores; &#x2265; 5 percentage difference in 24-hour quit attempts, &#x2265; 5 percentage difference in cotinine-confirmed 30-day point prevalence abstinence (PPA) from all non-therapeutic nicotine/tobacco.<br><br>RESULTS: Satisfaction with ACT on Vaping averaged 3.8, exceeding the acceptability benchmark. A higher proportion of participants in the ACT on Vaping arm reported a 24-hour quit attempt (87.5% vs. 75.9%), exceeding the efficacy benchmark. Both change in quit readiness (+0.96 in ACT on Vaping vs. +0.72 in control) and cotinine-confirmed 30-day PPA (4.2% in ACT on Vaping vs. 0% in control) were descriptively higher for ACT on Vaping but did not reach the benchmark level for efficacy.<br><br>CONCLUSIONS: ACT on Vaping had promising acceptability and preliminary efficacy. A fully-powered trial of ACT on Vaping is warranted to evaluate its efficacy.<br><br>IMPLICATIONS: Digital interventions are a promising yet under-researched approach for reaching and supporting young adults to quit vaping. This proof-of-concept pilot randomized controlled trial evaluated a novel mobile health application and associated text messaging program (ACT on Vaping) for young adult vaping cessation and found preliminary evidence for acceptability and efficacy relative to an incentivized text message control arm, warranting evaluation in a fully-powered trial as a next step.}, }
@article {pmid40412394, year = {2025}, author = {Bansi-Matharu, L and Moolla, H and Citron, DT and Stover, J and Pickles, M and Martin-Hughes, R and Boily, MC and Nyirenda, R and Mudimu, E and Ten Brink, D and Johnson, LF and Mugurungi, O and Cambiano, V and Dimitrov, D and Smith, J and Glaubius, R and Taramusi, I and Mpofu, A and Phillips, A and Bershteyn, A}, title = {Identifying gaps in the HIV treatment cascade in Africa: a model comparison study.}, journal = {The Lancet. Global health}, volume = {13}, number = {6}, pages = {e1006-e1019}, pmid = {40412394}, issn = {2214-109X}, support = {/WT_/Wellcome Trust/United Kingdom ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/epidemiology/drug therapy/transmission ; Female ; Male ; Adult ; Adolescent ; Young Adult ; Middle Aged ; Malawi/epidemiology ; Zimbabwe/epidemiology ; South Africa/epidemiology ; *Anti-HIV Agents/therapeutic use ; Africa/epidemiology ; Incidence ; Prevalence ; }, abstract = {BACKGROUND: Although HIV incidence has considerably decreased in eastern, central, and southern Africa, new HIV infections continue to be a major public health challenge in the region. We aimed to investigate where in the HIV treatment cascade new transmissions are occurring in Malawi, Zimbabwe, and South Africa (the three countries involved in the Modelling to Inform HIV Programmes in Sub-Saharan Africa project).<br><br>METHODS: In this model comparison study, we used six well described and independently calibrated HIV transmission dynamics models that have been used to inform HIV policy in Africa (Optima HIV, EMOD, Goals, Thembisa, PopART-IBM, and HIV Synthesis) to estimate and predict the proportion of annual new HIV transmissions attributable to people living with HIV who are undiagnosed, have been diagnosed but have not yet started antiretroviral therapy (ART), are receiving ART, and have interrupted ART in Malawi, Zimbabwe, and South Africa from 2010 to 2040 stratified by the age and sex of the individual acquiring HIV.<br><br>FINDINGS: Despite the different model structures and underlying assumptions, the six models were well aligned in relation to key HIV epidemic characteristics (including population estimates and HIV prevalence) in each of the three settings. There was, however, considerable variation in the predicted number of new infections, particularly in Malawi and Zimbabwe where this number ranged from fewer than 10&#x2008;000 new infections to over 30&#x2008;000 new infections in 2024. Most model results suggested that the mean age of HIV acquisition has been increasing since 2000, with men acquiring HIV at an older age than women in all three settings. All models attributed fewer than 5% of transmissions to individuals who had been diagnosed but had not yet started ART. In Malawi, the proportion of transmissions attributable to undiagnosed people with HIV in 2024 ranged from 33&#xb7;3% to 75&#xb7;3% across the models, and transmissions attributable to individuals who had experienced interrupted treatment ranged from 8&#xb7;4% to 20&#xb7;1%. In Zimbabwe, the proportion of transmissions attributable to undiagnosed individuals in 2024 ranged from 29&#xb7;8% to 64&#xb7;6% across the models and the proportion of transmissions attributable to individuals who had interrupted treatment ranged from 4&#xb7;7% to 21&#xb7;5%. In South Africa, 21&#xb7;8-46&#xb7;4% of transmissions in 2024 were attributable to undiagnosed individuals and 27&#xb7;6-58&#xb7;9% of transmissions were attributable to individuals who had interrupted treatment.<br><br>INTERPRETATION: Across the three study settings, a substantial proportion of new HIV transmissions were attributable to undiagnosed individuals and people who have received interrupted ART, reinforcing the importance of continuing HIV testing and ART re-engagement and retention interventions.<br><br>FUNDING: The Bill &amp; Melinda Gates Foundation.}, }
@article {pmid40412400, year = {2025}, author = {Leng, T and Kessou, L and Heitner, J and Guédou, FA and Béhanzin, L and Olodo, M and Diabaté, S and Silhol, R and Dimitrov, D and Vickerman, P and Alary, M and Boily, MC and Mitchell, KM}, title = {Potential impact and cost-effectiveness of oral HIV pre-exposure prophylaxis for men who have sex with men in Cotonou, Benin: a mathematical modelling study.}, journal = {The Lancet. Global health}, volume = {13}, number = {6}, pages = {e1111-e1121}, pmid = {40412400}, issn = {2214-109X}, support = {/WT_/Wellcome Trust/United Kingdom ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; *Cost-Benefit Analysis ; *Pre-Exposure Prophylaxis/economics/methods ; *HIV Infections/prevention &amp; control/epidemiology ; Benin/epidemiology ; *Homosexuality, Male/statistics &amp; numerical data ; Adult ; Models, Theoretical ; *Anti-HIV Agents/economics/administration &amp; dosage/therapeutic use ; Administration, Oral ; Young Adult ; Middle Aged ; Adolescent ; }, abstract = {BACKGROUND: Oral HIV pre-exposure prophylaxis (PrEP) can effectively reduce HIV incidence. A 2020-21 demonstration project assessed the feasibility and health outcomes of offering oral PrEP to men who have sex with men (MSM) in Cotonou, Benin. We evaluated the epidemiological impact and cost-effectiveness of this project and the potential scale-up of oral HIV PrEP for MSM in Cotonou.<br><br>METHODS: We calibrated an HIV transmission-dynamic model structured by age and risk within a Bayesian framework to MSM-specific HIV prevalence and treatment data, parameterised with project behavioural and cost (including PrEP drug, implementation, and HIV care costs) data. We estimated the impact and cost-effectiveness of the 2020-21 Cotonou demonstration project (PrEP coverage, 5-10% of all MSM who are not living with HIV in Grand Cotonou; and adherence, 13-21% taking at least four of seven required doses [ie, at least four doses per week for daily users and at least four of seven expected doses given reported sexual activity for on-demand users]) and of its potential scale-up over 5 years (from 2022 to 2027), reaching 30% coverage of MSM in Grand Cotonou and with demonstration project adherence levels. We additionally modelled ideal PrEP adherence (100% taking at least four of seven required doses). We estimated the percentage of cumulative new HIV infections averted among participating MSM over 1 year and among all MSM in Grand Cotonou and their female partners over 20 years, and cost-effectiveness as cost per disability-adjusted life-year (DALY) averted over 20 years. Costs and DALYs were discounted 3% annually.<br><br>FINDINGS: We found that the demonstration project averted an estimated 21&#xb7;5% (95% uncertainty interval 16&#xb7;6 to 26&#xb7;2) of HIV infections among participants over 1 year. With ideal adherence, cases that would be averted increased to 95&#xb7;2% (90&#xb7;8 to 98&#xb7;8). A 5-year PrEP scale-up could avert 3&#xb7;2% (1&#xb7;6 to 4&#xb7;8) of HIV infections among all MSM and female partners over 20 years, at US$388 (36 to 2792) per DALY averted. With ideal adherence, this decreased to -$28 (-126 to 589) per DALY averted.<br><br>INTERPRETATION: Low adherence to PrEP restricted the impact of the demonstration project. At 30% coverage among MSM by 2027, PrEP scale-up would be cost-effective at a $1225 threshold with 86&#xb7;6% probability, and it could be more cost-effective if high adherence could be reached without substantially increasing costs.<br><br>FUNDING: Canadian Institutes of Health Research and US National Institutes of Health.<br><br>TRANSLATION: For the French translation of the abstract see Supplementary Materials section.}, }
@article {pmid40413129, year = {2026}, author = {Raychaudhuri, R and Cheng, HH and Gulati, R and Schweizer, MT and Lin, A and Yezefski, T and Khan, HM and Yu, EY and Hawley, JE and Nelson, PS and Pritchard, CC and Montgomery, B}, title = {Results from a Phase 2 Study of Induction Docetaxel and Carboplatin Followed by Maintenance Rucaparib in the Treatment of Patients with Metastatic Castration-resistant Prostate Cancer with DNA Homologous Recombination Repair Deficiency.}, journal = {European urology oncology}, volume = {9}, number = {1}, pages = {37-44}, pmid = {40413129}, issn = {2588-9311}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/pathology ; *Docetaxel/administration &amp; dosage/therapeutic use ; Aged ; *Carboplatin/administration &amp; dosage/therapeutic use ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Recombinational DNA Repair ; *Indoles/administration &amp; dosage/therapeutic use ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/administration &amp; dosage ; Neoplasm Metastasis ; }, abstract = {BACKGROUND AND OBJECTIVE: Our aim was to determine whether induction chemotherapy followed by PARP inhibitor (PARPi) maintenance improves outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring alterations in homologous recombination repair (HRR) genes in comparison to a historical control cohort treated with PARPi monotherapy.<br><br>METHODS: This single-arm, open-label, investigator-initiated phase 2 trial (NCT02985021) enrolled 18 patients with mCRPC with pathogenic alterations in HRR genes between 2018 and 2021 at a single center. Patients received four cycles of induction chemotherapy with docetaxel (60&#xa0;mg/m[2]) and carboplatin (area under the curve 5) every 21&#xa0;d, followed by maintenance rucaparib (600&#xa0;mg twice daily) until progression or unacceptable toxicity. The primary outcome was radiographic progression-free survival (rPFS). Subsequent to study inception, multiple other studies reported alterations in genes of the BRCA complex (BRCA-C: BRCA1, BRCA2, PALB2) as most predictive of PARPi response; therefore, a post hoc analysis comparing patients with alterations in BRCA-C genes to a historical control cohort was performed.<br><br>KEY FINDINGS AND LIMITATIONS: After median follow-up of 40.3 mo (interquartile range 38.5-not reached [NR]), the median rPFS for all patients was 8.1 mo (95% confidence interval [CI] 6.5-31.2), similar to a historical control cohort treated with PARPi monotherapy. Among the 12 patients with BRCA-C alterations, median rPFS was 17.7 mo (95% CI 7.5-NR; p&#xa0;=&#xa0;0.05). A key limitation is the single-arm design.<br><br>Induction platinum-based chemotherapy followed by maintenance PARPi therapy did not improve outcomes for patients with mCRPC broadly selected for HRR deficiency. However, results were promising in the more stringently selected group with BRCA-C gene alterations. Further studies comparing this approach to PARPi monotherapy are warranted.}, }
@article {pmid40413188, year = {2025}, author = {Zanti, M and O'Mahony, DG and Parsons, MT and Dorling, L and Dennis, J and Boddicker, NJ and Chen, W and Hu, C and Naven, M and Yiangou, K and Ahearn, TU and Ambrosone, CB and Andrulis, IL and Antoniou, AC and Auer, PL and Baynes, C and Bodelon, C and Bogdanova, NV and Bojesen, SE and Bolla, MK and Brantley, KD and Camp, NJ and Campbell, A and Castelao, JE and Cessna, MH and Chang-Claude, J and Chen, F and Chenevix-Trench, G and ,  and Conroy, DM and Czene, K and De Nicolo, A and Domchek, SM and Dörk, T and Dunning, AM and Eliassen, AH and Evans, DG and Fasching, PA and Figueroa, JD and Flyger, H and Gago-Dominguez, M and García-Closas, M and Glendon, G and González-Neira, A and Grassmann, F and Hadjisavvas, A and Haiman, CA and Hamann, U and Hart, SN and Hartman, MBA and Ho, WK and Hodge, JM and Hoppe, R and Howell, SJ and ,  and Jakubowska, A and Khusnutdinova, EK and Ko, YD and Kraft, P and Kristensen, VN and Lacey, JV and Li, J and Lim, GH and Lindström, S and Lophatananon, A and Luccarini, C and Mannermaa, A and Martinez, ME and Mavroudis, D and Milne, RL and Muir, K and Nathanson, KL and Nuñez-Torres, R and Obi, N and Olson, JE and Palmer, JR and Panayiotidis, MI and Patel, AV and Pharoah, PDP and Polley, EC and Rashid, MU and Ruddy, KJ and Saloustros, E and Sawyer, EJ and Schmidt, MK and Southey, MC and Tan, VK and Teo, SH and Teras, LR and Torres, D and Trentham-Dietz, A and Truong, T and Vachon, CM and Wang, Q and Weitzel, JN and Yadav, S and Yao, S and Zirpoli, GR and Cline, MS and Devilee, P and Tavtigian, SV and Goldgar, DE and Couch, FJ and Easton, DF and Spurdle, AB and Michailidou, K}, title = {Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4852}, pmid = {40413188}, issn = {2041-1723}, support = {HHSN261201800009C/CA/NCI NIH HHS/United States ; UM1 CA176726/CA/NCI NIH HHS/United States ; R37 CA070867/CA/NCI NIH HHS/United States ; P30 CA014520/CA/NCI NIH HHS/United States ; HHSN261201800015I/CA/NCI NIH HHS/United States ; HHSN261201000091C/CA/NCI NIH HHS/United States ; HHSN261201800016C/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA064277/CA/NCI NIH HHS/United States ; P50 CA116201/CA/NCI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R35 CA253187/CA/NCI NIH HHS/United States ; HHSN261201800032I/CA/NCI NIH HHS/United States ; R01 CA264971/CA/NCI NIH HHS/United States ; U01 CA199277/CA/NCI NIH HHS/United States ; R01 CA225662/CA/NCI NIH HHS/United States ; R01 CA163353/CA/NCI NIH HHS/United States ; UM1 CA164917/CA/NCI NIH HHS/United States ; HHSN261201800032C/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; NU58DP006344/DP/NCCDPHP CDC HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN261201800011C/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; R01 CA098663/CA/NCI NIH HHS/United States ; U01 CA242954/CA/NCI NIH HHS/United States ; R01 CA148667/CA/NCI NIH HHS/United States ; HHSN261201800021C/CA/NCI NIH HHS/United States ; HHSN261201800016I/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; R01 CA077398/CA/NCI NIH HHS/United States ; P30 CA068485/CA/NCI NIH HHS/United States ; U01 CA164920/CA/NCI NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; HHSN261201800015C/CA/NCI NIH HHS/United States ; HHSN261201800001C/CA/NCI NIH HHS/United States ; HHSN261201800031C/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U24 CA258058/CA/NCI NIH HHS/United States ; R01 CA185623/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; HHSN261201800009I/CA/NCI NIH HHS/United States ; R01 CA100598/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; Case-Control Studies ; *BRCA2 Protein/genetics ; *Breast Neoplasms/genetics ; *BRCA1 Protein/genetics ; Genetic Predisposition to Disease ; Genetic Testing ; Germ-Line Mutation ; Middle Aged ; }, abstract = {Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyze germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 302,116 controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observe 11,207 BRCA1 and BRCA2 variants, with 6909 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control likelihood ratio (ccLR) evidence is highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.3% specificity for BRCA1 and 93.3% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 787 unclassified variants; these include 579 with strong or moderate benign evidence and 10 with strong pathogenic evidence for which ccLR evidence is sufficient to alter clinical classification.}, }
@article {pmid40414351, year = {2025}, author = {Ahmed, SO and El Fakih, R and Kharfan-Dabaja, MA and Syed, F and Mufti, G and Chabannon, C and Rondelli, D and Mohty, M and Al Ahmari, AA and Gauthier, J and Ruella, M and Perales, MA and Hashmi, S and Alfraih, F and Ghorashian, S and Alzahrani, M and Abba, Z and Koh, M and Pasquini, M and Ruggeri, A and Garderet, L and Albabtain, A and Weisdorf, D and Greinix, H and Samarkandi, H and Hamad, N and Atsuta, Y and Hamadani, M and Hari, P and Majhail, NS and Greco, R and Alzahrani, H and Sureda, A and Yakoub-Agha, I and Alahmari, AD and Niederwieser, D and Aljurf, M}, title = {Setting up a Chimeric Antigen Receptor T Cell Therapy Program: A Framework for Delivery from the Worldwide Network for Blood &amp; Marrow Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {8}, pages = {533-543}, doi = {10.1016/j.jtct.2025.05.012}, pmid = {40414351}, issn = {2666-6367}, mesh = {Humans ; *Receptors, Chimeric Antigen/immunology ; *Immunotherapy, Adoptive/methods ; *Bone Marrow Transplantation ; *Hematologic Neoplasms/therapy/immunology ; }, abstract = {Chimeric antigen receptor T cell (CAR-T) therapy is a genetically engineered cellular therapy that is currently integrated into the management of hematologic malignancies. Institutions treating patients with CAR-T therapy need to establish a framework of delivery that covers all the main components of the patient journey including intake of patients into the program from referring centers, patient selection according to established eligibility criteria, apheresis, logistics, bridging therapy, infusion, and postinfusion care. A CAR-T therapy program, with its unique requirements, needs to be delivered by a multidisciplinary team. Prior to the establishment of the program, a well-structured business plan should be developed with a clear financial and/or reimbursement model. Consideration should be given to overall capacity and staffing requirements. Standard operating procedures and guidelines are vital for ensuring that quality standards are clearly defined and adhered to. Institutions should develop a research plan for CAR-T therapy that may incorporate not only industry-sponsored trials, but also in-house manufacturing of investigational CAR-T products. This report presents recommendations from a group of international experts, highlighting the priorities and considerations when developing a new CAR-T program.}, }
@article {pmid40415587, year = {2025}, author = {Yang, Z and Rizopoulos, D and Heijnsdijk, EAM and Newcomb, LF and Erler, NS}, title = {Personalized Biopsy Schedules Using an Interval-Censored Cause-Specific Joint Model.}, journal = {Statistics in medicine}, volume = {44}, number = {10-12}, pages = {e70134}, pmid = {40415587}, issn = {1097-0258}, support = {R21 CA253910/CA/NCI NIH HHS/United States ; U01 CA224255/CA/NCI NIH HHS/United States ; CA253910/NH/NIH HHS/United States ; }, mesh = {Humans ; Biopsy/methods/statistics &amp; numerical data ; *Prostatic Neoplasms/pathology/diagnosis ; Male ; Disease Progression ; *Precision Medicine/methods ; *Models, Statistical ; Computer Simulation ; Likelihood Functions ; Watchful Waiting ; }, abstract = {Active surveillance (AS), where biopsies are conducted to detect cancer progression, has been acknowledged as an efficient way to reduce the overtreatment of prostate cancer. Most AS cohorts use fixed biopsy schedules for all patients. However, the ideal test frequency remains unknown, and the routine use of such invasive tests burdens the patients. An emerging idea is to generate personalized biopsy schedules based on each patient's progression-specific risk. To achieve that, we propose the interval-censored cause-specific joint model (ICJM), which models the impact of longitudinal biomarkers on cancer progression while considering the competing event of early treatment initiation. The underlying likelihood function incorporates the interval-censoring of cancer progression, the competing risk of treatment, and the uncertainty about whether cancer progression occurred since the last biopsy in patients that are right-censored or experience the competing event. The model can produce patient-specific risk profiles up to a horizon time. If the risk exceeds a certain threshold, a biopsy is conducted. The optimal threshold can be chosen by balancing two indicators of the biopsy schedules: The expected number of biopsies and the expected delay in detection of cancer progression. A simulation study showed that our personalized schedules could considerably reduce the number of biopsies per patient by 41%-52% compared to the fixed schedules, though at the cost of a slightly longer detection delay.}, }
@article {pmid40419020, year = {2025}, author = {Mehta, RS and Schmidt, G and Williams, K and Patel, SA and Schetelig, J and Savani, B and Askar, M and Petersdorf, E and Ringden, O and Kanakry, CG and Kanakry, JA and Stefanski, H and Arrieta-Bolaños, E and Betts, B and Benjamin, C and Gadalla, S and Wang, T and Saultz, J and Spellman, S and Jurdi, NE and Bolon, YT and Lee, SJ}, title = {Choosing Between HLA-Mismatched Unrelated and Haploidentical Donors: Donor Age Considerations.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {680-692}, pmid = {40419020}, issn = {2666-6367}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; U01 AI184132/AI/NIAID NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; UL1 TR001453/TR/NCATS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Adult ; Male ; Female ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; *Graft vs Host Disease/prevention &amp; control/etiology ; Middle Aged ; *Unrelated Donors ; Age Factors ; Retrospective Studies ; *Transplantation, Haploidentical/methods ; Young Adult ; Adolescent ; *HLA Antigens/immunology ; Aged ; Cyclophosphamide/therapeutic use ; }, abstract = {Haploidentical donors and HLA-mismatched unrelated donors (MMUDs) are increasingly utilized for hematopoietic cell transplantation (HCT), with post-transplantation cyclophosphamide (PTCy) emerging as an effective graft-versus-host disease (GVHD) prophylaxis strategy. Despite the growing use of these donor types, comparative data to guide donor selection remain limited. Donor age is a known predictor of HCT outcomes, yet its specific impact when choosing between haploidentical and MMUD donors with PTCy-based prophylaxis has not been thoroughly explored. This study aimed to evaluate the influence of donor age on HCT outcomes in patients receiving haploidentical or MMUD HCT with PTCy-based GVHD prophylaxis, hypothesizing that younger donors (<30 years) would be associated with improved outcomes compared to older donors (≥30 years) regardless of donor type. We conducted a retrospective analysis of 7116 patients with hematologic malignancies from the Center for International Blood and Marrow Transplant Research database, transplanted between 2013 and 2021. Donors were categorized into four groups: younger haploidentical (<30 years), older haploidentical (≥30 years), younger MMUD (<30 years), and older MMUD (≥30 years). The primary outcome was GVHD-free relapse-free survival (GRFS), defined as the absence of grade III to IV acute GVHD, chronic GVHD requiring systemic immunosuppressive therapy (IST), relapse, or death. Secondary outcomes included overall survival, treatment-related mortality (TRM), relapse, grade III to IV acute GVHD, overall chronic GVHD, and chronic GVHD requiring IST. Comparisons were made between (1) younger MMUD versus older haploidentical and (2) younger haploidentical versus older MMUD groups using multivariable Cox proportional hazards models. In multivariable analysis, the older MMUD group exhibited inferior GRFS (hazard ratio [HR] 1.20; 95% confidence interval [CI], 1.06 to 1.36; P = .003), higher TRM (HR 1.49; 95% CI, 1.13 to 1.96; P = .005), and increased grade III to IV acute GVHD (HR 2.88; 95% CI, 1.43 to 5.80; P = .003) compared to the younger haploidentical group. The younger MMUD group had modest GRFS improvement over the older haploidentical group (HR 0.87; 95% CI, 0.78 to 0.98; P = .02) and significantly reduced risks of grade II to IV acute GVHD (HR 0.67; 95% CI, 0.51 to 0.88; P = .003) and chronic GVHD (HR 0.78; 95% CI, 0.65 to 0.94; P = .009). Younger donor age is associated with superior HCT outcomes, emphasizing the importance of prioritizing donors aged <30 years regardless of donor type when feasible.}, }
@article {pmid40419022, year = {2025}, author = {Ahmed, S and Blosser, C and Israni, AK and Engels, EA}, title = {Reply to "Real-world registry evidence beware: Old-world risk analysis may not be applicable to new world belatacept utilization".}, journal = {American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons}, volume = {25}, number = {8}, pages = {1804-1805}, doi = {10.1016/j.ajt.2025.05.027}, pmid = {40419022}, issn = {1600-6143}, }
@article {pmid40419509, year = {2025}, author = {Dobersch, S and Yamamoto, N and Schutter, A and Cavender, SM and Robertson, TM and Kartha, N and Samraj, AN and Doron, B and Poole, LA and Wladyka, CL and Zhang, A and Jang, GH and Mahalingam, AH and Barreto, G and Raghavan, S and Narla, G and Notta, F and Eisenman, RN and Hsieh, AC and Kugel, S}, title = {HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4866}, pmid = {40419509}, issn = {2041-1723}, support = {R37 CA241472/CA/NCI NIH HHS/United States ; R01 GM135362/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA255015/CA/NCI NIH HHS/United States ; PF-24-1196662-01-RMC//American Cancer Society (American Cancer Society, Inc.)/ ; GM135362//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; 5R37CA241472-03//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R35 CA231989/CA/NCI NIH HHS/United States ; 465590102//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; R37 CA230617/CA/NCI NIH HHS/United States ; R01 CA276308/CA/NCI NIH HHS/United States ; 1R01CA255015-01//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; K08 CA260442/CA/NCI NIH HHS/United States ; }, mesh = {*HMGA2 Protein/metabolism/genetics ; *Pancreatic Neoplasms/metabolism/pathology/genetics ; Animals ; Humans ; *Carcinoma, Pancreatic Ductal/genetics/metabolism/pathology ; Mice ; RNA-Binding Proteins/metabolism/genetics ; Methylation ; Cell Line, Tumor ; Protein Phosphatase 2/metabolism/genetics ; Gene Expression Regulation, Neoplastic ; *Leucine/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; }, abstract = {Basal pancreatic ductal adenocarcinoma (PDAC) has the worst overall survival and is the only subtype that serves as an independent poor prognostic factor. We identify elevated levels of LIN28B and its downstream target, HMGA2, in basal PDAC. Notably, LIN28B significantly accelerates KRAS-driven PDAC progression in a mouse model. Here, we show that HMGA2 promotes basal PDAC pathogenesis by enhancing mRNA translation downstream of LIN28B. Mechanistically, HMGA2 suppresses leucine carboxyl methyltransferase 1 (LCMT1) at the chromatin level, reducing PP2A methylation and activity. This leads to increased phosphorylation of S6K and eIF4B, boosting mRNA translation. Additionally, HMGA2 downregulates B56α (PPP2R5A), disrupting functional PP2A holoenzyme assembly and further sustaining phosphorylated S6K levels. Impaired PP2A function mimics HMGA2's effects, reinforcing increased mRNA translation and basal lineage features. This work uncovers a critical link between the LIN28B/HMGA2 axis, protein synthesis, and PDAC lineage specificity via LCMT1-mediated PP2A methylation and B56α-PP2A disruption.}, }
@article {pmid40419513, year = {2025}, author = {Raychaudhuri, S and Gem, H and Chung, K and McLean, JS and Kerns, KA and Hullar, MAJ and Elmorr, E and Appelbaum, JB and Percival, MM and Walter, RB and Halpern, AB and Minot, SS and Kim, K and Zevin, AS and Rashidi, A}, title = {Distal gut colonization by oral bacteria during intensive chemotherapy: direct evidence from strain-level analysis of paired samples.}, journal = {NPJ biofilms and microbiomes}, volume = {11}, number = {1}, pages = {88}, pmid = {40419513}, issn = {2055-5008}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; n/a//Kuni Foundation/ ; P30 CA015704/CA/NCI NIH HHS/United States ; n/a//American Academy of Oral Medicine Research Advancement Committee/ ; T90 DE021984/DE/NIDCR NIH HHS/United States ; T32HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Feces/microbiology ; *Bacteria/classification/isolation &amp; purification/genetics/drug effects ; *Mouth/microbiology ; Male ; Female ; Saliva/microbiology ; *Gastrointestinal Microbiome ; Middle Aged ; Adult ; Aged ; *Antineoplastic Agents/therapeutic use/adverse effects ; }, abstract = {Oral bacteria have been found in the colon in pathologies such as inflammatory bowel disease. To ascertain niche coalescence, 2 elements are essential: (i) paired oral/fecal samples and (ii) strain-level resolution. We profiled the microbiota in 283 samples from 39 patients undergoing intensive chemotherapy at baseline (saliva: 49, plaque: 51, stool: 43), week 2 (saliva: 18, plaque: 17, stool: 17), week 3 (saliva: 18, plaque: 21, stool: 21), and week 4 (saliva: 8, plaque: 10, stool: 10) of chemotherapy. Through strain-level analysis of paired samples, we demonstrate strong evidence for a breakdown of niche separation in most patients. The extent of overlap increased with time, particularly in patients with intestinal mucositis. Our findings provide definitive evidence for ectopic colonization of the distal gut by oral bacteria in a disease state, likely facilitated by intestinal mucositis. Microbiota contribution by the mouth to the colon may have consequences for the host.}, }
@article {pmid40420384, year = {2025}, author = {Hansen, SG and Schell, JB and Marshall, EE and Ojha, S and Feltham, S and Morrow, D and Hughes, CM and Gilbride, RM and Ford, JC and Cleveland-Rubeor, HC and McArdle, MR and Whitmer, T and Barber-Axthelm, A and Bochart, R and Smedley, J and Oswald, K and Fast, R and Shoemaker, R and Kosmider, E and Edlefsen, PT and Lifson, JD and Malouli, D and Früh, K and Picker, LJ}, title = {Glycoprotein L-deleted single-cycle rhesus cytomegalovirus vectors elicit MHC-E-restricted CD8+ T cells that protect against SIV.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {214}, number = {8}, pages = {1969-1981}, pmid = {40420384}, issn = {1550-6606}, support = {R01 AI059457/AI/NIAID NIH HHS/United States ; P51 OD011092/OD/NIH HHS/United States ; P01 AI174856/AI/NIAID NIH HHS/United States ; 75N91019D00024/CA/NCI NIH HHS/United States ; 75N91019D00024/NH/NIH HHS/United States ; U19 AI128741/AI/NIAID NIH HHS/United States ; P51 OD011092/CD/ODCDC CDC HHS/United States ; OPP1107409//Bill and Melinda Gates Foundation/ ; R01 AI175459/AI/NIAID NIH HHS/United States ; P01 AI094417/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Macaca mulatta ; *CD8-Positive T-Lymphocytes/immunology ; *Cytomegalovirus/genetics/immunology ; *Simian Immunodeficiency Virus/immunology ; *Histocompatibility Antigens Class I/immunology ; *Genetic Vectors/immunology/genetics ; *Simian Acquired Immunodeficiency Syndrome/immunology/prevention &amp; control ; *SAIDS Vaccines/immunology ; Humans ; *Viral Envelope Proteins/genetics/immunology ; }, abstract = {Strain 68-1 rhesus CMV (RhCMV) vectors induce immune responses that mediate early, complete replication arrest of SIV infection in ∼60% of vaccinated rhesus macaques (RMs). This unique efficacy depends on the ability of these vectors to elicit effector memory (EM)-biased CD8+ T cells recognizing SIV peptides presented by MHC-E, rather than MHC-Ia. These efficacious responses still occurred when spread of the 68-1 vector was impaired by deletion of the viral anti-host intrinsic immunity factor phosphoprotein 71 (pp71), but efficacy was lost with a more stringent attenuation strategy based on destabilization of Rh108, the ortholog of the essential human CMV (HCMV) transcription factor UL79 that is required for late viral gene expression. Although unable to produce infectious progeny (ie single-cycle infection), Rh108-deficient vectors elicited durable, high frequency, EM-biased, SIV-specific CD8+ T-cell responses in RMs, but these responses were MHC-Ia-restricted and therefore non-efficacious. Here, we tested a different single-cycle attenuation strategy based on deletion (Δ) of the glycoprotein L (gL) that is essential for viral entry but allows for late gene expression and viral assembly. ΔgL 68-1 RhCMV/SIV vectors, grown on gL-complementing fibroblasts, were robustly immunogenic at doses above 105 PFU, generating high frequency, EM-biased, SIV-specific CD8+ T-cell responses that were also unconventionally restricted, including the MHC-E restriction associated with efficacy. Indeed, these single-cycle vectors manifested replication arrest efficacy in 70% of vaccinated RMs, further linking MHC-E restriction with efficacy, and demonstrating that 68-1 RhCMV/SIV efficacy does not require vector dissemination within the host.}, }
@article {pmid40421022, year = {2025}, author = {Paktinat, S and Gravett, MG and Tobey, C and Kirby, A and Horner, W and Shaffer, R and Fialkow, M and Nguyen, NP and Gornalusse, GG and Kalatehjari, M and Hughes, SM and Hladik, F and Vojtech, L}, title = {Extracellular vesicles from human semen induce unique tolerogenic phenotypes in vaginal dendritic cells and regulatory T lymphocytes.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1564002}, pmid = {40421022}, issn = {1664-3224}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI153342/AI/NIAID NIH HHS/United States ; R01 DA040386/DA/NIDA NIH HHS/United States ; }, mesh = {Humans ; *Dendritic Cells/immunology/metabolism ; Female ; *Semen/immunology/metabolism ; *T-Lymphocytes, Regulatory/immunology/metabolism ; *Extracellular Vesicles/immunology/metabolism ; *Immune Tolerance ; Cell Differentiation/immunology ; *Vagina/immunology/cytology ; Male ; Phenotype ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Cells, Cultured ; Pregnancy ; Coculture Techniques ; }, abstract = {INTRODUCTION: The regulation of immune responses to promote tolerance to the fetus is critical for successful pregnancy. An understudied aspect of this process is the initiation of regulation pre-conception via exposure to semen. Our study aimed to understand how semen impacts recipient dendritic cells (DCs) and their subsequent role in shaping CD4 T cell differentiation.<br><br>METHODS: Monocyte-derived DCs (MoDCs) were exposed to semen extracellular vesicles (SEV) or vesicle-depleted semen plasma (VDSP). Phenotypic and functional markers were analyzed using flow cytometry. We also exposed epithelial sheets from vaginal tissue to SEV and VDSP, and measured the number and marker expression of emigrating cells. Finally, we tested how SEV- or VDSP-exposed DCs altered CD4 T cell differentiation by co-culturing exposed MoDCs or tissue emigrated cells with autologous na&#xef;ve CD4 T cells.<br><br>RESULTS: MoDCs exhibited a significant increase of CD141, CD1a, CD38, and ILT4 expression when exposed to SEV or VDSP. A unique feature of semen-treated MoDCs was expression of indoleamine 2,3-dioxygenase (IDO), a potent contributor to the induction of regulatory T cells (Tregs). SEV but not VDSP significantly increased the emigration of intraepithelial DCs. Additionally, SEV significantly enhanced the expression of multiple immunoregulatory markers in the emigrated DCs. After co-culture, we observed significantly more FOXP3+ Tregs expressing high levels of TIGIT in the groups that were initially exposed to SEV.<br><br>DISCUSSION: These findings indicate that exposure to SEV induces a tolerogenic program in DCs that can direct differentiation of a unique memory Treg subset, primed for expansion and presumably destined to support a successful pregnancy.}, }
@article {pmid40421959, year = {2025}, author = {Spencer, KR and King, GG}, title = {MDM2 as a therapeutic target in advanced biliary tract cancers.}, journal = {The oncologist}, volume = {30}, number = {5}, pages = {}, pmid = {40421959}, issn = {1549-490X}, support = {//Boehringer Ingelheim Pharmaceuticals, Inc/ ; }, mesh = {Humans ; *Proto-Oncogene Proteins c-mdm2/genetics/antagonists &amp; inhibitors/metabolism ; *Biliary Tract Neoplasms/drug therapy/pathology/genetics ; Molecular Targeted Therapy ; Tumor Suppressor Protein p53/genetics/metabolism ; }, abstract = {Biliary tract cancers (BTCs) are a heterogeneous group of tumors arising from cells in the bile ducts and gallbladder. The 5-year overall survival rate for all BTC stages combined is ~20%, and treatment options for patients with unresectable disease are limited, leaving an unmet clinical need. In recent years, significant efforts have been made to refine and implement targeted therapeutic approaches for patients with BTC. The adoption of early and comprehensive molecular profiling is crucial to identifying patients who may be candidates for effective targeted therapies. Characterization of the molecular landscape of BTCs led to the identification of murine double minute 2 homolog gene (MDM2) amplification across all BTC subtypes. The MDM2 protein is a critical negative regulator of p53 stabilization and activity that is an emerging actionable biomarker in BTCs. There are multiple therapeutic approaches that aim to target MDM2 activity, thereby restoring the intrinsic tumor suppressor function of p53 and halting oncogenesis. However, these have been limited by our evolving understanding of the role of MDM2 in BTC pathogenesis. Here, we offer a review of the current understanding of the role of MDM2 in BTC biology and its therapeutic implications.}, }
@article {pmid40422973, year = {2025}, author = {Zeller, M and Chang, J and Trevisan, G and Gauger, PC and Zhang, J}, title = {Nextclade data set for the ORF5-based lineage classification of PRRSV-1.}, journal = {Microbiology resource announcements}, volume = {14}, number = {6}, pages = {e0030325}, pmid = {40422973}, issn = {2576-098X}, abstract = {A Nextclade data set for PRRSV-1 ORF5 based on a global nomenclature for standardized lineage classification was developed. This tool enables rapid sequence analysis, visualization, and comparison with reference strains and vaccines. By providing accessibility, it facilitates broader adoption of PRRSV-1 classification frameworks for research and surveillance.}, }
@article {pmid40425247, year = {2025}, author = {Tatunay, K and Cohen, S and Naylor, LV and Handford, CL and Jacobson, A and Shankaran, V and Oelschlager, B and Grady, WM and Sjoding, B and Lally, E and Facchini, L and Sun, Q and Laurino, MY and Pritchard, C and Konnick, EQ and Dubard-Gault, ME}, title = {Does paired genetic testing improve targeted therapy choices and screening recommendations for patients with upper gastrointestinal cancers and their families? A prospective cohort of 42 patients.}, journal = {BMJ open}, volume = {15}, number = {5}, pages = {e091745}, pmid = {40425247}, issn = {2044-6055}, mesh = {Humans ; Male ; Female ; *Genetic Testing/methods ; Prospective Studies ; Middle Aged ; Aged ; *Gastrointestinal Neoplasms/genetics/diagnosis/therapy ; *Esophageal Neoplasms/genetics/diagnosis/therapy ; *Early Detection of Cancer/methods ; Adult ; *Molecular Targeted Therapy ; *Stomach Neoplasms/genetics/diagnosis/therapy ; Genetic Predisposition to Disease ; }, abstract = {OBJECTIVES: Our study was designed to assess whether paired normal-tumour testing increased access to targeted therapy, clinical trials and influenced cancer screening recommendations given to patients and their families.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING: Academic cancer centre in the Pacific Northwest region of the USA.<br><br>PARTICIPANTS: Patients newly diagnosed between 01 January 2021 and 31 December 2022 with cancers of the oesophagus, gastro-oesophageal junction and stomach (CEGEJS) were included. All other cancer diagnoses such as head and neck, duodenal and lower gastrointestinal tract cancers were excluded.<br><br>INTERVENTION: Paired germline and tumour genetic test within 90 days of new patient visit.<br><br>PRIMARY OUTCOME MEASURES: Number of targeted therapies received (or not) when eligible, follow-up treatment data and number of inherited predispositions to cancers identified. No secondary outcome measures.<br><br>RESULTS: Of 42 patients, 32 (76.2%) were eligible for at least one targeted therapy. 19 patients received immunotherapy, when 16 had a biomarker predicting immunotherapy benefit, and benefit of immunotherapy was unclear for 3. Another 11 did not have this biomarker, and 6 of them received immunotherapy. Six pathogenic variants were identified in four high-risk genes. By 01 January 2024, 18 patients (42.9%) had died of complications of cancer.<br><br>CONCLUSION: More than 75% of patients who received tumour testing were eligible for a targeted therapy regardless of their stage at diagnosis, emphasising the need to expand access to testing with staging workup to improve survival outcomes. Six families received personalised screening recommendations, thanks to this study.}, }
@article {pmid40425412, year = {2025}, author = {Swaminathan, M and Holt, SK and Gore, JL and Nyame, YA and Wright, J and Shah, A and Sparks, JA and Makris, UE and Grivas, P and Suarez-Almazor, M and Psutka, S and Singh, N}, title = {Association Between Rheumatoid Arthritis, Frailty Status, and Mortality in Older Adults with Bladder Cancer.}, journal = {Clinical genitourinary cancer}, volume = {23}, number = {4}, pages = {102369}, pmid = {40425412}, issn = {1938-0682}, support = {R03 AG082857/AG/NIA NIH HHS/United States ; P30 AR072577/AR/NIAMS NIH HHS/United States ; R01 AR080659/AR/NIAMS NIH HHS/United States ; R01 AR078484/AR/NIAMS NIH HHS/United States ; HHSN261201800032I/CA/NCI NIH HHS/United States ; HHSN261201800015C/CA/NCI NIH HHS/United States ; HHSN261201800009I/CA/NCI NIH HHS/United States ; HHSN261201800032C/CA/NCI NIH HHS/United States ; R01 AR077607/AR/NIAMS NIH HHS/United States ; K23 AR079588/AR/NIAMS NIH HHS/United States ; HHSN261201800009C/CA/NCI NIH HHS/United States ; HHSN261201800015I/CA/NCI NIH HHS/United States ; P30 AR070253/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/mortality/complications ; Aged ; Male ; Female ; *Arthritis, Rheumatoid/epidemiology/complications ; *Frailty/epidemiology/complications ; Retrospective Studies ; Aged, 80 and over ; SEER Program/statistics &amp; numerical data ; United States/epidemiology ; Medicare/statistics &amp; numerical data ; Risk Factors ; }, abstract = {BACKGROUND: To evaluate the associations between rheumatoid arthritis (RA) and all-cause (ACM) and cancer-Specific mortality (CSM) in older adults with bladder cancer and examine how frailty may affect these associations.<br><br>METHODS: Retrospective cohort study derived from the Surveillance Epidemiology and End Results (SEER) cancer registry and linked to Medicare claims data (SEER-Medicare). The cohort consisted of patients &#x2265; 65 years diagnosed with bladder cancer between 2004 and 2017. RA and frailty status were derived using validated administrative algorithms. ACM and CSM as derived from the SEER registry.<br><br>RESULTS: Frailty modified the relationship between RA and mortality outcomes (interaction P value for ACM: .002 and for CSM: .007). We observed that RA was associated with a higher risk of CSM (aHR 1.17, 95% CI, 1.01-1.35) and ACM (aHR 1.12, 95% CI, 1.05-1.20) in nonfrail patients. In frail patients with bladder cancer, RA was not independently associated with CSM (aHR 0.81, 95% CI, 0.62-1.06) or ACM (aHR 0.93, 95% CI, 0.83-1.05).<br><br>CONCLUSION: Frailty is associated with adverse health outcomes. As people are living longer, it is becoming increasingly prevalent among patients with chronic conditions such as RA. We observed that RA is associated with increased risk of ACM and CSM among nonfrail older adults with bladder cancer. The lack of an association between RA and mortality in frail patients with RA suggests that the effect of frailty on mortality may overpower the effect that RA may exert-this information can help prognosticate outcomes in patients with bladder cancer, RA, and frailty.}, }
@article {pmid40425554, year = {2025}, author = {Borot, F and Humbert, O and Ehmsen, JT and Fields, E and Kohli, S and Radtke, S and Swing, K and Pande, D and Enstrom, MR and Laszlo, GS and Mayuranathan, T and Ali, AM and Weiss, MJ and Yen, JS and Newby, GA and Walter, RB and Liu, DR and Mukherjee, S and Kiem, HP}, title = {Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {4899}, pmid = {40425554}, issn = {2041-1723}, support = {K99 HL163805/HL/NHLBI NIH HHS/United States ; P51 OD010425/OD/NIH HHS/United States ; R00 HL163805/HL/NHLBI NIH HHS/United States ; T32 GM007471/GM/NIGMS NIH HHS/United States ; R50 CA274319/CA/NCI NIH HHS/United States ; R35 GM118062/GM/NIGMS NIH HHS/United States ; U01 AI142756/AI/NIAID NIH HHS/United States ; R01 CA266556/CA/NCI NIH HHS/United States ; P51 OD011092/OD/NIH HHS/United States ; R01 HL156647/HL/NHLBI NIH HHS/United States ; P01 HL053749/HL/NHLBI NIH HHS/United States ; R01 HL136135/HL/NHLBI NIH HHS/United States ; RM1 HG009490/HG/NHGRI NIH HHS/United States ; R01 HL151765/HL/NHLBI NIH HHS/United States ; U42 OD011123/OD/NIH HHS/United States ; }, mesh = {Humans ; Animals ; *Gene Editing/methods ; *Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism/immunology ; *Genetic Therapy/methods ; Hematopoietic Stem Cells/metabolism/drug effects ; Gemtuzumab/pharmacology ; *Immunotherapy/methods ; Polymorphism, Single Nucleotide ; CRISPR-Cas Systems ; Mice ; }, abstract = {The selection of genetically engineered immune or hematopoietic cells in vivo after gene editing remains a clinical problem and requires a method to spare on-target toxicity to normal cells. Here, we develop a base editing approach exploiting a naturally occurring CD33 single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. CD33 editing in human and nonhuman primate hematopoietic stem and progenitor cells protects myeloid progeny from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for improved immunotherapies with reduced off-leukemia toxicity. For broader application to gene therapies, we demonstrate highly efficient (>70%) multiplexed adenine base editing of the CD33 and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in nonhuman primates. Using the CD33 antibody-drug conjugate Gemtuzumab Ozogamicin, we show resistance of engrafted, multiplex edited human cells in vivo, and a 2-fold enrichment for edited cells in vitro. Together, our results highlight the potential of adenine base editors for improved immune and gene therapies.}, }
@article {pmid40425844, year = {2025}, author = {Kwan, EM and Ng, SWS and Tolmeijer, SH and Emmett, L and Sandhu, S and Buteau, JP and Iravani, A and Joshua, AM and Francis, RJ and Subhash, V and Lee, ST and Scott, AM and Martin, AJ and Stockler, MR and Donnellan, G and Annala, M and Herberts, C and Davis, ID and Hofman, MS and Azad, AA and Wyatt, AW and , }, title = {Lutetium-177-PSMA-617 or cabazitaxel in metastatic prostate cancer: circulating tumor DNA analysis of the randomized phase 2 TheraP trial.}, journal = {Nature medicine}, volume = {31}, number = {8}, pages = {2722-2736}, pmid = {40425844}, issn = {1546-170X}, support = {PCF Challenge Award//Prostate Cancer Foundation (PCF)/ ; Young Investigator Award//Prostate Cancer Foundation (PCF)/ ; BC Trainee Award//Michael Smith Foundation for Health Research (MSFHR)/ ; NHMRC Investigator Fellowship #1177837//Department of Health | National Health and Medical Research Council (NHMRC)/ ; NHMRC Practitioner Fellowship APP1102604//Department of Health | National Health and Medical Research Council (NHMRC)/ ; }, mesh = {Humans ; Male ; *Lutetium/therapeutic use ; *Dipeptides/therapeutic use ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/genetics/blood/pathology ; Aged ; *Circulating Tumor DNA/blood/genetics ; *Heterocyclic Compounds, 1-Ring/therapeutic use ; Radioisotopes/therapeutic use ; Middle Aged ; *Taxoids/therapeutic use ; Prostate-Specific Antigen ; Biomarkers, Tumor/blood/genetics ; Neoplasm Metastasis ; Aged, 80 and over ; }, abstract = {The prostate-specific membrane antigen (PSMA)-targeted radioligand [[177]Lu]Lu-PSMA-617 is a new standard treatment for metastatic castration-resistant prostate cancer (mCRPC), but predictive genomic biomarkers informing its rational use are unknown. We performed detailed dissection of prostate cancer driver genes across 290 serial plasma cell-free DNA samples from 180 molecular imaging-selected patients with mCRPC from the randomized TheraP trial of [[177]Lu]Lu-PSMA-617 (n = 97) versus cabazitaxel chemotherapy (n = 83). The primary endpoint was PSA50 biochemical response, with secondary endpoints of progression-free survival (PFS) and overall survival (OS). In this post-hoc biomarker analysis, a low pretreatment circulating tumor DNA (ctDNA) fraction predicted a superior biochemical response (100% versus 58%, P = 0.0067) and PFS (median 14.7 versus 6.0 months; hazard ratio 0.12, P = 2.5 × 10[-4]) on [[177]Lu]Lu-PSMA-617 independent of predictive PSMA-positron emission tomography imaging parameters, although this benefit did not extend to OS. Deleterious PTEN alterations were associated with worse PFS and OS on cabazitaxel, whereas ATM defects were observed in select patients with favorable [[177]Lu]Lu-PSMA-617 outcomes. Comparing pretreatment and progression ctDNA revealed population flux but no evidence that alterations in individual mCRPC genes (or FOLH1) are dominant causes of acquired [[177]Lu]Lu-PSMA-617 or cabazitaxel resistance. Our results nominate new candidate biomarkers for [[177]Lu]Lu-PSMA-617 selection and ultimately expand the mCRPC predictive biomarker repertoire. We anticipate our ctDNA fraction-aware analytical framework will aid future precision management strategies for [[177]Lu]Lu-PSMA-617 and other PSMA-targeted therapeutics. ClinicalTrials.gov identifier: NCT03392428 .}, }
@article {pmid40427141, year = {2025}, author = {Dahlberg, A and Stevenson, P and Bhatt, NS and Burroughs, L and Carpenter, PA and Summers, C and Tarlock, K and Thakar, MS and Milano, F and Deeg, HJ and Bleakley, M}, title = {Disease Burden at the Time of Transplantation Is a Primary Predictor of Outcomes in Pediatric MDS: A Single-Center Experience.}, journal = {Cancers}, volume = {17}, number = {10}, pages = {}, pmid = {40427141}, issn = {2072-6694}, support = {RC2 DK127989/DK/NIDDK NIH HHS/United States ; }, abstract = {BACKGROUND: Hematopoietic cell transplantation (HCT) remains the only curative therapy for pediatric myelodysplastic syndrome (MDS) in all but rare cases. While HCT outcomes for pediatric MDS are similar across the largest registry and single-center trials, factors identified as contributing to inferior outcomes vary from study to study. We performed an analysis to provide more clarity on the prognostic implications of disease characteristics, including blast burden and cytogenetic abnormalities, in the current era.<br><br>METHODS: We conducted a retrospective analysis of 36 consecutive children (<18 years of age at HCT) who underwent allogeneic HCT for MDS between June 2000 and October 2019 at the Fred Hutchinson Cancer Center.<br><br>RESULTS: Overall survival (OS) was 77% (95% CI 64-92%) and relapse-free survival (RFS) was 71% (95% CI 57-88%) at 2 years post-HCT. Patients with <5% blasts by morphology in the bone marrow at the time of HCT showed superior 2-year OS at 87% (95% CI 74-100%) as compared to 54% (95% CI 32-93%) in patients with &#x2265;5% blasts, consistent with an HR of 4.6 (CI 1.14-18.7, p = 0.03). The inferior outcomes in patients with &#x2265;5% blasts were due to increased relapse incidence (HR 7.6, CI 1.5-39.3) with no difference in NRM or acute GVHD.<br><br>CONCLUSIONS: OS and RFS were comparable to what has been observed in other large, single-center studies (OS 77%, RFS 71% at 2 years) and compared favorably to outcomes from the largest multi-center retrospective analyses.}, }
@article {pmid40434773, year = {2025}, author = {Andrews, LIB and Halloran, ME and Neuzil, KM and van der Laan, L and Huang, Y and Andriesen, J and Patel, M and Fisher, LH and Janes, H and Rouphael, N and Walsh, SR and Theodore, DA and Tieu, HV and Sobieszczyk, M and El Sahly, HM and Baden, LR and Falsey, AR and Campbell, TB and Kelley, CF and Healy, CM and Immergluck, L and Luft, B and Hirsch, I and de Bruyn, G and Truyers, C and Priddy, F and Sumner, KM and Flannery, B and Follmann, D and Gilbert, PB and , }, title = {Evaluating the Test-Negative Design for COVID-19 Vaccine Effectiveness Using Randomized Trial Data: A Secondary Cross-Protocol Analysis of 5 Randomized Clinical Trials.}, journal = {JAMA network open}, volume = {8}, number = {5}, pages = {e2512763}, pmid = {40434773}, issn = {2574-3805}, support = {UM1 AI148689/AI/NIAID NIH HHS/United States ; UM1 AI069476/AI/NIAID NIH HHS/United States ; UM1 AI148575/AI/NIAID NIH HHS/United States ; U01 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI148685/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI148573/AI/NIAID NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 AI045008/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 Vaccines/therapeutic use ; *COVID-19/prevention &amp; control/diagnosis ; *Vaccine Efficacy ; *Randomized Controlled Trials as Topic ; SARS-CoV-2/immunology ; Adult ; Female ; Male ; Middle Aged ; *Research Design ; }, abstract = {IMPORTANCE: The test-negative design (TND) has been widely used to assess postmarketing COVID-19 vaccine effectiveness but requires further evaluation for this application.<br><br>OBJECTIVE: To determine whether the TND reliably evaluates vaccine effectiveness against symptomatic COVID-19 using placebo-controlled vaccine efficacy randomized clinical trials (RCTs).<br><br>This secondary cross-protocol analysis constructed TND study datasets from study sites in 16 countries across 5 continents using the blinded phase cohorts of 5 harmonized phase 3 COVID-19 Prevention Network RCTs: COVE (Coronavirus Vaccine Efficacy and Safety), AZD1222, ENSEMBLE, PREVENT-19 (Prefusion Protein Subunit Vaccine Efficacy Novavax Trial COVID-19), and VAT00008. Participants included adults who received the intended number of doses, experienced COVID-19-like symptoms, and obtained SARS-CoV-2 testing. Start dates ranged from July 27, 2020, to October 19, 2021; data cutoff dates ranged from March 26, 2021, to March 15, 2022. Statistical analysis was performed from May 11, 2023, to February 25, 2025.<br><br>INTERVENTIONS: Participants received vaccines consisting of messenger RNA-1273 (COVE; 2 doses 28 days apart), ChAdOx1 nCoV-19 (AZD1222; 2 doses 28 days apart), Ad26.COV2.S (ENSEMBLE; 1 dose), NVX-CoV2373 (PREVENT-19; 2 doses 21 days apart), CoV2 preS dTM-AS03 (VAT00008; D614) (2 doses 21 days apart), or CoV2 preS dTM-AS03 (D614 plus B.1.351) (VAT00008; 2 doses 21 days apart) or placebo.<br><br>MAIN OUTCOMES AND MEASURES: Main outcomes were symptomatic COVID-19 according to each trial's primary efficacy definition and the Centers for Disease Control and Prevention definition. Vaccine effectiveness was estimated using targeted maximum likelihood estimation under a semiparametric logistic regression model and ordinary logistic regression. Noncase exchangeability, a core TND assumption for unbiased estimation, was also assessed by estimating vaccine efficacy against non-COVID-19 illness.<br><br>RESULTS: Among the 12&#x202f;157 participants included in the analysis, mean (SD) age was 45 (15) years, 6414 were female (53%), 5858 were vaccinated (48%), 2835 experienced primary COVID-19 (23%), and 2992 experienced Centers for Disease Control and Prevention-defined COVID-19 (25%). TND vaccine effectiveness estimates were concordant with RCT vaccine efficacy estimates (concordance correlation coefficient,&#x2009;0.86 [95% CI, 0.58-0.96] for both outcomes). The semiparametric method had 48% smaller variance estimates than ordinary logistic regression. Noncase exchangeability was generally supported with a median vaccine efficacy against non-COVID-19 illness of 7.7% (IQR, 2.7%-16.8%) across trial cohorts and most 95% CIs including 0.<br><br>CONCLUSIONS AND RELEVANCE: In this cross-protocol analysis, the TND provided reliable inferences on COVID-19 vaccine effectiveness in health care-seeking populations for multiple vaccines and symptom definitions when confounding and selection bias were absent. A machine-learning approach for robust confounding control in postmarketing TND studies was also introduced.}, }
@article {pmid40435263, year = {2025}, author = {Marsh, NM and MacEwen, MJS and Chea, J and Kenerson, HL and Kwong, AA and Locke, TM and Miralles, FJ and Sapre, T and Gozali, N and Hart, ML and Bammler, TK and MacDonald, JW and Sullivan, LB and Atilla-Gokcumen, GE and Ong, SE and Scott, JD and Yeung, RS and Sancak, Y}, title = {Mitochondrial calcium signaling regulates branched-chain amino acid catabolism in fibrolamellar carcinoma.}, journal = {Science advances}, volume = {11}, number = {22}, pages = {eadu9512}, pmid = {40435263}, issn = {2375-2548}, support = {R01 GM129090/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; S10 OD021502/OD/NIH HHS/United States ; R01 CA279997/CA/NCI NIH HHS/United States ; R35 GM147118/GM/NIGMS NIH HHS/United States ; F31 AG072716/AG/NIA NIH HHS/United States ; R35 GM136234/GM/NIGMS NIH HHS/United States ; }, mesh = {*Amino Acids, Branched-Chain/metabolism ; *Carcinoma, Hepatocellular/metabolism/genetics/pathology ; Humans ; *Liver Neoplasms/metabolism/pathology/genetics ; *Mitochondria/metabolism ; *Calcium Signaling ; Cell Line, Tumor ; Calcium Channels/metabolism/genetics ; Kruppel-Like Transcription Factors/metabolism/genetics ; Gene Expression Regulation, Neoplastic ; }, abstract = {Metabolic adaptations are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating mitochondrial metabolic pathways and calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate consequences of uniporter loss and gain of function using uniporter knockout cells and fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. We find that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated pathways. Reduced uniporter function boosts expression of BCAA catabolism genes and the urea cycle enzyme ornithine transcarbamylase. In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by the transcription factor KLF15, a master regulator of liver metabolism. Thus, the uniporter plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for the uniporter in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism.}, }
@article {pmid40435412, year = {2025}, author = {Escherich, CS and Li, Z and Barnett, KR and Li, Y and Walker, M and Yoshimura, S and Yang, W and Huang, X and Yu, J and Stock, W and Paietta, E and Konopleva, MY and Kornblau, SM and Jabbour, E and Litzow, MR and Inaba, H and Pui, CH and Loh, ML and Evans, WE and Savic, D and Yang, JJ}, title = {Differentiation-dependent EBF1 activity determines CD22 transcription and leukemia sensitivity to inotuzumab ozogamicin.}, journal = {Blood}, volume = {146}, number = {4}, pages = {471-481}, doi = {10.1182/blood.2024028215}, pmid = {40435412}, issn = {1528-0020}, mesh = {*Sialic Acid Binding Ig-like Lectin 2/genetics/metabolism ; Humans ; *Inotuzumab Ozogamicin/pharmacology/therapeutic use ; *Drug Resistance, Neoplasm/genetics ; *Trans-Activators/metabolism/genetics ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics/drug therapy/pathology/metabolism ; Cell Differentiation/drug effects ; Gene Expression Regulation, Leukemic/drug effects ; *Antineoplastic Agents, Immunological/pharmacology/therapeutic use ; *Transcription, Genetic/drug effects ; Cell Line, Tumor ; }, abstract = {Inotuzumab ozogamicin (InO) is an antibody-calicheamicin conjugate with high efficacy in lymphoid malignancies. It targets the B-cell surface protein CD22, which is expressed in most B-cell acute lymphoblastic leukemia (B-ALL) cases, albeit with variable intensity. However, factors governing CD22 expression and thus leukemia sensitivity to InO remain incompletely understood. Using multiomic characterization of 196 human B-ALL samples, coupled with ex vivo InO sensitivity profiling, we showed that early leukemia differentiation arrest at the pre-pro-B stage is associated with resistance to InO. Screening of 1639 transcription factor genes identified early B-cell factor 1 (EBF1) as a key regulator of CD22 expression (false discovery rate of 7.1 × 10-4). When comparing the assay for transposase-accessible chromatin with sequencing profiling results of the most InO-sensitive and -resistant cases (50% lethal concentration <10th vs >90th percentile, n = 18), the binding motif for EBF1 was strikingly enriched in regions with differential open chromatin status (P = 8 × 10-174). CRISPR interference targeting EBF1 binding sites at the CD22 locus led to an ∼50-fold reduction in cell surface CD22 expression and, consequently, an ∼22-fold increase in InO resistance in ALL cell lines. Interestingly, within BCR::ABL1 ALL, we observed intrasubtype heterogeneity linked to EBF1 transcriptional downregulation (P = 1.1 × 10-15) and/or somatic alteration (P = .004), which led to reduced CD22 expression (P = 8.3 × 10-11) and ex vivo and in vivo resistance to InO. Collectively, these findings point to the direct impact of EBF1 on CD22 expression during B-cell development, which, in turn, contributes to interpatient variability in InO response, even within the same subtype of B-ALL.}, }
@article {pmid40435434, year = {2025}, author = {Daca-Álvarez, M and Brunori, A and Carbone, A and Carbonell, C and Tangen, CM and Unger, JM and Lucia, MS and Oliva, M and De Censi, A and Brenner, DR and Thompson, IM and Balaguer, F}, title = {Emerging Strategies for Drug-Based Cancer Risk Reduction.}, journal = {American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting}, volume = {45}, number = {3}, pages = {e473708}, doi = {10.1200/EDBK-25-473708}, pmid = {40435434}, issn = {1548-8756}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/prevention &amp; control/epidemiology/drug therapy/etiology ; Risk Factors ; Chemoprevention/methods ; Risk Reduction Behavior ; Female ; }, abstract = {Chemoprevention has emerged as a promising strategy to reduce cancer incidence by using pharmacologic agents that interrupt the carcinogenesis process. This review discusses emerging insights and recent advancements in chemoprevention, emphasizing novel approaches in several cancer types. Specifically, we examine breast cancer prevention, focusing on optimized endocrine therapy dosing to enhance adherence and minimize adverse effects while maintaining efficacy. Additionally, the potential of glucagon-like peptide-1 receptor agonists to mitigate obesity-related cancer risks is evaluated, highlighting their role in addressing an increasingly prevalent risk factor in the general population. The review further explores strategies targeting colorectal cancer (CRC), specifically in familial adenomatous polyposis, a hereditary CRC syndrome that exemplifies the complex interplay between chemoprevention, genetic risk, and patient management. In prostate cancer, we highlight the evidence supporting the use of 5-alpha reductase inhibitors, detailing their effectiveness in reducing cancer incidence as well as their safety profile. Across these areas, this review underscores the importance of precision medicine, advocating for personalized approaches that balance efficacy, safety, and quality-of-life considerations. Ultimately, advancing chemopreventive strategies through targeted research and clinical trials is essential for reducing cancer burden and improving patient outcomes.}, }
@article {pmid40435447, year = {2025}, author = {Nakasone, ES and Cohen, SA}, title = {Secondary Acute Myeloid Leukemia following Treatment for Metastatic Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: A Cautionary Sequel to an Exceptional Response.}, journal = {Pancreas}, volume = {}, number = {}, pages = {}, doi = {10.1097/MPA.0000000000002520}, pmid = {40435447}, issn = {1536-4828}, }
@article {pmid40435511, year = {2025}, author = {Wudhikarn, K and Herr, MM and Chen, M and Martens, MJ and Baird, JH and Gowda, L and Rangarajan, HG and Abid, MB and Kharfan-Dabaja, MA and Williams, KM and Ganguly, S and Young, JH and Sharma, A and Fatobene, G and Jain, T and Kanakry, CG and Modi, D and Grover, NS and Salem, B and Batista, MV and Vergidis, P and Yin, DE and Beitinjaneh, AM and Kelkar, AH and Nishihori, T and Holter Chakrabarty, J and Gergis, U and Smith, M and El Boghdadly, Z and Dandoy, CE and Murthy, HS and Huppler, AR and Perales, MA and Chemaly, RF and Hill, JA and Riches, M and Auletta, JJ}, title = {Infection after CD19 chimeric antigen receptor T-cell therapy for large B-cell lymphoma: real-world analysis from CIBMTR.}, journal = {Blood advances}, volume = {9}, number = {21}, pages = {5460-5472}, pmid = {40435511}, issn = {2473-9537}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; U01 AI184132/AI/NIAID NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; *Immunotherapy, Adoptive/adverse effects/methods ; *Antigens, CD19/immunology ; *Lymphoma, Large B-Cell, Diffuse/therapy/complications/mortality ; Aged ; Adult ; *Receptors, Chimeric Antigen/immunology ; *Infections/etiology ; Young Adult ; Aged, 80 and over ; Risk Factors ; Adolescent ; Receptors, Antigen, T-Cell ; Biological Products ; }, abstract = {Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell-associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.}, }
@article {pmid40438096, year = {2025}, author = {Ackerley, CG and Edupuganti, S and Yu, C and Roxby, AC and Seaton, KE and Bekker, LG and Allen, M and DeRosa, SC and Yates, NL and Heptinstall, J and Mkhize, NN and Malahleha, M and Mngadi, K and Daniels, B and Innes, C and Furch, BD and Koutsoukos, M and Ferrari, G and Morris, L and Montefiori, DC and McElrath, MJ and Tomaras, GD and Laher, F and Moodie, Z}, title = {Retrospective analysis of sex-disaggregated immune responses to ALVAC-HIV and bivalent subtype C gp120/MF59 HIV vaccines.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1557009}, pmid = {40438096}, issn = {1664-3224}, support = {P30 AI050409/AI/NIAID NIH HHS/United States ; K23 AI177081/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI154463/AI/NIAID NIH HHS/United States ; UM1 AI069453/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; L60 AI164539/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage ; Male ; Female ; Adult ; Retrospective Studies ; *HIV Infections/immunology/prevention &amp; control/virology ; *HIV Envelope Protein gp120/immunology ; HIV Antibodies/immunology/blood ; *HIV-1/immunology ; Young Adult ; Adolescent ; Antibodies, Neutralizing/immunology/blood ; Antibody-Dependent Cell Cytotoxicity ; Sex Factors ; Immunogenicity, Vaccine ; *Squalene/immunology/administration &amp; dosage ; }, abstract = {INTRODUCTION: Generally, individuals assigned female at birth (AFAB) develop greater immunogenicity to various vaccines than individuals assigned male at birth (AMAB). Little is known about sex-disaggregated immunogenicity to HIV-1 vaccines. We disaggregated immune responses to an experimental HIV vaccine regimen.<br><br>METHODS: We retrospectively analyzed data from HVTN 100, a clinical trial conducted in South Africa during which 143 adults AMAB and 109 AFAB aged 18-40 years without HIV received ALVAC-HIV vCP2438 plus bivalent subtype C gp120/MF59 or placebo at 0, 1, 3, 6, and 12 months. Eligible data were from per-protocol vaccine recipients at month 6.5. We measured IgG binding antibodies, neutralizing antibodies, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and CD4+ IFN&#x3b3; and/or II-2 responses. We compared sex-based differences in response rates using Barnard's test and response magnitudes using Wilcoxon Rank Sum test. P-values were Holm-adjusted for multiple comparisons.<br><br>RESULTS: Of 185 vaccine recipients, 73 were AFAB and 112 were AMAB. Vaccine recipients AFAB had greater ADCC response rate (57.5% versus 29.5%; padj = 0.0003) and greater ADCC magnitude (area under the net % granzyme B activity vs log10 curve (AUC), 16.1 versus 11.2; padj = 0.05) to vaccine-matched antigen TV1.C gp120 compared to AMAB. Vaccine recipients AMAB had higher CD4+ T cell response rates to 2/3 vaccine-matched antigens at month 6.5 (ZM96.C gp120, [54.1% versus 36.8%; padj = 0.04]; 1086.C gp120, [44.1% versus 29.4%; padj = 0.05]) than AFAB. CD4+ T cell response magnitudes were similar by sex. IgG binding antibody response rate to B.CaseA V1V2 antigen (associated with reduced HIV acquisition risk in the RV144 trial) was 56.8% among AMAB vaccine recipients versus 38.9% among AFAB (padj = 0.08). There were no sex-based differences in neutralizing antibody or ADCP responses.<br><br>DISCUSSION: We identified sex-based differences in immune responses to an HIV vaccine regimen, but they varied by immunologic assay. While vaccine recipients AFAB demonstrated higher ADCC responses, AMAB exhibited higher CD4+ T cell response rates. Future analyses should investigate whether vaccine factors such as platform, dosing and adjuvants contribute to sex-based differences in immunogenicity of experimental HIV vaccines.}, }
@article {pmid40438119, year = {2025}, author = {Creighton, RL and Hughes, SM and Hladik, F and Gornalusse, GG}, title = {The intestinal interferon system and specialized enterocytes as putative drivers of HIV latency.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1589752}, pmid = {40438119}, issn = {1664-3224}, support = {KL2 TR002317/TR/NCATS NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI184122/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Enterocytes/immunology/virology/metabolism ; *HIV Infections/immunology/virology/metabolism ; *Virus Latency/immunology ; *Interferons/metabolism/immunology ; *HIV-1/physiology/immunology ; CD4-Positive T-Lymphocytes/immunology/virology ; Animals ; Virus Activation ; Intestinal Mucosa/immunology/metabolism ; Signal Transduction ; }, abstract = {The barrier to HIV cure is the HIV reservoir, which is composed of latently infected CD4[+] T cells and myeloid cells that carry stably integrated and replication-competent provirus. The gastrointestinal tract (GIT) contains a substantial part of the HIV reservoir and its immunophysiology could be especially conducive for HIV persistence and reactivation. However, the exact cellular microenvironment and molecular mechanisms that govern the renewal of provirus-harboring cells and proviral reactivation in the GIT remain unclear. In this review, we outline the evidence supporting an overarching hypothesis that interferon activity driven by specialized enterocytes creates a microenvironment that fosters proliferation of latently infected CD4[+] T cells and sporadic HIV reactivation from these cells. First, we describe unique immunologic features of the gastrointestinal associated lymphoid tissue (GALT), specifically highlighting IFN activity in specialized enterocytes and potential interactions between these cells and neighboring HIV susceptible cells. Then, we will describe dysregulation of IFN signaling in HIV infection and how IFN dysregulation in the GALT may contribute to the persistence and reactivation of the latent HIV reservoir. Finally, we will speculate on the clinical implications of this hypothesis for HIV cure strategies and outline the next steps.}, }
@article {pmid40439580, year = {2025}, author = {Bondeelle, L and Cheng, GS and Bergeron, A}, title = {What's new in the management of pulmonary complications in allogeneic stem cell transplantation?.}, journal = {Expert review of respiratory medicine}, volume = {19}, number = {9}, pages = {903-923}, doi = {10.1080/17476348.2025.2513519}, pmid = {40439580}, issn = {1747-6356}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Lung Diseases/therapy/diagnosis/etiology ; Risk Factors ; Transplantation, Homologous ; *Graft vs Host Disease/therapy/etiology/diagnosis ; Treatment Outcome ; }, abstract = {INTRODUCTION: As survival increases after allogeneic hematopoietic stem cell transplantation (allo-HCT), several organ complications have emerged, including those involving the lung, which require a multidisciplinary management approach. The constant evolution of allo-HCT procedures, advances in diagnostic tools for infections and pulmonary disease, as well as new treatment approaches, require frequent updating of knowledge in this field.<br><br>AREAS COVERED: We review the multiple infectious and noninfectious lung complications that occur both early and late after allo-HCT. This includes an updated description of these complications, risk factors, diagnostic approach and outcome. A literature search was performed using PubMed-indexed journals.<br><br>EXPERT OPINION: The diagnosis of pulmonary complications after allo-HCT remains challenging, further complicated by the frequent association of co-infections and/or links between infection and noninfectious complications. The development of metagenomic next-generation sequencing (mNGS) should enhance the diagnostic yield of bronchoalveolar lavage, but its clinical relevance remains to be evaluated. A better understanding of the pathophysiology of the lung chronic graft-versus-host disease (GVHD) and improved phenotyping are essential for advancing its diagnostic and therapeutic management. This requires a revision of diagnostic criteria and the identification of new biomarkers of early disease.}, }
@article {pmid40440038, year = {2025}, author = {Ding, Y and Naresh, KN}, title = {Primary myelofibrosis involving lymph nodes with the same mutational profile in bone marrow.}, journal = {Blood}, volume = {145}, number = {22}, pages = {2672}, doi = {10.1182/blood.2025028556}, pmid = {40440038}, issn = {1528-0020}, }
@article {pmid40440315, year = {2025}, author = {Agrawal, P and Khechaduri, A and Salladay, KR and MacCamy, A and Ralph, DK and Riker, A and Stuart, AB and Siddaramaiah, LK and Shen, X and Matsen, FA and Montefiori, D and Stamatatos, L}, title = {Increased immunogen valency improves the maturation of vaccine-elicited HIV-1 VRC01-like antibodies.}, journal = {PLoS pathogens}, volume = {21}, number = {5}, pages = {e1013039}, pmid = {40440315}, issn = {1553-7374}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; R01 AI143370/AI/NIAID NIH HHS/United States ; P01 AI138212/AI/NIAID NIH HHS/United States ; R01 AI177095/AI/NIAID NIH HHS/United States ; R56 AI177095/AI/NIAID NIH HHS/United States ; }, mesh = {*AIDS Vaccines/immunology ; *HIV Antibodies/immunology ; *HIV-1/immunology ; *Antibodies, Neutralizing/immunology ; Animals ; Humans ; *HIV Infections/immunology/prevention &amp; control ; *Antibodies, Monoclonal/immunology ; env Gene Products, Human Immunodeficiency Virus/immunology ; Mice ; Broadly Neutralizing Antibodies ; }, abstract = {Antibodies belonging to the VRC01-class display broad and potent neutralizing activities and have been isolated from several people living with HIV (PLWH). A member of that class, monoclonal antibody VRC01, was shown to reduce HIV-acquisition in two phase 2b efficacy trials. VRC01-class antibodies are therefore expected to be one component of an effective HIV-1 vaccine elicited response. In contrast to the VRC01-class antibodies that are highly mutated, their unmutated forms do not engage HIV-1 envelope (Env) and do not display neutralizing activities. Hence, specifically modified Env-derived proteins have been designed to engage the unmutated forms of VRC01-class antibodies, and to activate the corresponding naïve B cells. Selected heterologous Env must then be used as boost immunogens to guide the proper maturation of these elicited VRC01-class antibodies. Here we examined whether and how the valency of the prime and boost immunogens influences VRC01-class antibody-maturation. Our findings indicate that, indeed the valency of the immunogen affects the maturation of elicited antibody responses by preferentially selecting VRC01-like antibodies that have accumulated somatic mutations present in broadly neutralizing VRC01-class antibodies isolated from PLWH. As a result, antibodies isolated from animals immunized with the higher valency immunogens display broader Env cross-binding properties and improved neutralizing potentials than those isolated from animals immunized with the lower valency immunogens. Our results are relevant to current and upcoming phase 1 clinical trials that evaluate the ability of novel immunogens aiming to elicit cross-reactive VRC01-class antibody responses.}, }
@article {pmid40440319, year = {2025}, author = {Triplette, M and Omernik, B and Snidarich, M and Heffner, JL and Brooks, E and Crothers, K and Brown, MC and Murphy, NR and Louie, T}, title = {Tailored Patient Navigation to Support Lung Cancer Screening and Smoking Cessation in LGBTQ+ Individuals: A Pilot Study.}, journal = {Annals of the American Thoracic Society}, volume = {22}, number = {10}, pages = {1592-1600}, doi = {10.1513/AnnalsATS.202502-215OC}, pmid = {40440319}, issn = {2325-6621}, support = {/LUNG/LUNGevity Foundation/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Early Detection of Cancer/methods ; *Lung Neoplasms/diagnosis/prevention &amp; control ; *Patient Navigation ; Patient Satisfaction ; Pilot Projects ; Prospective Studies ; *Sexual and Gender Minorities ; *Smoking Cessation/methods ; }, abstract = {Rationale: Lung cancer is the leading cause of cancer death, with most cases attributable to cigarette smoking. People who identify as lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ+) are more likely to smoke; however, there are limited interventions to support lung cancer prevention in this community. Through prior community-engaged work, we developed a patient navigation intervention to support smoking cessation and lung cancer screening (LCS) for LGBTQ+ adults. Objectives: To conduct a prospective pilot study of the patient navigation intervention to evaluate patient satisfaction, acceptability, and knowledge change as well as LCS care completion and smoking cessation. Methods: We enrolled participants who currently smoked, identified as LGBTQ+, and were eligible for LCS in a patient navigation intervention and assessed outcomes over a 90-day period. We administered pre- and postintervention surveys, tracked navigation and LCS activities in the electronic health record, and verified tobacco cessation with exhaled carbon monoxide (CO) measurements. Primary outcomes included postintervention Acceptability of Intervention Measure scores, the Patient Satisfaction with Navigator Interpersonal Relationship score, and knowledge change on two validated measures. Secondary outcomes included being appropriately up-to-date on LCS and smoking cessation, measured as reported >7-day floating abstinence and end-of-study CO-confirmed [Formula: see text]30-day cessation. Results: Forty-one participants enrolled in the study and participated in the navigation program, with 34 completing postintervention surveys at Day 90. Acceptability (mean Acceptability of Intervention Measure score, 4.5) and patient satisfaction (mean Patient Satisfaction with Navigator Interpersonal Relationship score, 40.8) were both high. Fifty-nine percent of individuals were appropriately up-to-date on LCS at Day 90, as compared with 22% at baseline. Of postsurvey respondents, 41% reported a period of >7-day smoking abstinence during the study, with 18% reporting CO-confirmed abstinence of [Formula: see text]30 days at study end. Conclusions: Tailored patient navigation is a promising approach to enhance LCS uptake and smoking cessation in LCS-eligible LGBTQ+ individuals. Clinical trial registered with www.clinicaltrials.gov (NCT05304390).}, }
@article {pmid40441807, year = {2025}, author = {Seaton, KE and Paez, CA and Yu, C and Karuna, ST and Gamble, T and Miner, MD and Heptinstall, J and Zhang, L and Gao, F and Yacovone, M and Spiegel, H and Dumond, JB and Anderson, M and Piwowar-Manning, E and Dye, B and Tindale, I and Proulx-Burns, L and Trahey, M and Takuva, S and Takalani, A and Bailey, VC and Kalams, SA and Scott, H and Mkhize, NN and Weiner, JA and Ackerman, ME and McElrath, MJ and Pensiero, M and Barouch, DH and Montefiori, D and Tomaras, GD and Corey, L and Cohen, MS and Huang, Y and Mahomed, S and Siegel, M and Kelley, CF and , }, title = {Safety, pharmacokinetics, and neutralisation activity of PGDM1400LS, a V2 specific HIV-1 broadly neutralising antibody, infused intravenously or subcutaneously in people without HIV-1 in the USA (HVTN 140/HPTN 101 part A): a first-in-human, phase 1 randomised trial.}, journal = {The lancet. HIV}, volume = {12}, number = {6}, pages = {e405-e415}, pmid = {40441807}, issn = {2352-3018}, support = {UM1 AI154466/AI/NIAID NIH HHS/United States ; UM1 AI069469/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Adult ; Female ; Male ; Young Adult ; *HIV Antibodies/administration &amp; dosage/adverse effects/immunology ; *HIV-1/immunology ; Middle Aged ; Adolescent ; *HIV Infections/prevention &amp; control/immunology/drug therapy ; *Antibodies, Neutralizing/administration &amp; dosage/adverse effects/immunology ; United States ; *Broadly Neutralizing Antibodies/administration &amp; dosage/adverse effects ; Infusions, Intravenous ; *Antibodies, Monoclonal/administration &amp; dosage/pharmacokinetics/adverse effects ; }, abstract = {BACKGROUND: PGDM1400LS is a human monoclonal antibody targeting the HIV envelope V2 apex with a lysine-serine modification intended to enhance serum and tissue half-lives and is being considered for use in combination monoclonal antibody trials. We sought to test whether PGDM1400LS was safe and had favourable serum concentration, pharmacokinetics, and neutralising ability in healthy adults.<br><br>METHODS: HVTN 140/HPTN 101 part A is an open-label, dose escalation, first-in-human phase 1 trial of PGDM1400LS given intravenously or subcutaneously to healthy adults aged 18-50 years without HIV-1. The study enrolled participants at four sites in the USA, across five groups, each receiving one dose of PGDM1400-LS intravenously (group 1: 5 mg/kg; group 2: 20 mg/kg; and group 4: 40 mg/kg) or subcutaneously (group 3: 20 mg/kg; and group 5: 40 mg/kg). Participants in group 1 were enrolled sequentially without random assignment. Participants in groups 2 and 3 were block randomised and enrolled simultaneously after group 1 safety review. Groups 4 and 5 followed the same process, contingent on groups 2 and 3 safety review. The primary endpoints were safety and tolerability of PGDM1400LS, serum concentration of PGDM1400LS, and serum neutralising activity after single administration of PGDM1400LS. Serum PGDM1400LS concentrations collected at seven timepoints (day 0, day 3, day 6, day 28, day 56, day 112, and day 168) were assessed via an anti-idiotype binding assay and characterised via non-compartmental pharmacokinetic analysis. Serum neutralisation activity (ID80) was assessed by a TZM-bl assay. The study is registered with ClinicalTrials.gov, NCT05184452.<br><br>FINDINGS: Between Nov 15, 2021, and March 4, 2022, 15 participants were enrolled into the five study groups (three participants per group) with 6 months of follow-up. Ten of 15 participants were female, 14 of 15 participants were non-Hispanic, and 11 of 15 participants were White, with a median age of 27 years (range 24-47). PGDM1400LS was safe and well tolerated, with mild to moderate solicited symptoms. Serum concentrations showed dose proportionality by administration route, with peak concentrations observed immediately after intravenous infusion (range 95&#xb7;7-727&#xb7;4 &#x3bc;g/mL) or on day 6 after subcutaneous infusion (205&#xb7;6-547&#xb7;1 &#x3bc;g/mL). The median elimination half-life was 55 days (range 48-59), representing a 2-to-3-times increase versus parental PDGM1400. Estimated subcutaneous (vs intravenous) bioavailability was 50-60%. ID80 titres showed agreement with concentration-predicted ID80 titres, indicating maintenance of neutralisation activity in vivo.<br><br>INTERPRETATION: PGDM1400LS is a promising candidate for combination monoclonal antibody efficacy trials going forward.<br><br>FUNDING: National Institute of Allergy and Infectious Diseases-National Institutes of Health.}, }
@article {pmid40442371, year = {2025}, author = {Nugent, PJ and Park, H and Wladyka, CL and Yelland, JN and Sinha, S and Chen, KY and Bynum, C and Quarterman, G and Lee, SC and Hsieh, AC and Subramaniam, AR}, title = {Decoding post-transcriptional regulatory networks by RNA-linked CRISPR screening in human cells.}, journal = {Nature methods}, volume = {22}, number = {6}, pages = {1237-1246}, pmid = {40442371}, issn = {1548-7105}, support = {GM008268//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01 GM135362/GM/NIGMS NIH HHS/United States ; R01 CA292932/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; CA230617//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R35 GM119835/GM/NIGMS NIH HHS/United States ; 1846521//National Science Foundation (NSF)/ ; GM135362//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; S10 OD020069/OD/NIH HHS/United States ; R37 CA230617/CA/NCI NIH HHS/United States ; T32 GM008268/GM/NIGMS NIH HHS/United States ; R01 CA276308/CA/NCI NIH HHS/United States ; GM119835//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; CA276308//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *CRISPR-Cas Systems ; *Gene Regulatory Networks ; RNA, Guide, CRISPR-Cas Systems/genetics ; *Clustered Regularly Interspaced Short Palindromic Repeats ; HEK293 Cells ; Ribosomes/metabolism ; RNA, Messenger/genetics/metabolism ; *RNA/genetics/metabolism ; *RNA Processing, Post-Transcriptional ; }, abstract = {RNAs undergo a complex choreography of metabolic processes that are regulated by thousands of RNA-associated proteins. Here we introduce ReLiC, a scalable and high-throughput RNA-linked CRISPR approach to measure the responses of diverse RNA metabolic processes to knockout of 2,092 human genes encoding all known RNA-associated proteins. ReLiC relies on an iterative strategy to integrate genes encoding Cas9, single-guide RNAs (sgRNAs) and barcoded reporter libraries into a defined genomic locus. Combining ReLiC with polysome fractionation reveals key regulators of ribosome occupancy, uncovering links between translation and proteostasis. Isoform-specific ReLiC captures differential regulation of intron retention and exon skipping by SF3B complex subunits. Chemogenomic ReLiC screens decipher translational regulators upstream of messenger RNA (mRNA) decay and identify a role for the ribosome collision sensor GCN1 during treatment with the anti-leukemic drug homoharringtonine. Our work demonstrates ReLiC as a powerful framework for discovering and dissecting post-transcriptional regulatory networks in human cells.}, }
@article {pmid40443012, year = {2025}, author = {Brixner, D and Richardson, T and Lockhart, CM and Ramsey, S and Fox, J and Pritchard, D and Mcleod, H and Bobolts, L and Bourbeau, B and Crum, E}, title = {Optimization of oncology biomarker testing in managed care: Best practices and consensus recommendations from an AMCP Market Insights program.}, journal = {Journal of managed care &amp; specialty pharmacy}, volume = {31}, number = {6-a Suppl}, pages = {S1-S14}, pmid = {40443012}, issn = {2376-1032}, mesh = {Humans ; *Managed Care Programs/standards/organization &amp; administration ; *Biomarkers, Tumor/analysis ; *Precision Medicine/methods/standards/economics ; Delphi Technique ; *Neoplasms/diagnosis/therapy ; *Medical Oncology/standards ; Cost-Benefit Analysis ; Surveys and Questionnaires ; }, abstract = {Precision medicine in oncology using actionable molecular biomarkers to guide treatment selection has been associated with favorable outcomes; however, many potentially eligible patients do not receive it. This Academy of Managed Care Pharmacy Market Insights program sought to characterize unmet needs in biomarker testing among managed care stakeholders, to develop best practice and consensus recommendations to support addressing these needs, and to gain insights on potential quality measures related to biomarker testing. The program used a modified Delphi process and included in-depth interviews with expert panelists, a national survey of managed care professionals, and a consensus survey of experts. Areas of unmet need in biomarker testing identified were education, guidelines and protocols, timeliness, process, and equity. Twenty-two best practices were suggested by managed care experts and other stakeholders; 9 of these best practices achieved consensus. These consensus recommendations addressed biomarker test ordering and test performance, treatment decisions based on biomarker testing, cost-effectiveness of biomarker testing, and health disparities in access to biomarker testing. Opportunities for education and improvements in infrastructure to implement these recommendations were identified. Further investigation is needed to develop quality measures; although, valuable insights were gained.}, }
@article {pmid40444925, year = {2025}, author = {Jacobs, JM and Traeger, L and Freese, M and Barata, A and Newcomb, R and Rabideau, D and Horick, N and DeFilipp, Z and Chen, YB and Gray, T and Pepper, J and Caruso, E and Amonoo, HL and Lee, SJ and Greer, JA and Temel, JS and El-Jawahri, A}, title = {BMT-CARE App: A Randomized Controlled Trial of a Psychosocial Digital Application for Caregivers of Patients Undergoing Hematopoietic Stem-Cell Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {20}, pages = {2265-2275}, doi = {10.1200/JCO-25-00713}, pmid = {40444925}, issn = {1527-7755}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology ; *Caregivers/psychology ; Male ; Female ; Middle Aged ; Quality of Life ; *Mobile Applications ; Adult ; *Hematologic Neoplasms/therapy/psychology ; Anxiety ; Depression ; Aged ; Stress Disorders, Post-Traumatic/psychology ; }, abstract = {PURPOSE: Family and friend caregivers of patients undergoing hematopoietic stem-cell transplantation (HSCT) struggle with immense caregiving burden, leading to substantial quality of life (QOL) impairments and psychological distress. Yet, interventions to address caregivers' needs are limited.<br><br>MATERIALS AND METHODS: We conducted a randomized controlled trial of a psychosocial digital application (BMT-CARE App) versus usual care for adult caregivers of patients with hematologic malignancies undergoing HSCT. The BMT-CARE App included five modules combining psychoeducation and evidence-based behavior change strategies. Participants completed self-report measures at baseline and day 60 post-HSCT. The primary end point was QOL at day 60 assessed by the CareGiver Oncology QOL (CarGOQOL) measure. We also assessed caregiving burden (Caregiver Reaction Assessment), anxiety and depression symptoms (Hospital Anxiety and Depression Scale), and post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist [PCL-5]). We used analysis of covariance adjusting for baseline scores to assess the effect of the intervention on study outcomes.<br><br>RESULTS: Between February 2023 and July 2024, we enrolled 125 of 174 approached caregivers (71.8%). Participants assigned to the BMT-CARE App used the app for a median of 146.9 minutes (range, 0-384.8). At day 60, BMT-CARE App caregivers reported clinically and significantly better QOL than those assigned to usual care (adjusted means = 76.3 v 69.9, P = .006). BMT-CARE App participants also reported significantly lower caregiving burden (11.2 v 12.3, P = .023), depression (3.8 v 5.6, P = .002), and PTSD symptoms (26.1 v 31.3, P = .012). The groups did not differ significantly in anxiety symptoms at day 60.<br><br>CONCLUSION: The BMT-CARE App led to significantly improved QOL, caregiving burden, depression, and PTSD symptoms among HSCT caregivers. This intervention should be tested in a multicenter study with a diverse HSCT caregiver population to determine generalizability and scalability.}, }
@article {pmid40445115, year = {2025}, author = {Liang, M and Zhao, Y and Lin, DW and Cooperberg, M and Zheng, Y}, title = {Estimating optimally tailored active surveillance strategy under interval censoring.}, journal = {Biometrics}, volume = {81}, number = {2}, pages = {}, pmid = {40445115}, issn = {1541-0420}, support = {R01 CA236558/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; R01 CA236558/NH/NIH HHS/United States ; U24 CA086368/NH/NIH HHS/United States ; }, mesh = {Humans ; *Prostatic Neoplasms/pathology/diagnosis ; Male ; *Watchful Waiting/statistics &amp; numerical data/methods ; Computer Simulation ; Disease Progression ; Biopsy/statistics &amp; numerical data ; Cost-Benefit Analysis ; Models, Statistical ; Statistics, Nonparametric ; }, abstract = {Active surveillance (AS) using repeated biopsies to monitor disease progression has been a popular alternative to immediate surgical intervention in cancer care. However, a biopsy procedure is invasive and sometimes leads to severe side effects of infection and bleeding. To reduce the burden of repeated surveillance biopsies, biomarker-assistant decision rules are sought to replace the fix-for-all regimen with tailored biopsy intensity for individual patients. Constructing or evaluating such decision rules is challenging. The key AS outcome is often ascertained subject to interval censoring. Furthermore, patients will discontinue participation in the AS study once they receive a positive surveillance biopsy. Thus, patient dropout is affected by the outcomes of these biopsies. This work proposes a non-parametric kernel-based method to estimate a tailored AS strategy's true positive rates (TPRs) and true negative rates (TNRs), accounting for interval censoring and immediate dropouts. We develop a weighted classification framework based on these estimates to estimate the optimally tailored AS strategy and further incorporate the cost-benefit ratio for cost-effectiveness in medical decision-making. Theoretically, we provide a uniform generalization error bound of the derived AS strategy, accommodating all possible trade-offs between TPRs and TNRs. Simulation and application to a prostate cancer surveillance study show the superiority of the proposed method.}, }
@article {pmid40447392, year = {2025}, author = {Svatek, RS and Ankerst, DP and D' Amico, AV and Flaig, TW and Ford, LG and Goldkorn, A and Hernandez, J and Kumar, AP and Leach, RJ and Lerner, S and Liss, MA and McConkey, DJ and Minasian, L and Morilak, D and Mueller, EJ and Parekh, DJ and Platz, EA and Sudarshan, S and Unger, JM}, title = {A festschrift in honor of Ian M. Thompson Jr., MD.}, journal = {Urologic oncology}, volume = {43}, number = {7}, pages = {423-435}, doi = {10.1016/j.urolonc.2024.10.030}, pmid = {40447392}, issn = {1873-2496}, }
@article {pmid40447568, year = {2025}, author = {Hazelwood, E and Canson, DM and Deslandes, B and Wang, X and Kho, PF and Legge, D and Constantinescu, AE and Lee, MA and Bishop, DT and Chan, AT and Gruber, SB and Hampe, J and Le Marchand, L and Woods, MO and Pai, RK and Schmit, SL and Figueiredo, JC and Zheng, W and Huyghe, JR and Murphy, N and Gunter, MJ and Richardson, TG and Whitehall, VLJ and Vincent, EE and Glubb, DM and O'Mara, TA}, title = {Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5043}, pmid = {40447568}, issn = {2041-1723}, support = {MC_UU_00032/03//RCUK | Medical Research Council (MRC)/ ; C18281/A29019//Cancer Research UK (CRUK)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; APP1179170//Department of Health | National Health and Medical Research Council (NHMRC)/ ; U01 CA167551/CA/NCI NIH HHS/United States ; APP177524//Department of Health | National Health and Medical Research Council (NHMRC)/ ; C18281/A30905//Cancer Research UK (CRUK)/ ; T32 ES013678/ES/NIEHS NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P01 CA196569/CA/NCI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; 218495/Z/19/Z//Wellcome Trust (Wellcome)/ ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/pathology ; Female ; Male ; *Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Gene Expression Regulation, Neoplastic ; Transcriptome ; Sex Factors ; Polymorphism, Single Nucleotide ; *RNA Splicing/genetics ; Semaphorins/genetics ; Gene Expression Profiling ; }, abstract = {Genome-wide association studies have suggested numerous colorectal cancer (CRC) susceptibility genes, but their causality and therapeutic potential remain unclear. To prioritise causal associations between gene expression/splicing and CRC risk (52,775 cases; 45,940 controls), we perform a transcriptome-wide association study (TWAS) across six tissues with Mendelian randomisation and colocalisation, integrating sex- and anatomical subsite-specific analyses. Here we reveal 37 genes with robust causal links to CRC risk, ten of which have not previously been reported by TWAS. Most likely causal genes with evidence of cancer cell dependency show elevated expression linked to risk, suggesting therapeutic potential. Notably, SEMA4D, encoding a protein targeted by an investigational CRC therapy, emerges as a key risk gene. We also identify a female-specific association with CRC risk for CCM2 expression and subsite-specific associations, including LAMC1 with rectal cancer risk. These findings offer valuable insights into CRC molecular mechanisms and support promising therapeutic avenues.}, }
@article {pmid40447729, year = {2025}, author = {Sankaranarayanan, A and Khachaturov, G and Smythe, KS and Mittal, S}, title = {Quantitative benchmarking of nuclear segmentation algorithms in multiplexed immunofluorescence imaging for translational studies.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {836}, pmid = {40447729}, issn = {2399-3642}, mesh = {Humans ; *Cell Nucleus/metabolism ; Benchmarking ; *Algorithms ; *Fluorescent Antibody Technique/methods ; *Image Processing, Computer-Assisted/methods ; *Translational Research, Biomedical/methods ; }, abstract = {Multiplexed imaging techniques require identifying different cell types in the tissue. To utilize their potential for cellular and molecular analysis, high throughput and accurate analytical approaches are needed in parsing vast amounts of data, particularly in clinical settings. Nuclear segmentation errors propagate in all downstream steps of cell phenotyping and single-cell spatial analyses. Here, we benchmark and compare the nuclear segmentation tools commonly used in multiplexed immunofluorescence data by evaluating their performance across 7 tissue types encompassing ~20,000 labeled nuclei from human tissue samples. Pre-trained deep learning models outperform classical nuclear segmentation algorithms. Overall, Mesmer is recommended as it exhibits the highest nuclear segmentation accuracy with 0.67 F1-score at an IoU threshold of 0.5 on our composite dataset. Pre-trained StarDist model is recommended in case of limited computational resources, providing ~12x run time improvement with CPU compute and ~4x improvement with the GPU compute over Mesmer, but it struggles in dense nuclear regions.}, }
@article {pmid40448577, year = {2025}, author = {Shadman, M and Munir, T and Ma, S and Lasica, M and Tani, M and Robak, T and Flinn, IW and Brown, JR and Ghia, P and Ferrant, E and Tam, CS and Janowski, W and Jurczak, W and Xu, L and Tian, T and Lefebure, M and Agresti, S and Hirata, J and Tedeschi, A}, title = {Zanubrutinib and Venetoclax for Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma With and Without Del(17p)/TP53 Mutation: SEQUOIA Arm D Results.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {21}, pages = {2409-2417}, doi = {10.1200/JCO-25-00758}, pmid = {40448577}, issn = {1527-7755}, mesh = {Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Bridged Bicyclo Compounds, Heterocyclic/administration &amp; dosage/adverse effects/therapeutic use ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/genetics/pathology ; Mutation ; Piperidines/administration &amp; dosage/adverse effects ; *Pyrazoles/administration &amp; dosage/adverse effects/therapeutic use ; *Pyrimidines/administration &amp; dosage/adverse effects/therapeutic use ; *Sulfonamides/administration &amp; dosage/adverse effects/therapeutic use ; *Tumor Suppressor Protein p53/genetics ; }, abstract = {PURPOSE: Several chronic lymphocytic leukemia (CLL) studies have demonstrated promising efficacy with the combination of BCL2 and Bruton tyrosine kinase inhibitors; however, patients with CLL with del(17p) and/or TP53 mutation (TP53mut) comprised a small percentage of study populations or were excluded entirely. The purpose of the SEQUOIA Arm D cohort was to evaluate the combination of zanubrutinib + venetoclax in treatment-naïve (TN) patients with CLL/small lymphocytic lymphoma (SLL), in a large population of patients with TP53-aberrant disease.<br><br>PATIENTS AND METHODS: Arm D is a nonrandomized cohort of patients aged 65 years and older (or 18-64 years with comorbidities). Patients received zanubrutinib from cycle 1 and venetoclax from cycle 4 (ramp-up) to cycle 28, followed by continuous zanubrutinib monotherapy until progressive disease (PD), unacceptable toxicity, or meeting undetectable minimal residual disease (uMRD)-guided stopping criteria.<br><br>RESULTS: Between November 2019 and July 2022, 114 patients were enrolled: 66 (58%) with TP53-aberrant disease, 47 (41%) without TP53-aberrant disease, and 1 with missing TP53 results. At a median follow-up of 31.2 months, 85 patients (75%) remained on zanubrutinib monotherapy; 29 patients (25%) discontinued zanubrutinib because of adverse event, uMRD-guided stopping criteria, PD, or other. In the intention-to-treat population, 59% of patients achieved peripheral blood uMRD. The 24-month progression-free survival estimate was 92% (95% CI, 85% to 96%). The most common any-grade treatment-emergent AEs (TEAEs) were COVID-19 (54%), diarrhea (41%), contusion (32%), and nausea (30%). The most common grade &#x2265;3 TEAEs were neutropenia (17%), hypertension (10%), diarrhea (6%), and decreased neutrophil count (6%).<br><br>CONCLUSION: Zanubrutinib + venetoclax demonstrated impressive efficacy and a favorable safety profile in patients with TN CLL/SLL, regardless of the presence of TP53-aberrant disease.}, }
@article {pmid40448843, year = {2025}, author = {Hasenstab, KA and Lu, J and Leong, LT and Bossard, E and Pylarinou-Sinclair, E and Devi, K and Cunha, GM}, title = {Relationship between spleen volume and diameter for assessment of response to treatment on CT in patients with hematologic malignancies enrolled in clinical trials.}, journal = {Abdominal radiology (New York)}, volume = {50}, number = {12}, pages = {5799-5809}, pmid = {40448843}, issn = {2366-0058}, mesh = {Humans ; *Spleen/diagnostic imaging/pathology ; *Hematologic Neoplasms/therapy/diagnostic imaging/pathology ; Female ; *Tomography, X-Ray Computed/methods ; Male ; Middle Aged ; Organ Size ; Adult ; Aged ; Clinical Trials as Topic ; Prospective Studies ; Treatment Outcome ; }, abstract = {PURPOSE: Investigate spleen diameter (d) and volume (v) relationship in patients with hematologic malignancies (HM) by determining volumetric thresholds that best correlate to established diameter thresholds for assessing response to treatment. Exploratorily, interrogate the impact of volumetric measurements in response categories and as a predictor of response.<br><br>METHODS: Secondary analysis of prospectively collected clinical trial data of 382 patients with HM. Spleen diameters were computed following Lugano criteria and volumes using deep learning segmentation. d and v relationship was estimated using power regression model, volumetric thresholds ([Formula: see text]) for treatment response estimated; threshold search to determine percentual change ([Formula: see text] and minimum volumetric increase ([Formula: see text]) that maximize agreement with Lugano criteria performed. Spleen diameter and volume predictive performance for clinical response investigated using random forest model.<br><br>RESULTS: [Formula: see text] describes the relationship between spleen diameter and volume. [Formula: see text] for splenomegaly was 546&#xa0;cm&#xb3;. [Formula: see text], [Formula: see text], and [Formula: see text] for assessing response resulting in highest agreement with Lugano criteria were 570 cm[3], 73%, and 170 cm[3], respectively. Predictive performance for response between diameter and volume were not significantly different (P=0.78).<br><br>CONCLUSION: This study provides empirical spleen volume threshold and percentual changes that best correlate with diameter thresholds, i.e., Lugano criteria, for assessment of response to treatment in patients with HM. In our dataset use of spleen volumetric thresholds versus diameter thresholds resulted in similar response assessment categories and did not signal differences in predictive values for response.}, }
@article {pmid40450382, year = {2025}, author = {Cabahug, JPC and Cruzpero, RC and de Los Santos, LEF and Ford, EC and Yorke, AA}, title = {Radiotherapy medical physics in the Philippines: A contemporary overview.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {7}, pages = {e70129}, pmid = {40450382}, issn = {1526-9914}, support = {UH3 CA211310/CA/NCI NIH HHS/United States ; NCI 3UH3CA211310-04S1//NCI Diversity/ ; }, mesh = {Humans ; Philippines ; *Health Physics ; *Neoplasms/radiotherapy ; *Radiotherapy, Intensity-Modulated/methods ; Surveys and Questionnaires ; Radiosurgery/methods ; Radiotherapy Planning, Computer-Assisted/methods ; Particle Accelerators ; Radiotherapy Dosage ; *Radiation Oncology ; }, abstract = {PURPOSE: With cancer ranking as the third leading cause of death in the Philippines and a disparity in healthcare resources across regions, this research aimed to assess the state of radiotherapy medical physics in the country.<br><br>METHODOLOGY: The study utilized a comprehensive online survey with 94 structured questions answered by 19 clinics.<br><br>RESULTS: Most of the participants were within 1-3 years of training (41%), with a slight majority working in private hospitals (55%). linear accelerators (LINACs) were universally used with one Co-60 unit available, and High Dose Rate (HDR) brachytherapy was common. Intensity-Modulated Radiotherapy (IMRT) and 3D-Conformal Radiotherapy (3D-CRT) are practiced in all 19 clinics, with advanced techniques like Stereotactic Body Radiotherapy (SBRT), Stereotactic Radiosurgery (SRS), and Intraoperative Radiotherapy (IORT) limited to NCR, while modalities such as Volumetric Modulated Arc Therapy (VMAT) (21%) and 2D RT (68%) are more widely practiced. Imaging modalities included the wide adoption of Computed Tomography (CT), though only 64% of respondents had dedicated CT simulators in their clinics. Gynecologic and breast cancers were frequently treated, while bone marrow transplants (total body irradiation) were rare. For quality assurance (QA) devices, Solid Water Phantoms and Scanning Water Tanks (86%) were the most common devices for dosimetry and measurement. 82% reported performing patient-specific QA (PSQA), with EPID dosimetry being the most common (55%) PSQA device used. Quality management practices varied between Qualified Medical Physicists and Medical Physics Trainees, with most Qualified Medical Physicists performing routine checks. Treatment interruptions were mainly due to staffing and machine downtime, rather than power outages or natural disasters. Most clinics had their own systems (86%) to document safety incidents, but only a few reported incidents (32%) to the IAEA SAFRON program. Lastly, participants expressed a willingness to collaborate in research despite limited time.<br><br>CONCLUSION: This study provides an understanding of the current landscape of radiation therapy physics in the Philippines, highlighting the need to address workforce disparities, ensure equitable cancer treatment access, optimize dosimetric tools and QA devices, and prioritize resource allocation and research collaboration to advance radiation oncology practices.}, }
@article {pmid40450573, year = {2025}, author = {Stein, MN and Vinceneux, A and Robbrecht, D and Doger, B and Autio, KA and Schweizer, MT and Calvo, E and Medina, L and Van Dongen, M and Deville, JL and Bernard-Tessier, A and Ghosh, D and Shotts, K and Shen, F and Jaiprasart, P and Chaudhary, R and Wu, S and Cartee, L and Schnepp, R and Gaut, D and Lauring, J and Wang, SC and Villalobos, VM and Baldini, C}, title = {Pasritamig, a First-in-Class, Bispecific T-Cell Engager Targeting Human Kallikrein 2, in Metastatic Castration-Resistant Prostate Cancer: A Phase I Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {22}, pages = {2515-2526}, pmid = {40450573}, issn = {1527-7755}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Aged ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology/immunology ; Middle Aged ; *Antibodies, Bispecific/adverse effects/administration &amp; dosage/therapeutic use ; Aged, 80 and over ; *T-Lymphocytes/immunology/drug effects ; *Kallikreins/immunology/antagonists &amp; inhibitors ; *Tissue Kallikreins/immunology/antagonists &amp; inhibitors ; }, abstract = {PURPOSE: We report phase I trial results for pasritamig, a first-in-class, T-cell-engaging bispecific antibody targeting human kallikrein 2 (KLK2) expressed on the surface of prostate cancer (PC) cells.<br><br>METHODS: Participants had metastatic castration-resistant PC and &#x2265;1 prior therapy. Pasritamig was escalated from 0.5 mg to 2,000 mg for subcutaneous administration and from 150 mg to 900 mg for intravenous (IV) administration at dosing frequencies ranging from once every week to once every 6 weeks with different step-up dosing schedules. The primary objectives were to determine safety and the recommended phase II dose (RP2D) of pasritamig. Secondary objectives included preliminary assessment of antitumor activity.<br><br>RESULTS: One hundred seventy-four participants received pasritamig, with a median of 4 prior lines of systemic therapy. Treatment-related adverse events (TRAEs) occurred in 144 of 174 (82.8%) participants, with 17 of 174 (9.8%) experiencing grade &#x2265;3 TRAEs. The RP2D was determined to be 3.5 mg (day 1), 18 mg (day 8), 300 mg (day 15), and then 300 mg IV once every 6 weeks. In the RP2D safety population (n = 45), infusion-related reactions (11/45, 24.4%), fatigue (7/45, 15.6%), cytokine release syndrome (CRS; 4/45, 8.9%, all grade 1), and lipase increase (4/45, 8.9%) were the most frequent TRAEs; all were grade 1 or 2. In the RP2D efficacy population (n = 33), median radiographic progression-free survival was 7.85 (95% CI, 2.89 to not estimable) months, and 14 of 33 (42.4%) participants achieved a &#x2265;50% decrease from baseline in prostate-specific antigen.<br><br>CONCLUSION: Pasritamig demonstrated a favorable safety profile with very low rates of CRS and could be safely administered in an outpatient setting. Preliminary antitumor activity demonstrated proof of concept for KLK2 as a target in PC, warranting further development of pasritamig.}, }
@article {pmid40451158, year = {2025}, author = {Scadden, AW and Kakar, A and Litkowski, EM and Meyer, MC and Armstrong, ND and Buyske, S and Cai, Y and Cheng, I and Darst, BF and Fornage, M and Graff, M and Guo, B and Haiman, CA and Highland, HM and Kooperberg, C and Le Marchand, L and North, K and Peters, U and Rich, SS and Rotter, JI and Srinivasasainagendra, V and Tiwari, HK and Waldrop, S and Young, K and Raghavan, S and Lange, EM and Lange, LA and Irvin, MR and Stanislawski, MA}, title = {Type 2 Diabetes Polygenic Risk Score Interactions with Lifestyle Risk Factors in Black Americans.}, journal = {Lifestyle genomics}, volume = {18}, number = {1}, pages = {90-97}, pmid = {40451158}, issn = {2504-3188}, support = {N01 HC095168/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 HG004802/HG/NHGRI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; R01 HL086694/HL/NHLBI NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; U01 HG004402/HG/NHGRI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; K01 HL157658/HL/NHLBI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; UL1 RR025005/RR/NCRR NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; R01 HL136666/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 NS041588/NS/NINDS NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; HHSN268201800012I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; R01 NS136542/NS/NINDS NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; R35 HL155466/HL/NHLBI NIH HHS/United States ; U01 CA098758/CA/NCI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL087641/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; U01 CA136792/CA/NCI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Black or African American/genetics ; Body Mass Index ; Cohort Studies ; *Diabetes Mellitus, Type 2/genetics/epidemiology ; *Genetic Risk Score ; *Life Style ; Logistic Models ; Multifactorial Inheritance ; }, abstract = {INTRODUCTION: Prior work in predominantly European ancestry populations has explained how the risk associated with demographic, lifestyle, and health factors differs with underlying genetic susceptibility to type 2 diabetes (T2D), but less is known about these relationships in Black Americans.<br><br>METHODS: We used covariate-adjusted logistic regression models of T2D to examine interactions between a published trans-ancestry derived T2D polygenic risk score (PRS) and various demographic, lifestyle, and health-related factors among 28,251 self-identified Black Americans from six cohort studies.<br><br>RESULTS: The results are generally consistent with prior work in White populations. The PRS showed a significant interaction with body mass index, with a greater effect on T2D risk in individuals who were leaner (pinteraction = 0.038).<br><br>CONCLUSION: These results contribute to understanding the relationship between genetics and other T2D risk factors in Black Americans who have a high burden of T2D, potentially informing targeted prevention strategies.}, }
@article {pmid40451460, year = {2025}, author = {Kang, DW and Ficarra, S and Wilson, RL and Morgans, AK and Nguyen, PL and Rebbeck, TR and Einstein, DJ and Uno, H and Mossanen, M and Hill, DM and Gonzalo-Encabo, P and Norris, MK and Gardiner, J and Tjogas, D and Greer, J and Dieli-Conwright, CM}, title = {Exercise to enhance cardiovascular health among black men with prostate cancer with androgen deprivation therapy (the POWER trial): A study protocol.}, journal = {Contemporary clinical trials}, volume = {155}, number = {}, pages = {107973}, doi = {10.1016/j.cct.2025.107973}, pmid = {40451460}, issn = {1559-2030}, mesh = {Humans ; Male ; Middle Aged ; *Androgen Antagonists/therapeutic use ; *Black or African American ; *Cardiovascular Diseases/prevention &amp; control/ethnology ; *Exercise Therapy/methods ; Heart Disease Risk Factors ; *Prostatic Neoplasms/drug therapy/therapy/ethnology ; Randomized Controlled Trials as Topic ; Resistance Training/methods ; }, abstract = {BACKGROUND: Black men in the US are 1.8 and 2.2 times more likely to develop and die from prostate cancer (PCa) than non-Hispanic White men, respectively, and have the highest incidence globally. Furthermore, Black men undergoing androgen deprivation therapy (ADT) for PCa face a higher risk of cardiovascular disease (CVD) compared to men of other racial groups. Therefore, we have designed a randomized controlled trial (RCT) to investigate the impact of exercise on CVD risk factors among Black man undergoing ADT.<br><br>METHODS: The POWER trial is a dual-arm RCT designed to examine the effects of a 16-week, culturally tailored, remotely supervised cardiovascular and strength exercise program on Black men with PCa receiving ADT. Sixty-two patients will be randomized in a 1:1 allocation to either the exercise intervention or a waitlist control group. The patient population includes adult males who self-identify as Black, receiving ADT for at least four months prospectively at the time of recruitment. The primary outcome is the CVD risk assessed using the Framingham Risk Score. The secondary and exploratory outcomes include physical fitness and function, patient-reported outcomes, and clinical events at a one-year follow-up.<br><br>DISCUSSION: The POWER Trial evaluates a culturally tailored exercise program for Black men with PCa undergoing ADT, focusing on improving cardiovascular health. The findings of the study are expected to inform a larger phase clinical trial to examine long-term CVD-related clinical outcomes. Ultimately, our findings and subsequent trials would narrow the gap in health disparities among the communities of Black men with PCa.<br><br>TRIAL REGISTRATION: NCT05327465.}, }
@article {pmid40451709, year = {2025}, author = {St Laurent, MP and Psutka, SP}, title = {Reply to Chang-kun Mao, Chao-Yang, and Jun-ting Li's Letter to the Editor re: Marie-Pier St-Laurent, Bernard Bochner, James Catto, et al. Increasing Life Expectancy in Patients with Genitourinary Malignancies: Impact of Treatment Burden on Disease Management and Quality of Life. Eur Urol. 2025;88:11-20.}, journal = {European urology}, volume = {88}, number = {3}, pages = {e55}, doi = {10.1016/j.eururo.2025.02.004}, pmid = {40451709}, issn = {1873-7560}, }
@article {pmid40451731, year = {2026}, author = {Kmail, ZM and Shannon Dorcy, K and Laing, SS}, title = {Burnout Predictors Among Direct Clinical Services Health Care Professionals in Community Health Centers: A Cross-Sectional Study.}, journal = {American journal of health promotion : AJHP}, volume = {40}, number = {1}, pages = {28-37}, doi = {10.1177/08901171251348220}, pmid = {40451731}, issn = {2168-6602}, mesh = {Humans ; *Burnout, Professional/epidemiology ; Cross-Sectional Studies ; Female ; Male ; *Community Health Centers/organization &amp; administration/statistics &amp; numerical data ; Adult ; Middle Aged ; *Health Personnel/psychology/statistics &amp; numerical data ; Workload/psychology ; Work-Life Balance ; Surveys and Questionnaires ; Prevalence ; }, abstract = {PurposeAssess burnout prevalence, identify the healthcare professionals experiencing burnout, and identify organizational predictors of burnout in community health centers (CHCs) nationwide.ApproachIn 2022 the Health Resources and Services Administration administered surveys to assess health center workforce well-being among the 1400+ community health centers that it oversees. Our team statistically evaluated the findings to isolate the factors likely to predict burnout among center healthcare professionals.SettingData completed by staff in 694 CHCs.ParticipantsRespondents were 52 568 healthcare professionals.MethodsChi-squared tests derived homogeneity in burnout among occupations; proportion tests evaluated differences in burnout indicators; and structural equation modeling with latent variables estimated direct and indirect effects of organizational burnout predictors and mediators.ResultsUp to 77% of direct clinical service professionals endorsed at least one symptom of burnout and reported higher burnout rates than management (P < .001). The most significant burnout predictors were engagement (-0.263***), work-life balance (0.281***), workload (0.174***) and professional growth (0.143***). For engagement, a perception of disconnection with the CHC predicted heightened burnout. Work-life balance, workload, and professional growth each had a positive effect on burnout, demonstrating that higher perceived work demands, greater work-life imbalance, and increased professional growth opportunities equated to higher burnout.ConclusionResults highlight the need to redesign healthcare delivery models to mitigate burnout, promote provider engagement and enhance workforce well-being.}, }
@article {pmid40453059, year = {2024}, author = {DeZern, AE and Goll, JB and Jensen, TL and Nonavinkere Srivatsan, S and Gillis, NK and Abel, GA and Padron, E and Deeg, HJ and Al Baghdadi, T and Liu, JJ and Komrokji, RS and Gore, SD and Saber, W and Bejar, R and Walter, MJ and Lindsley, RC and Sherman, S and DiFronzo, N and Sekeres, MA}, title = {Correlation between peripheral blood and bone marrow mutations among patients with MDS from the National MDS Study.}, journal = {Blood neoplasia}, volume = {1}, number = {3}, pages = {100026}, pmid = {40453059}, issn = {2950-3280}, }
@article {pmid40454419, year = {2025}, author = {Stone, D and Takeuchi, R and Dulin, H and Loprieno, MA and Strongin, DE and Sathees, S and Cradick, TJ and Aubert, M and Roychoudhury, P and Gordon, J and Jerome, KR}, title = {Serum factors create species-specific barriers to hepatic gene transfer by lipid nanoparticles in liver-humanized mice.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {33}, number = {2}, pages = {101470}, pmid = {40454419}, issn = {2329-0501}, support = {R01 AI175949/AI/NIAID NIH HHS/United States ; T32 AI007509/AI/NIAID NIH HHS/United States ; }, abstract = {Lipid nanoparticles (LNPs) can efficiently deliver nucleic acid therapeutics to a range of tissues, particularly hepatocytes to treat diseases of the liver. We initially investigated whether three LNPs with different ionizable lipids, previously validated in non-human primates (NHPs), could deliver functional GFP mRNA to human hepatocytes in chimeric NSG-PiZ and FRG mice. After intravenous delivery, GFP expression was observed throughout the livers but was restricted to mouse hepatocytes because the payload mRNA was not internalized by human hepatocytes. LNP transfection was also restricted to mouse hepatocytes in NSG-PiZ mice administered a different LNP containing the ionizable lipid SM-102. In vitro, primary human hepatocytes (PHHs) were transfected by LNPs containing lipids SM-102, LP01, or ALC0315 in the presence of normal mouse serum, but not chimeric NSG-PiZ serum. SM-102 LNP transfection of PHH was also inhibited by naive untransplanted NSG-PiZ serum. However, serum from NSG mice supported PHH transfection by SM-102 LNP. These results suggest that inhibitory factors in NSG-PiZ mouse serum are responsible for the lack of human hepatocyte transduction in chimeric mice. Finally, we found that LNPs displaying trivalent N-acetylgalactosamine (TriGalNAc), which targets them to the asialoglycoprotein receptor, can overcome species restriction, transfecting both mouse and human hepatocytes in chimeric NSG-PiZ mice.}, }
@article {pmid40454483, year = {2025}, author = {Duan, Z and Shi, M and Kumaraswamy, A and Lin, D and Khokhani, D and Wang, Y and Zhang, C and Flores, D and Rodansky, E and Swaim, OA and Storck, WK and Beck, HN and Patel, RA and Sayar, E and Hanratty, BP and Xue, H and Dong, X and Maylin, ZR and Wan, R and Quigley, DA and Sjöström, M and Hu, YM and Zhao, F and Xia, Z and Cheng, S and Yu, X and Feng, FY and Zhang, L and Aggarwal, R and Small, EJ and Ravikumar, V and Rao, A and Bedi, K and Lee, JK and Morrissey, C and Coleman, I and Nelson, PS and Corey, E and Udager, AM and Rebernick, RJ and Cieslik, MP and Chinnaiyan, AM and Yates, JA and Haffner, MC and Wang, Y and Alumkal, JJ}, title = {PROX1 is an early driver of lineage plasticity in prostate cancer.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {11}, pages = {}, pmid = {40454483}, issn = {1558-8238}, support = {P50 CA275741/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R50 CA274336/CA/NCI NIH HHS/United States ; R01 GM147365/GM/NIGMS NIH HHS/United States ; T32 GM007863/GM/NIGMS NIH HHS/United States ; R37 CA214955/CA/NCI NIH HHS/United States ; R01 CA291986/CA/NCI NIH HHS/United States ; P50 CA186786/CA/NCI NIH HHS/United States ; R01 CA282005/CA/NCI NIH HHS/United States ; T90 DE030859/DE/NIDCR NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; P30 CA046592/CA/NCI NIH HHS/United States ; R01 CA251245/CA/NCI NIH HHS/United States ; }, mesh = {Male ; *Prostatic Neoplasms/pathology/metabolism/genetics ; Prospero-Related Homeobox 1 Protein ; Humans ; *Tumor Suppressor Proteins/genetics/metabolism ; *Homeodomain Proteins/genetics/metabolism ; Animals ; Mice ; Cell Line, Tumor ; DNA Methylation ; *Gene Expression Regulation, Neoplastic ; *Cell Lineage ; *Cell Plasticity ; }, abstract = {Lineage plasticity is recognized as a critical determinant of lethality and resistance to AR pathway inhibitors in prostate cancer. Lineage plasticity is a continuum, ranging from AR activity-low tumors, AR-null tumors that do not express a neuroendocrine prostate cancer (NEPC) program (i.e., double-negative prostate cancer [DNPC]), and AR-null NEPC tumors. Factors upregulated early in lineage plasticity are not well-characterized. The clarification of such factors is essential to identify tumors undergoing lineage plasticity or at risk of this occurring. Our integrative analysis of metastatic prostate cancer patient tumors, patient-derived xenografts, and cell models determined that PROX1 is upregulated early in the lineage plasticity continuum and progressively increases as tumors lose AR activity. We determined DNA methylation is a key regulator of PROX1 expression. PROX1 suppression in DNPC and NEPC reduces cell survival and impacts apoptosis and differentiation, demonstrating PROX1's functional importance. PROX1 is not directly targetable with standard drug development approaches. However, affinity immunopurification demonstrated histone deacetylases (HDACs) are among the top PROX1-interacting proteins; HDAC inhibition depletes PROX1 and recapitulates PROX1 suppression in DNPC and NEPC. Altogether, our results suggest PROX1 promotes the emergence of lineage plasticity, and HDAC inhibition is a promising approach to treat tumors across the lineage plasticity continuum.}, }
@article {pmid40455079, year = {2025}, author = {DiPeso, L and Pendyala, S and Huang, HZ and Fowler, DM and Hatch, EM}, title = {Image-based identification and isolation of micronucleated cells to dissect cellular consequences.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40455079}, issn = {2050-084X}, support = {T32CA009657/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; R35GM124766/GM/NIGMS NIH HHS/United States ; R35 GM124766/GM/NIGMS NIH HHS/United States ; P30CA015704/CA/NCI NIH HHS/United States ; Scholars Program//Rita Allen Foundation/ ; T32 CA009657/CA/NCI NIH HHS/United States ; RM1HG010461/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Micronuclei, Chromosome-Defective ; Transcriptome ; Cell Line ; *Cell Separation/methods ; Genomic Instability ; *Image Processing, Computer-Assisted/methods ; }, abstract = {Recent advances in isolating cells based on visual phenotypes have transformed our ability to identify the mechanisms and consequences of complex traits. Micronucleus (MN) formation is a frequent outcome of genome instability, triggers extensive changes in genome structure and signaling coincident with MN rupture, and is almost exclusively defined by visual analysis. Automated MN detection in microscopy images has proved challenging, limiting discovery of the mechanisms and consequences of MN. In this study we describe two new MN segmentation modules: a rapid model for classifying micronucleated cells and their rupture status (VCS MN), and a robust model for accurate MN segmentation (MNFinder) from a broad range of cell lines. As proof-of-concept, we define the transcriptome of non-transformed human cells with intact or ruptured MN after chromosome missegregation by combining VCS MN with photoactivation-based cell isolation and RNASeq. Surprisingly, we find that neither MN formation nor rupture triggers a strong unique transcriptional response. Instead, transcriptional changes appear correlated with small increases in aneuploidy in these cell classes. Our MN segmentation modules overcome a significant challenge with reproducible MN quantification, and, joined with visual cell sorting, enable the application of powerful functional genomics assays to a wide-range of questions in MN biology.}, }
@article {pmid40455131, year = {2025}, author = {van den Bruele, AB and Rosenberger, LH and Downs-Canner, S and Flanagan, MR}, title = {ASO Author Reflections: Contralateral Axillary Lymph Node Metastasis of Breast Cancer: Time to Re-evaluate Conventional Thinking.}, journal = {Annals of surgical oncology}, volume = {32}, number = {8}, pages = {5578-5579}, pmid = {40455131}, issn = {1534-4681}, }
@article {pmid40455622, year = {2025}, author = {Shaukat, A and Burke, CA and Chan, AT and Grady, WM and Gupta, S and Katona, BW and Ladabaum, U and Liang, PS and Liu, JJ and Putcha, G and Robertson, DJ and Schoen, RE and Meng, Z and Piscitello, A and Sun, CK and Xu, C and Lin, CJ and Lee, LC and Baldo, L and Levin, TR and , }, title = {Clinical Validation of a Circulating Tumor DNA-Based Blood Test to Screen for Colorectal Cancer.}, journal = {JAMA}, volume = {334}, number = {1}, pages = {56-63}, pmid = {40455622}, issn = {1538-3598}, support = {K08 CA230162/CA/NCI NIH HHS/United States ; U01 CA271884/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Circulating Tumor DNA/blood ; Colon/diagnostic imaging/pathology ; Colonoscopy ; *Colorectal Neoplasms/diagnosis/blood/pathology ; Cross-Sectional Studies ; *Early Detection of Cancer/methods ; *Precancerous Conditions/blood/diagnosis/pathology ; Prospective Studies ; Sensitivity and Specificity ; *Mass Screening/methods ; }, abstract = {IMPORTANCE: Colorectal cancer screening is widely recommended but underused. Blood-based screening offers the potential for higher adherence compared with endoscopy or stool-based testing but must first be clinically validated in a screening population.<br><br>OBJECTIVE: To evaluate the clinical performance of an investigational blood-based circulating tumor DNA test for colorectal cancer detection in an average-risk population using colonoscopy with histopathology as the reference method.<br><br>Prospective, multicenter, cross-sectional observational study enrolling participants between May 2020 and April 2022 who were asymptomatic adults aged 45 to 85 years, at average risk of colorectal cancer, and willing to undergo a standard-of-care screening colonoscopy. Participants, staff, and pathologists were blinded to blood test results, and laboratory testing was performed blinded to colonoscopy findings. The study was conducted at 201 centers across 49 US states and the United Arab Emirates. Site-based and mobile phlebotomy were used for blood collection.<br><br>EXPOSURES: Participants were required to complete a screening colonoscopy after blood collection.<br><br>MAIN OUTCOMES AND MEASURES: The primary end points were sensitivity for colorectal cancer, specificity for advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions), negative predictive value for advanced colorectal neoplasia, and positive predictive value for advanced colorectal neoplasia. The secondary end point was sensitivity for advanced precancerous lesions.<br><br>RESULTS: The median age of participants in the evaluable cohort (n&#x2009;=&#x2009;27&#x202f;010) was 57.0 years, and 55.8% were women. Sensitivity for colorectal cancer was 79.2% (57/72; 95% CI, 68.4%-86.9%) and specificity for advanced colorectal neoplasia was 91.5% (22&#x202f;306/24&#x202f;371; 95% CI, 91.2%-91.9%). The negative predictive value for advanced colorectal neoplasia was 90.8% (22&#x202f;306/24&#x202f;567; 95% CI, 90.7%-90.9%) and the positive predictive value for advanced colorectal neoplasia was 15.5% (378/2443; 95% CI, 14.2%-16.8%). All primary end points met prespecified acceptance criteria. The sensitivity for advanced precancerous lesions was 12.5% (321/2567; 95% CI, 11.3%-13.8%), which did not meet the prespecified acceptance criterion.<br><br>CONCLUSIONS AND RELEVANCE: In an average-risk colorectal cancer screening population, a blood-based test demonstrated acceptable accuracy for colorectal cancer detection, but detection of advanced precancerous lesions remains a challenge, and ongoing efforts are needed to improve test sensitivity.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04369053.}, }
@article {pmid40455801, year = {2025}, author = {Huang, Y and Prentice, RL}, title = {Biomarker-assisted reporting in nutritional epidemiology: addressing measurement error in exposure-disease associations.}, journal = {Biostatistics (Oxford, England)}, volume = {26}, number = {1}, pages = {}, pmid = {40455801}, issn = {1468-4357}, support = {R01 CA277133/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers/analysis ; Bias ; *Diet/statistics &amp; numerical data ; Cardiovascular Diseases/epidemiology/etiology ; Female ; Proportional Hazards Models ; Self Report ; }, abstract = {In nutritional epidemiology, self-reported dietary data are commonly used to investigate diet-disease relationships. However, the resulting association estimates are often subject to biases due to random and systematic measurement errors. Regression calibration has emerged as a crucial method for addressing these biases by refining self-reported nutrient intake with objective biomarkers, which differ from the true values only by a random "noise" component. This paper presents methodological tools for analyzing nutritional epidemiology cohort studies involving time-to-event data when a biomarker subsample is available alongside dietary assessments. We introduce novel regression calibration methods to tackle two common challenges in this field. First, a widely used approach assumes that the log hazard ratio (HR) follows a linear function of dietary exposure. However, assessing whether this assumption holds-or if a more flexible model is needed to capture potential deviations from linearity-is often necessary. Second, another prevalent analytical strategy involves estimating HRs based on categorized dietary exposure variables. New methods are critically needed to minimize bias in defining category boundaries and estimating hazard ratios within exposure categories, both of which can be distorted by measurement error. We apply these methods to reassess the relationship between sodium and potassium intake and cardiovascular disease risk using data from the Women's Health Initiative.}, }
@article {pmid40456294, year = {2025}, author = {Tsai, J and Grassberger, C and Nyflot, MJ and Thonglert, K and Zaki, P and Nguyen, MH and Schaub, SK and Apisarnthanarax, S and Bowen, SR}, title = {Functional liver imaging and dosimetry for risk stratification in patients with hepatocellular carcinoma undergoing radiotherapy: validation study.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {209}, number = {}, pages = {110963}, doi = {10.1016/j.radonc.2025.110963}, pmid = {40456294}, issn = {1879-0887}, mesh = {Humans ; *Carcinoma, Hepatocellular/radiotherapy/diagnostic imaging/mortality/pathology ; *Liver Neoplasms/radiotherapy/diagnostic imaging/mortality/pathology ; Female ; Male ; Middle Aged ; Aged ; Risk Assessment ; Radiotherapy Dosage ; Single Photon Emission Computed Tomography Computed Tomography ; Radiotherapy Planning, Computer-Assisted/methods ; Retrospective Studies ; Liver/diagnostic imaging/radiation effects ; }, abstract = {BACKGROUND: Functional liver imaging has potential to personalize management of Hepatocellular Carcinoma (HCC) by mitigating hepatotoxicity risk. We validated functional liver imaging and dosimetric parameters for risk-stratification in an expanded cohort of patients with HCC.<br><br>METHODS: We reviewed 109 consecutive patients who underwent Sulfur Colloid (SC)-SPECT/CT scans for radiation therapy (RT) planning and extracted previously reported functional liver imaging metrics. We generated elastic net multivariable Cox models with event-stratified and nested cross-validation folds to predict Overall Survival (OS) and increase in Child-Pugh score&#xa0;&#x2265;&#xa0;2 (CP+2). Test-fold patients were risk-stratified, and time-dependent model performance was characterized. ROC analysis generated prognostic cutoffs with confidence intervals to guide functional liver avoidance treatment planning.<br><br>RESULTS: Cross-validated model concordance was 0.70 (95% CI: 0.67-0.73) for OS and 0.67 (95% CI: 0.63-0.71) for CP+2. Top-ranked OS predictors included tumor volume (HR=1.56, 1.54-1.58), CP-score (HR=1.36, 1.34-1.38), Liver-GTV V20 (HR=1.310, 1.306-1.314), prior liver-directed therapy (HR=0.83, 0.82-0.85), functional liver volume dosimetry (FLV V20) (HR=1.19, 1.14-1.23), and RT-year (HR=0.89, 0.88-0.91). Top-ranked CP+2 predictors were total liver function (TLF) (HR=0.64, 0.63-0.66), Liver-GTV mean dose (HR=1.40, 1.36-1.49), and CP-score (HR=1.19, 1.16-1.23). Test-fold risk groups were defined for each endpoint (log-rank P<0.001). OS model performance stabilized beyond 2&#xa0;years; CP+2 model stability peaked within 1&#xa0;year. Optimal strata for 2-yr OS were FLV V20&#xa0;<&#xa0;25.8% and Liver-GTV V20&#xa0;<&#xa0;25.4%; 1-yr CP+2 strata were TLF&#xa0;<&#xa0;0.91 and Liver-GTV mean dose&#xa0;<&#xa0;18.9&#xa0;Gy.<br><br>CONCLUSION: Functional liver metrics on SC-SPECT/CT were validated alongside clinical and dosimetric factors within robust outcome models. Testing of personalized RT planning for patients with HCC to preserve liver function is warranted in clinical trials.}, }
@article {pmid40456670, year = {2025}, author = {Hoffman-Censits, J and Tsiatas, M and Chang, PM and Kim, M and Antonuzzo, L and Shin, SJ and Gakis, G and Blais, N and Kim, SH and Smith, A and Arranz Arija, JA and Su, YL and Zagouri, F and Maruzzo, M and Tournigand, C and Forget, F and Schneider, A and Tyroller, K and Jacob, N and Grivas, P and Valderrama, BP}, title = {Avelumab plus sacituzumab govitecan versus avelumab monotherapy as first-line maintenance treatment in patients with advanced urothelial carcinoma: JAVELIN Bladder Medley interim analysis.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {9}, pages = {1088-1095}, doi = {10.1016/j.annonc.2025.05.010}, pmid = {40456670}, issn = {1569-8041}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects/therapeutic use ; Male ; Female ; Aged ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; *Urinary Bladder Neoplasms/drug therapy/pathology/mortality ; *Camptothecin/analogs &amp; derivatives/administration &amp; dosage/adverse effects/therapeutic use ; *Antibodies, Bispecific/administration &amp; dosage/adverse effects/therapeutic use ; *Carcinoma, Transitional Cell/drug therapy/pathology/mortality ; Progression-Free Survival ; Aged, 80 and over ; Adult ; Maintenance Chemotherapy ; Immunoconjugates ; }, abstract = {BACKGROUND: Avelumab first-line maintenance is a recommended treatment option for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) without progression following platinum-based chemotherapy (PBC). The JAVELIN Bladder Medley phase II trial is investigating the efficacy and safety of maintenance treatment with avelumab combined with other antitumor agents versus avelumab monotherapy. We report an interim analysis of avelumab plus sacituzumab govitecan (SG) versus avelumab monotherapy.<br><br>PATIENTS AND METHODS: Patients with la/mUC without progression after first-line PBC were randomized 2 : 1 to receive avelumab (800 mg every 2 weeks) plus SG (10 mg/kg on days 1 and 8 of 21-day cycles) or avelumab monotherapy (800 mg every 2 weeks). Primary endpoints are investigator-assessed progression-free survival (PFS) and safety. For PFS and overall survival (OS), data in the avelumab monotherapy arm were extended per protocol using propensity score-weighted JAVELIN Bladder 100 data.<br><br>RESULTS: At data cut-off (16 September 2024), 38/74 patients (51.4%) in the avelumab plus SG arm and 10/37 patients (27.0%) in the avelumab monotherapy arm were still receiving study treatment. Median PFS with avelumab plus SG versus avelumab monotherapy was 11.17 versus 3.75 months, respectively [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.31-0.76; prespecified efficacy boundary: HR &#x2264; 0.60]. OS data were immature; median OS was not reached versus 23.75 months, respectively (HR 0.79, 95% CI 0.42-1.50). In patients treated with avelumab plus SG or avelumab monotherapy, any-grade treatment-related adverse events (TRAEs) occurred in 97.3% versus 63.9% (grade &#x2265;3 in 69.9% versus 0%), respectively.<br><br>CONCLUSION: In patients with la/mUC without progression after first-line PBC, PFS was prolonged with avelumab plus SG versus avelumab monotherapy as maintenance treatment. TRAEs were more frequent with the combination and were consistent with known safety profiles of SG and avelumab. Combining avelumab with anti-Trop-2 antibody-drug conjugates may be a promising strategy to improve patient outcomes in la/mUC.}, }
@article {pmid40457567, year = {2025}, author = {Marc, A and Schiffer, JT and Mentré, F and Perelson, AS and Guedj, J}, title = {Viral Dynamic Models During COVID-19: Are We Ready for the Next Pandemic?.}, journal = {CPT: pharmacometrics &amp; systems pharmacology}, volume = {14}, number = {8}, pages = {1289-1297}, pmid = {40457567}, issn = {2163-8306}, support = {R01 AI028433/AI/NIAID NIH HHS/United States ; R01 OD011095/OD/NIH HHS/United States ; R37 AI028433/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/epidemiology/virology/transmission ; *SARS-CoV-2 ; Pandemics ; *Models, Theoretical ; Animals ; Antiviral Agents/therapeutic use ; *Models, Biological ; }, abstract = {Mathematical models have been used for about 30 years to improve our understanding of virus-host interaction, in particular during chronic infections. During the COVID-19 pandemic, these models have been used to provide insights into the natural history of acute SARS-CoV-2 infection, optimize antiviral treatment strategies, understand factors associated with transmission, and optimize surveillance systems. The impact of modeling has been accelerated by the availability of unprecedented multidimensional immune data from animal and human systems, which enhanced partnerships between experimentalists and theorists and led to exciting new modeling and statistical developments. In this mini review, we examine the lessons learned from the COVID-19 pandemic and discuss the main insights provided by mathematical models of viral dynamics at the different stages of the outbreak. Although we focus on respiratory infection, we also consider the new areas for development in anticipation of future acute infections from new or reemerging pathogens.}, }
@article {pmid40458939, year = {2025}, author = {Appelbaum, FR}, title = {Graft-versus-leukemia.}, journal = {Haematologica}, volume = {110}, number = {6}, pages = {1243-1244}, pmid = {40458939}, issn = {1592-8721}, }
@article {pmid40460374, year = {2025}, author = {Owens, K and Rahman, A and Bozic, I}, title = {Spatiotemporal dynamics of tumor-CAR T-cell interaction following local administration in solid cancers.}, journal = {PLoS computational biology}, volume = {21}, number = {6}, pages = {e1013117}, pmid = {40460374}, issn = {1553-7358}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; }, mesh = {Mice ; Animals ; Humans ; *Neoplasms/therapy/immunology/pathology ; *Immunotherapy, Adoptive/methods ; *Receptors, Chimeric Antigen/immunology ; *T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Computer Simulation ; Computational Biology ; Spatio-Temporal Analysis ; }, abstract = {The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a simplified spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can reproduce tumor and CAR T-cell data from small imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors. In our simulations, assuming equal detectable tumor diameters at the time of treatment, low average tumor cell density is a better predictor of treatment success than total tumor burden or volume doubling time. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.}, }
@article {pmid40460679, year = {2025}, author = {García-Estévez, L and Bardia, A and Rugo, HS and Carey, LA and Diéras, VC and Loibl, S and Piccart, M and Gianni, L and Kalinsky, K and O'Shaughnessy, J and Hurvitz, SA and Harting, E and Valdez, T and Phan, S and Lai, C and Cortés, J}, title = {The association of high body mass index with the safety and efficacy of sacituzumab govitecan in patients with metastatic triple-negative breast cancer from the ASCENT study.}, journal = {ESMO open}, volume = {10}, number = {6}, pages = {105294}, pmid = {40460679}, issn = {2059-7029}, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Body Mass Index ; *Camptothecin/analogs &amp; derivatives/therapeutic use ; *Immunoconjugates/therapeutic use ; Neoplasm Metastasis ; Obesity/complications ; Treatment Outcome ; *Triple Negative Breast Neoplasms/drug therapy/pathology/mortality/complications ; }, abstract = {BACKGROUND: Sacituzumab govitecan (SG) is a trophoblast cell-surface antigen 2-directed antibody-drug conjugate (ADC) approved in multiple countries for relapsed/refractory metastatic triple-negative breast cancer (mTNBC) based on results from the phase III ASCENT study. The incidence of obesity has grown to epidemic proportions in recent decades; it is unclear what impact this has on treatment outcomes, especially for ADCs like SG that have weight-based dosing. We report the association of body mass index (BMI) with efficacy and safety of SG versus chemotherapy among patients with mTNBC from the ASCENT study.<br><br>PATIENTS AND METHODS: This ad hoc subgroup analysis included patients from the intent-to-treat population of ASCENT who received SG at 10 mg/kg of body weight or chemotherapy. BMI, assessed at baseline, was classified as normal (18.5 to <25 kg/m[2]), overweight (25 to <30 kg/m[2]), and obese (&#x2265;30 kg/m[2]).<br><br>RESULTS: A total of 509 patients were included. Longer progression-free survival was observed with SG versus chemotherapy in patients from all BMI subgroups [normal: 4.2 versus 2.1 months, hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.34-0.67, P < 0.0001; overweight: 4.6 versus 1.5 months, HR 0.31, 95% CI 0.20-0.47, P < 0.0001; obese: 5.9 versus 2.6 months, HR 0.34, 95% CI 0.21-0.53, P < 0.0001]. SG also led to improved overall survival and objective response rates versus chemotherapy in all evaluated BMI subgroups. With SG treatment, the incidence of treatment-emergent adverse events of grade &#x2265;3, and those leading to dose reductions and study drug interruptions, was higher in patients with overweight and obese BMI compared with normal BMI; however, the rates of treatment discontinuation remained low and similar across the subgroups.<br><br>CONCLUSIONS: To our knowledge, this is the first study evaluating the association of BMI with outcomes with ADCs. SG demonstrated improved efficacy versus chemotherapy and a manageable safety profile in all evaluated BMI subgroups from ASCENT.}, }
@article {pmid40461383, year = {2025}, author = {de Marinis, F and Kim, TM and Bonanno, L and Cheng, S and Kim, SW and Tiseo, M and Chu, Q and Proto, C and Sacher, A and Luo, YH and Novello, S and Hao, D and Baik, C and Bazhenova, L and Lee, JS and Cho, BC and Cadranel, J and Diep, TB and Metro, G and Narayanan, P and Yoneshima, Y and de Castro Carpeño, J and Baldotto, C and Nyhus, C and Yang, JC and Sequist, LV and Levy, B and Hartmaier, R and Igwegbe, I and Poole, L and Xu, W and Ahn, MJ}, title = {Savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification following disease progression on osimertinib: primary results from the phase II SAVANNAH study.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {8}, pages = {920-933}, doi = {10.1016/j.annonc.2025.04.003}, pmid = {40461383}, issn = {1569-8041}, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology/mortality ; Aniline Compounds/administration &amp; dosage ; Acrylamides/administration &amp; dosage ; *Lung Neoplasms/drug therapy/genetics/pathology/mortality ; ErbB Receptors/genetics ; Female ; Male ; Middle Aged ; Aged ; Mutation ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Proto-Oncogene Proteins c-met/genetics/metabolism ; Disease Progression ; Adult ; Gene Amplification ; Aged, 80 and over ; Indoles ; Pyrimidines ; }, abstract = {BACKGROUND: MET-based resistance following osimertinib treatment for epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) is common. We report the primary analysis of the phase II SAVANNAH study (NCT03778229) evaluating savolitinib plus osimertinib in this setting.<br><br>PATIENTS AND METHODS: Patients had EGFR-mutated, advanced NSCLC with MET overexpression and/or amplification. MET cut-offs were initially MET immunohistochemistry (IHC)3+/&#x2265;50% (3+ intensity in &#x2265;50% of tumor cells) and/or FISH5+ (&#x2265;5 MET gene copies or MET/chromosome 7 centromere ratio &#x2265;2), and increased to MET IHC3+/&#x2265;90% and/or FISH10+ after a preliminary analysis. Patients received oral savolitinib [300 mg twice daily (b.i.d.) or once daily (o.d.), or 600 mg o.d.] plus osimertinib 80 mg o.d., or savolitinib 300 mg b.i.d. plus placebo. A primary endpoint was investigator-assessed objective response rate (ORR) in patients with progression on first-line osimertinib and MET IHC3+/&#x2265;90% and/or FISH10+ status receiving savolitinib 300 mg b.i.d. plus osimertinib (primary efficacy population). Safety was analyzed in all patients receiving savolitinib plus osimertinib.<br><br>RESULTS: Of the 365 patients treated, 341 received savolitinib plus osimertinib, with 80 of these included in the primary efficacy population. Investigator-assessed confirmed ORR in the primary efficacy population was 56.3% [95% confidence interval (CI) 44.7% to 67.3%]; the median duration of response (mDoR) was 7.1 months (95% CI 5.6-9.6 months); the median progression-free survival (PFS) was 7.4 months (95% CI 5.5-7.6 months). Blinded independent central review was consistent: confirmed ORR 55.0% (95% CI 43.5% to 66.2%); mDoR 9.9 months (95% CI 6.0-13.7 months); median PFS 7.5 months (95% CI 6.4-11.3 months). The most common any grade adverse events in patients receiving savolitinib plus osimertinib were peripheral edema (46.0%), nausea (40.5%), and diarrhea (23.2%).<br><br>CONCLUSIONS: Savolitinib 300 mg b.i.d. plus osimertinib demonstrated high, clinically meaningful and durable responses in patients with EGFR-mutated, advanced NSCLC with MET IHC3+/&#x2265;90% and/or FISH10+ status following progression on first-line osimertinib. The combination was well tolerated and may provide a new oral targeted treatment approach in this setting.}, }
@article {pmid40462491, year = {2025}, author = {Karuna, S and Laher, F and Dadabhai, S and Yu, PC and Grove, D and Orrell, C and Makhema, J and Hosseinipour, MC and Mathew, CA and Brumskine, W and Mgodi, N and Andrew, P and Gama, L and Karg, C and Broder, G and Baepanye, K and Lucas, J and Andrasik, M and Takuva, S and Villaran, M and Takalani, A and Tressler, R and Soto-Torres, L and Woodward Davis, AS and Dhai, A and Sanne, IM and Cohen, MS and Corey, L and Gray, G and deCamp, AC and Bar, KJ}, title = {Analytical treatment interruption among women with HIV in southern Africa who received VRC01 or placebo in the Antibody Mediated Prevention Study: ATI stakeholder engagement, implementation and early clinical data.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {6}, pages = {e26495}, pmid = {40462491}, issn = {1758-2652}, support = {UM1AI068619//HPTN Leadership and Operations Center/ ; U01 AI068619/AI/NIAID NIH HHS/United States ; U01 AI069463/AI/NIAID NIH HHS/United States ; UM1 AI069518/AI/NIAID NIH HHS/United States ; UM1 AI154463/AI/NIAID NIH HHS/United States ; UM1AI068614//HVTN Leadership and Operations Center/ ; UM1 AI069463/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI069436/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV Infections/drug therapy/prevention &amp; control/immunology ; Adult ; Africa, Southern/epidemiology ; *HIV Antibodies ; Viral Load ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; *Broadly Neutralizing Antibodies ; HIV-1/immunology ; *Antibodies, Monoclonal/therapeutic use/administration &amp; dosage ; Middle Aged ; CD4 Lymphocyte Count ; Young Adult ; Treatment Interruption ; }, abstract = {INTRODUCTION: Antiretroviral therapy (ART) prevents and treats, but does not eradicate, HIV. Early ART initiation is associated with post-ART virologic control, particularly among African women, and anti-HIV-1 broadly neutralizing antibodies (bnAbs) may modulate immune responses to HIV. We evaluate whether early ART with or without anti-HIV-1 bnAb VRC01, present at HIV acquisition, is associated with later ART-free control in African women and we assess potential associations with observed control.<br><br>METHODS: Stakeholder engagement informed analytical treatment interruption (ATI) study design and implementation. Participants who received placebo or VRC01 and acquired HIV in the Antibody Mediated Prevention efficacy trial were assessed for ATI eligibility, including HIV acquisition within 8 weeks of receiving VRC01 or placebo, followed by early ART initiation and &#x2265;1 year of viral suppression. Participation facilitators and barriers were assessed. From May 2021 to February 2024, participants enrolled, stopped ART and received frequent viral load and CD4+ T-cell count monitoring for safety and assessment of meeting ART reinitiation criteria.<br><br>RESULTS: Thirteen women enrolled from southern Africa. No ATI-related serious adverse events (AEs), HIV transmissions, pregnancies or &#x2265;Grade 2 AEs were observed. Eight sexually transmitted infections were diagnosed in seven women during ATI. Two participants had tenofovir levels consistent with use during ATI; 2/11 (18%) who completed ATI without antiretroviral use exhibited ART-free control for &#x2265;32 weeks. The median time to confirmed VL&#x2265;200 was 5.4 weeks (range 2.7-112). The most common ART reinitiation criterion met was virologic (n = 7). VRC01 receipt proximate to HIV acquisition was not associated with control. Controllers versus non-controllers did not differ by early post-acquisition viral load kinetics, acquired virus characteristics, or time from estimated acquisition to closest infusion or to ART initiation.<br><br>CONCLUSIONS: In a safe, well-tolerated ATI, 18% of 11 African women exhibited post-intervention control. Design and implementation lessons inform future ATIs in Africa. Analyses of peri-acquisition and post-ATI host and viral characteristics can inform the development of interventions for HIV cure, prevention and treatment.<br><br>CLINICAL TRIAL REGISTRATION: NCT04860323.}, }
@article {pmid40462957, year = {2025}, author = {Esmaeili, S and Swan, DA and Jerome, KR and Schiffer, JT and Walter, M}, title = {Intracellular and extracellular dynamics of herpes simplex virus 1 DNA and infectious particles in epithelial and neuronal cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40462957}, issn = {2692-8205}, support = {R21 AI178255/AI/NIAID NIH HHS/United States ; }, abstract = {Herpes simplex virus 1 (HSV-1) infection of epithelial cells is lytic, while infection of neurons typically results in long-term latency. However, the rates at which HSV-1 replicates and spreads in epithelial cells versus neurons under low and high multiplicity of infection (MOI) conditions remain undefined. Identifying these rates requires the application of mathematical models to carefully designed viral kinetic experiments. It is also critical to differentiate the dynamics of infectious viral particles versus viral DNA, as both quantities are routinely measured in in vitro experiments and human studies using plaque assays and polymerase chain reactions, respectively. Here, we developed mechanistic mathematical models to describe HSV-1 dynamics after infection of epithelial Vero cells and neuronal N2A cells, at high (3) and low (0.01) MOI. Our model recapitulates the dynamics of cell-free and cell-associated viral DNA and plaque-forming units (PFU). In epithelial cells, the model describes a pre-productive eclipse phase with a mean duration of 10.9 and 12.8 hours prior to HSV DNA replication and PFU production, respectively. Cells exited the eclipse phase as early and late as 2.5 and 32 hours, respectively. Infected cells produced a single PFU for every 224 HSV DNA genomes. PFU egressed at a constant rate, whereas the HSV DNA egress rate increased over time, before saturating at a 15 times higher rate. Under low relative to high MOI conditions, Vero cells spent 7 hours longer in the eclipse phase, had a 12-hour delay prior to egress, and had a longer mean duration of productive infection (14 versus 3.5-hour half-life). Secondary epithelial cell infection in low MOI experiments was overwhelmingly due to cell-to-cell viral spread and originated from a small number of early-producer cells. Neuronal cells produced viruses at a 5-fold lower rate and had a longer (mean: 42 hours) and more variable eclipse phase, with some neurons remaining in eclipse for more than a week. Our results highlighted large differences in HSV egress rates, as well as infected cell eclipse phase duration and death rates, in epithelial cells versus neurons during low and high MOI infection. The observed viral dynamics in neurons reflect a balance between active replication and latency.}, }
@article {pmid40463192, year = {2025}, author = {Walsh, ME and Chetlapalli, K and Upadhyayula, S and King, GA and Ünal, E}, title = {A Conserved Disruption of the Nuclear Permeability Barrier in Meiosis is Controlled by a Kinase-Phosphatase Pair in Saccharomyces cerevisiae.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40463192}, issn = {2692-8205}, support = {R01 AG071801/AG/NIA NIH HHS/United States ; T32 GM007232/GM/NIGMS NIH HHS/United States ; }, abstract = {In eukaryotic organisms, the nucleus is remodeled to accommodate the space required for chromosome segregation. Remodeling strategies range from closed division, where the nuclear envelope remains intact, to open divisions, where the nuclear envelope is temporarily disassembled. While the budding yeast Saccharomyces cerevisiae undergoes closed mitosis, its meiotic nuclear division strategy is less understood. Here we investigate nuclear permeability during meiosis in budding yeast and discover that meiosis II represents a semi-closed division marked by bidirectional mixing between the nucleus and cytoplasm. This includes nuclear entry of the Ran GTPase activating protein (RanGAP), typically cytoplasmic, although RanGAP relocalization appears to be a consequence, rather than a cause of permeability changes. This intercompartmental mixing occurs without nuclear envelope breakdown or dispersal of nucleoporins and is independent of known nuclear pore complex remodeling events. This phenomenon, termed virtual nuclear envelope breakdown (vNEBD), represents a unique mechanism distinct from other semi-closed divisions. We demonstrate that vNEBD is integrated into the meiotic program and regulated by the conserved meiotic kinase Ime2 and the meiosis-specific protein phosphatase 1 regulatory subunit, Gip1. Remarkably, the vNEBD event is conserved between S. cerevisiae and the distantly related Schizosaccharomyces pombe, indicating a conserved, critical role in meiosis.}, }
@article {pmid40463375, year = {2025}, author = {Fredericks, MN and Kolodner, Z and Waalkes, A and Sawatzki, K and Hao, L and Long, DR and Penewit, K and Midkiff, CC and McCormick, CJ and Beraki, S and Edlefsen, PT and Barrow, J and Greninger, AL and Gale, M and Blair, RV and Salipante, SJ and Fuller, DH and O'Connor, MA}, title = {SIV/SARS-CoV-2 coinfection in rhesus macaques impacts viral shedding, host immunity, the microbiome, and viral evolution.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1587688}, pmid = {40463375}, issn = {1664-3224}, support = {K01 MH123258/MH/NIMH NIH HHS/United States ; P51 OD010425/OD/NIH HHS/United States ; P51 OD011104/OD/NIH HHS/United States ; S10 OD030347/OD/NIH HHS/United States ; }, mesh = {Animals ; Macaca mulatta ; *Virus Shedding ; *COVID-19/immunology/virology ; *SARS-CoV-2/immunology/physiology/genetics ; *Simian Immunodeficiency Virus/immunology/physiology ; *Simian Acquired Immunodeficiency Syndrome/immunology/virology ; *Coinfection/immunology/virology ; Disease Models, Animal ; *Microbiota/immunology ; Antibodies, Viral/immunology/blood ; }, abstract = {People living with HIV (PLWH) have an increased risk of severe COVID-19, including prolonged viral shedding and emergence of mutations. To investigate the simian immunodeficiency virus (SIV) macaque model for HIV/SARS-CoV-2 coinfection, seven SIV+ rhesus macaques were co-infected with SARS-CoV-2. COVID-19 in all macaques was mild. SARS-CoV-2 replication persisted in the upper, but not the lower respiratory tract for 14 days post-infection. Animals showed impaired generation of anti-SARS-CoV-2 antibodies and T-cells. Animals also displayed transient changes in microbial communities in the upper airway and gastrointestinal tract. Evidence of SARS-CoV-2 evolution was observed in the upper respiratory tract. This study demonstrates that SIV/SARS-CoV-2 coinfection in rhesus macaques recapitulates aspects of COVID-19 in PLWH. We show that SIV impairs anti-SARS-CoV-2 immunity, potentially leading to prolonged viral shedding, altered pathogenesis, and viral evolution. This highlights the importance of HIV status in COVID-19 and supports the use of this model for HIV/SARS-CoV-2 coinfection.}, }
@article {pmid40463521, year = {2025}, author = {Pi, S and Rutter, CM and Pineda-Antunez, C and Chen, JH and Goldhaber-Fiebert, JD and Alarid-Escudero, F}, title = {Discrete-Event Simulation Model for Cancer Interventions and Population Health in R (DESCIPHR): An Open-Source Pipeline.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40463521}, support = {T15 LM007033/LM/NLM NIH HHS/United States ; U01 CA253913/CA/NCI NIH HHS/United States ; U01 CA265750/CA/NCI NIH HHS/United States ; }, abstract = {Simulation models inform health policy decisions by integrating data from multiple sources and forecasting outcomes when there is a lack of comprehensive evidence from empirical studies. Such models have long supported health policy for cancer, the first or second leading cause of death in over 100 countries. Discrete-event simulation (DES) and Bayesian calibration have gained traction in the field of Decision Science because they enable efficient and flexible modeling of complex health conditions and produce estimates of model parameters that reflect real-world disease epidemiology and data uncertainty given model constraints. This uncertainty is then propagated to model-generated outputs, enabling decision makers to determine the optimal strategy to recommend, assess confidence in the recommendation, and estimate the value of collecting additional information. However, there is limited end-to-end guidance on structuring a DES model for cancer progression, estimating its parameters using Bayesian calibration, and applying the calibration outputs to policy evaluation and other downstream tasks. To fill this gap, we introduce the DES Model for Cancer Interventions and Population Health in R (DESCIPHR), an open-source framework and codebase integrating a flexible DES model for the natural history of cancer, Bayesian calibration for parameter estimation, and screening strategy evaluation. We also introduce an automated method to generate data-informed parameter prior distributions and enhance the accuracy and flexibility of a neural network emulator-based Bayesian calibration algorithm. We anticipate that the adaptable DESCIPHR modeling template will facilitate the construction of future decision models evaluating the risks and benefits of health interventions.}, }
@article {pmid40464563, year = {2025}, author = {Schiffer, JT and Mudd, JC and Antar, AAR and Spivak, AM and Reeves, DB}, title = {Applications and limitations of the passenger hypothesis for HIV reservoir persistence and cure.}, journal = {Journal of virology}, volume = {99}, number = {7}, pages = {e0071425}, pmid = {40464563}, issn = {1098-5514}, support = {11066-76-RPRL//The Foundation for AIDS Research/ ; K25 AI155224/AI/NIAID NIH HHS/United States ; R01 AI150500/AI/NIAID NIH HHS/United States ; R01 AI179457/AI/NIAID NIH HHS/United States ; P51 OD011104/OD/NIH HHS/United States ; R01 AI186721/AI/NIAID NIH HHS/United States ; R21 AI186783/AI/NIAID NIH HHS/United States ; R01 AI167644/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/drug therapy/virology/immunology ; *CD4-Positive T-Lymphocytes/virology/immunology ; *Virus Latency/drug effects ; *HIV-1/physiology/drug effects/genetics ; Virus Replication/drug effects ; Proviruses/genetics ; Anti-HIV Agents/therapeutic use ; Viral Load ; }, abstract = {Antiretroviral therapy (ART) suppresses HIV replication in people living with HIV (PWH), but a persistent population of reservoir cells prevents cure. Reservoir cells are mostly anatomically dispersed, latently infected CD4+ T cells harboring one copy of chromosomally integrated, replication-competent HIV proviral DNA. Despite their low frequency (0.01%-0.1%) among CD4+ T cells and the quiescence of most genetically intact proviruses, viremia usually recurs within weeks after ART cessation. When PWH are not on ART, the reservoir is sustained through viral infection and infected cell proliferation. During suppressive ART, HIV reservoir cells persist via mechanisms sustaining uninfected CD4+ T cells including antigen-responsive and homeostatic clonal proliferation, programmed cell death, and T cell subset differentiation. Rates of latently infected cell proliferation and death must exist in quasi-equilibrium to explain limited change in reservoir volume over decades of ART, and the rarity of cancers or lymphoproliferative disorders emerging from infected cells. Some reservoir cells are under additional selection forces during ART, illustrated by slightly higher clearance rates of genetically intact versus replication-defective HIV proviral DNA and by a gradual transition to a less transcriptionally active and more clonal reservoir. While a small but meaningful percentage of latently infected cells are negatively selected due to lytic viral replication or elimination by adaptive immune responses, most reservoir cell death occurs independently of harboring intact HIV DNA. Given that HIV is often a passenger in reservoir cells, CD4+ T cell proliferation, targeted death, and subset differentiation may be viable therapeutic targets for curative interventions.}, }
@article {pmid40465219, year = {2026}, author = {Chalian, M and Park, C}, title = {Use of RADS in Musculoskeletal Imaging: Point-We've Done Enough Talking, Let's Dive In!.}, journal = {AJR. American journal of roentgenology}, volume = {226}, number = {1}, pages = {e2533285}, doi = {10.2214/AJR.25.33285}, pmid = {40465219}, issn = {1546-3141}, }
@article {pmid40465842, year = {2025}, author = {Mack, PC and Redman, MW and Tukachinsky, H and Kozono, DE and Minichiello, K and Dragnev, KH and Tolba, KA and Neal, JW and Madison, RW and Waqar, SN and Aggarwal, C and Hirsch, FR and Patel, JD and Herbst, RS and Chiang, AC and Reckamp, KL and Kelly, K and Borghaei, H and Gray, JE and Gandara, DR}, title = {Elevated ctDNA Tumor Fraction Is Associated with Improved Mutation Detection but Worse Overall Survival in Advanced Non-Small Cell Lung Cancer: A Lung-MAP Study.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {16}, pages = {3550-3561}, pmid = {40465842}, issn = {1557-3265}, support = {P30 CA023108/CA/NCI NIH HHS/United States ; CA180868//National Cancer Institute (NCI)/ ; U10 CA180820/CA/NCI NIH HHS/United States ; U10 CA180868/CA/NCI NIH HHS/United States ; CA180888//National Cancer Institute (NCI)/ ; CA180820//National Cancer Institute (NCI)/ ; CA180819//National Cancer Institute (NCI)/ ; U10 CA180821/CA/NCI NIH HHS/United States ; CA180821//National Cancer Institute (NCI)/ ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; //Foundation for the National Institutes of Health (FNIH)/ ; }, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/genetics/mortality/blood/pathology/diagnosis ; *Circulating Tumor DNA/genetics/blood ; *Mutation ; Female ; Male ; *Lung Neoplasms/genetics/mortality/blood/pathology/diagnosis ; Middle Aged ; *Biomarkers, Tumor/genetics/blood ; Aged ; Prognosis ; Gene Frequency ; Adult ; Aged, 80 and over ; Neoplasm Staging ; }, abstract = {PURPOSE: ctDNA is a powerful diagnostic companion to tissue profiling. Tumor fraction (TF) is a global assessment of an individual's ctDNA burden. We evaluated the impact of plasma TF on mutation detection and clinical outcomes in patients with previously treated, advanced non-small cell lung cancer on the Lung Master Protocol (Lung-MAP).<br><br>EXPERIMENTAL DESIGN: Paired tumor tissue and plasma were collected prospectively from patients on the Lung-MAP study. Plasma was collected within 30 days of a new biopsy with no intervening therapies. Tissue and ctDNA genomic profiling and ctDNA TF levels were assessed by Foundation Medicine. TF was primarily calculated from tumor aneuploidy, defaulting to fragmentomics and maximum somatic allele frequencies when aneuploidy was not detectable. The effect of TF on tissue-plasma mutation concordance, overall survival, and its relation to variant allele frequencies was assessed using linear regression, Lin's coefficient, and Cox modeling/log-rank testing.<br><br>RESULTS: A total of 194 patients were eligible for analysis. TF &#x2265;1% was significantly associated with improved positive percent agreement between ctDNA and tissue across multiple alteration types with the exception of copy-number gains. For short variants, positive percent agreement improved from 51% when TF <1% to 95% when TF &#x2265;1%. TF showed a significant robust correlation with variant allele frequency for KRAS, STK11, and TP53-the three most common mutations. TF <1% was significantly associated with improved patient overall survival compared with TF &#x2265;1% or TF &#x2265;10%.<br><br>CONCLUSIONS: TF provides an accurate, clinically useful assessment of ctDNA plasma levels from patients with refractory, advanced non-small cell lung cancer. TF levels &#x2265;1% are associated with significantly worse overall survival but improved mutation detection in liquid biopsies.}, }
@article {pmid40466030, year = {2025}, author = {Liao, N and Li, C and Gradishar, WJ and Klimberg, VS and Roshal, JA and Yuan, T and Agarwala, SS and Valero, VK and Swain, SM and Margenthaler, JA and Rubio, IT and Hurvitz, SA and Geyer, CE and Lin, NU and Rugo, HS and Zhang, G and Liu, N and Balch, CM}, title = {Accuracy and Reproducibility of ChatGPT Responses to Breast Cancer Tumor Board Patients.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500001}, doi = {10.1200/CCI-25-00001}, pmid = {40466030}, issn = {2473-4276}, mesh = {Humans ; *Breast Neoplasms/therapy/diagnosis ; Female ; Reproducibility of Results ; Middle Aged ; Generative Artificial Intelligence ; }, abstract = {PURPOSE: We assessed the accuracy and reproducibility of Chat Generative Pre-Trained Transformer's (ChatGPT) recommendations in response to breast cancer patients by comparing generated outputs with consensus expert opinions.<br><br>METHODS: 362 consecutive breast cancer patients sourced from a weekly international breast cancer webinar series were submitted to a tumor board of renowned experts. The same 362 clinical patients were also prompted to ChatGPT-4.0 three separate times to examine reproducibility.<br><br>RESULTS: Only 46% of ChatGPT-generated content was entirely concordant with the recommendations of breast cancer experts, and only 39% of ChatGPT's responses demonstrated inter-response similarity. ChatGPT's responses demonstrated higher concordance with CEN experts in earlier stages of breast cancer (0, I, II, III) compared to advanced (IV) patients (P = .019). There were less accurate responses from ChatGPT when responding to patients involving molecular markers and genetic testing (P = .025), and in patients involving antibody drug conjugates (P = .006). ChatGPT's responses were not necessarily incorrect but often omitted specific details about clinical management. When the same prompt was independently sent to CEN into the model on three occasions, each time by difference users, ChatGPT's responses exhibited variable content and formatting in 68% (246 out of 362) of patients and were entirely consistent with one another in only 32% of responses.<br><br>CONCLUSION: Since this promising clinical decision-making support tool is widely used currently by physicians worldwide, it is important for the user to understand its limitations as currently constructed when responding to multidisciplinary breast cancer patients, and for researchers in the field to continue improving its ability with contemporary, accurate and complete breast cancer information. As currently constructed, ChatGPT is not engineered to generate identical outputs to the same input and was less likely to correctly interpret and recommend treatments for complex breast cancer patients.}, }
@article {pmid40467365, year = {2025}, author = {Bellmunt, J and Powles, T and Park, SH and Voog, E and Valderrama, BP and Gurney, H and Ullén, A and Loriot, Y and Sridhar, SS and Tsuchiya, N and Sternberg, CN and Aragon-Ching, JB and Petrylak, DP and Climent Duran, MA and Tyroller, K and Hoffman, J and Jacob, N and Grivas, P and Gupta, S}, title = {Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Long-term Outcomes from the JAVELIN Bladder 100 Trial in Patients with Nonvisceral or Lymph Node-only Disease.}, journal = {European urology}, volume = {88}, number = {4}, pages = {331-338}, doi = {10.1016/j.eururo.2025.05.017}, pmid = {40467365}, issn = {1873-7560}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Carcinoma, Transitional Cell/drug therapy/secondary/mortality/pathology ; *Urinary Bladder Neoplasms/drug therapy/pathology/mortality ; Lymphatic Metastasis ; Male ; Female ; Aged ; Middle Aged ; Treatment Outcome ; Time Factors ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Progression-Free Survival ; }, abstract = {In the JAVELIN Bladder 100 randomized phase 3 trial (N = 700), avelumab first-line maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS; primary endpoint) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) without progression after first-line platinum-based chemotherapy (PBC). Here, we report exploratory analyses of subgroups with nonvisceral metastases at the start of PBC (including bone metastases) or lymph node-only disease at randomization. The median OS with avelumab versus control in patients with nonvisceral metastases (n = 318) was 31.4 versus 17.1 mo (hazard ratio [HR], 0.60 [95% confidence interval {CI}, 0.45-0.79]), and in patients with lymph node-only disease (n = 102), it was 31.9 versus 22.7 mo (HR, 0.86 [95% CI, 0.51-1.47]). In patients with nonvisceral metastases, prolonged OS was observed with avelumab irrespective of the response to PBC or PBC regimen received. PFS analyses favored avelumab over control in all the subgroups. Incidences of avelumab-related adverse events were similar across the subgroups. Limitations include small sample sizes and the exploratory nature of analyses. Overall, exploratory analyses suggest that in first-line PBC-treated patients without progression, avelumab maintenance is effective and has a manageable toxicity profile in patients with aUC who have nonvisceral metastases or lymph node-only disease.}, }
@article {pmid40467920, year = {2025}, author = {Mooney, SJ and Smith, CM and Spalt, EW and Piepmeier, L and Gassett, AJ and Gunning, G and Carlson, JA and Evenson, KR and Chambers, EC and Daviglus, M and Lovasi, GS and Gullón, PT and Hirsch, JA and Plascak, JJ and Rundle, AG and Fry, D and Bader, MDM and Kaufman, JD and Kaplan, R}, title = {Built Environment Change over Time Using Google Street View Assessments of Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Cities.}, journal = {Journal of urban health : bulletin of the New York Academy of Medicine}, volume = {102}, number = {3}, pages = {670-679}, pmid = {40467920}, issn = {1468-2869}, support = {P30 ES007033/ES/NIEHS NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; R01ES030994/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Hispanic or Latino/statistics &amp; numerical data ; *Built Environment/statistics &amp; numerical data ; *Residence Characteristics/statistics &amp; numerical data ; *Geographic Information Systems ; *Neighborhood Characteristics/statistics &amp; numerical data ; Cities ; United States ; *Environment Design ; White ; }, abstract = {Google Street View's historical imagery is a promising data source for measuring neighborhood conditions over time. However, images are not available for all years. To assess bias that may arise due to a mismatch between the year imagery is available and the year of researcher interest, we assessed prevalence of change in 20 commonly assessed built environment features between the oldest and newest available high-quality images (median difference 10.5 years, range from 2007 to 2023) on Street View at 2118 total locations in four US cities representing the Hispanic Community Health Study/Study of Latinos (New York City, Chicago, Miami, and San Diego). Seventeen (85%) of the features were the same in more than 90% of images; only litter differed in more than 20%. Patterns of change were consistent across all four cities and not notably different in tracts with higher or lower median household incomes. For built environment features reflecting sidewalk conditions and disinvestment in neighborhoods not selected for their known rapid change, auditing an image that does not temporally match the time of etiological interest is unlikely to be a major source of bias.}, }
@article {pmid40469020, year = {2025}, author = {Hamilton, EL and Guo, X and Dadabhai, S and Panchia, R and Ogendo, A and Reynolds, D and Chen, Y and Sandfort, TGM and , }, title = {Stigma and other correlates of self-esteem and depression in cisgender men and transfeminine persons with HIV who have sex with men in Kenya, Malawi, and South Africa (HPTN 075).}, journal = {AIDS care}, volume = {37}, number = {7}, pages = {1181-1193}, pmid = {40469020}, issn = {1360-0451}, support = {R21 MH130217/MH/NIMH NIH HHS/United States ; P30 MH043520/MH/NIMH NIH HHS/United States ; UM1 AI069518/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Male ; *Social Stigma ; *Self Concept ; South Africa/epidemiology ; *HIV Infections/psychology/epidemiology ; Adult ; *Homosexuality, Male/psychology/statistics &amp; numerical data ; *Depression/psychology/epidemiology ; Kenya/epidemiology ; Malawi/epidemiology ; *Transgender Persons/psychology/statistics &amp; numerical data ; *Sexual and Gender Minorities/psychology ; Middle Aged ; Young Adult ; }, abstract = {ABSTRACTHIV-related stigma profoundly impacts individuals living with HIV, hindering self-esteem and access to treatment. Few studies, if any, have assessed the effects of stigma on depression and self-esteem among men who have sex with men (MSM) and transfeminine persons (TFP) with HIV in African settings. We explored factors, including various forms of stigma, contributing to low self-esteem and poor mental health among 71 MSM and TFP in Kenya, Malawi, and South Africa, using data from the HPTN (HIV Prevention Trials Network) 075 study. Lower self-esteem was associated with moderate to severe depression and was significantly lower among those who experienced HIV as a stigma. Moreover, participants who had encountered MSM-related stigma in healthcare settings were more likely to exhibit moderate to severe depression. Being employed was a protective factor against depression. These results suggest that interventions aimed at reducing MSM-related stigma in healthcare settings and enhancing self-esteem through employment opportunities for MSM and TFP living with HIV might contribute toward ending the HIV epidemic.}, }
@article {pmid40469175, year = {2025}, author = {Mugisha, NM and Pinder, LF and Menon, MP}, title = {Editorial: Cervical screening awareness week 2023: integrating cervical cancer screening and precancer treatments.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1614832}, pmid = {40469175}, issn = {2234-943X}, }
@article {pmid40469752, year = {2025}, author = {Stone, D and Mietzsch, M and Ronzitti, G}, title = {Advancing AAV technology: From capsid design to scalable manufacturing.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {33}, number = {2}, pages = {101477}, pmid = {40469752}, issn = {2329-0501}, }
@article {pmid40469905, year = {2025}, author = {Fang, H and Eacker, SM and Wu, Y and Neufeld-Kaiser, W and Laurino, M and Keel, S and Horwitz, MS and Liu, YJ}, title = {Genetic and functional characterization of inherited complex chromosomal rearrangements in a family with multisystem anomalies.}, journal = {Genetics in medicine open}, volume = {3}, number = {}, pages = {103423}, pmid = {40469905}, issn = {2949-7744}, support = {R44 HD104323/HD/NICHD NIH HHS/United States ; }, abstract = {PURPOSE: Complex chromosomal rearrangements (CCRs) are rare structural variants involving 3 or more chromosomal breakpoints. Most de novo-reported CCRs pose challenges for diagnosis and management. They often require karyotyping, fluorescence in situ hybridization, and chromosomal microarray analysis (CMA) for clinical diagnosis because of the limitations of each method. Here, we report an inherited, exceptionally complex CCR involving 4 chromosomes and 13 breakpoints in a family with multisystem anomalies.<br><br>METHODS: We evaluated the CCRs using karyotyping, fluorescence in situ hybridization, CMA, and 2 emerging genomic technologies: high-throughput chromosome conformation capture sequencing aka genomic proximity mapping and optical genome mapping. We also performed functional studies using transcriptome and methylome analyses.<br><br>RESULTS: The proband, who had intellectual disability and immune deficiency, shared CCRs with her unaffected mother involving chromosomes 1, 7, and 11 by karyotyping. However, CMA revealed a duplication and 3 deletions in the proband, in contrast to her mother's balanced genome. High-throughput chromosome conformation capture sequencing aka genomic proximity mapping and optical genome mapping detected the CCRs and copy-number alterations but also uncovered additional breakpoints at high resolution, including an insertion in 4p and 2 cryptic rearrangements at 7p. Transcriptome and methylome analyses identified likely biological pathways associated with the proband's phenotypes.<br><br>CONCLUSION: Combining cytogenetic and genomic methods provided comprehensive characterization and defined the breakpoints at high resolution in both proband and mother. This underscores the value of novel cytogenetic and genomic techniques in deciphering complex genome rearrangements and the significance of integrative genomic analysis and functional characterization in understanding clinical phenotypes.}, }
@article {pmid40471097, year = {2025}, author = {Jadvar, H and Rahbar, K and Ahmadzadehfar, H and Heidari, P and Esfahani, SA and Afshar-Oromieh, A and Iravani, A}, title = {Combination prostate-specific membrane antigen-targeted radiopharmaceutical therapy in metastatic prostate cancer.}, journal = {The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...}, volume = {69}, number = {2}, pages = {174-179}, pmid = {40471097}, issn = {1827-1936}, support = {K08 CA259626/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Radiopharmaceuticals/therapeutic use ; *Prostatic Neoplasms/pathology/radiotherapy ; Neoplasm Metastasis ; *Antigens, Surface/metabolism ; *Glutamate Carboxypeptidase II/metabolism ; *Molecular Targeted Therapy/methods ; Combined Modality Therapy ; }, abstract = {Radiopharmaceutical therapy is emerging rapidly as an effective and safe pillar in cancer management. The regulatory approvals for [177]Lu-PSMA-617 radiopharmaceutical therapy in both the pre- and post-chemotherapy metastatic castration resistant prostate cancer clinical space have paved the way for the implementation of this life-prolonging therapy in clinical practice. However, the emergence of resistance to radiopharmaceutical therapy is inevitable, and therefore, combination therapies will be needed to synergize treatment efficacy without untoward collective toxicity. Biologically rational combination therapies across various phases of prostate cancer will lead to more optimal patient outcomes than what can be achieved with monotherapy. This article summarizes select clinical trials on prostate-specific membrane antigen-targeted radiopharmaceutical therapy in combination with other treatments that are either actively accruing or have provided preliminary results.}, }
@article {pmid40472801, year = {2025}, author = {Kurniansyah, N and Strausz, SJ and Chittoor, G and Gupta, S and Justice, AE and Hrytsenko, Y and Keenan, BT and Cade, BE and Spitzer, BW and Wang, H and Huffman, J and Moll, MR and Haring, B and Jung, SY and Raffield, LM and Kaplan, R and Rotter, JI and Rich, SS and Gharib, SA and Bartz, TM and Liu, PY and Chen, H and Fornage, M and Hou, L and Levy, D and Morrison, AC and Ochs-Balcom, HM and Psaty, BM and Wilson, PWF and Cho, K and Pack, AI and Ollila, HM and Redline, S and Gottlieb, DJ and Sofer, T and ,  and ,  and , }, title = {Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease.}, journal = {EBioMedicine}, volume = {117}, number = {}, pages = {105790}, pmid = {40472801}, issn = {2352-3964}, support = {P01 HL160471/HL/NHLBI NIH HHS/United States ; R01 HL161012/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 AG080598/AG/NIA NIH HHS/United States ; R01 HL172803/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Sleep Apnea, Obstructive/genetics/complications/epidemiology ; Female ; Male ; *Cardiovascular Diseases/etiology/genetics/epidemiology ; *Multifactorial Inheritance ; *Genetic Predisposition to Disease ; Middle Aged ; Aged ; Body Mass Index ; Risk Factors ; Phenotype ; Odds Ratio ; Polymorphism, Single Nucleotide ; Obesity/genetics ; }, abstract = {BACKGROUND: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors.<br><br>METHODS: Using race/ethnic diverse samples from over 1.2 million individuals from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger's MyCode, MGB Biobank, and the Human Phenotype Project, we developed and assessed PGSs for OSA, both without (BMIunadjOSA-PGS) and with adjustment for the genetic contributions of BMI (BMIadjOSA-PGS).<br><br>FINDINGS: Adjusted odds ratios (ORs) for OSA per 1 standard deviation of the PGSs ranged from 1.38 to 2.75. The associations of BMIadjOSA- and BMIunadjOSA-PGSs with CVD outcomes in AoU shared both common and distinct patterns. Only BMIunadjOSA-PGS was associated with type 2 diabetes, heart failure, and coronary artery disease, while both BMIadjOSA- and BMIunadjOSA-PGSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA-PGS association with hypertension was driven by females (OR = 1.1, p-value = 0.002, OR = 1.01 p-value = 0.2 in males). OSA PGSs were also associated with body fat measures with some sex-specific associations.<br><br>INTERPRETATION: Distinct components of OSA genetic risk are related and independent of obesity. Sex-specific associations with body fat distribution measures may explain differing OSA risks and associations with cardiometabolic morbidities between sexes.<br><br>FUNDING: R01AG080598.}, }
@article {pmid40473107, year = {2025}, author = {Mascaux, C and Sen, T and Sanchez-Cespedes, M and Ortiz-Cuaran, S and Bossé, Y and Dammeijer, F and Cavic, M and Barr, MP and Arulananda, S and Armisen, R and Berger, AH and Bianchi, F and Carbone, DP and Cerciello, F and Lockwood, WW and Mitsudomi, T and Ohara, S and Politi, K and Qin, S and Roisman, LC and Samstein, R and Skoulidis, F and Tan, AC and Thomas, A and Zhang, J and Wynes, MW and John, T and Tsao, MS and , }, title = {Advances in Lung Cancer Basic and Translational Research in 2025 - Overview and Perspectives Focusing on NSCLC.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {20}, number = {10}, pages = {1369-1391}, pmid = {40473107}, issn = {1556-1380}, support = {R37 CA252050/CA/NCI NIH HHS/United States ; ZIA BC011793/ImNIH/Intramural NIH HHS/United States ; R01 CA262556/CA/NCI NIH HHS/United States ; Z99 CA999999/ImNIH/Intramural NIH HHS/United States ; R01 CA284585/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/pathology/therapy ; *Carcinoma, Non-Small-Cell Lung/pathology/therapy ; *Translational Research, Biomedical ; }, abstract = {Basic and translational research in lung cancer is a rapidly evolving field with a transformational impact on early detection, diagnosis, therapeutic development, and personalization of care. Recent advances have greatly increased our understanding of the molecular genomics, proteomics, pathogenesis, and cellular biology of this deadly malignancy. The International Association for the Study of Lung Cancer (IASLC) recently formed a Basic and Translational Science (BaTS) Committee to further enhance the scientific leadership of IASLC in thoracic cancer research. This review by members of the committee highlights the breadth of current research in NSCLC, with a focus on molecular risk factors and processes in tumorigenesis, heterogeneity, phenotypic plasticity, metabolic reprogramming, immunobiology, the immune microenvironment, and microbiome. This review also identifies future research areas that may lead to further improvement in survival outcomes and curative therapies especially for patients with advanced NSCLC.}, }
@article {pmid40473616, year = {2025}, author = {Mazziotta, F and Martin, LE and Egan, DN and Bar, M and Kinsella, S and Paulson, KG and Voillet, V and Lahman, MC and Hunter, D and Schmitt, TM and Duerkopp, N and Yeung, CCS and Tang, TH and Gottardo, R and Asano, Y and Wilcox, EC and Lee, B and Zhang, T and Lopedote, P and Penter, L and Wu, CJ and Milano, F and Greenberg, PD and Chapuis, AG}, title = {A phase I/II trial of WT1-specific TCR gene therapy for patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation: skewing towards NK-like phenotype impairs T cell function and persistence.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5214}, pmid = {40473616}, issn = {2041-1723}, support = {n/a//Fred Hutchinson Cancer Research Center (Hutchinson Center)/ ; P01 CA018029/CA/NCI NIH HHS/United States ; 5K08CA169485//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; K08 CA169485/CA/NCI NIH HHS/United States ; n/a//Damon Runyon Cancer Research Foundation (Cancer Research Fund of the Damon Runyon-Walter Winchell Foundation)/ ; T32 CA080416/CA/NCI NIH HHS/United States ; n/a//V Foundation for Cancer Research (V Foundation)/ ; n/a//Gabrielle's Angel Foundation for Cancer Research (Gabrielle's Angel Foundation)/ ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/therapy/immunology/genetics ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *WT1 Proteins/immunology/genetics ; Female ; Middle Aged ; Male ; Adult ; *Receptors, Antigen, T-Cell/genetics/immunology ; *Genetic Therapy/methods/adverse effects ; *Killer Cells, Natural/immunology ; Transplantation, Homologous ; CD8-Positive T-Lymphocytes/immunology ; Herpesvirus 4, Human/immunology ; Cytomegalovirus/immunology ; Aged ; T-Lymphocytes/immunology ; Young Adult ; Treatment Outcome ; }, abstract = {Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8[+] T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (TTCR-C4) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific TTCR-C4 in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, TTCR-C4 cells did not clearly improve outcomes despite EBV-specific TTCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific TTCR-C4. Investigating the fate of persisting TTCR-C4, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting TTCR-C4 persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.}, }
@article {pmid40473660, year = {2025}, author = {Bottomly, D and Mathieson, C and Vigoda, M and Jeng, S and Evans, N and Anderson, A and Blucher, A and Lesch, A and Zheng, C and Laderas, T and Jacobs, J and Kulesz-Martin, M and McWeeney, S}, title = {Assessing individual head and neck squamous cell carcinoma patient response to therapy through integration of functional and genomic data.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {19742}, pmid = {40473660}, issn = {2045-2322}, support = {T32 CA106195/CA/NCI NIH HHS/United States ; S10 OD034224/OD/NIH HHS/United States ; P30 CA069533/CA/NCI NIH HHS/United States ; R01 CA192405/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Squamous Cell Carcinoma of Head and Neck/genetics/drug therapy/pathology ; *Head and Neck Neoplasms/genetics/drug therapy ; *Genomics/methods ; Mutation ; DNA Copy Number Variations ; Precision Medicine ; }, abstract = {Even though head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, there are only two PD-1 targeted immunotherapies (pembrolizumab and nivolumab) and one tumor intrinsic EGFR targeted therapy (cetuximab) that are FDA approved for treatment of HNSCC. Taking advantage of a high throughput inhibitor assay and computational tools originally showing success in leukemia, we designed and employed HNSCC-specific inhibitor panels that capture the diversity of aberrational pathways in HNSCC to test viable cells derived from patients' HNSCC tumors. This provides a functional context to the multi-omic readouts conducted on these samples (mutations, protein expression and copy number alterations). In addition to generating these deeply characterized functional genomics datasets, we also developed additional visual analytics that have the potential to provide greater insight into HNSCC drug response patterns and potentially aid precision oncology tumor boards in evaluation and assessment of effective targeted therapeutic agents.}, }
@article {pmid40473829, year = {2025}, author = {Cheung, KJ and Horne-Badovinac, S}, title = {Collective migration modes in development, tissue repair and cancer.}, journal = {Nature reviews. Molecular cell biology}, volume = {26}, number = {10}, pages = {741-758}, pmid = {40473829}, issn = {1471-0080}, support = {R01 CA277045/CA/NCI NIH HHS/United States ; R35 GM148285/GM/NIGMS NIH HHS/United States ; R37 CA234488/CA/NCI NIH HHS/United States ; }, mesh = {*Cell Movement/physiology ; Humans ; *Neoplasms/pathology/metabolism ; Animals ; Signal Transduction ; Cell Adhesion ; Cell Communication ; }, abstract = {Migrating cells have key functions in shaping tissues during development, repairing tissues after development and supporting cancer invasion and metastasis. In all these contexts, cells often maintain contact with their neighbours and move as a group, in a process termed collective migration. In this Review, we describe the elegant mechanisms used by collectively migrating cells in vivo to coordinate their movements and obtain directional information. We start by highlighting the diverse physiological roles that migrating collectives have within the body and then focus on dominant paradigms for the organization of migrating collectives including the roles of leader and follower cells, local cell-cell adhesion and signalling, and external guidance cues. By comparing collective migrations occurring during development and cancer, we bring into focus shared principles for collective cell movement and distinct strategies used by cancer cells for their own dispersal. Throughout, we pay particular attention to how migrating collectives display emergent properties not exhibited by individually migrating cells and how these properties provide the robustness needed for efficient cell movement.}, }
@article {pmid40475393, year = {2025}, author = {Quaye, ANM and Addison, ECDK and Osei, E and Yorke, AA}, title = {A Feasibility Study for Clinical Implementation of hypo fractionated SBRT Program at a Clinic in an LMIC Using Locally Designed Lung Phantom.}, journal = {Advances in radiation oncology}, volume = {10}, number = {6}, pages = {101752}, pmid = {40475393}, issn = {2452-1094}, abstract = {PURPOSE: This study aims to assess the feasibility of implementing a hypofractionated radiation therapy (HFRT) program at the Oncology Directorate of Komfo Anokye Teaching Hospital in Ghana, addressing specific infrastructure limitations that hinder patient care and treatment efficiency. Hence, we conducted a feasibility study to start a HFRT lung stereotactic body radiation therapy (SBRT) program using currently available resources. The goal is to alleviate the burden on patients and health care providers, particularly in the context of limited resources.<br><br>METHODS AND MATERIALS: A lung phantom was designed from locally sourced materials consisting of wood slabs to mimic the lung, a perspex tank filled with water for tissue equivalence, and a 3-cm diameter acrylic ball to simulate the tumor. A motion platform was also designed for the phantom to simulate patients breathing in the superior-inferior direction. We acquired 3 computed tomography (CT) scan data sets using a slow CT scan technique for target motions of 0 cm (no_target_motion), 0.5 cm (0.5-cm_target_motion), and 1 cm (1-cm_target_motion) displacements. Treatment plans were generated for each phantom CT image data set using 9-field 6-Mega-Voltage (MV) photon beams in the eclipse treatment planning system. We also generated a treatment plan using an actual patient CT data set to assess the doses to target in the lung and critical organs at risk during a typical lung SBRT treatment. The quality of each treatment plan was evaluated using the near maximum (D2%), near minimum (D98%), mean (Dmean), V100, V95, V90, heterogeneity index (HI), conformity index (CI), the ratio of 50% prescription isodose volume to the PTV volume, (R50%), maximum dose (in % of dose prescribed) at 2 cm from PTV in any direction (D2cm, Gy) and dose-volume-histograms for the planning target volume (PTV). The near maximum (D2%), mean, V5, V10, V15, and V20 values were used as the dose metrics to evaluate the dose to the lung. Maximum dose was used to evaluate the dose to the spinal cord, and the maximum and mean doses were used to evaluate doses to the esophagus, heart, trachea, and ribs.<br><br>RESULTS: We quantitatively assessed the quality of the phantom treatment plans by calculating the CI, HI, R50%, and D2cm for each plan. The CI values for the PTV for the no_target_motion, 0.5-cm_target_motion, and 1-cm_target_motion are 1.07, 1.08, and 1.06, respectively. The HIs for the PTV for no_target_motion, 0.5-cm_target_motion, and 1-cm_target_motion are 1.20, 1.10, and 1.20 respectively. The R50% for the no_target_motion, 0.5-cm_target_motion, and 1-cm_target_motion are 3.98, 3.86, and 3.82, respectively, and the corresponding D2cm values are 27.30, 31.64, and 30.47, respectively. The CI, HI, R50%, and D2cm values for the PTV using the actual patient CT data set are 1.08, 1.22, 7.1, and 58.7 respectively. Therefore, our data demonstrate good dose conformity and heterogeneity within the PTV, with a sharp dose fall-off for all cases. The point dose measurements made in the phantom also show good agreement with treatment planning data.<br><br>CONCLUSIONS: Our results demonstrate that implementing HFRT using 3-dimensional conformal radiation therapy for lung SBRT is feasible with the current infrastructure of our institution. Although the proposed treatment plan is effective, future research on motion management and image guidance technologies is necessary to optimize treatment fidelity. These findings suggest that HFRT could be a viable option for addressing resource constraints in radiation therapy delivery in similar settings.}, }
@article {pmid40475394, year = {2025}, author = {Ebadi, M and Gem, H and Sebastian, G and Abasaeed, R and Lloid, M and Tseng, YD and Mian, OY and Minot, S and Dean, DR and Rashidi, A}, title = {Different Patterns of Oral Mucositis and Microbiota Injury After Total Body Irradiation- Versus Chemotherapy-Based Myeloablative Allogeneic Hematopoietic Cell Transplantation.}, journal = {Advances in radiation oncology}, volume = {10}, number = {6}, pages = {101787}, pmid = {40475394}, issn = {2452-1094}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Oral mucositis (OM) is a common complication of allogeneic hematopoietic cell transplantation, causing pain, infections, swallowing/speech impairment, and poor quality of life. We hypothesized that patterns (severity and dynamics) of OM and oral microbiota disruptions may be different after high-dose total body irradiation (TBI)- versus chemotherapy-based myeloablative conditioning.<br><br>METHODS AND MATERIALS: We conducted an exploratory study including comprehensive, longitudinal mucositis assessment, paired with supragingival plaque and saliva collection. OM was assessed at baseline and days +7, +14, +21, +28, and +84. Total mucositis score at each timepoint was calculated from objective findings in 2 domains and 9 oral sites using a validated scoring system. Plaque and saliva samples (baseline and days +14, +28, and +84) were profiled using shotgun metagenomic sequencing.<br><br>RESULTS: A total of 249 OM assessments were performed and 342 samples were collected from 47 patients (27 chemotherapy-based, 20 TBI-based). Salivary flow rate remained stable in the chemotherapy-based cohort, but steadily declined in the TBI-based cohort, reaching a significantly lower level in the TBI-based cohort at day +84 both compared to baseline and the chemotherapy-based cohort. OM severity peaked at day +7 in the TBI-based cohort versus day +14 in the chemotherapy-based cohort. Day +14 OM was significantly more severe in the chemotherapy-based cohort; other timepoints were not different. Although the cohorts were similar in plaque microbiota composition at baseline, they became significantly different at all post- hematopoietic cell transplantation timepoints. Salivary microbiota composition was not significantly different between the 2 cohorts. Day +84 plaque microbiota diversity was significantly higher in the TBI-based cohort.<br><br>CONCLUSIONS: We demonstrated different patterns of OM, microbiota injury, and salivary flow rate after TBI- versus chemotherapy-based conditioning. If validated in future studies, our findings could enhance evidence-based pretransplant counseling on oral toxicity and have implications for short- and long-term oral health in transplant survivors.}, }
@article {pmid40475489, year = {2025}, author = {Hart, SFM and Alcala, N and Feder, AF and Harris, K}, title = {A signature-agnostic test for differences between tumor mutation spectra reveals carcinogen and ancestry effects.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40475489}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; R35 GM133428/GM/NIGMS NIH HHS/United States ; T32 HG000035/HG/NHGRI NIH HHS/United States ; }, abstract = {Mutational signatures contain valuable information about the mutational processes shaping cancer genomes. However, despite dozens of tools to identify signatures in cancer samples, there is not an established metric for statistically comparing mutational signature results and quantifying the overall significance of differences among complex mixtures of signatures. To close this methodological gap, we demonstrate that a signature-agnostic metric for measuring differences in mutation spectra - the aggregate mutation spectrum distance permutation method (AMSD) - can discover differences overlooked by signature analysis. First, we reanalyzed a study of carcinogen exposure in mice, identifying statistically significant shifts in mutation spectra caused by eleven of twenty tested carcinogens. Only three carcinogens were previously reported to induce distinct mutation signatures, suggesting that many carcinogens perturb mutagenesis by altering the composition of endogenous signatures rather than introducing unique signatures. Next, we used human tumor data to determine whether patient ancestry has a measurable impact on tumor mutation spectra, finding significant ancestry-associated differences across ten cancer types: for example, Africans have elevated SBS4 in lung adenocarcinomas, East Asians have elevated SBS16 in esophageal and liver cancers plus elevated SBS10a/b in uterine and colorectal cancers, and Europeans have elevated SBS17b in esophageal cancers plus elevated SBS2/13 in bladder cancers. These examples suggest that AMSD is a robust tool for detecting differences among tumor mutation spectra, complementing signature-based approaches and enabling the discovery of environmental and genetic influences on mutagenesis in large datasets.}, }
@article {pmid40475599, year = {2025}, author = {Mage, PL and Konecny, AJ and Mair, F}, title = {Measurement and prediction of unmixing-dependent spreading in spectral flow cytometry panels.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40475599}, issn = {2692-8205}, support = {R01 AI123323/AI/NIAID NIH HHS/United States ; R56 DE032009/DE/NIDCR NIH HHS/United States ; }, abstract = {Advances in spectral cytometry instrumentation and fluorescent reagents have led to the possibility of ultra-high-parameter panels exceeding 50 colors. However, panel size is limited in practice by unmixing-dependent spreading (UDS), a mathematical phenomenon which leads to a progressive deterioration of unmixed signal-to-noise ratios in panels that contain fluorochrome combinations with significant spectral overlap. Choosing spectrally compatible sets of fluorochromes that avoid UDS is a complex and labor-intensive task involving substantial trial-and-error experimentation. Here, we provide a detailed explanation of UDS and practical strategies for handling UDS in large spectral panels. We describe the empirical hallmarks of UDS, demonstrate how to quantify its impact, and dissect its underlying mathematical cause in terms of spectral collinearity. We present novel computational metrics that can be used to select optimal combinations of fluorochromes in a platform-agnostic fashion based on publicly available reference data, providing a general tool for spectral panel design.}, }
@article {pmid40475658, year = {2025}, author = {Yu, TC and Kikawa, C and Dadonaite, B and Loes, AN and Englund, JA and Bloom, JD}, title = {Pleiotropic mutational effects on function and stability constrain the antigenic evolution of influenza hemagglutinin.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40475658}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {The evolution of human influenza virus hemagglutinin (HA) involves simultaneous selection to acquire antigenic mutations that escape population immunity while preserving protein function and stability. Epistasis shapes this evolution, as an antigenic mutation that is deleterious in one genetic background may become tolerated in another. However, the extent to which epistasis can alleviate pleiotropic conflicts between immune escape and protein function/stability is unclear. Here, we measure how all amino acid mutations in the HA of a recent human H3N2 influenza strain affect its cell entry function, acid stability, and neutralization by human serum antibodies. We find that epistasis has entrenched certain mutations so that reverting to the ancestral amino acid identity in earlier strains is no longer tolerated. Epistasis has also enabled the emergence of antigenic mutations that were detrimental to HA's cell entry function in earlier strains. However, epistasis appears insufficient to overcome the pleiotropic costs of antigenic mutations that impair HA's stability, explaining why some mutations that strongly escape human antibodies never fix in nature. Our results refine our understanding of the mutational constraints that shape recent H3N2 influenza evolution: epistasis can enable antigenic change, but pleiotropic effects can restrict its trajectory.}, }
@article {pmid40475854, year = {2025}, author = {Shriver, MC and Milletich, PL and Moreno, A and Larsen, SE and Posavad, CM and Berube, BJ and Wali, B and Ellis, M and Manning, K and Moore, KM and Zhu, Z and Grewal, N and Cadena, IA and Cardemil, CV and Munoz, FM and Neuzil, KM and Coler, RN and Suthar, MS and Pasetti, MF and , }, title = {Development and Concordance of Binding and Neutralizing Assays to Determine SARS-CoV-2 Antibody Activity in Human Milk.}, journal = {Pathogens &amp; immunity}, volume = {10}, number = {2}, pages = {97-121}, pmid = {40475854}, issn = {2469-2964}, support = {U19 AI145825/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: Maternal immunization provides vaccine-specific immunity to the infant via breast milk. Multiple studies have reported the presence of SARS-CoV-2 antibodies in human breast milk (HBM) from infected and/or vaccinated women. However, there is limited information on the analytical performance, consistency, and quality of the methods used. Standardized and rigorous assays are needed to meet clinical study endpoints and for comparisons across studies.<br><br>METHODS: We optimized high-throughput multiplex immunoassays for quantification of SARS-CoV-2 immunoglobulin (Ig)G and IgA in HBM and determined antibody levels in HBM samples from 236 SARS-CoV-2 vaccinated (infected and non-infected) and 50 pre-pandemic (unexposed) lactating women. Additionally, SARS-CoV-2 neutralizing activity was examined in a subset of 75 SARS-CoV-2 HBM from vaccinated (infected and non-infected) women using live virus focus reduction neutralization and pseudovirus assays. Concordance between SARS-CoV-2 binding and live virus neutralization outcomes was examined.<br><br>RESULTS: The multiplex SARS-CoV-2 assays had adequate analytical sensitivity, repeatability, precision, and assay linearity and were reliable for quantification of IgG and IgA in HBM. Positivity thresholds for Spike- and Nucleocapsid-specific IgG and IgA were established; IgG discriminated positive/negative SARS-CoV-2-immune HBM with high sensitivity and specificity, while IgA reactivity overlapped. A strong correlation was observed between live SARS-CoV-2 and pseudovirus neutralization activity. HBM Spike IgA and neutralization titers were highly correlated.<br><br>CONCLUSIONS: SARS-CoV-2 binding and neutralizing antibody activity in HBM was determined using standardized and rigorous assays. HBM positivity cutoff values for SARS-CoV-2 vaccination and infection were established. The methods and approach described here could be applied to other pathogens and mucosal secretions.}, }
@article {pmid40480020, year = {2025}, author = {Lundin, JI and Peters, U and Hu, Y and Ammous, F and Benjamin, EJ and Bis, JC and Brody, JA and Cushman, M and Fuller, H and Gignoux, C and Guo, X and Haessler, J and Haiman, C and Joehanes, R and Kasela, S and Kenny, E and Lappalainen, T and Levy, D and Liu, C and Liu, Y and Loos, RJF and Matise, T and North, KE and Park, SL and Ratliff, SM and Reiner, A and Rich, SS and Rotter, JI and Smith, JA and Sotoodehnia, N and Tracy, R and Van den Berg, D and Ye, T and Zhao, W and Raffield, LM and Kooperberg, C and , }, title = {Epigenetic mechanisms underlying variation of IL-6, a well-established inflammation biomarker and risk factor for cardiovascular disease.}, journal = {Atherosclerosis}, volume = {407}, number = {}, pages = {120219}, pmid = {40480020}, issn = {1879-1484}, support = {U01 HL080295/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; N01 HC055222/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; N01 HC085080/HL/NHLBI NIH HHS/United States ; R01 HL103612/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201500001C/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; N01 HC085082/HL/NHLBI NIH HHS/United States ; R01 HL092577/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01 HC085083/HL/NHLBI NIH HHS/United States ; N01 HC085086/HL/NHLBI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; R01 HL076784/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; K08 HL116640/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; N01 HC025195/HL/NHLBI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; N01 HC085079/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; 75N92019D00031/HL/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 AG028321/AG/NIA NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; N01 HC085081/HL/NHLBI NIH HHS/United States ; R01 HL111089/HL/NHLBI NIH HHS/United States ; R01 HL116747/HL/NHLBI NIH HHS/United States ; R01 HL092111/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Interleukin-6/genetics/blood ; *Cardiovascular Diseases/genetics/blood/ethnology ; *Epigenesis, Genetic ; *DNA Methylation ; Male ; *Inflammation/genetics/blood ; Female ; CpG Islands ; Biomarkers/blood ; Middle Aged ; Risk Factors ; Receptors, Interleukin-6/genetics ; Genetic Predisposition to Disease ; Heart Disease Risk Factors ; Cytokine Receptor gp130 ; }, abstract = {BACKGROUND AND AIMS: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, yet the underlying molecular mechanisms remain less understood. Chronic low-grade inflammation is a complex immune response contributing to the pathophysiology of cardiovascular disease. This response is signaled in part by interleukin-6 (IL-6), a pleiotropic, pro-inflammatory cytokine. Phenotypic variance in circulating IL-6 level may be explained in part by DNA methylation which is increasingly being associated with cardiovascular effects.<br><br>METHODS: In this study we evaluated methylated DNA (CpG sites) associated with blood IL-6 levels across &#x223c;4,400 ancestrally diverse individuals (81&#xa0;% self-reported White; 9&#xa0;% Black or African American, 8&#xa0;% Hispanic or Latino/a, and 2&#xa0;% Chinese American).<br><br>RESULTS: We identified 178 CpG sites associated with IL-6 (p<0.05/&#x223c;395,000). Among the sites, cg04437762 is located within the transcription unit of IL6R, a current therapeutic target for inflammatory disease, and cg26692003 and cg00464927 were significant for IL6 and IL6ST trans-CpG-gene transcripts. Functional gene expression downstream of methylation identified cellular response to IL-6 and B-cell regulation and activation pathways. Four genes were linked with both a genetic component of cardiovascular disease and an IL-6 associated CpG site. Three CpG sites identified through Mendelian randomization analyses supported inference of a causal effect on IL-6 levels, including the LYN gene that regulates immune cell signaling and has been previously associated with atherosclerosis.<br><br>CONCLUSIONS: Overall, we identified several novel IL-6-CpG sites and downstream pathways affected by methylation. Follow-up functional studies including the regulation of IL-6 would complement current knowledge of CVD pathophysiology and potential therapeutic targets.}, }
@article {pmid40480199, year = {2025}, author = {Park, MS and Kumar, RD and Ovadiuc, C and Folta, A and McEwen, AE and Snyder, A and Villani, RM and Spurdle, AB and Fowler, DM and Rubin, AF and Shirts, BH and Starita, LM and Stergachis, AB}, title = {Insights on improving accessibility and usability of functional data to unlock their potential for variant interpretation.}, journal = {American journal of human genetics}, volume = {112}, number = {6}, pages = {1468-1478}, pmid = {40480199}, issn = {1537-6605}, support = {R01 HG013025/HG/NHGRI NIH HHS/United States ; UM1 HG011969/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Genetic Variation/genetics ; Surveys and Questionnaires ; Male ; Female ; Genetic Testing ; Adult ; }, abstract = {Variant-level functional data are a core component of clinical variant classification and can aid in reinterpreting variants of uncertain significance (VUSs). However, the usage of functional data by genetics professionals is currently unknown. An online survey was developed and distributed in the spring of 2024 to individuals actively engaged in variant interpretation. Quantitative and qualitative methods were used to assess responses. 190 eligible individuals responded, with 93% reporting interpreting 26 or more variants per year. The median respondent reported 11-20 years of experience. The most common professional roles were laboratory medical geneticists (23%) and variant review scientists (23%). 77% reported using functional data for variant interpretation in a clinical setting, and overall, respondents felt confident assessing functional data. However, 67% indicated that functional data for variants of interest were rarely or never available, and 91% considered insufficient quality metrics or confidence in the accuracy of data as barriers to their use. 94% of respondents noted that better access to primary functional data and standardized interpretation of functional data would improve usage. Respondents also indicated that handling conflicting functional data is a common challenge in variant interpretation that is not performed in a systematic manner across institutions. The results from this survey showed a demand for a comprehensive database with reliable quality metrics to support the use of functional evidence in clinical variant interpretation. The results also highlight a need for guidelines regarding how putatively conflicting functional data should be used for variant classification.}, }
@article {pmid40480553, year = {2025}, author = {Petrykey, K and Chen, Y and Neupane, A and French, JN and Wang, H and Xiang, H and Dixon, SB and Vukadinovich, C and Im, C and Ehrhardt, MJ and Mulrooney, DA and Sharafeldin, N and Wang, X and Howell, RM and Jefferies, JL and Burridge, PW and Oeffinger, KC and Gramatges, MM and Bhatia, S and Robison, LL and Ness, KK and Hudson, MM and Chow, EJ and Armstrong, GT and Yasui, Y and Sapkota, Y}, title = {Predicting the 10-year risk of cardiomyopathy in long-term survivors of childhood cancer.}, journal = {Annals of oncology : official journal of the European Society for Medical Oncology}, volume = {36}, number = {10}, pages = {1203-1211}, pmid = {40480553}, issn = {1569-8041}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; R01 HL173881/HL/NHLBI NIH HHS/United States ; R01 CA261898/CA/NCI NIH HHS/United States ; R21 CA261833/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U01 CA195547/CA/NCI NIH HHS/United States ; R01 CA216354/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/statistics &amp; numerical data ; Female ; Male ; *Cardiomyopathies/epidemiology/chemically induced/etiology/diagnosis ; Adult ; *Neoplasms/complications/drug therapy/therapy ; Anthracyclines/adverse effects ; Risk Factors ; Young Adult ; Child ; Risk Assessment ; Adolescent ; }, abstract = {BACKGROUND: Considering the heightened risk of cancer treatment-related cardiomyopathy and cardiac death in long-term survivors of childhood cancer, we aimed to develop and validate a clinically applicable risk prediction model for cardiomyopathy.<br><br>PATIENTS AND METHODS: Childhood cancer survivors from the St. Jude Lifetime Cohort, [SJLIFE, model-development; n = 3479; median age 32.3 years, interquartile range (IQR) 24.4-40.9 years] and the Childhood Cancer Survivor Study (CCSS, model-validation; n = 6875; median age 33.2 years, IQR 27.9-38.9 years) were assessed for demographic and cardiovascular risk factors, treatment exposures, and polygenic risk scores (PRSs) for cardiomyopathy, heart failure, cardiac structure and function, and anthracycline-related cardiomyopathy risk. Multivariable Poisson regression predicted the 10-year risk of cardiomyopathy (Common Terminology Criteria for Adverse Events grade &#x2265;3: requiring heart failure medications or heart transplantation or leading to death) following baseline visit/survey. Model performance was assessed by area under the receiver operating characteristic curve (AUC).<br><br>RESULTS: Cardiomyopathy was clinically identified in 75 (2.2%, SJLIFE) and self-reported in 87 (1.3%, CCSS) survivors within 10 years of the baseline assessment. AUC of the clinical model with sex, age at cancer diagnosis, cumulative anthracycline, and mean heart radiation doses was 0.833 (SJLIFE) and 0.812 (CCSS). Age at baseline, hypertension, and genetic ancestry showed associations with higher cardiomyopathy rates in SJLIFE but did not increase AUC in CCSS (0.812). Adding PRSs for hypertrophic cardiomyopathy and left ventricular end-systolic volume improved AUC in CCSS (0.822; P = 0.016). Compared with existing survivorship-care guidelines, the PRS model classified fewer survivors as high-risk or moderate-risk, while identifying survivors in those categories as having 1.5-times greater risk.<br><br>CONCLUSIONS: We developed and validated models with highest-to-date performance for estimating the 10-year risk of cardiomyopathy in survivors of childhood cancer. Results could enhance identification of at-risk survivors beyond current guidelines.}, }
@article {pmid40480658, year = {2025}, author = {Cabanski, CR and Yang, E and Stewart, MD and Allen, JD and Connolly, JE and Dugan, U and Greenberg, PD and Mackall, CL and June, CH and Marson, A and Maus, MV and Ribas, A}, title = {Intentional heterogeneity in autologous cell-based gene therapies: strategic considerations for first-in-human trials.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {6}, pages = {}, pmid = {40480658}, issn = {2051-1426}, mesh = {Humans ; *Genetic Therapy/methods ; Clinical Trials as Topic ; *Neoplasms/therapy/immunology/genetics ; *Cell- and Tissue-Based Therapy/methods ; Gene Editing ; *Immunotherapy, Adoptive/methods ; }, abstract = {Cell-based gene therapies, including chimeric antigen receptor-T, T-cell receptor-T, and tumor-infiltrating lymphocyte therapies, have transformed the treatment landscape for certain cancers, yet their efficacy in solid tumors remains limited. Next-generation therapies aim to overcome biological barriers, enhance potency and safety, and streamline development timelines through innovative approaches. Recent advances in genome editing technologies have identified hundreds of gene edits that improve T-cell functionality in preclinical models. However, the limited direct translatability of these findings and the impracticality of testing each of the individual edits in a traditional clinical trial highlight the need for more efficient strategies.This article provides an overview of genome-wide screens that identify gene knockouts and knock-ins to enhance T-cell function and the limitations with translating these results to human trials. Next, we propose a novel clinical trial design for testing multiple gene modifications simultaneously within a single T-cell infusion product. This approach would enable head-to-head evaluation of edits in an internally controlled setting, accelerating the identification of promising candidate edits. Key considerations for Chemistry, Manufacturing, and Controls, non-clinical evaluation, and clinical protocols are discussed, with an emphasis on patient safety and ethical transparency.This framework is informed by insights shared at the "Unlocking Complex Cell-based Gene Therapies" workshop, held on May 6, 2024. Co-hosted by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy, the event brought together participants from academia, the US Food and Drug Administration, and patient advocacy groups. By fostering collaboration among these stakeholders, this innovative approach aims to accelerate the development of effective cell-based therapies for complex diseases.}, }
@article {pmid40480832, year = {2025}, author = {Wang, L and Taylor, T and Rathnakumar, K and Khyzha, N and Liang, M and Alizada, A and Campitelli, LF and Pour, SE and Patel, ZM and Antounians, L and Tobias, IC and Hou, H and Hughes, TR and Roy, S and Mitchell, JA and Fish, JE and Wilson, MD}, title = {Multi-species analysis of inflammatory response elements reveals ancient and lineage-specific contributions of transposable elements to NF-kB binding.}, journal = {Genome research}, volume = {35}, number = {7}, pages = {1544-1559}, pmid = {40480832}, issn = {1549-5469}, support = {R01 HG010045/HG/NHGRI NIH HHS/United States ; }, mesh = {Animals ; Humans ; *DNA Transposable Elements/genetics ; Mice ; Cattle ; *Transcription Factor RelA/metabolism/genetics ; Evolution, Molecular ; *NF-kappa B/metabolism/genetics ; Species Specificity ; *Inflammation/genetics ; Binding Sites ; *Response Elements ; Protein Binding ; Tumor Necrosis Factor-alpha/pharmacology ; Endothelial Cells/metabolism ; }, abstract = {Transposable elements (TEs) provide a source of transcription factor (TF) binding sites that can rewire gene regulatory networks. NF-kB is an evolutionarily conserved TF complex primarily involved in innate immunity and inflammation. The extent to which TEs have contributed to NF-kB responses during mammalian evolution is not well established. Here, we perform a multi-species analysis of TEs bound by the NF-kB subunit RELA in response to the proinflammatory cytokine TNF. By comparing RELA ChIP-seq data from TNF-stimulated primary aortic endothelial cells isolated from human, mouse, and cow, we find that 55 TE subfamilies are associated with RELA-bound regions, many of which reside near TNF-responsive genes. A prominent example of lineage-specific contribution of transposons comes from the bovine SINE subfamilies Bov-tA1/2/3 which collectively contributed over 14,000 RELA-bound regions in cow. By comparing RELA binding data across species, we also find several examples of RELA motif-bearing TEs that colonized the genome prior to the divergence of the three species and contributed to species-specific RELA binding. For example, we find human RELA-bound MER81 instances are enriched for the interferon gamma pathway and demonstrate that one RELA-bound MER81 element can control the TNF-induced expression of interferon gamma receptor 2 (IFNGR2). Using ancestral reconstructions, we find that RELA containing MER81 instances rapidly decayed during early primate evolution (>50 million years ago [MYA]) before stabilizing since the separation of Old World monkeys (<50 MYA). Taken together, our results suggest ancient and lineage-specific transposon subfamilies contributed to mammalian NF-kB regulatory networks.}, }
@article {pmid40480929, year = {2025}, author = {Rajan, A and Keene, AC}, title = {The ABCs of lipid exposure in maintaining neural health.}, journal = {Trends in neurosciences}, volume = {48}, number = {7}, pages = {461-463}, pmid = {40480929}, issn = {1878-108X}, support = {R01 NS131628/NS/NINDS NIH HHS/United States ; R35 GM124593/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; Humans ; *ATP-Binding Cassette Transporters/metabolism ; Drosophila ; *Drosophila Proteins/metabolism ; *Lipid Metabolism/physiology ; Neurodegenerative Diseases/metabolism ; Neuroglia/metabolism ; *Neurons/metabolism ; }, abstract = {ABC transporters modulate lipid homeostasis and are implicated in neurodegenerative diseases. In a recent study, Chen et al. uncovered unexpected dual roles for the Drosophila ABCA protein eater of debris (Eato), which suppresses phospholipid exposure in both neurons and phagocytes, conferring opposite functional outcomes in each cell type. This challenges classical models of ATP-binding cassette (ABC) transporter function and reveals new mechanisms by which lipid signaling regulates neuron-glia interactions in neurodegenerative contexts.}, }
@article {pmid40481491, year = {2025}, author = {Wood, KA and Jin, Y and Krafty, RT and James, JH and Iyer, SK and Badhwar, N}, title = {Concurrent validity testing of the patient perspective of arrhythmia questionnaire.}, journal = {Health and quality of life outcomes}, volume = {23}, number = {1}, pages = {59}, pmid = {40481491}, issn = {1477-7525}, mesh = {Humans ; Male ; Female ; Middle Aged ; Cross-Sectional Studies ; *Arrhythmias, Cardiac/psychology ; *Quality of Life/psychology ; Reproducibility of Results ; Surveys and Questionnaires/standards ; *Patient Reported Outcome Measures ; Aged ; Psychometrics ; Adult ; }, abstract = {BACKGROUND: Disease-specific patient reported outcome measures (PROMs) are widely used to evaluate not only a patient's view of their symptoms, functional status, and health related quality of life, but also clinical benefit of treatments. The Patient Perspective of Arrhythmia Questionnaire (PPAQ) was initially developed as a self-administered, disease-specific PROM for patients with supraventricular tachycardia (SVT) assessing the impact of the arrhythmia and symptoms on patients' daily activities and physical, emotional, and social functioning. Preliminary evidence of content and construct validity has been previously demonstrated, but only in SVT patients in the U.S. and Poland. The aim of this study was to further evaluate the concurrent validity of the PPAQ in patients having a variety of arrhythmias and to explore whether differences in symptoms existed by gender.<br><br>METHODOLOGY: In this cross-sectional study, adult cardiac arrhythmia outpatients from a tertiary care, academic medical center completed the 6-item PPAQ, the SF-12, a Fatigue Visual Analog Scale (VAS), the Brief Symptom Inventory (BSI), and the Patient Health Questionnaire (PHQ-9). Included were patients with atrial fibrillation (82.4%), ventricular tachycardia (15.7%), and atrial tachycardia (2%). Descriptive statistics and independent t-tests, pairwise comparisons with Pearson correlations, Goodman Kruskal gamma statistic for ordinal associations, Cronbach's alpha, and Kuder-Richardson-20 (KR-20) were used to determine concurrent construct validity and internal consistency reliability.<br><br>RESULTS: Participants (n=51) had a mean age of 59.4 years (&#xb1; 12.6), were majority male (66.7%) and Caucasian (75%). Preliminary evidence of concurrent construct validity was found based on moderate to strong correlations (range from 0.4 to 0.7) between the PPAQ and other validated measures, as well as strong internal reliability (KR-20 of 0.80 and Cronbach's alpha of 0.91). The most common symptoms reported were fatigue (60.8%) and heart fluttering (52.9%). Blurred vision (p<0.04), dizziness (p<0.01), and fatigue (p<0.04) were seen significantly more frequently in men compared to women.<br><br>CONCLUSIONS: Results present additional evidence of the validity and reliability of the PPAQ. The PPAQ comprehensively measures the burden of the disease from cardiac arrhythmia patients' perspective. Validated, reliable, disease-specific PROMs are needed to direct personalized clinical decision-making.}, }
@article {pmid40481728, year = {2025}, author = {Fladeboe, KM and O'Daffer, A and Engelberg, RA and Salsman, JM and Merluzzi, T and Baker, KS and Yi-Frazier, JP and Rosenberg, AR}, title = {Developing a skill-based intervention to address social health needs of adolescents and young adults with cancer: an ORBIT Phase 1 Study.}, journal = {Annals of behavioral medicine : a publication of the Society of Behavioral Medicine}, volume = {59}, number = {1}, pages = {}, pmid = {40481728}, issn = {1532-4796}, support = {K99 CA267481/CA/NCI NIH HHS/United States ; R00 CA267481/CA/NCI NIH HHS/United States ; K99CA267481/CA/NCI NIH HHS/United States ; R00CA267481/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; *Neoplasms/psychology ; Young Adult ; Female ; Male ; *Behavior Therapy/methods ; *Adaptation, Psychological ; Child ; Pilot Projects ; *Social Support ; Adult ; *Stress, Psychological/therapy ; }, abstract = {BACKGROUND: Few interventions have improved social health of adolescents and young adults (AYAs) with cancer. Following the obesity-related behavioral intervention trials model, we developed a skill-based social needs module for integration within the Promoting Resilience in Stress Management (PRISM) behavioral intervention.<br><br>METHODS: The social needs module targeting social relationship coping efficacy included behavioral skills adapted to AYAs. The module was refined through 2 separate pilot studies. For Study 1, AYAs 12-24 years old completed the module and a feedback interview. Rapid assessment process methods assessed acceptability, appropriateness, understandability, and informed content revisions. For Study 2, AYAs completed PRISM&#xa0;plus the social needs module (PRISM + Social Needs)&#xa0;and a feedback interview. Rapid assessment process methods assessed acceptability of program and session length, timing, and format.<br><br>RESULTS: For Study 1, 6 AYAs completed the initial module focused on identifying and seeking support (mean age&#x2005;=&#x2005;16 years); most found content acceptable and appropriate (4/6) but suggested adding skills for maintaining social connections and managing cancer-related conversations. Seven AYAs completed the revised module and interview (M&#x2005;=&#x2005;16 years old); most found content acceptable (6/7) and appropriate (7/7) and suggestions were minimal. For Study 2, 7 AYAs completed the revised full program (M&#x2005;=&#x2005;16 years old). Most were satisfied with program length (4/7) and duration (7/7); preferred in-person over virtual delivery (6/7); and wanted PRISM + Social Needs&#xa0;early in treatment (5/7).<br><br>CONCLUSIONS: A skill-based social needs module may be acceptable, appropriate, and promising for AYAs. The PRISM + Social Needs intervention may be best delivered in-person and early in treatment, suggesting AYAs value face-to-face connection. Findings inform subsequent proof-of-concept studies.}, }
@article {pmid40483257, year = {2025}, author = {Stephens, DM and Stewart, C and Avruch, L and Coombs, CC and Danilov, A and Hill, B and Shadman, M and Gerrie, A and Jensen, CE and Hoffmann, M and Winter, A and Ermann, DA and Barr, PM and O'Brien, S and Koffman, B and Byrd, JC}, title = {Feasibility of Bruton's Tyrosine Kinase Inhibitor Discontinuation in Chronic Lymphocytic Leukemia: The Patient Perspective.}, journal = {Clinical lymphoma, myeloma &amp; leukemia}, volume = {25}, number = {9}, pages = {e663-e667}, doi = {10.1016/j.clml.2025.05.011}, pmid = {40483257}, issn = {2152-2669}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Male ; Female ; *Protein Kinase Inhibitors/therapeutic use/adverse effects/administration &amp; dosage ; Middle Aged ; Aged ; Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; Quality of Life ; Aged, 80 and over ; Adult ; Feasibility Studies ; Tyrosine Kinase Inhibitors ; }, abstract = {BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKi) have prolonged survival in chronic lymphocytic leukemia (CLL), however continuous administration increases toxicity. Little is known about clinical outcomes of patients who discontinue BTKi for reasons other than CLL progression. We aimed to report these outcomes.<br><br>PATIENTS/METHODS: With the CLL Society, we solicited volunteers with CLL who self-reported BTKi discontinuation for reasons other than CLL progression to participate in a web-based survey.<br><br>RESULTS: In 170 patients, BTKi was discontinued for toxicity, because CLL was in remission, or personal choice in 62%, 14% and 8%, respectively. When asked how they felt about stopping the BTKi, most were relieved that they may eliminate toxicity (45%), could focus less on CLL (11%), and would not have to pay for the medicine (7%), while 29% experienced anxiety. A statistically significant increase in perceived quality of life (QOL) was observed from prior- versus post-BTKi discontinuation. Of patients who reported that they experienced clinical CLL progression (n = 80), 46% reported that these events did not happen for &#x2265; 1 year after BTKi discontinuation. Those that were on a BTKi for &#x2265; 2 years before discontinuation had more time without CLL relapse.<br><br>CONCLUSIONS: These data provide a unique report of patient experiences. The data suggest that BTKi may be feasible and result in a period of treatment-free remission. The data also indicate that patients are generally relieved when they anticipate BTKi discontinuation and observe significant QOL improvements after BTKi discontinuation. As such, these data should prompt prospective study of time-limited BTKi therapy for CLL.}, }
@article {pmid40485091, year = {2025}, author = {Huang, Y and Zhang, L and Lemos, MP and Astronomo, RD and Narpala, S and Prabhakaran, M and Garcia, NMG and Lu, Y and Mize, GJ and Glantz, H and Colegrove, H and Mann, P and Paez, CA and Andersen-Nissen, E and Hutter, J and Dumond, J and McDermott, AB and Mascola, JR and Koup, RA and Bekker, LG and McElrath, MJ}, title = {Pharmacokinetics Analysis of Serum and Rectal Tissue Concentrations of a Pair of Anti-HIV Monoclonal Antibodies, VRC01 and VRC01LS, in Adults Without HIV.}, journal = {Journal of clinical pharmacology}, volume = {65}, number = {11}, pages = {1506-1516}, pmid = {40485091}, issn = {1552-4604}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; U01 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; U01 AI068618/AI/NIAID NIH HHS/United States ; U01 AI068614/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Adult ; Male ; Female ; Middle Aged ; *Rectum/metabolism ; *HIV Antibodies/blood/administration &amp; dosage ; *Antibodies, Monoclonal/pharmacokinetics/blood/administration &amp; dosage ; Broadly Neutralizing Antibodies ; Young Adult ; HIV Infections ; Tissue Distribution ; Models, Biological ; }, abstract = {VRC01 and VRC01LS are a pair of parental and LS-modified anti-HIV IgG1-backboned monoclonal antibodies. In a Phase 1 clinical trial HVTN 116, 79 participants without HIV received intravenously one dose of VRC01 (30 mg/kg, n = 16) or VRC01LS (30 mg/kg, n = 10), four doses of VRC01 (10 mg/kg, n = 23 or 30 mg/kg, n = 23) every 2 months, or three doses of VRC01LS (30 mg/kg, n = 7) every 3 months. Participants were followed for 6 (VRC01) or 12 (VRC01LS) months after the last dose. Using nonlinear mixed-effects models, we conducted the first population pharmacokinetics analysis of VRC01/LS concentrations in serum and rectal tissue, a primary site of HIV transmission. Serum concentration was described as a one-compartment model in equilibrium with one tissue compartment, with first-order elimination in both compartments. The model was parameterized with micro-constants to estimate volumes of distribution for serum and tissue, serum-tissue distribution rates (K12, K21), and elimination rate constants; distribution and elimination half-life estimates were derived from the governing differential equations. To account for rectal biopsy heterogenicity between individuals, three normalization approaches were used: tissue weight adjusted, IgG concentration adjusted, and protein concentration adjusted. All three approaches rendered consistent estimates. Based on protein-concentration-normalized data, VRC01LS (vs VRC01) exhibited ∼10-fold higher concentrations over time in blood and rectal tissues, and faster blood-to-tissue distribution (K12 = 0.61 vs 0.13/day). Median elimination half-life estimates were 20 days for VRC01 and 63 days for VRC01LS in serum and rectal tissues. These data support lower dosage and/or less frequent dosing of LS monoclonal antibodies providing potentially more immediate protection against HIV exposure in the rectum.}, }
@article {pmid40487272, year = {2025}, author = {Phipps, AI and Hill, CM and Lin, G and Malen, RC and Reedy, AM and Kahsai, O and Ammar, H and Curtis, K and Ma, N and Randolph, TW and Ma, J and Ogino, S and Newcomb, PA and Hullar, MA}, title = {Fusobacterium nucleatum Enrichment in Colorectal Tumor Tissue: Associations With Tumor Characteristics and Survival Outcomes.}, journal = {Gastro hep advances}, volume = {4}, number = {6}, pages = {100644}, pmid = {40487272}, issn = {2772-5723}, support = {R01 CA217970/CA/NCI NIH HHS/United States ; R01 GM145772/GM/NIGMS NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Fusobacterium nucleatum (Fn) is linked to colorectal cancer (CRC) etiology and survival. We hypothesized that CRC tumor attributes and survival are associated with the amount and presence of Fn in tumors.<br><br>METHODS: Fn abundance was measured via droplet digital polymerase chain reaction in patient-matched CRC tumor and normal tissue samples from 859 Puget Sound CRC Cohort participants. Fn enrichment was defined as the continuous difference in normalized abundance between patient-matched tumor and normal tissue samples. Fn presence in tumor was classified categorically as not present, low, or high, regardless of Fn status in matched normal tissue. Associations of Fn enrichment and presence with tumor site, stage, DNA mismatch repair (MMR) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutation status, and molecular subtypes based on combinations of tumor markers were assessed using logistic regression. Associations of Fn enrichment and presence with CRC survival was estimate with Cox regression.<br><br>RESULTS: Fn was present in 20% of tumor tissues and 10% of normal tissues, with higher average abundance in tumors. High Fn presence was independently associated with deficient MMR (dMMR) status and in the context of molecular subtypes for type 1 tumors (dMMR, CIMP-high, BRAF-mutated) and type 5 tumors (dMMR, CIMP-low or negative, BRAF-wildtype). Fn enrichment was associated with type 5 and type 2 tumors (proficient MMR, CIMP-high, BRAF-mutated). Fn enrichment and presence were associated with poorer CRC survival, with some suggestion that associations differed by MMR status.<br><br>CONCLUSION: Detectable Fn in CRC tissue is associated with certain CRC tumor attributes and survival; however, associations may vary based on Fn definition.}, }
@article {pmid40487589, year = {2025}, author = {Ronsley, R and Bradford, MC and Crotty, EE and Vitanza, NA and Runco, DV and Stevens, J and Hoeppner, C and Holtzclaw, SL and Wein, AR and Lee, A and Cole, BL and Ermoian, R and Leary, SES}, title = {Children with medulloblastoma treated with modified ACNS0821 temozolomide, irinotecan, and bevacizumab: The Seattle Children's Hospital experience.}, journal = {Neuro-oncology practice}, volume = {12}, number = {3}, pages = {489-497}, pmid = {40487589}, issn = {2054-2577}, abstract = {BACKGROUND: Effective therapy for medulloblastoma at the time of relapse is limited. The objective of this study is to review outcomes from the Seattle Children's Hospital (SCH) institutional standard therapy for relapsed medulloblastoma, modified from the published ACNS0821 regimen.<br><br>METHODS: Retrospective review of patients treated for relapsed medulloblastoma from 2012-2024 treated with modified ACNS0821 therapy, including combination bevacizumab, irinotecan, and temozolomide, referred to as "TIB." Each TIB cycle includes oral temozolomide (200 mg/m[2]/day) for the first 5 days, intravenous (IV) bevacizumab (10 mg/kg/dose), and IV irinotecan (125 mg/m[2]/dose or 340 mg/m[2]) on days 1 and 15 of each cycle. Patient medical history, prior treatment, therapy toxicity, response, and outcome were collected. The analysis included Kaplan-Meier estimates of 3-year overall survival (OS) and 3-year progression-free survival.<br><br>RESULTS: Fifteen patients were treated with TIB for relapsed medulloblastoma at SCH (median age 5.81 (0.21-23.6) years, 60% male). Twelve patients completed planned therapy. Therapy was discontinued for toxicity (n&#x2005;=&#x2005;1) and family preference (n&#x2005;=&#x2005;1). The most common toxicities were thrombocytopenia (n&#x2005;=&#x2005;7), neutropenia (n&#x2005;=&#x2005;4), nausea (n&#x2005;=&#x2005;5), vomiting (n&#x2005;=&#x2005;5), and diarrhea (n&#x2005;=&#x2005;3). Five patients required dose modification of one agent for toxicity. Median follow-up from TIB therapy start was 1.61 (0.47-7.66) years. Three-year OS was 48% (95% CI: 18%-74%) and 3-year event-free survival was 16% (95% CI: 1%-49%).<br><br>CONCLUSIONS: TIB was well-tolerated in pediatric patients with relapsed medulloblastoma, and outcomes were similar to those published in clinical trials. TIB therapy should be considered for patients with relapsed medulloblastoma, especially patients with limited access to care due to travel barriers.}, }
@article {pmid40488365, year = {2025}, author = {Bloom, JD}, title = {The Data are Insufficient to Confidently Root the SARS-CoV-2 Phylogenetic Tree.}, journal = {Molecular biology and evolution}, volume = {42}, number = {6}, pages = {}, pmid = {40488365}, issn = {1537-1719}, support = {S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {*Phylogeny ; *SARS-CoV-2/genetics/classification ; COVID-19/virology ; Humans ; Genome, Viral ; }, abstract = {Several years ago, I published a paper that described the discrepancy between outgroup and date-based methods for rooting the SARS-CoV-2 phylogenetic tree, and proposed the discrepancy could arise from biases among the available early viral sequences. Here, I explain why the root remains uncertain, including via an interactive narrative at https://nextstrain.org/groups/jbloomlab/narratives/SARS2-rooting/early-SARS2-trees-v1 that enables the reader to examine the underlying data and understand discrepancies that lead different methods to reach different inferences about the root. I also demonstrate clear evidence of bias among the earliest available sequences, and explain why the root of the SARS-CoV-2 tree cannot be conclusively resolved with the current data.}, }
@article {pmid40488826, year = {2025}, author = {Lee, CJ and Carpenter, PA}, title = {Modern-Era Challenges in the Clinical Management of Graft-Versus-Host Disease.}, journal = {Advances in experimental medicine and biology}, volume = {1475}, number = {}, pages = {103-128}, pmid = {40488826}, issn = {0065-2598}, mesh = {*Graft vs Host Disease/therapy/diagnosis/immunology/etiology ; Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Animals ; Disease Management ; }, abstract = {For several decades, graft-versus-host disease (GVHD) has been a long-standing barrier to successful allogenic hematopoietic cell transplantation and a significant cause of post-transplant morbidity and mortality. Initially described as secondary disease or wasting syndrome in transplanted mice, the pathobiology of GVHD is increasingly understood as a dynamic interplay between innate and adaptive immunity in response to initial tissue damage, leading to inflammation and end-organ damage. In parallel, more uniform symptom capture, diagnosis, and response criteria have facilitated rigorous clinical trial design and conduct; together, these advancements have facilitated the development of novel GVHD prevention and treatment strategies. While these advancements have improved the GVHD treatment paradigm, new questions arise within this complex patient population. This chapter discusses several of the most pertinent current clinical practice challenges in GVHD, including its earlier diagnosis, risk stratification, initial and more advanced stage management, as well as a renewed focus on supportive care, given our increased understanding of key roles played by the human microbiome.}, }
@article {pmid40488832, year = {2025}, author = {Bhatt, NS and Richards, A and Beebe, KL and Khera, N}, title = {Challenges and Opportunities in the Care of Hematopoietic Cell Transplant Survivors in the Modern Era.}, journal = {Advances in experimental medicine and biology}, volume = {1475}, number = {}, pages = {209-226}, pmid = {40488832}, issn = {0065-2598}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Survivors ; *Graft vs Host Disease/etiology/prevention &amp; control/therapy ; }, abstract = {With the constantly changing field of hematopoietic cell transplant (HCT) and cellular therapy and a growing number of survivors, there is an ongoing need for work to understand the changing landscape of late effects and develop interventions to optimize the long-term outcomes of survivors. In this chapter, we summarize the studies published in last 5 years describing late effects after HCT. We specifically discuss the available literature or the lack thereof for the late effects as it relates to the changes in transplant practices such as increased use of post-transplant cyclophosphamide, newer drugs to treat chronic graft vs. host disease, and chimeric antigen receptor T-cell therapy as a bridge to HCT or for a post-HCT relapse. We also summarize the recently updated recommendations for screening and management of late effects and a monitoring plan to cater to late effects specific to patients undergoing transplants for non-malignant diseases. We discuss the specific considerations such as challenges for adolescent and young adult HCT survivors, especially as they transition from pediatric to adult care. With the information discussed here, we outline challenges and opportunities for research and clinical practice highlighting the role of health care delivery models in addressing some of these issues.}, }
@article {pmid40489013, year = {2025}, author = {Wang, X and Guillem-Marti, J and Kumar, S and Lee, DS and Cabrerizo-Aguado, D and Werther, R and Alamo, KAE and Zhao, YT and Nguyen, A and Kopyeva, I and Huang, B and Li, J and Hao, Y and Li, X and Brizuela-Velasco, A and Murray, A and Gerben, S and Roy, A and DeForest, CA and Springer, T and Ruohola-Baker, H and Cooper, JA and Campbell, MG and Manero, JM and Ginebra, MP and Baker, D}, title = {De Novo Design of Integrin α5β1 Modulating Proteins to Enhance Biomaterial Properties.}, journal = {Advanced materials (Deerfield Beach, Fla.)}, volume = {37}, number = {34}, pages = {e2500872}, pmid = {40489013}, issn = {1521-4095}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35GM147414/NH/NIH HHS/United States ; SCR_022611//Fred Hutchinson Cancer Center/ ; //ICREA Academia Award/ ; T90 DE021984/DE/NIDCR NIH HHS/United States ; R01DE033016/NH/NIH HHS/United States ; 63-8301-2021//BMGF Prometheus/ ; 2024FI-100198//Fred Hutchinson Cancer Center/ ; R35 GM138036/GM/NIGMS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; R01GM109463/NH/NIH HHS/United States ; T32CA080416/NH/NIH HHS/United States ; PG117878//The Audacious Project/ ; T90DE021984/NH/NIH HHS/United States ; //Pew Biomedical Scholars/ ; R35 GM147414/GM/NIGMS NIH HHS/United States ; R01 DE033016/DE/NIDCR NIH HHS/United States ; R01-HL-131729/HL/NHLBI NIH HHS/United States ; HR0011-21-2-0012//Defense Sciences Office, DARPA/ ; RYC2022-038006-I//Spanish National Plan for Scientific and Technical Research and Innovation/ ; HDTRA1-21-1-0007//Department of the Defense, Defense Threat Reduction Agency/ ; R01 GM109463/GM/NIGMS NIH HHS/United States ; DGE1762114//National Science Foundation/ ; R35GM138036/GM/NIGMS NIH HHS/United States ; PID2021-125150OB-I00//European Regional Development Fund/ ; DTRAJ5B_ML-MACROCYCLES-62-5503-2021//Department of the Defense, Defense Threat Reduction Agency/ ; R35GM138036/NH/NIH HHS/United States ; 1F31HL174166/HL/NHLBI NIH HHS/United States ; R01-HL-131729/NH/NIH HHS/United States ; RRID//Fred Hutchinson Cancer Center/ ; HR0011-21-2-0012//DARPA program Harnessing Enzymatic Activity for Lifesaving Remedies (HEALR)/ ; GF124659//The Nordstrom Barrier Institute for Protein Design Directors Fund/ ; 2021UPC-MZ-67143//Universitat Polit&#xe8;cnica de Catalunya/ ; PG117866//The Audacious Project/ ; OFD/BTREC/CTRECFacultyCareerDevelopmentFellowship//Boston Children's Hospital/ ; F31 HL174166/HL/NHLBI NIH HHS/United States ; GF151772//Wu Tsai Protein Innovation Fund/ ; }, mesh = {*Integrin alpha5beta1/metabolism/chemistry ; *Biocompatible Materials/chemistry ; Animals ; Titanium/chemistry ; Hydrogels/chemistry ; Humans ; Fibronectins/chemistry/metabolism ; Cell Adhesion/drug effects ; Oligopeptides/chemistry ; Mice ; }, abstract = {Integrin α5β1 is crucial for cell attachment and migration in development and tissue regeneration, and α5β1 binding proteins can have considerable utility in regenerative medicine and next-generation therapeutics. We use computational protein design to create de novo α5β1-specific modulating miniprotein binders, called NeoNectins, that bind to and stabilize the open state of α5β1. When immobilized onto titanium surfaces and throughout 3D hydrogels, the NeoNectins outperform native fibronectin (FN) and RGD peptides in enhancing cell attachment and spreading, and NeoNectin-grafted titanium implants outperformed FN- and RGD-grafted implants in animal models in promoting tissue integration and bone growth. NeoNectins should be broadly applicable for tissue engineering and biomedicine.}, }
@article {pmid40490100, year = {2025}, author = {Kim, DY and Huhmann, L and Hippe, DS and Wheless, L and Pavlis, M and Hwang, JC and Brophy, MT and Do, NV and Nghiem, P and Fillmore, N and Hartman, RI}, title = {Treatment and disease-specific survival differences among veterans with Merkel cell carcinoma.}, journal = {Journal of the American Academy of Dermatology}, volume = {93}, number = {4}, pages = {1103-1106}, doi = {10.1016/j.jaad.2025.06.007}, pmid = {40490100}, issn = {1097-6787}, support = {IK2 CX002452/CX/CSRD VA/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; }, }
@article {pmid40491440, year = {2025}, author = {Li, X and Johnston, JM and Homan, C and Marsh, TL and Kim, NJ and Liu, Y and VoPham, T and Grady, WM and Mera, J and McMahon, BJ and Ioannou, GN and Feng, Z and He, Q}, title = {Modeling 5-Year Hepatocellular Carcinoma Risk in Alaska Native Peoples With Hepatitis B Virus Infection.}, journal = {Gastro hep advances}, volume = {4}, number = {7}, pages = {100661}, pmid = {40491440}, issn = {2772-5723}, support = {P20 CA252732/CA/NCI NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; R01 CA223498/CA/NCI NIH HHS/United States ; R01 GM105785/GM/NIGMS NIH HHS/United States ; }, abstract = {BACKGROUND AND AIMS: Modeling hepatocellular carcinoma (HCC) risk in Alaska Native (AN) peoples with chronic hepatitis B virus (HBV) infection is important for risk stratification and surveillance. Existing HCC risk prediction models use baseline characteristics ascertained at the time of HBV diagnosis, rather than predicting HCC risk within 5 years of a relevant time point (such as a clinic visit), and do not include the HBV genotype (GT). We aimed to develop an HCC risk prediction model that addresses these limitations.<br><br>METHODS: We used longitudinal data from a cohort of 1163 AN peoples with HBV. We considered age, sex, GT, serum alpha fetoprotein (AFP), along with serum alanine transaminase, albumin, aspartate aminotransferase, bilirubin, hepatitis B-e-antigen, platelet count, and fibrosis 4 score. To build a 5-year risk model, we structured the longitudinal data into multiple 5-year segments, using AFP as the landmark biomarker. We used the generalized estimation equation approach as well as the Random Forest approach to build risk prediction models.<br><br>RESULTS: Among the 11 predictors included in our final models, AFP was the most important followed by platelet count and GT. Based on cross-validation, the generalized estimation equation model had an area under the receiver operating characteristic curve of 0.81, with 46.5% sensitivity at 90% specificity for 5-year HCC risk prediction. The Random Forest model was superior with an area under the receiver operating characteristic curve of 0.88 and 70% sensitivity at 90% specificity, outperforming the PAGE-B, mPAGE-B, REACH-B and REAL-B models.<br><br>CONCLUSION: We developed an HCC risk prediction model using rich information from different time points in a patient's disease trajectory. Our model can accurately estimate HCC risk at different time points during follow-up for risk stratification and risk-based surveillance.}, }
@article {pmid40491924, year = {2025}, author = {Shen, Q and Wang, S and Wu, K and Wang, L and Gong, W and Lu, G and Chen, W and Yuan, C and Tu, B and Li, W and Wang, Y and Yang, W}, title = {Identification of Grb2 protein as a potential mediator of macrophage activation in acute pancreatitis based on bioinformatics and experimental verification.}, journal = {Frontiers in immunology}, volume = {16}, number = {}, pages = {1575880}, pmid = {40491924}, issn = {1664-3224}, mesh = {*GRB2 Adaptor Protein/genetics/metabolism/immunology ; *Pancreatitis/immunology/metabolism/genetics/pathology ; Animals ; *Macrophage Activation/immunology/genetics ; Mice ; Computational Biology/methods ; *Macrophages/immunology/metabolism ; Male ; Humans ; Signal Transduction ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Acute Disease ; }, abstract = {INTRODUCTION: Macrophage activation is closely associated with Acute pancreatitis (AP). We screened and found that Growth factor receptor bound protein 2 (Grb2) is highly expressed in macrophages during AP. However, the relationship between Grb2 and AP is still poorly understood. In this study, we explored the role of Grb2 in AP.<br><br>METHODS: We screened for gene affecting macrophage activation in AP by combining transcriptomics with Single-cell RNA-sequence analysis. Next, the expression of Grb2 in M1/M2 macrophage activation was detected by Single-cell RNA-sequence analysis and western blot. Furthermore, the effect of Grb2 on M1/M2 macrophage activation was detected by flow cytometry. The severity of AP was assessed by histological analysis, serum amylase, serum lipase and serum inflammatory factors in vivo. NOD-like receptor thermal protein domain associated protein 3 (Nlrp3) and Nuclear factor kappa-B (NF-kB) signaling pathways were also evaluated.<br><br>RESULTS: Grb2 is mainly expressed in macrophages of pancreas in AP and up-regulated in M1 macrophage activation. Inhibiting Grb2 could alleviate AP by preventing M1 macrophage activation through down-regulating Nlrp3 and NF-&#x3ba;B.<br><br>DISCUSSION: Inhibition of Grb2 can effectively prevent M1 macrophage activation and alleviate AP. Grb2 may potentially be an effective target of macrophage activation for the treatment of AP.}, }
@article {pmid40492758, year = {2025}, author = {Ashby, E and Zhang, B and Fouda, GG and Fong, Y and Janes, H}, title = {Negative Control Outcome Adjustment in Early-Phase Randomized Trials: Estimating Vaccine Effects on Immune Responses in HIV Exposed Uninfected Infants.}, journal = {Statistics in medicine}, volume = {44}, number = {13-14}, pages = {e70142}, pmid = {40492758}, issn = {1097-0258}, support = {UM1AI068632//National Institute of Allergy and Infectious Diseases/ ; U01 AI068632/AI/NIAID NIH HHS/United States ; UM1 AI068632/AI/NIAID NIH HHS/United States ; U01 AI046749/AI/NIAID NIH HHS/United States ; U01AI068632//International Maternal Pediatric Adolescent AIDS Clinical Trials Network/ ; UM1 AI068616/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI106716/AI/NIAID NIH HHS/United States ; DGE-2140004//National Science Foundation/ ; UM1AI106716//National Institute of Allergy and Infectious Diseases/ ; UM1AI068616//National Institute of Allergy and Infectious Diseases/ ; UM1AI068635//National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Humans ; *HIV Infections/immunology/prevention &amp; control ; *Randomized Controlled Trials as Topic/methods/statistics &amp; numerical data ; Infant ; Models, Statistical ; Computer Simulation ; Infant, Newborn ; Female ; }, abstract = {Adjustment for prognostic baseline variables can reduce bias due to covariate imbalance and increase efficiency in randomized trials. While the use of covariate adjustment in late-phase trials is justified by favorable large-sample properties, it is seldom used in small, early-phase studies, due to uncertainty in which variables are prognostic and the potential for precision loss, type I error rate inflation, and undercoverage of confidence intervals. To address this problem, we consider adjustment for a valid negative control outcome (NCO), or an auxiliary post-randomization outcome believed to be completely unaffected by treatment but more highly correlated with the primary outcome than baseline covariates. We articulate the assumptions that permit adjustment for NCOs without producing post-randomization selection bias, and describe plausible data-generating models where NCO adjustment can improve upon adjustment for baseline covariates alone. In numerical experiments, we illustrate performance and provide practical recommendations regarding model selection and finite-sample variance corrections. We apply our methods to the reanalysis of two early-phase vaccine trials in HIV exposed uninfected (HEU) infants, where we demonstrate that adjustment for auxiliary post-baseline immunological parameters can enhance the precision of vaccine effect estimates relative to standard approaches that avoid adjustment or adjust for baseline covariates alone.}, }
@article {pmid40492914, year = {2025}, author = {Kim, HJ and Partridge, SC and Lee, J and Yoen, H and Moon, WK and Ha, SM}, title = {Preoperative Diagnosis of Ipsilateral and Contralateral Breast Cancer: Role of Diffusion-weighted MRI.}, journal = {Radiology}, volume = {315}, number = {3}, pages = {e242423}, pmid = {40492914}, issn = {1527-1315}, support = {R01 CA190299/CA/NCI NIH HHS/United States ; R01 CA207290/CA/NCI NIH HHS/United States ; }, mesh = {Retrospective Studies ; Humans ; Female ; Middle Aged ; Sensitivity and Specificity ; Observer Variation ; Reference Values ; *Breast Neoplasms/diagnostic imaging ; *Dynamic Contrast Enhanced Magnetic Resonance Imaging/methods/statistics &amp; numerical data ; *Diffusion Magnetic Resonance Imaging/methods/statistics &amp; numerical data ; Multimodal Imaging/methods/statistics &amp; numerical data ; *Preoperative Care/methods/statistics &amp; numerical data ; *Breast/diagnostic imaging ; Aged ; }, abstract = {Background The interpretation of the multiparametric MRI, which combines dynamic contrast-enhanced (DCE) MRI with diffusion-weighted imaging (DWI), has the potential to increase MRI diagnostic accuracy. Purpose To investigate and validate the potential of DWI with an apparent diffusion coefficient (ADC) cutoff in evaluating additional lesions detected at preoperative MRI in patients with breast cancer. Materials and Methods In this retrospective review, data from patients with additional lesions (Breast Imaging Reporting and Data System [BI-RADS] category 3 or higher) who underwent MRI between June 2019 and June 2021 were evaluated. Two breast radiologists independently evaluated additional enhanced lesions and measured the ADC values. The optimal ADC cutoff for downgrading lesions was determined according to the Youden index and was applied to a separate validation cohort. The efficacy of prespecified ADC values (1.53 × 10[-3] mm[2]/sec and 1.3 × 10[-3] mm[2]/sec) was investigated. Diagnostic performance was evaluated and compared using generalized estimating equations. Results Data from 219 patients (mean age, 50.8 years ± 10.2 [SD]) with 292 additional lesions were evaluated. The optimal ADC cutoff was 1.0 × 10[-3] mm[2]/sec, which, compared with that for DCE MRI alone, increased specificity (from 28.7% to 73.1%; P < .001) but decreased sensitivity (from 99.2% to 89.6%; P < .001) of MRI. In the validation cohort (104 patients, 133 additional lesions), 48 of 133 (36.1%) lesions were diagnosed as cancer, and applying the ADC cutoff derived from the development cohort increased specificity (from 21.2% to 68.2%; P < .001) but decreased sensitivity (from 97.9% to 83.3%; P = .01). For ipsilateral lesions, specificity increased (from 8.7% to 65.2%; P < .001), but the sensitivity did not decrease significantly (from 97.1% to 85.3%; P = .052). For contralateral lesions, similar performance improvements were observed for specificity (from 35.9% to 71.8%; P < .001), but a greater decrease in sensitivity was observed (from 100% to 78.6%; P < .001). Application of the prespecified ADC cutoffs achieved higher sensitivity values but smaller improvements in specificity. Conclusion The ADC cutoff based on MRI with DWI improved the performance of preoperative MRI in diagnosing additional lesions in patients with breast cancer. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.}, }
@article {pmid40493363, year = {2025}, author = {Appelbaum, JS and Percival, ME and Scott, BL}, title = {A cure for the kiss of death?.}, journal = {Blood advances}, volume = {9}, number = {11}, pages = {2855-2856}, pmid = {40493363}, issn = {2473-9537}, }
@article {pmid40493417, year = {2025}, author = {Roudier, MP and Gulati, R and Sayar, E and Patel, RA and Tratt, M and Richards, HM and Cejas, P and Munoz Gomez, M and Qiu, X and Xie, Y and Hanratty, B and Zaidi, S and Zhao, JL and Adil, M and Mittal, C and Zhao, Y and Dumpit, R and Coleman, I and Low, JY and Persse, T and Galipeau, P and Lee, JK and Tretiakova, M and Chambers, M and Vakar-Lopez, F and True, LD and Perrone, M and Lam, HM and Kollath, LA and Ding, CC and Harmon, S and Cheng, HH and Yu, EY and Montgomery, RB and Hawley, JE and Lin, DW and Corey, E and Schweizer, MT and Setty, M and Ha, G and Sawyers, CL and Morrissey, C and Long, H and Nelson, PS and Haffner, MC}, title = {Patterns of intra- and intertumor phenotypic heterogeneity in lethal prostate cancer.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {15}, pages = {}, pmid = {40493417}, issn = {1558-8238}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R50 CA274336/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P01 CA265768/CA/NCI NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; K08 CA282978/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; R01 CA193837/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA280056/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/pathology/genetics/metabolism ; *Genetic Heterogeneity ; Neoplasm Metastasis ; Aged ; Phenotype ; Single-Cell Analysis ; Middle Aged ; }, abstract = {Metastatic prostate cancer (mPC) is a clinically and molecularly heterogeneous disease. While there is increasing recognition of diverse tumor phenotypes across patients, less is known about the molecular and phenotypic heterogeneity present within an individual. In this study, we aimed to define the patterns, extent, and consequences of inter- and intratumoral heterogeneity in lethal prostate cancer. By combining and integrating in situ tissue-based and sequencing approaches, we analyzed over 630 tumor samples from 52 patients with mPC. Our efforts revealed phenotypic heterogeneity at the patient, metastasis, and cellular levels. We observed that intrapatient intertumoral molecular subtype heterogeneity was common in mPC and showed associations with genomic and clinical features. Additionally, cellular proliferation rates varied within a given patient across molecular subtypes and anatomic sites. Single-cell sequencing studies revealed features of morphologically and molecularly divergent tumor cell populations within a single metastatic site. These data provide a deeper insight into the complex patterns of tumoral heterogeneity in mPC with implications for clinical management and the future development of diagnostic and therapeutic approaches.}, }
@article {pmid40497723, year = {2025}, author = {Schleiss, MR and Fernández-Alarcón, C and Bierle, CJ and Geballe, AP and Badillo-Guzman, A and Tanna, CE and Tsriwong, K and Blackstad, M and Wang, JB and McVoy, MA}, title = {Replication-deficient whole-virus vaccines against cytomegalovirus induce protective immunity in a guinea pig congenital infection model.}, journal = {Journal of virology}, volume = {99}, number = {7}, pages = {e0020725}, pmid = {40497723}, issn = {1098-5514}, support = {T35AI118620/NH/NIH HHS/United States ; R01 HD098866/HD/NICHD NIH HHS/United States ; G.E.R.M. Award//Infectious Diseases Society of America/ ; T35 AI118620/AI/NIAID NIH HHS/United States ; R25 HL088728/HL/NHLBI NIH HHS/United States ; R01HD098866//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; NHLBI R25HL088728/HL/NHLBI NIH HHS/United States ; }, mesh = {Animals ; Guinea Pigs ; *Cytomegalovirus Infections/prevention &amp; control/immunology/congenital ; *Cytomegalovirus/immunology/genetics ; Female ; *Cytomegalovirus Vaccines/immunology/administration &amp; dosage ; Disease Models, Animal ; Virus Replication ; Antibodies, Viral/blood/immunology ; *Roseolovirus/immunology/genetics ; Pregnancy ; Humans ; Viremia/prevention &amp; control ; }, abstract = {Vaccines are needed to prevent congenital human cytomegalovirus (HCMV) infections. This study used the guinea pig cytomegalovirus (GPCMV) model to examine replication-deficient whole-virus vaccines for protection against maternal viremia and congenital CMV infection. Two recombinant GPCMVs, GP51-DD and GP52-DD, were engineered with destabilization domains fused to the essential viral late proteins GP51 and GP52. These viruses, predicted to replicate in the presence of the synthetic ligand Shield-1 but not in its absence, were evaluated for Shield-1 dependence in vitro and for safety, immunogenicity, and efficacy in the GPCMV model. GP52-DD was profoundly Shield-1-dependent, producing no detectable infectious progeny in its absence. In contrast, the replication of GP51-DD was delayed in the absence of Shield-1 but reached similar peak titers with or without the compound. GPCMV-seronegative guinea pigs received two subcutaneous injections of phosphate-buffered saline, GP51-DD, GP52-DD, or wild-type GPCMV (WT-GPCMV). DNAemia attributable to vaccination was noted in 10/10 (100%) of WT-GPCMV-immunized animals but in only 10/28 animals (36%) immunized with DD vaccines (P < 0.001). GPCMV-specific ELISA and interferon-gamma ELISpot responses were similar in all vaccinated groups. When immunized animals were bred and challenged during pregnancy with virulent GPCMV, DNAemia was detected in all sham-immunized controls and in 44% of GP52-DD-immunized dams (at significantly reduced levels) but was absent in dams immunized with GP51-DD or WT-GPCMV. Immunization with GP52-DD, GP51-DD, or WT-GPCMV significantly reduced congenital GPCMV transmission compared to placebo (protective efficacies of 89, 94, and 100%, respectively). Thus, replication-impaired GP51-DD and replication-deficient GP52-DD vaccines were comparable to WT-GPCMV in immunogenicity and protective efficacy.IMPORTANCECongenital HCMV infections could potentially be prevented by a vaccine, but most vaccines that have advanced in clinical trials have been modestly effective, at best. Subunit HCMV vaccines chiefly target envelope glycoproteins, but none has proven effective at engendering durable protective immunity. A vaccine that confers immune responses to a broader repertoire of immunogens than a subunit vaccine, such as a whole-virus, live-attenuated vaccine, could confer improved protection. However, there are safety concerns for live-attenuated HCMV vaccines. Using the GPCMV model of congenital infection, this study demonstrates that two replication-impaired whole virus vaccines, though attenuated in animals, are highly immunogenic and induce preconception immunity that protects against maternal viremia and fetal infection after wild-type GPCMV challenge during pregnancy.}, }
@article {pmid40498998, year = {2025}, author = {Marcos-Kovandzic, L and Avagliano, M and Ben Khelil, M and Srikanthan, J and Abdallah, R and Petrocelli, V and Rengassamy, J and Alfaro, A and Bied, M and Fidelle, M and Ferrere, G and Daillère, R and Arbab, A and Amine-Hneineh, R and Pages, A and Dartigues, P and Ly, P and Simon, S and Durand, S and Gottschlich, A and Ginhoux, F and Blériot, C and Liu, P and Zhao, L and Creusot, L and Rolhion, N and Derosa, L and Kroemer, G and Menger, L and Kobold, S and Castilla-Llorente, C and Sokol, H and Casola, S and Pasolli, E and Zitvogel, L and Bigenwald, C}, title = {Gut Microbiota Modulation through Akkermansia spp. Supplementation Increases CAR T-cell Potency.}, journal = {Cancer discovery}, volume = {15}, number = {9}, pages = {1905-1926}, pmid = {40498998}, issn = {2159-8290}, support = {955575//HORIZON EUROPE Framework Programme (Horizon Europe)/ ; ANR-21-RHUS-0017//Agence Nationale de la Recherche (ANR)/ ; IG #23747//Agence Nationale de la Recherche (ANR)/ ; INCa-DGOS-Inserm-ITMO Cancer_18002.//Institut National Du Cancer (INCa)/ ; ANR-23-IAHU-0002//Agence Nationale de la Recherche (ANR)/ ; 101052444//HORIZON EUROPE European Research Council (ERC)/ ; 756017//HORIZON EUROPE European Research Council (ERC)/ ; }, mesh = {*Gastrointestinal Microbiome/immunology ; Humans ; Mice ; Animals ; *Akkermansia/immunology ; *Immunotherapy, Adoptive/methods ; Receptors, Aryl Hydrocarbon/metabolism ; *Receptors, Chimeric Antigen/immunology/metabolism ; Female ; *Lymphoma, B-Cell/therapy/immunology/microbiology ; Dysbiosis ; Male ; Antigens, CD19/immunology ; }, abstract = {UNLABELLED: This study investigates the clinical relevance of the gut microbiome at taxonomic and metabolic levels in anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, both in patients and in a preclinical syngeneic tumor model. Patients with B-cell lymphoma treated with CD19 CAR T cells exhibited profound intestinal dysbiosis, exacerbated after CAR T-cell infusion. This dysbiosis was characterized by low bacterial richness, low soluble MAdCAM-1, and loss of Akkermansia species, associated with resistance to therapy. Mechanistically, oral Akkermansia massiliensis supplementation increased CAR T-cell infiltration into the bone marrow, inverted the CD4/CD8 CAR T-cell ratio, favored Tc1 CD8+ T-cell polarization, and promoted the release of tryptophan-derived indole metabolites, leading to better tumor control. The clinical benefit of Akkermansia spp. supplementation was abolished when CAR T cells were genetically deficient in the indole receptor, aryl hydrocarbon receptor (AhR). AhR-agonistic indoles alone failed to replicate the bacterium's anticancer effects. These findings suggest that Akkermansia supplementation could improve CAR T-cell potency in patients with intestinal Akkermansia deficiency.<br><br>SIGNIFICANCE: B-cell lymphoma patients treated with CAR T cells harbor major gut microbiota perturbations and related metabolism that restrain CAR T-cell therapy. Reprogramming the gut microbiota ecosystem by oral A. massiliensis supplementation induces CAR T-cell niching and Tc1 differentiation in the bone marrow, promoting tumor control in an AhR-dependent manner.}, }
@article {pmid40499013, year = {2025}, author = {Pershad, Y and Uddin, MM and Xue, L and Haessler, J and Collins, JM and Mack, TM and Glick, E and Glaser, V and Zhao, K and Jaiswal, S and Manson, JE and Pandey, U and Desai, P and Natarajan, P and Honigberg, MC and Kooperberg, C and Whitsel, EA and Kitzman, JO and Bick, AG and Reiner, AP}, title = {Correlates and consequences of clonal hematopoiesis expansion rate: a 16-year longitudinal study of 6976 women.}, journal = {Blood}, volume = {146}, number = {9}, pages = {1078-1087}, pmid = {40499013}, issn = {1528-0020}, support = {R01 HL148565/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Clonal Hematopoiesis/genetics ; Longitudinal Studies ; Aged ; Middle Aged ; Mutation ; Janus Kinase 2/genetics ; Dioxygenases ; Postmenopause ; DNA Methyltransferase 3A ; }, abstract = {Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality and malignancy risk, yet the determinants of clonal expansion remain poorly understood. We performed sequencing at a depth of coverage of >4000× for CHIP mutations in 6976 postmenopausal women from the Women's Health Initiative (WHI) at 2 time points: the WHI baseline examination and ∼16 years later at the Long Life Study (LLS) visit. Among 3685 CH mutations detected at baseline (variant allele fraction [VAF] of ≥0.5%), 24% were not detected at LLS, 26% were micro-CH at LLS (0.5% ≤ VAF < 2%), and 50% were CHIP (VAF ≥ 2%). We confirmed that clonal expansion is highly dependent on initial clone size and CHIP driver gene, with SF3B1 and JAK2 mutations exhibiting the fastest growth rate. We identified germ line variants in TERT, IL6R, TCL1A, and MSI2 that modulate clonal expansion rate. Measured baseline leukocyte telomere length showed differential effects on incident CHIP risk, with shorter baseline leukocyte telomere length predisposing to incident PPM1D mutations and longer baseline leukocyte telomere length favoring incident DNMT3A mutations. We discovered that the IL6R missense variant p.Asp358Ala specifically impairs TET2 clonal expansion, supported by direct measurements of soluble interleukin-6 receptor and interleukin-6. Faster clonal growth rate was associated with increased risk of cytopenia, leukemia, and all-cause mortality. Notably, CHIP clonal expansion rate mediated 34.4% and 43.7% of the clonal hematopoiesis risk score's predictive value for leukemia and all-cause mortality, respectively. These findings reveal key biological determinants of CHIP progression and suggest that incorporating growth rate measurements could enhance risk stratification.}, }
@article {pmid40499462, year = {2025}, author = {Robinson, HR and Lakritz, S and Pavlick, DC and Davis, SL and Lieu, CH and Eule, CJ and Graham, LS and Spiess, PE and Li, R and Kamat, AM and Grivas, P and Jacob, JM and Bratslavsky, G and Basnet, A and Wong, KA and Lin, DI and Necchi, A and Ross, JS and Lam, ET}, title = {Squamous cell carcinoma of unknown primary (SCCUP): a genomic landscape study.}, journal = {ESMO open}, volume = {10}, number = {6}, pages = {105312}, pmid = {40499462}, issn = {2059-7029}, mesh = {Humans ; *Neoplasms, Unknown Primary/genetics/pathology ; *Carcinoma, Squamous Cell/genetics/pathology ; Female ; Male ; Middle Aged ; Aged ; Genomics/methods ; Biomarkers, Tumor/genetics ; Microsatellite Instability ; Mutation ; Aged, 80 and over ; Adult ; B7-H1 Antigen ; }, abstract = {BACKGROUND: Squamous cell carcinoma (SCC) of unknown primary (SCCUP) refers to any SCC for which the primary tumor origin cannot be identified despite guideline-directed evaluation. Although strategies employing comprehensive genomic profiling (CGP) to identify targets for non-SCC carcinomas of unknown primary (CUPs) have shown benefit, the genomic landscape in SCCUP remains poorly defined. Here we describe results of CGP in patients with SCCUP to identify potential therapy targets and characteristic biomarkers.<br><br>PATIENTS AND METHODS: Cases of advanced SCCUP were identified in the FoundationCORE&#xae; database by review of clinical history and pathology records. Samples underwent DNA extraction and sequencing to identify genomic alterations (GAs), microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic mutational signatures, and viral reads. Programmed death-ligand 1 (PD-L1) expression was determined by immunohistochemistry.<br><br>RESULTS: 443 SCCUP cases were identified. Common presentation sites included lymph nodes (41.1%), liver (15.6%), and soft tissue (15.1%). A mean of 6.5 GAs were observed per case. The most frequent non-targetable GAs involved TP53 (62.5%), CDKN2A (37.0%), CDKN2B (19.6%), KMT2D (18.3%), and TERT (16.0%); the most frequent GAs potentially targetable in biomarker-driven trials included PIK3CA (27.3%), PTEN (15.1%), MTAP (13.1%), KRAS (10.4%), and NOTCH1 (8.4%). Among all SCCUP cases, 2.0% had MSI-high (MSI-H) status and 33.9% had TMB &#x2265;10 mutations/megabase. Among 204 cases with available PD-L1 testing, 39.2% were low-positive [tumor proportion score (TPS) 1%-49%] and 29.9% were high-positive (TPS &#x2265;50%). SCCUP cases presenting with liver involvement had fewer GAs per tumor and lower TMB compared with other SCCUP cases. In contrast, cases presenting with inguinal, pelvic, or retroperitoneal involvement were more likely to demonstrate evidence of human papilloma virus (HPV) infection and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) genomic signatures.<br><br>CONCLUSIONS: CGP of this SCCUP cohort identified GAs that may guide consideration of molecularly targeted therapy via tumor-agnostic indications and/or treatment in biomarker-driven trials. SCCUPs frequently exhibit biomarkers associated with response to immune checkpoint inhibitors.}, }
@article {pmid40499589, year = {2025}, author = {Aelvoet, AS and Dekker, E and Cruise, MW and Grady, WM and Idos, GE and Kelly, K and Kieber-Emmons, A and Kupfer, SS and Markowitz, AJ and Samadder, NJ and Weiss, JM and Yurgelun, MB and Burke, CA}, title = {Gastric Polyposis and Cancer in Western Patients With Familial Adenomatous Polyposis: Epidemiology, Detection, and Management.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {6}, pages = {}, doi = {10.6004/jnccn.2025.7027}, pmid = {40499589}, issn = {1540-1413}, mesh = {Humans ; *Adenomatous Polyposis Coli/epidemiology/complications/diagnosis/therapy ; *Stomach Neoplasms/epidemiology/diagnosis/therapy/etiology ; Risk Factors ; Disease Management ; Adenomatous Polyps ; }, abstract = {Patients with familial adenomatous polyposis (FAP) are at increased risk of developing cancer, with the most common sites being colorectal, duodenal/ampullary and thyroid. In the last decade, an alarming increase in gastric cancer has been reported in the Western FAP population. These cancers are often diagnosed at an advanced stage with poor prognosis, even in patients undergoing regular upper endoscopic surveillance. Most gastric cancers in Western patients with FAP occur in the proximal stomach, where a carpeting of fundic gland polyposis hampers visualization of gastric cancer and its precursor lesions during endoscopic surveillance. Although fundic gland polyps are the most prevalent proximal polyp, several different dysplastic lesions can be found in the stomachs of patients with FAP. including fundic gland polyps with dysplasia, foveolar-type adenomas, pyloric gland adenomas, and intestinal-type adenomas. Although adenomas are the most likely precursors to gastric cancer, the exact lesions responsible for gastric cancer in FAP are not yet fully understood. This review focuses on gastric polyposis and the characteristics of gastric cancer in Western patients with FAP, including risk factors, lesion detection, surveillance and management of gastric polyposis, and areas for future research.}, }
@article {pmid40499654, year = {2025}, author = {Baillie, HT and Tinker, LF and An, P and Brasky, TM and Liu, S and Manson, JE and Snetselaar, L and Tabung, FK and Lampe, JW and Neuhouser, ML}, title = {Dietary Supplement Use Is Associated with Select Serum Nutrient Biomarkers among Postmenopausal Women: Results from a Controlled Feeding Study.}, journal = {The Journal of nutrition}, volume = {155}, number = {8}, pages = {2745-2754}, pmid = {40499654}, issn = {1541-6100}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; HHSN261201700010C/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, abstract = {BACKGROUND: Dietary supplement use is common among older adults; however, the association between supplement use and corresponding nutrient biomarkers in this population is less well understood.<br><br>OBJECTIVES: This study aimed to determine whether older women using dietary supplements had higher serum concentrations of corresponding biomarkers and whether those using multiple supplement sources of the nutrient had incrementally higher serum nutrient concentrations.<br><br>METHODS: Participants from the Women's Health Initiative enrolled in a 2-wk feeding study (n = 153). Women consumed an individualized menu and maintained intake of usual dietary supplements. Serum vitamin B12, lutein + zeaxanthin, and phospholipid fatty acids were measured at the end of the feeding period. Multiple linear regression of dietary supplement use, and participant characteristics on log-transformed serum biomarker concentrations was used to evaluate the association. One-way analysis of variance determined whether there were significant differences in mean serum biomarkers among participants based on the number of sources of a nutrient consumed via dietary supplement.<br><br>RESULTS: In multiple linear regression models (n = 152), users of vitamin B12 supplements had 58% higher geometric mean serum concentrations of vitamin B12 than nonusers (P < 0.001). Users of omega-3 fatty acid dietary supplements had geometric mean serum phospholipid docosahexaenoic acid + eicosapentaenoic acid that were 38%-46% higher than nonusers (P < 0.0001). In contrast, use of lutein + zeaxanthin-containing supplements was not associated with serum lutein + zeaxanthin (P = 0.72). Users of 2 sources of vitamin B12 and lutein + zeaxanthin-containing dietary supplements had higher corresponding serum biomarkers than users of only a multivitamin and users of neither (P < 0.0001).<br><br>CONCLUSIONS: The use of vitamin B12 and omega-3 fatty acid supplements were associated with higher serum biomarkers, respectively. Dietary supplements containing lutein + zeaxanthin may not increase serum biomarkers among postmenopausal women.<br><br>TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT00000611.}, }
@article {pmid40500115, year = {2026}, author = {Fogel, JM and Salih, MA and Haddaway, K and Marzinke, MA and Marshall, C and Wang, Z and Cummings, V and Piwowar-Manning, E and Rooney, JF and McCauley, M and Grinsztejn, B and Landovitz, RJ and Eshleman, SH}, title = {Use of DNA profiling to resolve HIV status in a person using injectable cabotegravir for HIV pre-exposure prophylaxis.}, journal = {Journal of clinical pathology}, volume = {79}, number = {2}, pages = {142-144}, pmid = {40500115}, issn = {1472-4146}, support = {U01 AI069476/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI069476/AI/NIAID NIH HHS/United States ; UM1 AI069424/AI/NIAID NIH HHS/United States ; }, }
@article {pmid40501778, year = {2025}, author = {Schattgen, S and Vegesana, K and Hazelton, WD and Minervina, A and Valkiers, S and Slowikowski, K and Smith, N and ,  and Villani, AC and Thomas, PG and Bradley, P}, title = {Diverse modes of T cell receptor sequence convergence define unique functional and cellular phenotypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501778}, issn = {2692-8205}, support = {U01 AI150747/AI/NIAID NIH HHS/United States ; T32 AR007258/AR/NIAMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R21 AI169085/AI/NIAID NIH HHS/United States ; DP2 CA247831/CA/NCI NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; }, abstract = {Single-cell techniques allow concurrent study of gene activity and T cell receptor (TCR) sequences, identifying connections between TCR structure and cell traits. Expanding on our CoNGA software, we present a "metaCoNGA" analysis of 6 million T cells from 91 diverse studies, mapping TCR sequence similarity across tissues and diseases. This approach exposes shared TCR features within specific T cell subsets, including those associated with infection, cancer, and autoimmunity. We introduce a method to identify T cell groups with similar gene expression and biased TCR amino acid composition, providing a systematic framework for classifying diverse unconventional T cells, including KIR+ CD8+ T cells, CD4+ regulatory T cells, and subsets of NKT and MAIT cells. A new TCR clustering approach identifies thousands of convergent TCR sequence clusters hypothesized to target shared antigens. These clusters show coherent gene expression, highlighting the role of antigen exposure in shaping T cell behavior. Finally, we provide a tool for users to merge new data with this resource and rapidly identify T cell features in their data sets. This resource empowers investigations into the complex relationship between TCR sequence and T cell function in human health.}, }
@article {pmid40501795, year = {2025}, author = {McKellar, SA and Pineda, JMB and Lattupally, R and Codd, AS and Newell, EW and Lu, SX and Bradley, RK}, title = {Chorionic Gonadotropin Beta 7 is a marker of immune evasion in cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501795}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 HL128239/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; R01 CA251138/CA/NCI NIH HHS/United States ; T32 GM007266/GM/NIGMS NIH HHS/United States ; T32 GM153182/GM/NIGMS NIH HHS/United States ; }, abstract = {Human chorionic gonadotropin beta (beta-hCG) is an oncofetal antigen expressed by trophoblast cells of the placenta, with minimal expression in adult somatic tissues. Numerous studies have demonstrated that beta-hCG-encoding genes are expressed in various cancers, but expression of these genes (CGB3, CGB5, CGB7, and CGB8) across diverse cancers has not been systematically evaluated. Here, we report that CGB genes are more widely expressed across diverse cancer types than previously appreciated and that secreted beta-hCG is readily detected. In particular, CGB genes are expressed in the majority of urothelial bladder cancers, where CGB7 is most frequently expressed and significantly associated with an immunosuppressed tumor microenvironment, including decreased CD8[+] T cell infiltration. Multiple CGB genes are associated with failure to respond to immune checkpoint inhibitor (ICI) therapy, and CGB7 is particularly strongly predictive of poor prognosis. Overall, our findings indicate that beta-hCG is a clinically accessible, predictive biomarker of immunotherapeutic response.}, }
@article {pmid40501893, year = {2025}, author = {Robertson, AJ and Kerr, B and Feder, AF}, title = {Intracellular interactions shape antiviral resistance outcomes in poliovirus via eco-evolutionary feedback.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501893}, issn = {2692-8205}, support = {T32 GM136534/GM/NIGMS NIH HHS/United States ; }, abstract = {Antiviral resistance evolution poses a major obstacle for controlling viral infections. A promising strategy is to target shared viral proteins that allow drug susceptible viruses to sensitize resistant ones during cellular coinfection, muting selection for resistance. Pocapavir, a poliovirus capsid inhibitor, employs this sociovirological strategy. While susceptible viruses significantly suppressed resistance in the presence of pocapavir in cell culture, a pocapavir clinical trial observed widespread resistance evolution and limited improvements to clearance times. To reconcile these findings, we present an intra-host eco-evolutionary model of poliovirus in the presence of pocapavir, which reproduces both the potent interference observed in vitro and the resistance emergence seen in patients. In the short term, our model predicts that a high density of susceptible viruses sensitizes resistant ones to pocapavir, mirroring cell culture results. However, over multiple replication cycles, pocapavir's high potency collapses viral density, which reduces coinfection and allows resistance to evolve as observed in the clinical trial. Since coinfection is essential to suppress resistance, enabling greater survival of susceptible viruses could offer therapeutic advantages. Counterintuitively, we demonstrate that this can be achieved by lessening antiviral potency, which can limit resistance evolution while also maintaining a low viral load. These findings suggest that antivirals that rely on viral intracellular interaction must balance immediate neutralization with the preservation of future coinfection, yielding more sustained inhibition. Explicitly considering the eco-evolutionary feedback encompassing viral density, shared phenotypes and absolute fitness not only provides new insights into designing effective therapies but also illuminates viral evolutionary dynamics more broadly.}, }
@article {pmid40501932, year = {2025}, author = {Otto, DJ and Arriaga-Gomez, E and Thieme, E and Yang, R and Lee, SC and Setty, M}, title = {Comparing phenotypic manifolds with Kompot: Detecting differential abundance and gene expression at single-cell resolution.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40501932}, issn = {2692-8205}, support = {R01 CA292932/CA/NCI NIH HHS/United States ; R35 GM147125/GM/NIGMS NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; }, abstract = {Kompot is a statistical framework for holistic comparison of multi-condition single-cell datasets, supporting both differential abundance and differential expression. Differential abundance captures changes in how cells populate the phenotypic manifold across conditions, while differential expression identifies condition-specific changes in gene regulation that may be localized to particular regions of that manifold. Kompot models the distribution of cells and gene expression as continuous functions over a low-dimensional representation of cell states, enabling single-cell resolution inference with calibrated uncertainty estimates. Applying Kompot to aging murine bone marrow, we identified a continuum of shifts in hematopoietic stem cell and mature cell states, transcriptional remodeling of monocytes independent of compositional changes, and divergent regulation of oxidative stress response genes across cell types. By capturing both global and cell-state-specific effects of perturbation, Kompot reveals how aging reshapes cellular identity and regulatory programs across the hematopoietic landscape. This framework is broadly applicable to dissecting condition-specific effects in complex single-cell landscapes.}, }
@article {pmid40502094, year = {2025}, author = {Hurlburt, NK and Lubow, J and Goo, L and Pancera, M}, title = {Structural basis for antibody cross-neutralization of Dengue and Zika viruses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40502094}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 GM124169/GM/NIGMS NIH HHS/United States ; S10 OD028581/OD/NIH HHS/United States ; }, abstract = {Safe and effective vaccines against co-circulating mosquito-borne orthoflaviviruses such as Zika virus (ZikV) and the four serotypes of Dengue virus (DenV1-4) must elicit broadly neutralizing antibodies (bnAbs) to prevent the risk of enhancement of infection by non-neutralizing antibodies. We recently discovered new orthoflavivirus-directed bnAbs, including F25.S02, which neutralizes DenV1-4 and ZikV with comparable or superior potency to the previously characterized E dimer epitope (EDE) bnAbs. Mutagenesis studies of viral envelope proteins showed that the epitope specificity of F25.S02 is distinct from EDE1 bnAbs. Here, we used cryoEM and X-ray crystallography to understand the basis of cross-neutralization of F25.S02 at the molecular level. We obtained a ~4.2 Å cryoEM structure of F25.S02 Fab bound to a stabilized DenV3 soluble E protein dimer and a 2.3 Å crystal structure of F25.S02 Fab bound to ZikV soluble E protein dimer. Like previously described EDE1 bnAbs, the structural epitope of F25.S02 is at the E dimer interface, encompassing predominantly conserved regions in domain II, including the fusion loop. However, unlike EDE1 bnAbs, F25.S02 binding is almost entirely dependent on the heavy chain and is shifted slightly away from the dimer symmetry axis. Our findings emphasize the importance of this cross-neutralizing site of vulnerability for DenV and ZikV that can facilitate rational design of vaccines and therapeutics.}, }
@article {pmid40502162, year = {2025}, author = {Bernard, MJ and Ruiz, A and Diaz, JA and Nunley, NM and Dove, RN and Zhang, S and Lee, E and Heering, KY and Bopardikar, S and Gallardo, A and Hashimoto, T and Agrawal, R and Smith, CM and Wilde, BR and Matulionis, N and Richards, HM and Lee, SCS and Sharifi, MN and Lang, JM and Zhao, SG and Haffner, MC and Shackelford, DB and Boutros, PC and Christofk, HR and Goldstein, AS}, title = {OGDHL regulates tumor growth, neuroendocrine marker expression, and nucleotide abundance in prostate cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40502162}, issn = {2692-8205}, support = {T32 GM152342/GM/NIGMS NIH HHS/United States ; TL1 DK132768/DK/NIDDK NIH HHS/United States ; U2C CA271894/CA/NCI NIH HHS/United States ; U2C DK119889/DK/NIDDK NIH HHS/United States ; R37 CA286450/CA/NCI NIH HHS/United States ; R01 CA208642/CA/NCI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; U2C DK119886/DK/NIDDK NIH HHS/United States ; P50 CA092131/CA/NCI NIH HHS/United States ; P30 CA016042/CA/NCI NIH HHS/United States ; R01 CA267721/CA/NCI NIH HHS/United States ; T32 GM007185/GM/NIGMS NIH HHS/United States ; OT2 OD030544/OD/NIH HHS/United States ; R01 CA270108/CA/NCI NIH HHS/United States ; R01 CA215185/CA/NCI NIH HHS/United States ; }, abstract = {As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL profoundly alters Androgen Receptor inhibition-induced plasticity, including suppressing the neuroendocrine markers DLL3 and HES6, induces accumulation of the DNA damage response marker ƔH2AX, and reduces nucleotide synthesis. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of prostate cancer plasticity and nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer.}, }
@article {pmid40503682, year = {2025}, author = {Haddox, HK and Angehrn, G and Sesta, L and Jennings-Shaffer, C and Temple, SD and Galloway, JG and Hinrichs, AS and DeWitt, WS and Bloom, JD and Iv, FAM and Neher, RA}, title = {The mutation rate of SARS-CoV-2 is highly variable between sites and is influenced by sequence context, genomic region, and RNA structure.}, journal = {Nucleic acids research}, volume = {53}, number = {11}, pages = {}, pmid = {40503682}, issn = {1362-4962}, support = {BAA 200-2021-11554/CC/CDC HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; 2919.02//National Science Foundation/ ; //Schmidt Sciences/ ; 310030_188547/SNSF_/Swiss National Science Foundation/Switzerland ; //National Defense Science and Engineering/ ; 75D30124C20302/CC/CDC HHS/United States ; //James S. McDonnell Foundation/ ; S10OD028685/RI/ORIP NIH HHS/United States ; NSF PHY-2309135/GF/NIH HHS/United States ; //LLC/ ; //Gordon and Betty Moore Foundation/ ; //Kavli Institute for Theoretical Physics/ ; /HHMI/Howard Hughes Medical Institute/United States ; R01 AI146028/SNSF_/Swiss National Science Foundation/Switzerland ; }, mesh = {*SARS-CoV-2/genetics ; *Genome, Viral ; *RNA, Viral/genetics/chemistry ; *Mutation Rate ; Nucleic Acid Conformation ; COVID-19/virology ; Humans ; Evolution, Molecular ; Mutation ; Silent Mutation ; }, abstract = {RNA viruses like SARS-CoV-2 have high mutation rates, which contribute to their rapid evolution. Mutation rates depend on mutation type and can vary between sites in a virus's genome. Understanding this variation can shed light on the mutational processes at play, and is crucial for quantitative modeling of viral evolution. Using millions of SARS-CoV-2 full-genome sequences, we estimate rates of synonymous mutations for each mutation type and examine how much these rates vary between sites. We find a surprisingly high level of variability. A substantial fraction of this variability can be explained by local sequence context, genomic region, and RNA secondary structure. We estimate fitness effects of each mutation based on the number of times it actually occurs versus the number of times it is expected to occur based on a model of the above features. We identify small regions of the genome where synonymous or noncoding mutations occur much less often than expected, indicative of strong purifying selection on the RNA sequence independent of protein sequence. Overall, this work expands our basic understanding of SARS-CoV-2's evolution by characterizing the virus's mutation process at the level of individual sites and uncovering several striking mutational patterns that arise from unknown mechanisms.}, }
@article {pmid40504533, year = {2025}, author = {Unger, JM}, title = {Inclusive Cancer Clinical Trial Participation-A Recipe for New Treatment Advances.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2515210}, doi = {10.1001/jamanetworkopen.2025.15210}, pmid = {40504533}, issn = {2574-3805}, support = {UG1 CA189974/CA/NCI NIH HHS/United States ; }, }
@article {pmid40505527, year = {2025}, author = {Snyder, LB and Newton, KM and Ng, HX and Reed, SD and Guthrie, KA and Zambrano, V and LaCroix, AZ}, title = {Positive impact of a menopause website - MyMenoplan.org - on treatment intentions, knowledge, and decision making: A randomized controlled trial.}, journal = {Maturitas}, volume = {199}, number = {}, pages = {108630}, doi = {10.1016/j.maturitas.2025.108630}, pmid = {40505527}, issn = {1873-4111}, mesh = {Humans ; Female ; *Menopause/psychology ; *Internet ; *Health Knowledge, Attitudes, Practice ; Middle Aged ; *Decision Making ; Adult ; Intention ; Adaptation, Psychological ; *Patient Education as Topic ; }, abstract = {OBJECTIVE: Assess the impact of a new website, MyMenoplan.org, on menopause knowledge, decision-making progress, treatment and coping intentions among people experiencing perimenopause and menopause. The website was designed to provide women and their clinicians with comprehensive, evidence-based information and decision-making tools about a broad range of symptoms and treatments, address common questions and facilitate conversations with clinicians when desired.<br><br>STUDY DESIGN: Women were recruited online and randomized to interact with the MyMenoplan.org website created by MsFLASH investigators (n&#xa0;=&#xa0;200) or control websites (n&#xa0;=&#xa0;210) for at least 20&#xa0;min before completing an online survey. Women in the control arm could choose any website(s), including three suggested high-quality websites from governmental or non-profit organizations. Fraud-detection protocols were followed. Outcome differences by arm were estimated via adjusted linear regression models.<br><br>PRIMARY OUTCOMES: Behavioral change intentions, menopause knowledge, decision-making progress, and user website experience.<br><br>RESULTS: 99&#xa0;% of controls visited at least one recommended website. Compared with the control arm, the MyMenoplan.org arm reported significantly higher levels of intent to change treatment (3.87 vs. 3.61), knowledge of menopause symptoms and treatments (4.17 vs. 3.85), treatment decision-making progress (3.94 vs. 3.71), clarity about benefits and risks of treatments (4.04 vs. 3.81), perceived website quality (4.05 vs. 3.70), intentions to return to the website (4.40 vs. 3.97), and likelihood of recommending it to others (4.35 vs. 4.04; each p&#xa0;<&#xa0;0.001).<br><br>CONCLUSION: MyMenoplan.org is the first NIH-funded website shown to be effective in helping women learn and make decisions about management of the menopause transition. The website serves as a model for providing much-needed, evidence-based information for health-care providers and women nearing or in perimenopause and menopause.<br><br>ClinicalTrials.gov ID NCT05299983.}, }
@article {pmid40505814, year = {2025}, author = {Gao, L and Nelson, A and Barata, A and Horick, N and Wekwerth, B and Wood, A and Fernandes, A and Lee, SJ and LeBlanc, TW and Amonoo, HL and El-Jawahri, A and Newcomb, R}, title = {Prolonged Hospitalization for Hematopoietic Cell Transplantation: Characteristics, Risk Factors and Associations with Patient-Reported and Clinical Outcomes.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {697.e1-697.e12}, pmid = {40505814}, issn = {2666-6367}, support = {R01 CA222014/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Male ; Female ; Middle Aged ; *Patient Reported Outcome Measures ; Quality of Life ; Risk Factors ; Adult ; *Hospitalization ; *Length of Stay ; Prospective Studies ; Aged ; *Hematologic Neoplasms/therapy ; Depression ; Treatment Outcome ; }, abstract = {Patients hospitalized for hematopoietic cell transplantation (HCT) may experience prolonged length of stay (PLOS). However, the associations between PLOS and patient-reported outcomes (PROs) during and after HCT hospitalization is unknown. We aimed to evaluate the associations of pre-HCT demographic and disease characteristics and PROs with PLOS, as well as the associations between PLOS and trajectory of PROs and risk of rehospitalization in the first year post-HCT. We conducted a secondary analysis of data from adult patients with hematologic malignancies undergoing HCT who were enrolled in a prospective observational study or one of two randomized clinical trials evaluating integrated specialty palliative care during HCT hospitalization. PLOS was defined as ≥30 continuous days for allogeneic HCT and ≥21 continuous days for autologous HCT. Quality of life (QOL; Functional Assessment of Cancer Therapy Bone Marrow Transplant), symptom burden (Edmonton Symptom Assessment Scale), anxiety and depression symptoms (Hospital Anxiety and Depression Scale and Patient Health Questionnaire-9), and posttraumatic stress symptoms (PCL) were measured at time of admission (ie, prior to HCT), 2 weeks, and 3 and 6 months post-HCT. Multivariate logistic regression was used to assess the association between pre-HCT PROs and PLOS adjusting for relevant covariates. Linear mixed-effects models were used to characterize the trajectory of PROs by PLOS during and after HCT. Cox proportional hazards regression was used to evaluate differences between LOS groups in time to readmission or death in the first year post-HCT. A total of 606 patients (mean age = 55.7 years [18.3 to 78.0 years]; 56.6% male; 81.5% White; 53.1% allogeneic HCT) were included. Patients with PLOS were younger (mean 53.3 versus 56.6 years, P = .004), in complete remission prior to HCT (52.8% versus 46.3%, P = .02), diagnosed with acute leukemia (34.2% versus 26.1%, P < .001), and underwent allogeneic HCT (62.1% versus 49.9%, P < .0001). In multivariate analyses, worse pre-HCT QOL (OR 0.99, P = .003), symptom burden (OR 1.02, P = .01), and depressive symptoms (OR 1.07, P = .01) were associated with higher risk of PLOS. Patients with PLOS reported worse QOL at 2 weeks (∆ = -12.3, P < .0001), 3 months (∆ = -6.9, P = .002), and 6 months post-HCT (∆ =-4.8, P = .02) compared to those without PLOS. Patients with PLOS reported greater symptom burden at 2 weeks (∆ = 10.2, P < .0001) and 3 months (∆ = 3.9, P = .04), but not 6 months post-HCT (∆ = 0.5, P = .79). Patients with PLOS reported higher depression burden at 2 weeks (∆ = 2.5, P < .0001) and 3 months (∆ = 1.1, P = .03), but not 6 months post-HCT (∆ = 0.6, P = .19). Patients with PLOS experienced shorter time to death or re-admission in the first year post-HCT (median 221 days versus not reached, HR 1.7; CI 1.3 to 2.2, P < .001). Pre-HCT PROs including QOL, symptom burden, and depressive symptoms were associated with PLOS. Moreover, patients with PLOS go on to experience worse QOL, symptom burden, and depressive symptoms up to 6 months post-HCT and are at an increased risk of mortality and greater healthcare utilization. Patients with PLOS may have unique needs compared to the usual HCT population and may benefit from augmented supportive care during and after HCT.}, }
@article {pmid40506647, year = {2025}, author = {Elbur, AI and Donnell, D and Hosek, S and Dye, BJ and Velloza, J and Delany-Moretlwe, S and Celum, C}, title = {Correction: The Association between Use of Adherence Support Interventions and Adherence To HIV Preexposure Prophylaxis among Young South African and Zimbabwean Women in HPTN 082.}, journal = {AIDS and behavior}, volume = {29}, number = {8}, pages = {2495}, doi = {10.1007/s10461-025-04807-7}, pmid = {40506647}, issn = {1573-3254}, }
@article {pmid40507311, year = {2025}, author = {King, GG and Baker, KK and Coveler, AL and Harris, WP and Cohen, SA and Shankaran, V and Zhen, DB and Safyan, RA and Lee, HH and Alidina, A and Hensel, J and Hibbert, R and Durm, GA and LaFary, YC and Younger, A and Kugel, S and Collisson, E and Konnick, EQ and Redman, MW and Schneider, BP and Pritchard, CC and Shahda, S and Chiorean, EG}, title = {Phase Ia/Ib Study of Afatinib with Capecitabine in Patients with Refractory Solid Tumors and Pancreaticobiliary Cancers.}, journal = {Cancers}, volume = {17}, number = {11}, pages = {}, pmid = {40507311}, issn = {2072-6694}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; TBD//Boehringer-Ingelheim Pharmaceuticals, Inc./ ; }, abstract = {BACKGROUND: The epidermal growth factor receptor (EGFR) is overactive in many tumors. This phase I trial evaluated the safety and preliminary efficacy of afatinib plus capecitabine in refractory pancreatic ductal adenocarcinoma (PDA), biliary tract cancers (BTC), and other solid tumors.<br><br>PATIENTS AND METHODS: The phase Ia study had a 3 + 3 design with capecitabine 1000 mg/m[2] twice daily on days 1-14 and afatinib 20 mg, 30 mg, or 40 mg daily in 21-day cycles. In phase Ib, 15 patients, each with PDA and BTC, were treated at maximum tolerated dose (MTD).<br><br>RESULTS: A total of 41 patients were enrolled. No dose-limiting toxicities were observed, and the MTD was 40 mg afatinib plus capecitabine. Among 36 response-evaluable patients, one had a partial response (3%), and eight (22%) had stable disease. Median progression-free survival (PFS) was 1.9 months (95% CI 1.0, 2.0) for PDA and 1.9 months (95% CI 1.6, 3.4) for BTC. Median overall survival (OS) was 3.2 months (95% CI 2.0, 5.8) for PDA, and 4.6 months (95% CI 1.9, 6.1) for BTC. Median OS was 5.8 months (95% CI 2.0, 9.6) for KRAS[WT] PDA, and 5.0 months (95% CI 1.6, 6.1) for KRAS[WT] BTC, vs. 3.9 months (95% CI 1.9, 5.8) for KRAS[MUT] PDA and 3.1 months (95% CI 1.0, 22.8) for KRAS[MUT] BTC, respectively.<br><br>CONCLUSIONS: Afatinib plus capecitabine is tolerable but does not have clinically meaningful efficacy in refractory PDA/BTC. Future studies should test novel anti-EGFR/HER2 therapies in KRAS[WT] cancers further selected with a comprehensive molecular profile.}, }
@article {pmid40509873, year = {2025}, author = {Hazelton, WD and Prest, M and Chen, L and Rouse, K and Elkin, EB and Ferris, JS and Xu, X and Bickell, NA and Kong, CY and Blank, S and Feuer, EJ and Samimi, G and Heckman-Stoddard, BM and Layne, TM and Wright, JD and Myers, ER and Havrilesky, LJ}, title = {Trends in uterine cancer incidence and mortality: insights from a natural history model.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {9}, pages = {1891-1903}, pmid = {40509873}, issn = {1460-2105}, support = {U01 CA265739/CA/NCI NIH HHS/United States ; U01CA265739//Cancer Intervention and Surveillance Modeling Network Uterine Incubator/ ; /CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Black or African American/statistics &amp; numerical data ; Body Mass Index ; Hysterectomy/statistics &amp; numerical data ; Incidence ; Nutrition Surveys ; Reproductive History ; Risk Factors ; SEER Program ; United States/epidemiology ; *Uterine Neoplasms/epidemiology/mortality/pathology ; White/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Uterine cancer incidence and mortality are increasing, with concomitant disparities in outcomes between racial groups. Natural history modeling can evaluate risk factors, predict future trends, and simulate approaches to reducing mortality and disparities.<br><br>METHODS: We designed a natural history model of uterine cancer using a multistage clonal expansion design. The model is informed by National Health and Nutrition Examination Survey, National Health Examination Survey, age, time period, birth cohort, and birth certificate data on reproductive histories and body mass index (BMI). We fit and calibrated the model to Surveillance, Epidemiology, and End Results data by race and ethnicity as well as histologic subgroup. We projected future incidence and estimated the degree of contribution of BMI, reproductive history, and competing hysterectomy to excess uterine cancer incidence.<br><br>RESULTS: The model accurately replicated Surveillance, Epidemiology, and End Results incidence for endometrioid, nonendometrioid, and sarcoma subgroups for non-Hispanic Black and non-Hispanic White patients. For endometrioid, nonendometrioid, and sarcomas, BMI-attributable risks are greater for non-Hispanic White than for non-Hispanic Black patients; reproductive history-attributable risks are greater for non-Hispanic Black patients. Between 2018 and 2050, endometrioid incidence is projected to rise by 64.9% in non-Hispanic Black individuals and17.5% in non-Hispanic White individuals; the projected rise for the nonendometrioid subgroup is 41.4% in non-Hispanic Black individuals and 22.5% in non-Hispanic White individuals; the sarcoma incidence projected increase is 36% in non-Hispanic Black individuals and 29.2% in non-Hispanic White individuals.<br><br>CONCLUSIONS: Uterine cancer risk is substantially explained by reproductive history and BMI, with differences observed between non-Hispanic Black and non-Hispanic White individuals and future projections indicating perpetuation of disparities. Lower rates of hysterectomy and rising obesity rates will likely contribute to continued increases in uterine cancer incidence.}, }
@article {pmid40510739, year = {2025}, author = {Goodman, K and Cook, C and Weatherbee, D and Yadav, S and Mudaranthakam, DP and Sexton, R and Mahaffey, N and Garcia, L and Ta, T and Cebula, E and Smart, J and Goudeau, T and Annis, S and Gilmore, A and Chugina, D and Ahmadzai, P and Hoering, A and LeBlanc, M}, title = {Automating Data Entry from Electronic Health Record to Electronic Data Capture Using a Trusted Cloud-Based Application in Multisite Cancer Clinical Trials.}, journal = {Journal of the Society for Clinical Data Management}, volume = {5}, number = {1}, pages = {1-16}, pmid = {40510739}, issn = {2694-1473}, support = {P30 CA168524/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, abstract = {INTRODUCTION: For more than two decades, researchers have sought to develop and to improve technologies to seamlessly move data from electronic health record (EHR) systems to study forms in electronic data capture (EDC) systems. The goal is to utilize advancing technology to improve study data accuracy and quality while decreasing the burden of data collection on busy clinical research professionals.<br><br>OBJECTIVES: This report discusses findings from the SWOG Cancer Research Network's use of a secure and trusted third-party cloud-based application as a technology link between EHR databases and the clinical trial EDC application. The objectives are to ease the burden on site staff and improve data accuracy and completeness.<br><br>METHODS: Three SWOG sites used a cloud-based EHR-to-EDC application to enter study data for two follow-up tumor assessment case report forms for six patients each. This software-assisted method was compared to manual medical record abstraction. Time savings, error rate, and interrater reliability were measured.<br><br>RESULTS: A comparison of the two methods demonstrated substantial time savings and improvements in data quality. This is especially true for data fields that can be automatically captured using the application for clinical trials using the software-assisted approach.<br><br>CONCLUSIONS: Using a secure and trusted cloud-based application to access the EHR to assist in data collection for clinical trials resulted in welcome time savings for clinical research professionals and higher data accuracy.}, }
@article {pmid40513032, year = {2025}, author = {Curtis, DJ and Patil, SS and Reynolds, J and Purtill, D and Lewis, C and Ritchie, DS and Gottlieb, DJ and Yeung, DT and Wong, E and Tey, SK and Perera, T and Moore, J and Koldej, RM and De Abreu Lourenco, R and Stubbs, J and Morrissey, CO and Munsef, N and Arenas, A and Hill, GR and , }, title = {Graft-versus-Host Disease Prophylaxis with Cyclophosphamide and Cyclosporin.}, journal = {The New England journal of medicine}, volume = {393}, number = {3}, pages = {243-254}, doi = {10.1056/NEJMoa2503189}, pmid = {40513032}, issn = {1533-4406}, support = {Lifting Clinical Trials and Registries Capacity AP//Australian Government/ ; 20.01//Cancer Society of New Zealand/ ; 2121002//Auckland Medical Research Foundation/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Cyclophosphamide/administration &amp; dosage/adverse effects ; *Cyclosporine/administration &amp; dosage/adverse effects ; Disease-Free Survival ; Drug Therapy, Combination ; *Graft vs Host Disease/prevention &amp; control/mortality/epidemiology ; *Hematologic Neoplasms/mortality/therapy ; Immunosuppressive Agents/administration &amp; dosage/adverse effects ; Kaplan-Meier Estimate ; Methotrexate/therapeutic use/adverse effects ; *Peripheral Blood Stem Cell Transplantation/adverse effects ; Transplantation Conditioning/methods ; Transplantation, Homologous/adverse effects/methods ; Calcineurin Inhibitors/administration &amp; dosage/adverse effects ; Neoplasm Recurrence, Local/epidemiology/prevention &amp; control ; }, abstract = {BACKGROUND: Allogeneic peripheral-blood stem-cell transplantation (SCT) from a matched related donor after myeloablative conditioning is the preferred curative treatment for patients with high-risk blood cancers. The combination of a calcineurin inhibitor and an antimetabolite remains standard care for graft-versus-host disease (GVHD) prophylaxis in these patients. Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched donor when it is added to or replaces the antimetabolite. However, the effects of post-transplantation cyclophosphamide specifically after SCT from a matched related donor remain uncertain, and effects in the context of myeloablative conditioning are unclear.<br><br>METHODS: We randomly assigned adults who were undergoing SCT from a matched related donor after myeloablative or reduced-intensity conditioning to receive either post-transplantation cyclophosphamide-cyclosporin (experimental prophylaxis) or cyclosporin-methotrexate (standard prophylaxis). The primary end point was GVHD-free, relapse-free survival.<br><br>RESULTS: Among 134 patients who underwent randomization, 66 were assigned to receive experimental prophylaxis and 68 to receive standard prophylaxis. GVHD-free, relapse-free survival was significantly longer with experimental prophylaxis (median, 26.2 months; 95% confidence interval [CI], 9.1 to not reached) than with standard prophylaxis (median, 6.4 months; 95% CI, 5.6 to 8.3; P<0.001 by a log-rank test). GVHD-free, relapse-free survival at 3 years was 49% (95% CI, 36 to 61) with experimental prophylaxis and 14% (95% CI, 6 to 25) with standard prophylaxis (hazard ratio for GVHD, relapse, or death, 0.42; 95% CI, 0.27 to 0.66). The cumulative incidence of grade III to IV acute GVHD at 3 months was 3% (95% CI, 1 to 10) in the experimental-prophylaxis group and 10% (95% CI, 4 to 19) in the standard-prophylaxis group. At 2 years, overall survival was 83% and 71%, respectively (hazard ratio for death, 0.59; 95% CI, 0.29 to 1.19). The incidence of serious adverse events was similar in the two groups in the first 100 days after SCT.<br><br>CONCLUSIONS: The combination of post-transplantation cyclophosphamide and a calcineurin inhibitor led to longer GVHD-free, relapse-free survival than standard prophylaxis after transplantation from a matched related donor with either reduced-intensity or myeloablative conditioning in patients with blood cancers. (Funded by the Australian Government Medical Research Future Fund and others; ALLG BM12 CAST Australian-New Zealand Clinical Trials Registry number, ACTRN12618000505202.).}, }
@article {pmid40513563, year = {2025}, author = {Khan, AT and Adebamowo, C and Fullerton, SM and Hirbo, J and Konigsberg, IR and Kraft, P and Martin, I and Nelson, SC and Ramsay, M and Wojcik, GL and Adebamowo, SN and Conomos, MP and Darst, BF and Hysong, MR and Li, Y and Martin, AR and Mathias, RA and Rich, SS and Sakoda, LC and Schrider, DR and Sharma, J and Smith, JL and Sun, Q and Zhang, Y and ,  and Gogarten, SM}, title = {A data model for population descriptors in genomic research.}, journal = {American journal of human genetics}, volume = {112}, number = {7}, pages = {1504-1514}, pmid = {40513563}, issn = {1537-6605}, support = {U01 HG011717/HG/NHGRI NIH HHS/United States ; U01 CA261339/CA/NCI NIH HHS/United States ; T32 HL007111/HL/NHLBI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; U01 HG011723/HG/NHGRI NIH HHS/United States ; U01 HG011710/HG/NHGRI NIH HHS/United States ; U01 HG011715/HG/NHGRI NIH HHS/United States ; R35 HG011944/HG/NHGRI NIH HHS/United States ; U01 HG011697/HG/NHGRI NIH HHS/United States ; U01 HG011719/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Genomics/methods ; *Genetics, Population ; Multifactorial Inheritance/genetics ; }, abstract = {Population descriptors used in genetic studies have broad social and translational implications. There are no globally agreed-upon definitions or usages of common population descriptors (e.g., race, ethnicity, nationality, and tribe), many of which are applied ad hoc and/or derived from political or bureaucratic conventions. Recent recommendations have encouraged the retention of as much granularity in population descriptors as possible during data preparation, analysis, and interpretation of research results. However, genomic research infrastructures (i.e., current practices, resources, and workflows in genomic research) often lack systematic and flexible organization, structure, and harmonization of multifaceted and detailed population descriptor data. This can lead to loss of information, barriers to international collaboration, and potential issues in clinical translation. Here, we describe a data model, developed by the NIH-funded Polygenic Risk Methods in Diverse Populations (PRIMED) Consortium, that organizes and retains detailed population descriptor data for future research use. The model supports a versatile, traceable, and reproducible harmonization system that offers multiple benefits over existing data structures. This data model affords researchers the flexibility to thoughtfully choose and scientifically justify their choice of population descriptors. It avoids the conflation of social identities with biological categories and guards against harmful typological inferences. Genomic research tools of this kind will be crucial for producing scientifically robust findings that minimize potential harms of descriptor misuse while maximizing benefits for diverse communities.}, }
@article {pmid40514010, year = {2025}, author = {Kharfan-Dabaja, MA and Kumar, A and Pinilla-Ibarz, J and Brown, JR and Shadman, M and Awan, FT and Kenderian, SS and Siddiqi, T and Abramson, JS and Al-Juhaishi, T and Brander, DM and Coombs, CC and Furman, RR and Jain, N and Khan, N and Saba, NS and Collins, JM and Beitinjaneh, A and Stephens, DM and Woyach, J and Hamadani, M}, title = {Clinical Practice Recommendations on the Role Of Allogeneic Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapy in Patients With Chronic Lymphocytic Leukemia on Behalf of the American Society for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {8}, pages = {494-504}, doi = {10.1016/j.jtct.2025.06.002}, pmid = {40514010}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Immunotherapy, Adoptive/methods ; *Leukemia, Lymphocytic, Chronic, B-Cell/therapy ; *Receptors, Chimeric Antigen/immunology ; Societies, Medical ; Transplantation, Homologous ; United States ; }, abstract = {Chimeric antigen receptor T-cell therapy (CAR T-cell) is a new treatment option for relapsed and/or refractory (R/R) chronic lymphocytic leukemia (CLL). Novel therapies including Bruton's tyrosine kinase inhibitors (BTK), covalent or noncovalent, and an inhibitor of the B-cell leukemia/lymphoma 2 protein (BCL-2), venetoclax, have replaced chemoimmunotherapy (CIT) regimens in the front-line and the R/R setting, and have relegated allogeneic hematopoietic cell transplantation (allo-HCT) to later treatment stages. Updating the 2016 clinical practice recommendations on allo-HCT in CLL is necessary to help guide contemporary clinical practice. A panel of 18 physicians with diverse expertise across different CLL treatment modalities and one methodologist participated in this effort. Any recommendation receiving ≥ 70% votes was considered a consensus. CAR T-cell therapy is recommended for patients not responding or relapsing after at least 2 lines of therapy consisting of a covalent BTK inhibitor and a BCL-2 inhibitor. In addition, CAR T-cell therapy is recommended for patients who subsequently received a noncovalent BTK inhibitor in the third-line or later setting, regardless of response. CAR T-cell therapy is also recommended in CLL relapsing after an allo-HCT, assuming that patients are fit for the procedure. In those CLL patients who are candidates, allo-HCT is recommended if disease is R/R to CAR T-cell therapy provided that an objective response is demonstrated prior to the allograft. Allo-HCT is also recommended in patients with clonally-related Richter transformation (RT) after demonstrating an objective response to front-line CIT or other treatments. CAR T-cell therapy is recommended in R/R RT. We emphasize the importance of enrolling patients in clinical trials whenever available to continue to advance the field and improve prognosis of R/R CLL. We acknowledge that there are unique clinical scenarios not covered herein which may require a case-by-case approach.}, }
@article {pmid40514012, year = {2025}, author = {Schoettler, ML and Gavriilaki, E and Carreras, E and Bo-Kyoung, C and Dandoy, CE and Ho, VT and Jodele, S and Moiseev, I and Sánchez-Ortega, I and Srivastava, A and Atsuta, Y and Carpenter, PA and Koreth, J and Kröger, N and Ljungman, P and Page, K and Popat, U and Shaw, BE and Sureda, AM and Soiffer, R and Vasu, S}, title = {An ASTCT, CIBMTR, EBMT, and APBMT Consensus Statement Defining Response Criteria for Hematopoietic Cell Transplantation Associated Thrombotic Microangiopathy (TA-TMA) Directed Therapy.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {610-623}, pmid = {40514012}, issn = {2666-6367}, support = {L40 AI140344/AI/NIAID NIH HHS/United States ; R01 HD093773/HD/NICHD NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Thrombotic Microangiopathies/etiology/therapy/diagnosis ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; }, abstract = {BACKGROUND: Transplant associated thrombotic microangiopathy (TA-TMA) confers significant morbidity and mortality in hematopoietic cell transplant recipients. The safety and efficacy of multiple TA-TMA directed therapeutic agents are being tested in ongoing clinical trials. In the absence of approved drugs, several treatments are used off-label. Response definitions to TA-TMA directed therapy from retrospective studies and ongoing interventional clinical trials vary widely, limiting cross study comparisons. An expert panel from multiple international blood and marrow transplant societies (ASTCT, CIBMTR, EBMT, APBMT) who initially convened to harmonize diagnostic and risk stratification criteria for TA-TMA extended its mandate to review response criteria.<br><br>OBJECTIVE: Our objective was to propose clinically meaningful response criteria for TA-TMA directed therapy to enhance consistent evaluation of therapeutic agents in clinical practice, interventional trials, and registry studies.<br><br>METHODS: After a relevant literature review, the Delphi method was used to achieve consensus on proposed response criteria.<br><br>RESULTS: The panel focused on the 3 key concepts. First, due to ongoing concurrent co-morbidities and severity of illness, the complete resolution of TA-TMA manifestations may be difficult to achieve immediately after initiating treatment, making the definition of clinically meaningful partial responses essential to assess early efficacy of TA-TMA-directed therapies. Second, because hematologic manifestations may resolve faster than organ damage, we suggest assessing hematologic/biochemical and organ manifestations independently, in addition to having an overall response assessment. Finally, using the previously established diagnostic criteria as a framework, we propose objective response definitions for each TA-TMA criterion and organ manifestation. While consensus was achieved on response definitions, due to the lack of evidence, there was no agreement on standardized time points for assessing response or when to consider alternative therapies for patients unresponsive to initial treatments. Hematologic and biochemical response assessments include anemia and thrombocytopenia, with criteria accounting for transfusion dependence or independence at the time of treatment, schistocytes, lactate dehydrogenase, and soluble C5b-9. Patients with other established etiologies of cytopenias (i.e. poor graft function or relapsed hematologic malignancy) should be considered unevaluable for hematologic response. Responses for involved organ manifestations were also proposed. In an overall assessment, the best overall response is limited by the lowest hematologic/biochemical or organ response. NR of either hematologic/biochemical or organ is considered an overall NR.<br><br>CONCLUSION: The consensus response criteria proposed by this expert panel are a step towards standardizing the assessment of treatment responses of TA-TMA directed agents for future studies and interventional clinical trials. Adoption of these criteria will enhance consistency of response assessment and facilitate the comparison of TA-TMA treatments. Since achieving an early overall CR may be challenging/protracted in patients with organ injury; establishment of criteria for clinically meaningful PR is important and may be a more useful early endpoint in studies. Given the complexity of these patients and assessment of response, these definitions may need be revised in the future after application in large cohorts diverse in age, HCT approaches, and interventional agents.}, }
@article {pmid40516378, year = {2025}, author = {Huang, Y and Zhang, L and Gelderblom, H and Seaton, KE and Yates, NL and Paez, CA and Karuna, ST and Andrew, P and Gamble, T and Robinson, ST and Ledgerwood, JE and Hyrien, O and Walsh, SR and Gay, CL and Gwira, JA and Spiegel, HML and Sobieszczyk, ME and Mannheimer, SB and Edupuganti, S and Hurt, CB and Stephenson, KE and Yu, C and Kelley, CF and Mahomed, S and Siegel, M and Yacovone, M and Pensiero, MN and Donnell, D and Cohen, MS and Corey, L and Gilbert, PB and Koup, RA and Tomaras, GD and , }, title = {Fixed dosing versus weight-based dosing of HIV-1 prophylactic monoclonal antibodies in adults: a post-hoc, cross-protocol pharmacokinetics modelling study.}, journal = {EBioMedicine}, volume = {117}, number = {}, pages = {105804}, pmid = {40516378}, issn = {2352-3964}, support = {UM1 AI154466/AI/NIAID NIH HHS/United States ; U01 AI069470/AI/NIAID NIH HHS/United States ; UM1 AI069469/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI154468/AI/NIAID NIH HHS/United States ; UM1 AI069412/AI/NIAID NIH HHS/United States ; UM1 AI069470/AI/NIAID NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Adult ; *HIV Infections/prevention &amp; control/immunology/virology/drug therapy ; Female ; *HIV-1/immunology ; Male ; *Body Weight ; *Antibodies, Monoclonal/administration &amp; dosage/pharmacokinetics ; *HIV Antibodies/administration &amp; dosage/immunology ; Middle Aged ; *Models, Biological ; Young Adult ; Broadly Neutralizing Antibodies/administration &amp; dosage ; }, abstract = {BACKGROUND: Pharmacokinetic (PK) modelling and simulations have been used to support label changes of dosing levels or strategies for multiple marketed therapeutic monoclonal antibodies (mAbs). Using data from early-phase clinical trials in adults without HIV-1, we compared fixed and weight-based dosing strategies for three HIV-1 broadly neutralising mAbs planned for prevention efficacy evaluation: PGDM1400LS, PGT121.414.LS, and VRC07-523LS.<br><br>METHODS: We used a two-compartment population PK model to describe overall trends and inter-individual variability in post-administration serum concentrations over time from individuals administered PGDM1400LS (n = 95), PGT121.414.LS (n = 113), or VRC07-523LS (n = 251) subcutaneously or intravenously. We evaluated the effect of body weight on various PK parameters, including clearance rate, and simulated mAb concentrations after fixed and weight-based dosing administrations using sex-specific weights observed in participants from two recent HIV-1 mAb efficacy trials. We compared magnitudes and inter-individual variabilities of concentrations at specific post-administration timepoints, areas under the time-concentration curves (AUC), and predicted neutralisation titres against representative HIV-1 virus strains.<br><br>FINDINGS: For all three mAbs, we observed a modest effect of body weight on clearance rate and volumes of the central and peripheral compartments. The population-level magnitude and variability in time-specific concentrations, AUC, and predicted neutralisation titres were comparable between the two dosing strategies for both sexes. The relationship between body weight and concentrations differed between the two dosing strategies with a positive correlation for weight-based dosing and a negative correlation for fixed dosing. For individuals with body weight below the 15th or above the 85th percentiles, fixed dosing resulted in <3% difference in median AUC compared to the overall population. For lower weight individuals, fixed dosing improved AUC, potentially correcting the underdosing seen in the previous weight-based mAb efficacy trials. For higher weight individuals (e.g., >100 kg), body weight-based dosing or a higher fixed dose may be preferred.<br><br>INTERPRETATION: For HIV-1 prophylactic mAbs, a fixed-dose approach, possibly banded by weight categories may be advantageous over weight-based dosing, as it offers increased operational efficiency while maintaining comparable pharmacokinetics and inter-individual consistency.<br><br>FUNDING: NIAID.}, }
@article {pmid40516446, year = {2025}, author = {Dasari, AKR and Bhatt, N and Haque, MA and Irving, R and Kayed, R and Lim, KH}, title = {Cryo-EM structural analyses reveal diverse porous structures in brain-derived tau oligomers.}, journal = {Biochemical and biophysical research communications}, volume = {776}, number = {}, pages = {152189}, pmid = {40516446}, issn = {1090-2104}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AG054025/AG/NIA NIH HHS/United States ; R01 NS097490/NS/NINDS NIH HHS/United States ; R01 NS094557/NS/NINDS NIH HHS/United States ; U24 AG072458/AG/NIA NIH HHS/United States ; }, mesh = {Cryoelectron Microscopy ; *tau Proteins/chemistry/ultrastructure/metabolism ; *Brain/metabolism ; Humans ; Alzheimer Disease/metabolism/pathology ; Microscopy, Atomic Force ; Porosity ; Protein Multimerization ; Protein Folding ; }, abstract = {Misfolding and aggregation of tau into oligomers and neurofibrillary tangles are associated with Alzheimer's disease and related dementia (ADRD). Misfolded oligomeric species are widely believed to play a critical role in both disrupting cellular functions and propagating protein misfolding between cells. Characterization of the misfolded oligomers is crucial for understanding the mechanisms underlying protein aggregation and its role in disease pathogenesis. However, structural characterization of these misfolded oligomers has proven challenging due to their transient and heterogeneous nature. Here we report structural features of brain-derived tau oligomers extracted from Alzheimer's brains. Initial screening using negative staining transmission electron microscopy (TEM) and atomic force microscopy (AFM) reveal that tau (2N4R) forms a diverse array of pore-like oligomers with a diameter of 5-20 nm and a height of ∼2-8 nm. Higher-resolution structural analyses using cryo-EM on oligomers with diameters of 10-20 nm revealed the presence of two distinct layers within the pore-like structures, resolved at 2.5-4 Å. Our structural studies support the hypothesis that misfolded proteins may function as pore-forming toxins, potentially disrupting cellular membranes.}, }
@article {pmid40516922, year = {2025}, author = {Batista, MV and El Chaer, F and Englund, JA and Boeckh, M and Carpenter, PA and Dadwal, SS and Waghmare, A and Navarro, D and Hirsch, HH and Piñana, JL and Papanicolaou, GA and Chemaly, RF}, title = {American Society for Transplantation and Cellular Therapy Series #10: Management of Parainfluenza and Human Metapneumovirus Infections in Hematopoietic Cell Transplantation and Cellular Therapy Recipients.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {624-638}, doi = {10.1016/j.jtct.2025.06.016}, pmid = {40516922}, issn = {2666-6367}, mesh = {Humans ; *Cell- and Tissue-Based Therapy/methods/adverse effects ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Metapneumovirus/pathogenicity ; *Paramyxoviridae Infections/therapy/etiology ; United States ; }, abstract = {In 2019, The Practice Guidelines Committee of the American Society for Transplantation and Cellular Therapy partnered with its Transplant Infectious Diseases Special Interest Group to update the 2009 compendium-style infectious disease guidelines for hematopoietic cell transplantation (HCT). The new format is now structured around frequently asked questions (FAQs), concise tables, and figures to better support clinical providers. Here, a panel of experts in HCT and infectious diseases identified relevant FAQs, which they graded based on the strength of clinical practice recommendations and the level of supporting evidence, as described herein. In the ninth set of guidelines in the series, the focus is on parainfluenza virus and human metapneumovirus, with FAQs addressing epidemiology, incidence, clinical manifestations, risk factors, diagnosis, prevention (including vaccines), and therapeutic management in recipients of HCT and chimeric antigen receptor T cells (cellular therapy). Special considerations for pediatric patients, unmet needs, and future research directions are conveyed in the guidelines.}, }
@article {pmid40518799, year = {2025}, author = {Grzelak, CA and Ghajar, CM}, title = {Incorporating Centrally Tolerized Mice as a Design Principle to Circumvent Reporter Immunogenicity in Cancer Research Models.}, journal = {Cancer research}, volume = {85}, number = {12}, pages = {2143-2145}, doi = {10.1158/0008-5472.CAN-25-1055}, pmid = {40518799}, issn = {1538-7445}, mesh = {Animals ; Mice ; *Disease Models, Animal ; Mice, Transgenic ; *Neoplasms/immunology/pathology ; *Immune Tolerance ; Humans ; Genes, Reporter/immunology ; Luminescent Proteins/immunology/genetics ; }, abstract = {The study of tumor progression and metastasis in a physiologic setting commonly involves implantation of tumor cells into immunocompetent mice. For this purpose, tumor cells are labeled routinely with bioluminescent and/or fluorescent proteins prior to transplantation, despite the fact that these foreign proteins generate adaptive immune responses. We have described previously how incorporating centrally tolerized mouse strains into tumor and metastasis modeling can be used as a study design principle to properly control for artifactual immune responses against such reporters. In this issue of Cancer Research, Khan and colleagues applied a tolerized mouse strain-the Tol mouse-to overcome limitations associated with the use of xenoantigenic fluorescent and bioluminescent reporters in immunocompetent settings. The authors showed how antigenic responses against such proteins can confound interpretation of study results when measuring the efficacy of immunotherapy regimens. This study readily demonstrates the utility of employing centrally tolerized transgenic models to improve preclinical investigations of cancer metastasis and therapeutic resistance. See related article by Khan et al., p. 2165.}, }
@article {pmid40519326, year = {2025}, author = {Mittal, A and Jones, T and Karkar, R and Suh, J and Williams, S and Zheng, Y and Andris, LM and Bates, N and Bauer, AM and Lostutter, TW and Fann, JR and Fogarty, J and Hsieh, G}, title = {SCOPE: Examining Technology-Enhanced Collaborative Care Management of Depression in the Cancer Setting.}, journal = {Proceedings of the ACM on human-computer interaction}, volume = {9}, number = {2}, pages = {}, pmid = {40519326}, issn = {2573-0142}, support = {R01 CA244171/CA/NCI NIH HHS/United States ; P50 MH115837/MH/NIMH NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; R01 LM012810/LM/NLM NIH HHS/United States ; }, abstract = {Collaborative care management is an evidence-based approach to integrated psychosocial care for patients with comorbid cancer and depression. Prior work highlights challenges in patient-provider collaboration in navigating parallel cancer care and psychosocial care journeys of these patients. We design and deploy SCOPE, a platform for technology-enhanced collaborative care combining a patient-facing mobile app with a provider-facing registry. We examine SCOPE through a total of 45 interviews with patients and providers conducted in SCOPE's 15 months of design and development and 24 months of SCOPE's deployment for actual care in 6 cancer clinics. We find that: (1) SCOPE supported patient engagement in its underlying collaborative care and behavioral activation interventions, (2) patient-generated data in SCOPE improved patient-provider collaboration between and within in-person sessions, (3) SCOPE supported providers in delivering care and improved care team collaboration, (4) experience with SCOPE created evolving expectations for collaboration around data, and (5) SCOPE's deployment in actual care surfaced important implementation barriers. We discuss the implications of our findings in terms of designing for engagement with behavioral health interventions, negotiating patient data sharing and provider responsiveness, supporting personalized self-tracking goals in evidence-based interventions, exploring the role of digital health navigators in technology-enhanced care, and the need for flexibility in aligning technology-supported interventions to patient needs.}, }
@article {pmid40521388, year = {2024}, author = {Puleo, J and Buchanan, A and Katenka, N and Halloran, ME and Friedman, SR and Nikolopoulos, G}, title = {Assessing Spillover Effects of Medications for Opioid Use Disorder on HIV Risk Behaviors among a Network of People Who Inject Drugs.}, journal = {Stats}, volume = {7}, number = {2}, pages = {549-575}, pmid = {40521388}, issn = {2571-905X}, support = {DP1 DA034989/DA/NIDA NIH HHS/United States ; DP2 DA046856/DA/NIDA NIH HHS/United States ; P30 DA011041/DA/NIDA NIH HHS/United States ; R01 AI085073/AI/NIAID NIH HHS/United States ; }, abstract = {People who inject drugs (PWID) have an increased risk of HIV infection partly due to injection behaviors often related to opioid use. Medications for opioid use disorder (MOUD) have been shown to reduce HIV infection risk, possibly by reducing injection risk behaviors. MOUD may benefit individuals who do not receive it themselves but are connected through social, sexual, or drug use networks with individuals who are treated. This is known as spillover. Valid estimation of spillover in network studies requires considering the network's community structure. Communities are groups of densely connected individuals with sparse connections to other groups. We analyzed a network of 277 PWID and their contacts from the Transmission Reduction Intervention Project. We assessed the effect of MOUD on reductions in injection risk behaviors and the possible benefit for network contacts of participants treated with MOUD. We identified communities using modularity-based methods and employed inverse probability weighting with community-level propensity scores to adjust for measured confounding. We found that MOUD may have beneficial spillover effects on reducing injection risk behaviors. The magnitudes of estimated effects were sensitive to the community detection method. Careful consideration should be paid to the significance of community structure in network studies evaluating spillover.}, }
@article {pmid40522215, year = {2025}, author = {Lin, N and Vitonis, AF and Mongiovi, JM and Farland, LV and Huang, T and Terry, KL and Eliassen, AH and Townsend, MK and Zhang, C and Hu, FB and Sasamoto, N}, title = {History of Breastfeeding in Relation to Circulating Inflammatory and Metabolic Biomarkers.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {9}, pages = {1525-1533}, pmid = {40522215}, issn = {1538-7755}, support = {R03CA259659//National Institutes of Health (NIH)/ ; U01CA176726//National Institutes of Health (NIH)/ ; R01 CA067262/CA/NCI NIH HHS/United States ; P30 ES006694/ES/NIEHS NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; UM1CA186107//National Institutes of Health (NIH)/ ; R03 CA259659/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; W81XWH2110320//U.S. Department of Defense (DOD)/ ; }, mesh = {Humans ; Female ; *Breast Feeding/statistics &amp; numerical data ; *Biomarkers/blood ; Middle Aged ; Adult ; *Inflammation/blood ; Insulin-Like Growth Factor I/metabolism ; }, abstract = {BACKGROUND: Breastfeeding history has been associated with reduced risk of chronic diseases, although the underlying biological link is unclear.<br><br>METHODS: The study included 16,165 parous women in the Nurses' Health Studies who reported lactation history and biomarkers measured using plasma samples collected at midlife. We calculated multivariable-adjusted geometric means of 10 inflammatory biomarkers [high-sensitivity C-reactive protein, IL6, IL8, IL10, insulin-like growth factor 1 (IGF1), soluble TNF&#x3b1; receptor 2, B cell-activating factor, C-X-C motif chemokine ligand 13, soluble IL2 receptor &#x3b1;, and soluble IL6 receptor-&#x3b1;] and eight metabolic biomarkers (triglyceride, total cholesterol, high- and low-density lipoprotein, leptin, soluble leptin receptor, adiponectin, and retinol-binding protein 4) by the self-reported history of breastfeeding prior to blood collection. The FDR was used for multiple testing corrections.<br><br>RESULTS: The average age at blood collection was 52.6 years. Ever breastfeeding was associated with higher IGF1 (149.22 vs. 143.76 ng/mL; P value = 0.0002/FDR = 0.004) compared with never breastfeeding. Longer breastfeeding duration was associated with lower IL10 (P-trend = 0.001/FDR = 0.01) and higher IGF1 (P-trend = 0.0005/FDR = 0.01). No significant associations were observed for other biomarkers. Longer breastfeeding duration was associated with higher IGF1 among premenopausal women but not among postmenopausal women (P-interaction = 0.02). Longer breastfeeding duration was associated with lower soluble leptin receptor levels among those with body mass index &#x2265;25 kg/m2 (P-trend = 0.01/FDR = 0.09) but not among those with body mass index <25 kg/m2 (P-interaction = 0.0002).<br><br>CONCLUSIONS: Ever breastfeeding and longer breastfeeding duration were associated with higher IGF1 levels measured in midlife.<br><br>IMPACT: Our results support the potential long-term systemic impact of breastfeeding on circulating IGF1 levels, which may influence future chronic disease risk.}, }
@article {pmid40522834, year = {2025}, author = {Kulsuptrakul, J and Emerman, M and Mitchell, PS}, title = {CARD8 inflammasome activation during HIV-1 cell-to-cell transmission.}, journal = {eLife}, volume = {13}, number = {}, pages = {}, pmid = {40522834}, issn = {2050-084X}, support = {DP1 DA051110/DA/NIDA NIH HHS/United States ; DP2 AI154432/AI/NIAID NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; DP1 DA051110/NH/NIH HHS/United States ; T32 GM007270/NH/NIH HHS/United States ; DP2 AI 154432-01/NH/NIH HHS/United States ; T32 GM136534/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *HIV-1/physiology ; *CARD Signaling Adaptor Proteins/metabolism/genetics ; *Inflammasomes/metabolism ; *HIV Infections/virology/transmission/immunology ; Macrophages/virology/immunology ; HIV Protease/metabolism/genetics ; T-Lymphocytes/virology ; Neoplasm Proteins ; }, abstract = {Our previous work demonstrated that CARD8 detects HIV-1 infection by sensing the enzymatic activity of the HIV protease, resulting in CARD8-dependent inflammasome activation (Kulsuptrakul et al., 2023). CARD8 harbors a motif in its N-terminus that functions as a HIV protease substrate mimic, permitting innate immune recognition of HIV-1 protease activity, which when cleaved by HIV protease triggers CARD8 inflammasome activation. Here, we sought to understand CARD8 responses in the context of HIV-1 cell-to-cell transmission via a viral synapse. We observed that cell-to-cell transmission of HIV-1 between infected T cells and primary human monocyte-derived macrophages induces CARD8 inflammasome activation in a manner that is dependent on viral protease activity and largely independent of the NLRP3 inflammasome. Additionally, to further evaluate the viral determinants of CARD8 sensing, we tested a panel of HIV protease inhibitor-resistant clones to establish how variation in HIV protease affects CARD8 activation. We identified mutant HIV-1 proteases that differentially cleave and activate CARD8 compared to wildtype HIV-1, thus indicating that natural variation in HIV protease affects not only the cleavage of the viral Gag-Pol polyprotein but also likely impacts innate sensing and inflammation.}, }
@article {pmid40523203, year = {2025}, author = {Rutherford, SC and Li, H and Herrera, AF and LeBlanc, M and Ahmed, S and Davison, K and Parsons, SK and Unger, JM and Perry, AM and Casulo, C and Bartlett, NL and Tuscano, JM and Hess, BT and Torka, P and Kumar, P and Jacobs, R and Song, JY and Castellino, SM and Kahl, B and Leonard, JP and Smith, SM and Friedberg, JW and Evens, AM}, title = {Nivolumab-AVD Versus Brentuximab Vedotin-AVD in Older Patients With Advanced-Stage Classic Hodgkin Lymphoma Enrolled on S1826.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {27}, pages = {2968-2973}, pmid = {40523203}, issn = {1527-7755}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; U10 CA180820/CA/NCI NIH HHS/United States ; P30 CA272302/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; R50 CA285409/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Age Factors ; *Antineoplastic Combined Chemotherapy Protocols/administration &amp; dosage/adverse effects ; *Brentuximab Vedotin/administration &amp; dosage/adverse effects ; *Hodgkin Disease/drug therapy/pathology/mortality ; Neoplasm Staging ; *Nivolumab/administration &amp; dosage/adverse effects ; Progression-Free Survival ; }, abstract = {Older patients with classic Hodgkin lymphoma (cHL) have inferior survival compared with younger patients. We report a subset analysis of older patients (60 years and older) enrolled in the phase three S1826 trial conducted by SWOG that randomly assigned patients with newly diagnosed advanced-stage (III-IV) cHL to six cycles of nivolumab (N)-AVD or brentuximab vedotin (BV)-AVD. Of 103 enrolled patients 60 years and older, 99 were eligible. At a median follow-up of 2.1 years, the 2-year progression-free survival was 89% after N-AVD (n = 50) and 64% after BV-AVD (n = 49, HR 0.24, 95%CI 0.09-0.63, 1-sided stratified log-rank P = .001). The 2-year OS was 96% with N-AVD versus 85% with BV-AVD (HR 0.16, 95%CI 0.03-0.75 stratified 1-sided log-rank P = .005). Six cycles were delivered without dose reduction in 69% on N-AVD and 26% on BV-AVD; 55% discontinued BV, and 14% discontinued nivolumab. The nonrelapse mortality was 16% with BV-AVD and 6% with N-AVD. Despite more neutropenia with N-AVD, febrile neutropenia, sepsis, and infections were higher with BV-AVD, as was peripheral neuropathy. Patient-reported outcomes of key adverse events confirmed the improved toxicity profile of N-AVD over BV-AVD. N-AVD was better tolerated and more effective than BV-AVD and is therefore a new standard of care for older patients with advanced-stage cHL fit for anthracycline-based combination therapy.}, }
@article {pmid40523534, year = {2025}, author = {Dominitz, JA and Ladabaum, U and Holub, JL and Issaka, RB and Ko, CW and Robertson, DJ}, title = {Association Between Adenoma Detection Rate and Prevalent Colorectal Cancer Detection Rate in a National Colonoscopy Registry.}, journal = {Gastroenterology}, volume = {169}, number = {7}, pages = {1489-1498.e3}, doi = {10.1053/j.gastro.2025.06.009}, pmid = {40523534}, issn = {1528-0012}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; P01 DK042502/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Colonoscopy/statistics &amp; numerical data ; *Colorectal Neoplasms/epidemiology/diagnosis/pathology/diagnostic imaging ; *Adenoma/epidemiology/diagnosis/pathology/diagnostic imaging ; Male ; Female ; Cross-Sectional Studies ; Middle Aged ; *Early Detection of Cancer/statistics &amp; numerical data/methods ; Aged ; Registries/statistics &amp; numerical data ; Prevalence ; United States/epidemiology ; Missed Diagnosis/statistics &amp; numerical data ; }, abstract = {BACKGROUND &amp; AIMS: Although the adenoma detection rate (ADR) is associated with postcolonoscopy colorectal cancer risk, it is unknown to what extent this reflects missed colorectal cancer (CRC) vs missed precancerous lesions. The association between physician ADR and prevalent CRC detection during colonoscopy were evaluated.<br><br>METHODS: The study used the cross-sectional 2019-2022 GI Quality Improvement Consortium data for more than 1.73 million colonoscopies performed by 3567 endoscopists for screening or abnormal fecal test follow-up from 683 US endoscopy units. Endoscopist ADR and sessile serrated lesion detection rate (SSLDR) were determined based on screening examinations.<br><br>RESULTS: CRC was detected in 0.3% of screening and 1.5% of follow-up colonoscopies. From lowest to highest endoscopist ADR quintile, CRC detection increased from 26.6 (95% CI, 24.4-27.9) to 33.1 (95% CI, 29.7-33.7), and from 107.8 (95% CI, 96.2-129.4) to 164.7 (95% CI, 140.8-188.6) per 10,000 screening and abnormal fecal test follow-up colonoscopies, respectively. In multivariable models with lowest ADR quintile as reference, the odds ratios of CRC detection in the highest ADR quintile were 1.27 (95% CI, 1.14-1.41) for screening and 1.50 (95% CI, 1.16-1.93) for abnormal fecal test follow-up colonoscopies. Compared with high-ADR/high-SSLDR endoscopists, the ORs of CRC detection were lower for low-ADR endoscopists irrespective of SSLDR (high-SSLDR, 0.87; 95% CI, 0.80-0.96; low-SSLDR 0.92; 95% CI, 0.85-0.98), but similar for high-ADR/low-SSLDR endoscopists.<br><br>CONCLUSIONS: ADR reflects prevalent CRC detection as well as detection and removal of CRC precursors. Our findings suggest that postcolonoscopy CRC is not uncommonly due to missed CRC, especially among endoscopists with low ADR.}, }
@article {pmid40526835, year = {2025}, author = {Poh, C and Voutsinas, JM and Shadman, M and Lynch, RC and Warren, EH and Crimp, CA and Till, BG and Ujjani, CS and Di, M and Raghunathan, V and Smith, SD and Wu, QV and Shinohara, MM and Gopal, AK}, title = {Pralatrexate is effective in cytotoxic cutaneous T-cell lymphomas.}, journal = {Blood advances}, volume = {9}, number = {15}, pages = {4037-4042}, pmid = {40526835}, issn = {2473-9537}, mesh = {Humans ; *Aminopterin/analogs &amp; derivatives/therapeutic use/adverse effects/administration &amp; dosage ; *Lymphoma, T-Cell, Cutaneous/drug therapy/mortality/diagnosis/pathology ; Female ; Male ; Middle Aged ; Aged ; Adult ; *Skin Neoplasms/drug therapy/mortality ; Treatment Outcome ; Aged, 80 and over ; Retrospective Studies ; }, abstract = {Cytotoxic cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of T-cell lymphomas with variable prognoses and no standard of care. We identified patients with primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ PCAETL), primary cutaneous γδ T-cell lymphoma (PCGDTL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL), who were treated with ≥1 dose of pralatrexate between 2015 and 2024 at the University of Washington/Fred Hutchinson Cancer Center. Eighteen patients met criteria, 3 with CD8+ PCAETL, 6 with PCGDTL, and 9 with SPTCL. The median number of prior systemic therapies was 1 (range, 0-4), and the median pralatrexate treatment duration was 14 (range, 8-43) weeks. The overall response rate was 100%, with 12 (67%) achieving complete response (CR). Median duration of progression-free survival and overall survival was 5.6 months and not reached, respectively. Among patients who achieved CR , the median response duration was 22 months. At a median follow-up of 45 months, 6 (33%) patients remain in sustained remission. This retrospective analysis is the first to evaluate pralatrexate's efficacy in this aggressive disease population, demonstrating its effectiveness and association with durable responses in cytotoxic CTCL.}, }
@article {pmid40527319, year = {2025}, author = {Purice, MD and Quitevis, EJA and Manning, RS and Severs, LJ and Tran, NT and Sorrentino, V and Finkbeiner, C and Wu, F and Zager, M and Setty, M and Singhvi, A}, title = {Molecular profiling of adult C. elegans glia across sexes by single-nuclear RNA-seq.}, journal = {Developmental cell}, volume = {60}, number = {19}, pages = {2659-2678.e10}, pmid = {40527319}, issn = {1878-1551}, support = {T32 AG066574/AG/NIA NIH HHS/United States ; R35 GM147125/GM/NIGMS NIH HHS/United States ; R01 NS114222/NS/NINDS NIH HHS/United States ; T32 CA080416/CA/NCI NIH HHS/United States ; U24 HG002223/HG/NHGRI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; P41 HG002223/HG/NHGRI NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; }, mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Neuroglia/metabolism/cytology ; Female ; Male ; *Transcriptome/genetics ; RNA-Seq/methods ; Sex Characteristics ; Neurons/metabolism ; Single-Cell Analysis ; Sequence Analysis, RNA ; }, abstract = {A comprehensive understanding of nervous system function requires molecular insight into the diversity and sex dimorphism of both its component cell types, glia and neurons. Here, we present a single-nuclear RNA sequencing (RNA-seq) census of all neuroectoderm-derived glia in the adult C. elegans nervous system, across sexes. By iteratively coupling computational modeling and custom analytics with in vivo validations, we uncovered molecular markers for all glia, as well as class-specific and pan-glial molecular signatures. These identified that each glia is functionally heterogeneous across the nervous system and variably sex dimorphic between sexes. Thus, this glial transcriptome (wormglia.org) offers deep mechanistic insights into glial biology brain wide. Complementing the existing C. elegans neuronal transcriptome and mapped connectome, it also enables single-cell and molecular resolution insight into the entire nervous system of an adult metazoan.}, }
@article {pmid40528125, year = {2025}, author = {Bilen, MA and Burbage, S and Rossi, C and Khilfeh, I and Diaz, L and Wang, Y and Pilon, D and Brown, G and Shore, N and Lowentritt, B and Lin, DW}, title = {Comparison of Real-World Outcomes between Patients with BRCA1/2-Positive and Homologous Recombination Repair-Negative Metastatic Castration-Sensitive Prostate Cancer.}, journal = {Advances in therapy}, volume = {42}, number = {8}, pages = {3945-3959}, pmid = {40528125}, issn = {1865-8652}, mesh = {Humans ; Male ; Aged ; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/mortality/drug therapy/therapy ; *BRCA2 Protein/genetics ; *BRCA1 Protein/genetics ; Middle Aged ; Recombinational DNA Repair ; Mutation ; Time-to-Treatment ; Neoplasm Metastasis ; Aged, 80 and over ; Retrospective Studies ; }, abstract = {INTRODUCTION: This real-world study compared time-to-next-treatment (TTNT), time-to-castration resistance (TTCR), and overall survival between patients with BRCA1/2-positive (BRCA+) and homologous recombination repair-negative (HRR-) metastatic castration-sensitive prostate cancer (mCSPC).<br><br>METHODS: Patients who received a genetic test and initiated treatment for mCSPC (index date) after 1/1/2018 were selected from the Flatiron Health-Foundation Medicine, Inc. Metastatic PC Clinico-Genomic Database (1/1/2017-12/31/2022). Outcomes were compared between patients with&#xa0;&#x2265;&#xa0;1 positive BRCA test (BRCA+) and those without detected HRR mutations (HRR-) using weighted Kaplan-Meier analyses and Cox proportional hazards models after baseline characteristics (12 months pre-index) were balanced using inverse-probability of treatment weighting.<br><br>RESULTS: In total, 149 patients with BRCA+&#xa0;and 1066 with HRR- mCSPC were included. Baseline characteristics were well-balanced after weighting. By 24 months after treatment initiation, a significantly higher proportion of the BRCA+&#xa0;than the HRR- cohort progressed to next treatment [69.7% vs. 56.8%; hazard ratio (HR)&#xa0;=&#xa0;1.45 (95% confidence interval (CI)&#xa0;1.10, 1.92), p&#xa0;=&#xa0;0.009]; median TTNT was shorter in the BRCA+&#xa0;than the HRR- cohort (10.9 vs. 18.7 months). By 24 months, a significantly higher proportion of the BRCA+&#xa0;than the HRR- cohort progressed to castration resistance [72.2% vs. 61.4%; HR&#xa0;=&#xa0;1.46 (95% CI&#xa0;1.16, 1.84), p&#xa0;=&#xa0;0.001]; median TTCR was shorter in the BRCA+&#xa0;than HRR- cohort (12.9 vs. 16.9 months). Numerically fewer patients in the BRCA+&#xa0;than the HRR- cohort survived 24 months after PC diagnosis [80.6% vs. 85.4%; HR&#xa0;=&#xa0;1.46 (95% CI&#xa0;0.99, 2.14), p&#xa0;=&#xa0;0.054].<br><br>CONCLUSION: Findings demonstrate worse outcomes for patients with BRCA+&#xa0;mCSPC treated with available advanced therapies, supporting the need for effective genetically targeted therapies in this population.}, }
@article {pmid40531856, year = {2025}, author = {McTiernan, A}, title = {In Motion: Experimental Evidence on Exercise and Breast Cancer in Women and Mice.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {16}, pages = {3353-3355}, doi = {10.1158/1078-0432.CCR-25-1313}, pmid = {40531856}, issn = {1557-3265}, support = {BCRF-24-107//Breast Cancer Research Foundation (BCRF)/ ; }, mesh = {*Breast Neoplasms/prevention &amp; control/epidemiology ; Female ; Humans ; Animals ; Mice ; *Exercise ; Disease Models, Animal ; *Physical Conditioning, Animal ; }, abstract = {Strong evidence from observational studies shows that high levels of physical activity are associated with a reduced risk of breast cancer, with a dose-response effect. Human trials and animal models have identified mechanisms explaining these associations, which aid in designing prescriptions and guidelines for exercise in breast cancer prevention. See related article by Jones et al., p. 3377.}, }
@article {pmid40532127, year = {2025}, author = {Fay, M and Liao, RS and Lone, ZM and Reddy, CA and Muhammad, H and Xie, C and Jain, P and Huang, W and Basu, HS and Nair, SS and Chakravarty, D and Williamson, SR and Gupta, S and Weight, C and Roy, R and Wilding, G and Tewari, AK and Klein, EA and Mian, OY}, title = {Artificial Intelligence-Based Digital Histologic Classifier for Prostate Cancer Risk Stratification: Independent Blinded Validation in Patients Treated With Radical Prostatectomy.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2400292}, pmid = {40532127}, issn = {2473-4276}, support = {R01 CA290438/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/surgery/pathology/diagnosis/mortality ; *Prostatectomy/methods ; *Artificial Intelligence ; Middle Aged ; Aged ; Retrospective Studies ; Prognosis ; Risk Assessment/methods ; Neoplasm Grading ; Follow-Up Studies ; }, abstract = {PURPOSE: Artificial intelligence (AI) tools that identify pathologic features from digitized whole-slide images (WSIs) of prostate cancer (CaP) generate data to predict outcomes. The objective of this study was to evaluate the clinical validity of an AI-enabled prognostic test, PATHOMIQ_PRAD, using a clinical cohort from the Cleveland Clinic.<br><br>METHODS: We conducted a retrospective analysis of PATHOMIQ_PRAD using CaP WSIs from patients who underwent radical prostatectomy (RP) between 2009 and 2022 and did not receive adjuvant therapy. Patients also had Decipher genomic testing available. WSIs were deidentified, anonymized, and outcomes were blinded. Patients were stratified into high-risk and low-risk categories on the basis of predetermined thresholds for PATHOMIQ_PRAD scores (0.45 for biochemical recurrence [BCR] and 0.55 for distant metastasis [DM]).<br><br>RESULTS: The study included 344 patients who underwent RP with a median follow-up of 4.3 years. Both PathomIQ and Decipher scores were associated with rates of biochemical recurrence-free survival (BCRFS; PathomIQ score >0.45 v &#x2264;0.45, P <.001; Decipher score >0.6 v &#x2264;0.6, P = .002). There were 16 patients who had DM, and 15 were in the high-risk PathomIQ group (Mets Score >0.55). Both PathomIQ and Decipher scores were associated with rates of metastasis-free survival (PathomIQ score >0.55 v &#x2264;0.55, P <.001; Decipher score >0.6 v &#x2264;0.6, P = .0052). Despite the low event rates for metastasis, multivariable regression demonstrated that high PathomIQ score was significantly associated with DM (>0.55 v &#x2264;0.55, hazard ratio, 10.10 [95% CI, 1.28 to 76.92], P = .0284).<br><br>CONCLUSION: These findings independently validate PATHOMIQ_PRAD as a reliable predictor of clinical risk in the postprostatectomy setting. PATHOMIQ_PRAD therefore merits prospective evaluation as a risk stratification tool to select patients for adjuvant or early salvage interventions.}, }
@article {pmid40532178, year = {2025}, author = {Uppaluri, R and Haddad, RI and Tao, Y and Le Tourneau, C and Lee, NY and Westra, W and Chernock, R and Tahara, M and Harrington, KJ and Klochikhin, AL and Braña, I and Vasconcelos Alves, G and Hughes, BGM and Oliva, M and Pinto Figueiredo Lima, I and Ueda, T and Rutkowski, T and Schroeder, U and Mauz, PS and Fuereder, T and Laban, S and Oridate, N and Popovtzer, A and Mach, N and Korobko, Y and Costa, DA and Hooda-Nehra, A and Rodriguez, CP and Bell, RB and Manschot, C and Benjamin, K and Gumuscu, B and Adkins, D and , }, title = {Neoadjuvant and Adjuvant Pembrolizumab in Locally Advanced Head and Neck Cancer.}, journal = {The New England journal of medicine}, volume = {393}, number = {1}, pages = {37-50}, doi = {10.1056/NEJMoa2415434}, pmid = {40532178}, issn = {1533-4406}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects ; Antineoplastic Agents, Immunological/administration &amp; dosage/adverse effects ; B7-H1 Antigen/analysis/metabolism/antagonists &amp; inhibitors ; Chemotherapy, Adjuvant/adverse effects/methods ; *Head and Neck Neoplasms/drug therapy/mortality/pathology/surgery ; Intention to Treat Analysis ; *Neoadjuvant Therapy/adverse effects/methods ; Progression-Free Survival ; *Squamous Cell Carcinoma of Head and Neck/drug therapy/mortality/pathology/surgery ; Treatment Outcome ; }, abstract = {BACKGROUND: The benefit of the addition of perioperative pembrolizumab to standard care with surgery and adjuvant therapy for patients with locally advanced head and neck squamous-cell carcinoma (HNSCC) is unclear.<br><br>METHODS: In this phase 3, open-label trial, we randomly assigned participants with locally advanced HNSCC in a 1:1 ratio to receive 2 cycles of neoadjuvant pembrolizumab and 15 cycles of adjuvant pembrolizumab (both at a dose of 200 mg every 3 weeks) in addition to standard care (pembrolizumab group) or standard care alone (control group). Standard care was surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary end point was event-free survival, sequentially assessed in participants whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS) of 10 or more (CPS-10 population), participants whose tumors expressed PD-L1 with a CPS of 1 or more (CPS-1 population), and all the participants. A higher CPS indicates a higher proportion of cells that express PD-L1.<br><br>RESULTS: A total of 363 participants (234 with a CPS of &#x2265;10 and 347 with a CPS of &#x2265;1) were assigned to the pembrolizumab group and 351 (231 with a CPS of &#x2265;10 and 335 with a CPS of &#x2265;1) to the control group. Surgery was completed in approximately 88% of the participants in each group. At the first interim analysis, the median follow-up was 38.3 months. Event-free survival at 36 months was 59.8% in the pembrolizumab group and 45.9% in the control group (hazard ratio for progression, recurrence, or death, 0.66; 95% confidence interval [CI], 0.49 to 0.88; two-sided P&#x2009;=&#x2009;0.004) in the CPS-10 population; 58.2% and 44.9%, respectively (hazard ratio, 0.70; 95% CI, 0.55 to 0.89; two-sided P&#x2009;=&#x2009;0.003), in the CPS-1 population; and 57.6% and 46.4%, respectively (hazard ratio, 0.73; 95% CI, 0.58 to 0.92; two-sided P&#x2009;=&#x2009;0.008), in the total population. Grade 3 or higher treatment-related adverse events occurred in 44.6% of the participants in the pembrolizumab group and in 42.9% of those in the control group, including death in 1.1% and 0.3%, respectively. Potentially immune-mediated adverse events of grade 3 or higher occurred in 10.0% of the participants in the pembrolizumab group.<br><br>CONCLUSIONS: The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC. Neoadjuvant pembrolizumab did not affect the likelihood of surgical completion. No new safety signals were identified. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-689 ClinicalTrials.gov number, NCT03765918.).}, }
@article {pmid40532592, year = {2025}, author = {Jeong, D and Richards, AR and Jean-Baptiste, E and Gomez, MF and Thomas, KL and Mo, Q and Gigic, B and Figueiredo, JC and Li, CI and Shibata, D and Toriola, AT and Byrd, DA and Ulrich, CM and Stewart, PA and Siegel, EM and Kresovich, JK}, title = {Comparison of volumetric and single-slice computed tomography body composition metrics for colorectal cancer survival.}, journal = {European journal of radiology}, volume = {190}, number = {}, pages = {112241}, pmid = {40532592}, issn = {1872-7727}, support = {P30 CA076292/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/mortality/diagnostic imaging ; Male ; Female ; *Body Composition ; Middle Aged ; Aged ; *Tomography, X-Ray Computed/methods ; Case-Control Studies ; Survival Rate ; }, abstract = {BACKGROUND: Body composition is associated with colorectal cancer (CRC) survival. However, body composition measurements have traditionally relied on single-slice, axial imaging. Fully automated volumetric body composition analysis is widely available, but associations with CRC survival have yet to be examined in detail.<br><br>METHODS: Among a nested case-control sample of CRC patients with existing CT scans, volumetric and single-slice body composition analysis was performed, including total area and proportional skeletal muscle (SM), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT). Body composition was measured from the T12 vertebra to the sacrum, with the mid-L3 level used for single-slice analysis. We used multivariable Cox regression models to estimate associations between height-indexed volumetric and single-slice body composition metrics with all-cause mortality.<br><br>RESULTS: The mean age of the 121 enrolled patients was 61, and 38 (31&#xa0;%) died over a mean follow-up of 7.7&#xa0;years. The T12-sacrum, T12-L3, and L3-sacrum volumetric measurements were correlated with each other and their corresponding mid-L3 metric (all &#x3c1;&#xa0;>&#xa0;0.8). In adjusted models, the T12-sacrum VAT index proportion yielded the strongest association with CRC survival (per 1-SD increase, HR: 2.07, 95&#xa0;% CI: 1.13, 3.80, P&#xa0;=&#xa0;0.02). Mid-L3 and volumetric composition metrics showed similar associations with CRC survival.<br><br>CONCLUSIONS: Volumetric body composition metrics are associated with CRC survival but did not outperform single-slice metrics in predicting CRC survival. Proportional metrics, which account for total abdominal muscle and adipose tissue area, may be a novel computational technique for assessing body composition.}, }
@article {pmid40532705, year = {2025}, author = {Ganesan, A and Moore, AR and Zheng, H and Toh, J and Freedman, M and Magis, AT and Heath, JR and Khatri, P}, title = {A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.}, journal = {Immunity}, volume = {58}, number = {8}, pages = {2104-2119.e5}, doi = {10.1016/j.immuni.2025.05.020}, pmid = {40532705}, issn = {1097-4180}, support = {U19 AI057229/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Risk Factors ; Male ; Female ; Transcriptome ; Middle Aged ; *Infections/immunology ; Severity of Illness Index ; Aged ; Proteomics/methods ; Adult ; Gene Expression Profiling ; Asthma/immunology ; }, abstract = {Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with an increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single-cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature was associated with each of these risk factors prior to infection. Furthermore, this conserved immune signature was modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted the individuals with sepsis who would be harmed by hydrocortisone treatment and individuals with asthma who would not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of the baseline immune state and response to chronic, subacute, and acute illnesses.}, }
@article {pmid40532723, year = {2025}, author = {Jabbour, E and Lussana, F and Martínez-Sánchez, P and Torrent, A and Rifón, JJ and Agrawal, V and Tormo, M and Cassaday, RD and Cluzeau, T and Huguet, F and Papayannidis, C and Hernández-Rivas, JM and Rijneveld, A and Fleming, S and Vucinic, V and Böll, B and Ikezoe, T and Abdul-Hay, M and Savoie, ML and Schuh, AC and Berthon, C and Schwartz, S and Chiaretti, S and Yuda, J and Miyazaki, T and González-Campos, J and Chen, Y and Wong, H and Choudhry, J and Zugmaier, G and Guest, E and Gordon, P and Kantarjian, H}, title = {Subcutaneous blinatumomab in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: post-hoc safety and activity analysis from a multicentre, single-arm, phase 1/2 trial.}, journal = {The Lancet. Haematology}, volume = {12}, number = {7}, pages = {e529-e541}, doi = {10.1016/S2352-3026(25)00144-9}, pmid = {40532723}, issn = {2352-3026}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antibodies, Bispecific/administration &amp; dosage/pharmacokinetics ; *Antineoplastic Agents/administration &amp; dosage/pharmacokinetics ; Injections, Subcutaneous ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Recurrence ; Treatment Outcome ; }, abstract = {BACKGROUND: Two doses of subcutaneous blinatumomab in patients with relapsed or refractory B-cell acute lymphoblastic leukaemia were identified as preliminary recommended phase 2 doses, based on the dose-escalation phase of this multicentre single-arm, phase 1/2 trial. Here, we aim to further study the safety, activity, and pharmacokinetics of these doses in all participants who have received them, including those treated in the completed phase 1b expansion part of the study.<br><br>METHODS: We did a post-hoc analysis of data from patients enrolled in the dose-escalation and dose-expansion phases and in the pharmacokinetic evaluation cohort of this multicentre, single-arm, phase 1/2 study. Patients were recruited from 44 hospitals in 11 countries. Eligible participants were aged 18 years or older with relapsed or refractory B-cell acute lymphoblastic leukaemia, at least 5% of blasts in the bone marrow, and an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients received either 250 &#x3bc;g subcutaneous blinatumomab once daily in week 1 of cycle 1 and then 500 &#x3bc;g three times weekly thereafter (250 &#x3bc;g/500 &#x3bc;g group), or 500 &#x3bc;g and then 1000 &#x3bc;g subcutaneous blinatumomab on the same schedule (500 &#x3bc;g/1000 &#x3bc;g group), previously identified as the preliminary recommended phase 2 doses. Each treatment cycle included a 4-week treatment period and a 1-week treatment-free interval. Patients received between two and five cycles. The primary endpoint for the dose-expansion phase was complete remission or complete remission with partial haematological recovery within the first two cycles, which was used as the primary outcome for this study. Data were pooled from all cohorts of the same dose level to form two dose groups. The response rates, adverse event incidence, and pharmacokinetics were summarised in each dose group separately and compared descriptively. Response was calculated with two-sided exact 80% CIs (Clopper-Pearson method). This study is registered with ClinicalTrials.gov, NCT04521231; phase 1 is complete, and phase 2 is active but not recruiting.<br><br>FINDINGS: Participants were recruited from Oct 18, 2021, to Sept 23, 2024, and median follow-up for the analyses was 5 months (IQR 3-9). Of the 88 patients included in the analysis at the data cutoff of Nov 28, 2024, 36 (41%) were treated with the 250 &#x3bc;g/500 &#x3bc;g regimen and 52 (59%) with the 500 &#x3bc;g/1000 &#x3bc;g regimen. The enrolled population comprised 55 (63%) male and 33 (38%) female participants; 56 (64%) were White, six (7%) Asian, three (3%) Black or African American, two (2%) American Indian or Alaska Native, and 20 (23%) other. Hispanic or Latino ethnicity was reported for 33 (38%) patients. 27 (75%) of 36 patients in the 250 &#x3bc;g/500 &#x3bc;g group and 41 (79%) of 52 in the 500 &#x3bc;g/1000 &#x3bc;g group showed complete remission or complete remission with partial haematological recovery. The most common grade 3-4 adverse events were neutropenia (19 [22%] patients), cytokine release syndrome (CRS; 18 [20%] patients), and immune effector cell-associated neurotoxicity syndrome (ICANS; 15 [17%] patients). Serious adverse events occurred in 70 (80%) of 88 patients and included CRS (33 [38%] patients), ICANS (20 [23%] patients), and neurotoxicity (six [7%] patients). No treatment-related deaths were reported. Consistent pharmacokinetics with dose-proportional exposures was observed following subcutaneous administration. Based on the totality of data, including efficacy, safety, and pharmacokinetic data, the subcutaneous blinatumomab dose regimen of 250 &#x3bc;g/500 &#x3bc;g was selected as the recommended phase 2 dose.<br><br>INTERPRETATION: Treatment with subcutaneous blinatumomab at the two dose regimens of 250 &#x3bc;g/500 &#x3bc;g and 500 &#x3bc;g/1000 &#x3bc;g resulted in promising preliminary activity and a manageable safety profile in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. The phase 2 part of the trial is ongoing to further evaluate subcutaneous blinatumomab activity and duration of response.<br><br>FUNDING: Amgen.}, }
@article {pmid40533069, year = {2025}, author = {Shatila, M and Devalaraju, S and Takigawa, K and Catinis, C and Lee, I and Baerman, E and Ngo, S and Mittal, N and Glombicki, S and Machado, AP and Lu, L and Aleem, AS and Thompson, J and Funchain, P and Grover, S and Zhang, HC and Thomas, AS and Wang, Y}, title = {Worse Survival and Gastrointestinal Toxicity Outcomes Among Patients Receiving Proton Pump Inhibitors During Checkpoint Inhibitor Therapy.}, journal = {Journal of the National Comprehensive Cancer Network : JNCCN}, volume = {23}, number = {7}, pages = {}, doi = {10.6004/jnccn.2025.7023}, pmid = {40533069}, issn = {1540-1413}, mesh = {Humans ; *Proton Pump Inhibitors/adverse effects/therapeutic use ; *Immune Checkpoint Inhibitors/adverse effects ; Female ; Male ; Retrospective Studies ; Aged ; Middle Aged ; *Gastrointestinal Diseases/chemically induced/mortality ; *Neoplasms/drug therapy/mortality/immunology ; Aged, 80 and over ; }, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICIs) for cancer carry a risk of immune-related adverse events (irAEs). Upper and lower gastrointestinal tract inflammation are common toxicities. Proton pump inhibitors (PPIs) are used to treat upper gastrointestinal irAEs. Studies have suggested these agents may also worsen lower gastrointestinal irAEs. Our study evaluated the effect of PPI exposure on gastrointestinal irAE severity.<br><br>METHODS: This was a single-center retrospective chart review including all patients receiving ICIs between January 2010 and February 2024 who developed upper or lower gastrointestinal toxicity. Patients were grouped based on PPI use, defined as receiving a PPI any time from 3 months before ICI initiation until gastrointestinal toxicity diagnosis.<br><br>RESULTS: A total of 1,228 patients were included: 88 (7.2%) with upper gastrointestinal toxicity and 1,140 (92.8%) with lower toxicity. Upper gastrointestinal irAEs were more severe among PPI users (69.6% with grade 3 toxicity in the PPI group vs 29.6% in the non-PPI group; P<.05). Similarly, lower gastrointestinal irAEs were more severe among PPI users, with a higher need for multiple lines of biologic treatment, higher hospitalization rates, and longer hospital stays (P<.05 for all). PPI use was associated with significantly worse overall survival among patients receiving ICIs (P<.05).<br><br>CONCLUSIONS: Our study is the largest to date showing the impact of PPI use on immunotherapy toxicity. PPI use may predispose to more severe toxicities and worse outcomes. PPIs may also reduce immunotherapy efficacy, as reflected by worse overall survival. These findings support the judicious use of PPIs in patients receiving ICIs and call for prospective studies to validate our results.}, }
@article {pmid40533557, year = {2025}, author = {Li, Y and Zhang, H and Sun, C and Dong, XD and Xie, C and Liu, YT and Lin, RB and Kong, XW and Hu, ZL and Ma, XY and Dai, DL and Zhu, QY and Li, YC and Li, Y and Liu, SX and Yuan, L and Zhou, PH and Gao, S and Tang, YP and Yang, JY and Han, P and McGuire, AT and Zhao, B and Bei, JX and Robertson, E and Zeng, YX and Zhong, Q and Zeng, MS}, title = {R9AP is a common receptor for EBV infection in epithelial cells and B cells.}, journal = {Nature}, volume = {644}, number = {8075}, pages = {205-213}, pmid = {40533557}, issn = {1476-4687}, support = {//National Key Research and Development Program of China/ ; }, mesh = {Humans ; *B-Lymphocytes/virology/metabolism ; *Herpesvirus 4, Human/physiology/pathogenicity/metabolism ; *Epithelial Cells/virology/metabolism ; *Virus Internalization ; *Receptors, Virus/metabolism/genetics/chemistry ; *Epstein-Barr Virus Infections/virology/metabolism ; Cell Line ; Viral Proteins/metabolism ; Viral Envelope Proteins ; }, abstract = {Epstein-Barr virus (EBV) persistently infects more than 90% of the human population, causing infectious mononucleosis[1], susceptibility to autoimmune diseases[2] and multiple malignancies of epithelial or B cell-origin[3]. EBV infects epithelial cells and B cells through interaction between viral glycoproteins and different host receptors[4], but it has remained unknown whether a common receptor mediates infection of its two major host cell targets. Here, we establish R9AP as a crucial EBV receptor for entry into epithelial and B cells. R9AP silencing or knockout, R9AP-derived peptide and R9AP monoclonal antibody each significantly inhibit, whereas R9AP overexpression promotes, EBV uptake into both cell types. R9AP binds directly to the EBV glycoprotein gH/gL complex to initiate gH/gL-gB-mediated membrane fusion. Notably, the interaction of R9AP with gH/gL is inhibited by the highly competitive gH/gL-neutralizing antibody AMMO1, which blocks EBV epithelial and B cell entry. Moreover, R9AP mediates viral and cellular membrane fusion in cooperation with EBV gp42-human leukocyte antigen class II or gH/gL-EPHA2 complexes in B cells or epithelial cells, respectively. We propose R9AP as the crucial common receptor of B cells and epithelial cells and a potential prophylactic and vaccine target for EBV.}, }
@article {pmid40534492, year = {2025}, author = {Portuguese, AJ and Liang, EC and Huang, JJ and Jeon, Y and Dima, D and Banerjee, R and Kwok, M and Cicero, KI and Hirayama, AV and Basom, R and Khouderchah, C and Shadman, M and Fong, L and Cowan, AJ and Gauthier, J}, title = {Extramedullary disease is associated with severe toxicities following B-cell maturation antigen CAR T-cell therapy in multiple myeloma.}, journal = {Haematologica}, volume = {110}, number = {12}, pages = {3065-3077}, pmid = {40534492}, issn = {1592-8721}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; T32 GM145449/GM/NIGMS NIH HHS/United States ; T32 HL007093/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/therapy/mortality/pathology/immunology/complications ; Male ; Female ; Aged ; *Immunotherapy, Adoptive/adverse effects/methods ; Middle Aged ; Retrospective Studies ; *B-Cell Maturation Antigen/immunology ; Aged, 80 and over ; Adult ; *Receptors, Chimeric Antigen ; }, abstract = {Extramedullary disease (EMD) in multiple myeloma (MM) is associated with poor outcomes following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T therapy, yet its impact on treatment-related toxicity remains unclear. This study evaluates the impact of active EMD on toxicity, efficacy, and survival in patients with MM treated with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel). We conducted a retrospective cohort study of all patients with MM who received ide-cel (N=32) or cilta-cel (N=76) as standard-of-care therapy at our institution from August 2021 to October 2024. EMD was defined as the presence of soft tissue masses in extraosseous locations, and outcomes were compared based on EMD status. Among 108 patients, 26 (24%) had EMD. Patients with EMD experienced higher rates of grade (G)1+ (38% vs. 17%; P=0.022) and G3+ immune effector cell-associated neurotoxicity syndrome (19% vs. 1.2%; P=0.003), as well as G1+ (96% vs. 78%; P=0.041) and G3+ early immune effector cell-associated hematoxicity (31% vs. 0; P<0.001). Patients with EMD had more prolonged severe neutropenia (median: 7 vs. 2 days; P<0.001), greater cefepime use (median 10 vs. 6 doses; P=0.039), and higher rates of bacteremia (15% vs. 2.4%; P=0.029). In terms of efficacy, patients with EMD had lower complete response rates (20% vs. 59%; P<0.001), shorter median progression-free survival (7.6 vs. 24.6 months; P<0.001), and shorter median overall survival (20 months vs. not reached; P<0.001; 1-year estimates, 53% vs. 96%) and higher 1-year non-relapse mortality (21% vs. 2.5%; P=0.003). EMD is associated with increased toxicity, delayed hematologic recovery, more infectious complications, and reduced survival in patients with MM receiving CAR T therapy.}, }
@article {pmid40534994, year = {2025}, author = {Tratt, M and Bandhlish, A and Eaton, KD and Gooley, T and Giustini, N and Deng, L}, title = {Survival Outcomes of Lung Adenocarcinoma With Intestinal Differentiation in the Era of Immunotherapy.}, journal = {JTO clinical and research reports}, volume = {6}, number = {7}, pages = {100827}, pmid = {40534994}, issn = {2666-3643}, abstract = {INTRODUCTION: Lung adenocarcinoma (LUAD) with intestinal differentiation (LAID) comprises a rare and heterogeneous NSCLC of invasive mucinous, enteric, and colloid characteristics. In the era of chemotherapy, LAID was associated with a poorer prognosis compared with other LUADs. Leveraging the National Cancer Database, we assessed survival outcomes of LAID in the era of immunotherapy.<br><br>METHODS: The National Cancer Database was queried for stage IV adenocarcinoma cases diagnosed from 2016 to 2019. LAID was defined as invasive mucinous adenocarcinoma, colloid adenocarcinoma, or enteric adenocarcinoma. An unadjusted comparison of survival distributions was performed using a log-rank test and adjusted by Cox multivariable regression.<br><br>RESULTS: A total of 40,516 patients were identified, of whom 855 had LAID and 39,661 had other LUAD. Among the cases of LAID, 593 were classified as colloid, 253 as mucinous, and nine as enteric. Patients with LAID had a higher risk of death compared with other LUAD subtypes, with a hazard ratio (HR) of 1.31 (95% confidence interval: 1.21-1.43) and a median survival of 9.19 months and 11.81 months, respectively. This was relatively consistent across all treatment subgroups (HR = 1.40: immunotherapy alone, HR = 1.29: chemoimmunotherapy; HR = 1.25: chemotherapy alone). Patients with LAID treated with chemoimmunotherapy had a median overall survival of 11.16 months, 9.19 months when treated with immunotherapy alone, and 7.09 months when treated with chemotherapy alone.<br><br>CONCLUSIONS: Compared with other LUADs, LAID remains associated with poorer survival in the era of immunotherapy. Nevertheless, exposure to immunotherapy may be associated with improved survival compared with chemotherapy alone in this rare subgroup.}, }
@article {pmid40535475, year = {2025}, author = {Raychaudhuri, S and Gooley, TA and Rasmussen, A and Quach, K and Gill, E and Halpern, AB and Appelbaum, JS and Ghiuzeli, CM and Hendrie, PC and Cassaday, RD and Walter, RB and Percival, MM}, title = {Phase 1 trial of venetoclax with cladribine, cytarabine, G-CSF, and mitoxantrone for AML and high-grade myeloid neoplasm.}, journal = {Blood neoplasia}, volume = {2}, number = {3}, pages = {100085}, pmid = {40535475}, issn = {2950-3280}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {Intensifying induction by combining venetoclax with a high-dose cytarabine regimen may improve outcomes for high-risk populations such as adult patients with adverse-risk newly diagnosed or relapsed acute myeloid leukemia. In a phase 1 trial testing the novel combination of venetoclax and CLAG-M (cladribine, high-dose cytarabine, granulocyte colony-stimulating factor [G-CSF], and mitoxantrone), the maximum tolerated dose was venetoclax 400 mg on days 1 through 14, combined with cladribine 5 mg/m[2] on days 1 through 5, cytarabine 1.5 g/m[2] on days 1 through 5, G-CSF 5 μg/kg on days 0 through 5, and mitoxantrone 16 or 18 mg/m[2] on days 1 through 3 (for relapsed/refractory and newly diagnosed adverse-risk patients, respectively). The 28-day mortality rate was 5%. Composite complete remission (CR) rate (CR + CR with incomplete hematologic recovery) was 65%. These findings support further phase 2 study of venetoclax in combination with CLAG-M. This trial was registered at www.ClinicalTrials.gov as #NCT04797767.}, }
@article {pmid40536977, year = {2025}, author = {Sinnott-Armstrong, N and Forsythe, D and Benoit, JM and Chappell, CR and Coe, LSY and de Oliveira, BFR and Evans, N and Fagre, AC and Gilligan, JM and Hamilton, M and Henneberry, CM and Ishaq, SL and Johnston, J and Krichilsky, E and Lopez, JA and McMonigal, K and Ortiz Alvarez de la Campa, M and Rahman, R and Schwartz, NE and Talluto, L and Taylor, EJ and Vargas-Muñiz, JM and Weissman, JL}, title = {Protect transgender scientists.}, journal = {Science (New York, N.Y.)}, volume = {388}, number = {6753}, pages = {1283-1284}, doi = {10.1126/science.ady0962}, pmid = {40536977}, issn = {1095-9203}, }
@article {pmid40537474, year = {2025}, author = {Bradshaw, CS and Plummer, EL and Muzny, CA and Mitchell, CM and Fredricks, DN and Herbst-Kralovetz, MM and Vodstrcil, LA}, title = {Bacterial vaginosis.}, journal = {Nature reviews. Disease primers}, volume = {11}, number = {1}, pages = {43}, pmid = {40537474}, issn = {2056-676X}, mesh = {Humans ; Female ; *Vaginosis, Bacterial/physiopathology/epidemiology/complications/diagnosis/microbiology/therapy ; Vagina/microbiology/physiopathology ; Anti-Bacterial Agents/therapeutic use/pharmacology ; Microbiota/physiology ; Quality of Life/psychology ; Prevalence ; }, abstract = {Bacterial vaginosis (BV) is a vaginal microbiome disorder that is associated with preterm birth and spontaneous abortion, increased risk of HIV infection and sexually transmitted infections, and has negative effects on quality of life. BV affects one in four women globally, with the highest burden in resource-limited settings. Marked alterations in vaginal microbiome composition, in pro-inflammatory cytokines and chemokines, and in the proteome and metabolome characterize BV and contribute to adverse sequelae. Despite its prevalence, the exact aetiologic agent of BV is unknown and its pathophysiology is poorly understood. These knowledge gaps impede diagnostic and management approaches, with recommended treatment strategies resulting in recurrence that exceeds 50% over 3-6 months. New data on the sexual transmission of BV, including evidence that male-partner treatment improves cure, have improved our understanding of its aetiology and pathogenesis, and provide opportunities for developing optimal diagnostic, treatment and prevention strategies. Other factors probably also contribute to the low efficacy of current treatments, including biofilm and/or antimicrobial resistance, and failure to recolonize a favourable vaginal microbiome after treatment. The complex pathophysiology of BV highlights that individualized and multifaceted management approaches will be required to manage the refractory and adverse sequelae of BV.}, }
@article {pmid40537477, year = {2025}, author = {Bentley, AR and Brown, MR and Musani, SK and Schwander, KL and Winkler, TW and Sims, M and Kilpeläinen, TO and Aschard, H and Bartz, TM and Bielak, LF and Chai, JF and Chitrala, KN and Franceschini, N and Graff, M and Guo, X and Hartwig, FP and Horimoto, ARVR and Lim, E and Liu, Y and Manning, AK and Nolte, IM and Noordam, R and Richard, MA and Smith, AV and Sung, YJ and Vojinovic, D and Wang, R and Wang, Y and Feitosa, MF and Harris, SE and Lyytikäinen, LP and Pistis, G and Rauramaa, R and van der Most, PJ and Ware, E and Weiss, S and Wen, W and Yanek, LR and Arking, DE and Arnett, DK and Ballantyne, C and Boerwinkle, E and Chen, YI and Daviglus, ML and de Las Fuentes, L and de Vries, PS and Delaney, JAC and Fretts, AM and Ekunwe, L and Faul, JD and Gallo, LC and Heikkinen, S and Homuth, G and Ikram, MA and Isasi, CR and Jonas, JB and Keltikangas-Järvinen, L and Komulainen, P and Kraja, AT and Krieger, JE and Launer, L and ,  and Liu, J and Lohman, K and Luik, AI and Manichaikul, AW and Marques-Vidal, P and Milaneschi, Y and Mwasongwe, SE and O'Connell, JR and Rice, K and Rich, SS and Schreiner, PJ and Schwettmann, L and Shikany, JM and Shu, XO and Smith, JA and Snieder, H and Sotoodehnia, N and Tai, ES and Taylor, KD and Tinker, L and Tsai, MY and Uitterlinden, AG and van Duijn, CM and van Heemst, D and Waldenberger, M and Wallace, RB and Wee, HL and Weir, DR and Wei, WB and Willems van Dijk, K and Wilson, G and Yao, J and Young, KL and Zhang, X and Zhao, W and Zhu, X and Zonderman, AB and Deary, IJ and Gieger, C and Grabe, HJ and Lakka, TA and Lehtimäki, T and Oldehinkel, AJ and Preisig, M and Wang, YX and Zheng, W and Evans, MK and Province, M and Gauderman, J and Gudnason, V and Hartman, CA and Horta, BL and Kardia, SLR and Kooperberg, C and Liu, CT and Mook-Kanamori, DO and Penninx, BW and Pereira, AC and Peyser, PA and Psaty, BM and Rotter, JI and Sim, X and North, KE and Rao, DC and Bierut, L and Miller, CL and Morrison, AC and Rotimi, CN and Fornage, M and Fox, ER}, title = {Multi-ancestry genome-wide association analyses incorporating SNP-by-psychosocial interactions identify novel loci for serum lipids.}, journal = {Translational psychiatry}, volume = {15}, number = {1}, pages = {207}, pmid = {40537477}, issn = {2158-3188}, support = {P30 ES005605/ES/NIEHS NIH HHS/United States ; Z01HG200362//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; Z01 HG200362/ImNIH/Intramural NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 HL118305/HL/NHLBI NIH HHS/United States ; R01 HL156991/HL/NHLBI NIH HHS/United States ; R01 HL172803/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Male ; *Lipids/blood/genetics ; Female ; *Gene-Environment Interaction ; Adult ; Genetic Loci ; Middle Aged ; Social Support ; }, abstract = {Serum lipid levels, which are influenced by both genetic and environmental factors, are key determinants of cardiometabolic health and are influenced by both genetic and environmental factors. Improving our understanding of their underlying biological mechanisms can have important public health and therapeutic implications. Although psychosocial factors, including depression, anxiety, and perceived social support, are associated with serum lipid levels, it is unknown if they modify the effect of genetic loci that influence lipids. We conducted a genome-wide gene-by-psychosocial factor interaction (G×Psy) study in up to 133,157 individuals to evaluate if G×Psy influences serum lipid levels. We conducted a two-stage meta-analysis of G×Psy using both a one-degree of freedom (1df) interaction test and a joint 2df test of the main and interaction effects. In Stage 1, we performed G×Psy analyses on up to 77,413 individuals and promising associations (P < 10[-5]) were evaluated in up to 55,744 independent samples in Stage 2. Significant findings (P < 5 × 10[-8]) were identified based on meta-analyses of the two stages. There were 10,230 variants from 120 loci significantly associated with serum lipids. We identified novel associations for variants in four loci using the 1df test of interaction, and five additional loci using the 2df joint test that were independent of known lipid loci. Of these 9 loci, 7 could not have been detected without modeling the interaction as there was no evidence of association in a standard GWAS model. The genetic diversity of included samples was key in identifying these novel loci: four of the lead variants displayed very low frequency in European ancestry populations. Functional annotation highlighted promising loci for further experimental follow-up, particularly rs73597733 (MACROD2), rs59808825 (GRAMD1B), and rs11702544 (RRP1B). Notably, one of the genes in identified loci (RRP1B) was found to be a target of the approved drug Atenolol suggesting potential for drug repurposing. Overall, our findings suggest that taking interaction between genetic variants and psychosocial factors into account and including genetically diverse populations can lead to novel discoveries for serum lipids.}, }
@article {pmid40539461, year = {2025}, author = {Pandrangi, VC and Liao, JJ and de Almeida, JR and El-Sayed, IH and Hanna, G and Su, SY and Tsang, R and Won, TB and Witterick, I and Choby, G and Kuan, EC and Geltzeiler, M}, title = {Current Trends in the Management of Recurrent Nasopharyngeal Carcinoma.}, journal = {Head &amp; neck}, volume = {47}, number = {9}, pages = {2611-2621}, doi = {10.1002/hed.28219}, pmid = {40539461}, issn = {1097-0347}, mesh = {Humans ; *Nasopharyngeal Carcinoma/therapy/mortality/pathology ; *Neoplasm Recurrence, Local/therapy/mortality/pathology ; *Nasopharyngeal Neoplasms/therapy/mortality/pathology ; Combined Modality Therapy ; }, abstract = {BACKGROUND: Recurrent nasopharyngeal carcinoma (NPC) is associated with challenges in treatment due to the complex anatomic location and impact of prior treatment modalities such as radiation therapy. The purpose of this review is to discuss modern treatment strategies for recurrent NPC, potential challenges, and outcomes.<br><br>METHODS: A narrative review was performed, evaluating management strategies of recurrent NPC, survival measures, and advancements in treatment considerations.<br><br>RESULTS: Treatment options including radiation, surgery, and chemotherapy are discussed, including data on survival outcomes and treatment-related morbidity. We review additional considerations including advances in endoscopic surgery, operative management of the internal carotid artery (ICA), novel radiation and chemotherapy protocols, and the introduction of immune checkpoint inhibitors.<br><br>CONCLUSION: This review describes contemporary management strategies for recurrent NPC, highlighting evolving management strategies that may reduce treatment-associated morbidity and improve survival.}, }
@article {pmid40540274, year = {2025}, author = {Neupane, A and Petrykey, K and Li, K and French, J and Zhou, X and Wang, J and Im, C and Dixon, SB and Ehrhardt, MJ and Mulrooney, DA and Jefferies, JL and Gramatges, MM and Chow, EJ and Bhatia, S and Robison, LL and Ness, KK and Hudson, MM and Burridge, PW and Armstrong, GT and Yasui, Y and Sapkota, Y}, title = {TTN and BAG3 in Cancer Therapy-Related Cardiomyopathy Among Long-Term Survivors of Childhood Cancer.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2515793}, pmid = {40540274}, issn = {2574-3805}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; R01 HL173881/HL/NHLBI NIH HHS/United States ; R01 CA261898/CA/NCI NIH HHS/United States ; R21 CA261833/CA/NCI NIH HHS/United States ; R01 CA216354/CA/NCI NIH HHS/United States ; U01 CA195547/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Cancer Survivors/statistics &amp; numerical data ; *Adaptor Proteins, Signal Transducing/genetics ; Retrospective Studies ; *Apoptosis Regulatory Proteins/genetics ; *Cardiomyopathies/genetics/etiology/epidemiology ; Adult ; Child ; *Neoplasms/therapy ; *Connectin/genetics ; Adolescent ; Anthracyclines/adverse effects ; Prospective Studies ; Young Adult ; }, abstract = {IMPORTANCE: Cancer therapy-related cardiomyopathy (CCM) is an important concern for childhood cancer survivors. In the general population, rare variants in TTN and BAG3 are associated with an increased risk of familial dilated cardiomyopathy, and common variants are associated with a decreased risk of sporadic dilated cardiomyopathy.<br><br>OBJECTIVES: To examine associations of common and rare protein-altering variants (PAVs) in TTN and BAG3 with late-onset CCM risk in childhood cancer survivors.<br><br>This retrospective cohort study with a prospective follow-up included childhood cancer survivors from the St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS) with prior exposure to anthracyclines and/or chest-directed radiation. Cancer therapy-related cardiomyopathy was clinically assessed in SJLIFE and self-reported in CCSS, with severity graded using Common Terminology Criteria for Adverse Events, version 4.03. The data analysis was conducted from January 4, 2023, to March 6, 2025.<br><br>EXPOSURE: Late-onset CCM.<br><br>MAIN OUTCOME AND MEASURES: Multivariable logistic regression was used to evaluate the association of common variants in TTN and BAG3 with late-onset CCM risk, adjusting for relevant demographic and cancer treatment exposures. In SJLIFE alone, 7 echocardiographic parameters were assessed. Rare PAVs were examined using Fisher exact test. Cohort-specific results were combined using meta-analytic approaches.<br><br>RESULTS: The cohort included 1843 childhood cancer survivors from SJLIFE (median [IQR] age at CCM diagnosis, 34.9 [28.0-42.3] years; 53.2% male) and 4577 from CCSS (median [IQR] age at CCM diagnosis, 32.0 [23.0-41.0] years; 51.6% female). In the combined sample of European ancestry survivors from SJLIFE (205 with CCM grade &#x2265;2) and CCSS (248 with CCM grade &#x2265;2), common variants rs3829746-C in TTN (odds ratio,&#x2009;0.81; 95% CI, 0.68-0.97) and rs2234962-C in BAG3 (odds ratio,&#x2009;0.79; 95% CI, 0.65-0.95) were associated with a decreased risk of late-onset CCM. In SJLIFE African ancestry survivors, no association was observed with either of the common variants. Rare PAVs were not associated with late-onset CCM in European or African ancestry survivors. In European ancestry survivors, both rs3829746-C and rs2234962-C were also associated with reduced left ventricular end-systolic volume (&#x3b2;&#x2009;[SE],&#x2009;-1.90 [0.65] and -2.68 [0.64], respectively) and global longitudinal peak strain (&#x3b2;&#x2009;[SE], -0.31 [0.13] and -0.30 [0.12]) and with increased left ventricular ejection fraction (&#x3b2;&#x2009;[SE],&#x2009;0.62 [0.27] and 0.86 [0.27], respectively).<br><br>CONCLUSIONS AND RELEVANCE: The findings of this cohort study show that common variants in TTN and BAG3 are associated with a decreased risk of late-onset CCM among childhood cancer survivors, while rare PAVs showed no association.}, }
@article {pmid40540276, year = {2025}, author = {Banerjee, R and Acob, YC}, title = {Telehealth and Time Burden in Patients With Advanced Cancer.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2516769}, doi = {10.1001/jamanetworkopen.2025.16769}, pmid = {40540276}, issn = {2574-3805}, }
@article {pmid40540800, year = {2025}, author = {Tsilifis, C and Raedler, J and Renke, J and Medinger, M and Laberko, A and Haraldsson, &#xc1; and Patel, N and Ciznar, P and Wong, M and Keogh, SJ and Gray, P and Mitchell, R and Bigley, V and Elcombe, S and Hauck, F and Albert, MH and Tholouli, E and Herwadkar, A and Elkhalifa, S and Kosmidis, C and Callisti, G and Burroughs, LM and Chen, K and Carpenter, B and Fox, TA and Morris, EC and Uppuluri, R and Raj, R and Yanagimachi, M and Buddingh, EP and Oikonomopoulou, C and Gonzalez, C and Dimitrova, D and Kanakry, JA and Arnold, D and Pai, SY and Slatter, MA and Pearce, MS and Worth, A and Freeman, AF and Gennery, AR}, title = {Allogeneic hematopoietic stem cell transplantation for STAT3 hyper-IgE syndrome: a worldwide study.}, journal = {Blood advances}, volume = {9}, number = {16}, pages = {4126-4135}, pmid = {40540800}, issn = {2473-9537}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; *Job Syndrome/therapy/mortality/diagnosis ; Adolescent ; Male ; Female ; Adult ; Child ; Young Adult ; Middle Aged ; Child, Preschool ; *STAT3 Transcription Factor/genetics/metabolism ; Transplantation, Homologous ; Retrospective Studies ; Graft vs Host Disease/etiology ; Treatment Outcome ; }, abstract = {Signal transduction and activator of transcription 3 hyperimmunoglobulin E syndrome (STAT3-HIES) is a multisystem disorder causing recurrent skin and respiratory infection with bronchiectasis, pneumatoceles, and aspergillosis; lymphoma; and extraimmune manifestations including fractures and vasculopathy. Published data on immune and extraimmune hematopoietic stem cell transplant (HSCT) outcomes focus on case reports or small cohorts. We conducted an international multicenter retrospective study of HSCT in STAT3-HIES. Primary end points were overall survival (OS) and event-free survival (EFS; events were death, graft failure, chronic graft-versus-host disease [GVHD]). We identified 41 patients over a 28-year period. HSCT indication was infection (93%) or lymphoma (7%). Median age at HSCT was 14 years (range, 4-45). Most patients had pre-HSCT respiratory disease (93%), including parenchymal lung disease (68%), and prior suspected/confirmed pulmonary fungal infection (32%). Patients received peripheral blood stem cells (51%) or marrow (49%) from HLA 10/10-matched unrelated donors (44%), matched family donors (44%), mismatched family donors (10%), or 1 9/10-mismatched unrelated donor (2%). Conditioning regimens were predominantly treosulfan-based (59%; with thiotepa, 34%); other patients received busulfan-based (24%) or melphalan-based (17%) regimens. Median follow-up for surviving patients was 5 years (0.8-28). The 5-year OS was 93%, and 5-year EFS 90%. Cumulative incidence of grade 2 to 4 acute GVHD was 22%. Median whole blood donor chimerism at latest follow-up was 100%. Eighty-seven percent of patients have reduced or no bacterial or fungal respiratory infection. After HSCT, 20% developed new skeletal fractures. This worldwide study expanded data on HSCT for STAT3-HIES to 41 patients; despite significant pre-HSCT pulmonary morbidity, OS was high, and patients have improved skin and respiratory disease though the impact on extraimmune manifestations appears limited.}, }
@article {pmid40541542, year = {2025}, author = {Gee-Rodriguez, K and Indorf, A and Swisher, EM and Bialick, K and Banda, K}, title = {Human epidermal growth factor receptor 2 targeted agents in gynecologic cancers: an updated review.}, journal = {International journal of gynecological cancer : official journal of the International Gynecological Cancer Society}, volume = {35}, number = {12}, pages = {101948}, doi = {10.1016/j.ijgc.2025.101948}, pmid = {40541542}, issn = {1525-1438}, mesh = {Humans ; Female ; *Erb-b2 Receptor Tyrosine Kinases/antagonists &amp; inhibitors/metabolism ; *Genital Neoplasms, Female/drug therapy/metabolism ; Molecular Targeted Therapy/methods ; *Antineoplastic Agents/therapeutic use ; }, abstract = {Human epidermal growth factor receptor 2 (HER2) is a well-established oncogenic target across several solid tumor types and is associated with advanced disease and aggressive biology among gynecologic cancers. Experts have recommended HER2 testing algorithms to guide the treatment of advanced or recurrent endometrial cancers, but these guidelines utilize an outdated version of the recommendations for HER2 testing in breast cancers. Additionally, similar consensus guidelines do not exist for HER2 testing and reporting in ovarian or cervical cancers, leading to inconsistent HER2 measurement in clinical trials and real-world practice across all 3 gynecologic cancer types. Nonetheless, accumulating data support the efficacy of HER2-targeted treatment in gynecologic cancers, generating urgency to standardize HER2 measurement for these cancers. Practitioners also need to gain familiarity with the potential impacts on cardiac and respiratory function and the concomitant drug interactions of existing and developing HER2-targeted therapies. This review clarifies HER2 terminology and testing, discusses completed and ongoing clinical trials, and synthesizes recommendations for the use of HER2-directed agents in gynecologic cancers.}, }
@article {pmid40542609, year = {2025}, author = {Menz, BD and Modi, ND and Abuhelwa, AY and Kuderer, NM and Lyman, GH and Swain, SM and Kichenadasse, G and Shahnam, A and Haseloff, M and Vitry, A and Rammant, E and Ramsey, I and Chan, RJ and McKinnon, RA and Rowland, A and Sorich, MJ and Hopkins, AM}, title = {Patient-reported outcome thresholds and their associations with survival, adverse events, and quality of life in a pooled analysis of breast cancer trials.}, journal = {International journal of cancer}, volume = {157}, number = {10}, pages = {2135-2145}, pmid = {40542609}, issn = {1097-0215}, support = {APP2008119//National Health and Medical Research Council/ ; APP2030913//National Health and Medical Research Council/ ; RSP-117-FY2023//Tour de Cure/ ; 2023-S-DTFA-005//Hospital Research Foundation/ ; }, mesh = {Humans ; *Breast Neoplasms/mortality/pathology/therapy/drug therapy/psychology ; Female ; *Quality of Life ; *Patient Reported Outcome Measures ; Middle Aged ; Aged ; Adult ; Progression-Free Survival ; }, abstract = {Researchers at the EORTC recently recommended clinical thresholds for the QLQ-C30 to facilitate actionable insights in clinical practice. We evaluate the distribution of these thresholds and associations with outcomes in breast cancer. Data were pooled from two early-stage and six advanced-stage breast cancer trials. EORTC thresholds were applied to available QLQ-C30 data to identify clinically important PRO domains. Associations between the number of clinically important PRO domains at baseline with overall survival (OS), invasive-disease-free survival (IDFS), progression-free survival (PFS), grade ≥3 adverse events (AEs), and serious AEs were evaluated using Cox-regression. Data from 8544 breast cancer patients, of whom 2428 (41%) of the 5893 early-stage and 1486 (56%) of the 2651 advanced-stage patients reported ≥3 clinically important PRO domains. In the early-stage, each additional clinically important PRO domain was associated with worsened grade ≥3 AEs (HR, 1.03 [95%CI, 1.01-1.04], p = 0.001) and serious AEs (1.05 [1.03-1.07], p < 0.001). In the advanced-stage, each additional clinically important PRO domain was associated with worsened OS (1.05 [1.03-1.07], p < 0.001), PFS (1.03 [1.01-1.04], p = 0.002), grade ≥3 AEs (1.04 [1.02-1.06], p < 0.001), and serious AEs (1.07 [1.04-1.11], p < 0.001). A substantial proportion of breast cancer patients report clinically important PRO domains at baseline, with increasing numbers associated with worsening AEs, survival, and quality-of-life.}, }
@article {pmid40542813, year = {2025}, author = {Kouwenberg, TW and van Dalen, EC and Mulder, RL and Armenian, S and Feijen, EAM and Chow, EJ and Kosmidis, H and Vormoor-Bürger, BJ and Kiyotani, C and Nathan, PC and Kapusta, L and Grotenhuis, HB and Engels, FK and Teske, AJ and Tragiannidis, A and Slieker, MG and Ozono, S and Nohria, A and Sláma, T and Skinner, R and Hudson, MM and Kremer, LCM and Ehrhardt, MJ and Mavinkurve-Groothuis, AMC}, title = {IGHG Recommendations for Anthracycline and Anthraquinone Cardiac Dysfunction Equivalence Ratios After Childhood Cancer: JACC: CardioOncology Expert Panel.}, journal = {JACC. CardioOncology}, volume = {7}, number = {6}, pages = {683-690}, pmid = {40542813}, issn = {2666-0873}, abstract = {Anthracycline and anthraquinone agents are major contributors to cancer therapy-related cardiac dysfunction in childhood cancer. However, evidence-based equivalence ratios for estimating individual risk have not been incorporated into international surveillance guidelines. The International Late Effects of Childhood Cancer Guideline Harmonization Group systematically reviewed the literature on equivalence ratios for doxorubicin, daunorubicin, epirubicin, idarubicin, and mitoxantrone. Based on available evidence, benefit-harm considerations, and expert consensus, the panel concluded that the risk of cardiac dysfunction is lower with daunorubicin and higher with mitoxantrone compared with doxorubicin (moderate-quality evidence; strong recommendation). The panel recommends using an approximate ratio of 0.6 to convert daunorubicin to a doxorubicin-equivalent dose and a ratio of 10.5 for mitoxantrone (low-quality evidence; moderate recommendation). No recommendation was made for epirubicin or idarubicin due to inconclusive evidence.}, }
@article {pmid40543557, year = {2025}, author = {Nunley, BE and Weixler, A and Kim, HG and Xie, H and Sereewit, J and Hajian, P and Ellis, S and Mills, MG and Pérez-Osorio, AC and Goya, S and Gov, J and Dewar, R and Fernandes, G and Templeton, KE and Maloney, DM and Greninger, AL and Roychoudhury, P}, title = {Clinical Performance Evaluation of a Tiling Amplicon Panel for Whole-Genome Sequencing of Respiratory Syncytial Virus.}, journal = {The Journal of molecular diagnostics : JMD}, volume = {27}, number = {9}, pages = {819-831}, doi = {10.1016/j.jmoldx.2025.05.005}, pmid = {40543557}, issn = {1943-7811}, mesh = {Humans ; *Respiratory Syncytial Virus Infections/virology/diagnosis ; *Respiratory Syncytial Virus, Human/genetics ; *Genome, Viral ; *Whole Genome Sequencing/methods ; High-Throughput Nucleotide Sequencing/methods ; Reproducibility of Results ; Sensitivity and Specificity ; }, abstract = {Accurate genomic characterization of respiratory syncytial virus (RSV) is crucial for studies of epidemiology and viral evolution, including monitoring potential escape from newly authorized vaccines and prophylactic monoclonal antibodies. A viral genome tiling amplicon panel (UW-ARTIC) was adapted to develop a custom bioinformatic pipeline for high-throughput, cost-effective sequencing of both RSV-A and RSV-B subgroups. Genome acceptability criteria were established and the performance characteristics of the panel were determined, including assay sensitivity, specificity, breadth of genome recovery, accuracy, and precision, using contrived and remnant clinical specimens. High-quality genomes (>95% genome completeness; >500× and >1000× average depth for whole genome and fusion gene, respectively) were recovered from samples with cycle threshold ≤ 30 (approximately 594 and 2004 copies per reaction for RSV-A and RSV-B, respectively). Minor variants were accurately identified at >5% allele frequency. The assay showed high accuracy when compared with Sanger, shotgun metagenomic, and hybridization capture-based sequencing, as well as high repeatability and reproducibility. The UW-ARTIC RSV panel has utility for cost-effective RSV genome recovery in public health, clinical, and research applications. It has been used to generate US Food and Drug Administration-reportable data for clinical trials of RSV antiviral products, with robust performance in global samples from as recently as the 2023/2024 season. Continued genomic surveillance and future updates to primers will be essential for continued recovery of genomes as RSV continues to evolve.}, }
@article {pmid40543709, year = {2025}, author = {Brehm, V and Wang, Z and Rocha, L and Jones, B and Jenq, RR and Chang, CC and Cheng, GS and Hsu, J and Sharifi, H and Yanik, G and Luna, L and Waqar, A and Zaveri, J and Dickey, BF and Bashoura, L and Shpall, EJ and Zinter, M and O'Dwyer, D and Champlin, RE and Chen, G and Alousi, A and Paczesny, S and Peterson, CB and Sheshadri, A}, title = {Inflammatory Markers and Microbiome Dysbiosis in Hematopoietic Cell Transplant Recipients with Lung Graft-versus-Host Disease.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {668.e1-668.e12}, doi = {10.1016/j.jtct.2025.06.020}, pmid = {40543709}, issn = {2666-6367}, mesh = {Humans ; *Graft vs Host Disease/etiology/blood ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Male ; *Dysbiosis/etiology ; *Biomarkers/blood ; Middle Aged ; Adult ; *Bronchiolitis Obliterans/etiology/diagnosis ; Gastrointestinal Microbiome ; *Inflammation ; }, abstract = {Bronchiolitis obliterans (BOS) is a manifestation of pulmonary chronic graft-versus-host disease (cGVHD) and is a devastating complication of allogeneic hematopoietic stem cell transplantation (HCT). Early detection and treatment of BOS may improve outcomes, but biomarkers that accurately identify BOS early are lacking. We aimed to determine whether certain validated cGVHD markers could also accurately diagnose BOS as compared with patients without BOS and with or without extrapulmonary cGVHD. In addition, we sought to determine whether dysbiosis of the gut or oral microbiomes was associated with BOS or with inflammatory biomarkers. We enrolled 43 recipients of allogeneic HCT, 16 of whom had BOS. For each patient, we obtained pulmonary function tests, measured the levels of 9 serum biomarkers utilizing enzyme-linked immunosorbent assays, and analyzed both the oral and gut microbiome using microbial DNA amplification and sequencing. We compared biomarker levels to lung function, both at baseline and over time, as well as to microbiome diversity. Higher IL1RL1 (P = .002) and IL-17 (P = .041) at enrollment were negatively correlated with FEV1% (forced expiratory volume in 1 second) lung function over time. Increases in IL1RL1 (P = .035), IL-17 (P = .009), and WFDC2 (P = .045) levels over time were associated with worsened lung function/FEV1% over time. There were minimal correlations between gut microbiome diversity and lung function or serum biomarkers. Oral microbiome alpha diversity was lower in subjects with BOS than without (P = .00057), and oral beta diversity was associated with FEV1% and with levels of several biomarkers. Our pilot study suggests that certain serum cGVHD markers may identify recipients of allogeneic HCT at higher risk for pulmonary impairment over time and that these markers should be followed with robust, controlled studies.}, }
@article {pmid40544207, year = {2025}, author = {Fernandez, M and Todeschini, L and Keenan, BP and Rosenberg, D and Hernandez, S and Zampese, M and Qiao, G and Pollini, T and Maker, AV}, title = {Novel Computational Analysis Identifies Cytotoxic Lymphocyte-to-Monocyte Balance in Tumors as a Predictor of Recurrence-Free Survival in Colorectal Carcinoma.}, journal = {Annals of surgical oncology}, volume = {32}, number = {9}, pages = {6980-6990}, pmid = {40544207}, issn = {1534-4681}, support = {K12 CA260225/CA/NCI NIH HHS/United States ; R37 CA238435/CA/NCI NIH HHS/United States ; R37CA238435//Basic Research Laboratory/ ; }, mesh = {Humans ; *Colorectal Neoplasms/pathology/immunology/mortality/genetics ; *Neoplasm Recurrence, Local/immunology/pathology/mortality/genetics ; *Monocytes/immunology/pathology ; *T-Lymphocytes, Cytotoxic/immunology/pathology ; Prognosis ; Tumor Microenvironment/immunology ; *Biomarkers, Tumor/genetics ; Survival Rate ; Female ; Male ; *Computational Biology/methods ; Follow-Up Studies ; Gene Expression Profiling ; }, abstract = {The microenvironment and immune infiltrate population of colorectal tumors can serve as a stronger predictor of patient survival than microsatellite-status or traditional T- or N-staging. This study aimed to leverage transcriptomic techniques to identify specific immune cell populations and their ratios associated with cancer recurrence in colorectal cancer patients. The goal was to identify patients who could benefit from early adjuvant interventions, identify those at higher risk of recurrence for surveillance, and identify potential combinatorial immunotherapy strategies tailored to this disease. We found that a lower ratio of cytotoxic lymphocyte: monocytic lineage cells, and not microsatellite-status, was associated with cancer recurrence. Additional differential gene expression analysis of the monocytic lineage demonstrated that genes specifically associated with tumor associated macrophages and a protumoral phenotype were overexpressed in the tumor microenvironment in patients that went on to have recurrent disease. Gene Ontology analysis revealed that pathways associated with pro-tumoral extracellular matrix remodeling were suppressed in tumors exhibiting a high cytotoxic lymphocyte: monocytic lineage ratio, suggesting a diminished propensity for tumor progression. The development of these prognostic markers not only associates with colorectal cancer recurrence, aiding in risk stratification and guiding adjuvant therapy decisions for resected early-stage patients, but also suggests that effective colon cancer treatments will likely require a combination of cytotoxic T-cell-directed immunomodulation and targeted inhibition of tumor-associated macrophages.}, }
@article {pmid40544344, year = {2025}, author = {Gilbert, PB and Peng, J and Han, L and Lange, T and Lu, Y and Nie, L and Shih, MC and Waddy, SP and Wiley, K and Yann, M and Zafari, Z and Ghosh, D and Follmann, D and Juraska, M and Díaz, I}, title = {A surrogate endpoint-based provisional approval causal roadmap, illustrated by vaccine development.}, journal = {Biostatistics (Oxford, England)}, volume = {26}, number = {1}, pages = {}, pmid = {40544344}, issn = {1468-4357}, support = {//National Institute of Allergy and Infectious Diseases/ ; /VA/VA/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; /NH/NIH HHS/United States ; //United States Government/ ; R37AI054165/NH/NIH HHS/United States ; }, mesh = {Humans ; *Biomarkers ; *Clinical Trials, Phase III as Topic/methods ; *Endpoint Determination/methods ; *Vaccines ; Randomized Controlled Trials as Topic ; Observational Studies as Topic ; Biostatistics ; }, abstract = {For many rare diseases with no approved preventive interventions, promising interventions exist. However, it has proven difficult to conduct a pivotal phase 3 trial that could provide direct evidence demonstrating a beneficial effect of the intervention on the target disease outcome. When a promising putative surrogate endpoint(s) for the target outcome is available, surrogate-based provisional approval of an intervention may be pursued. Following the general Causal Roadmap rubric, we describe a surrogate endpoint-based provisional approval causal roadmap. Based on an observational study data set and a phase 3 randomized trial data set, this roadmap defines an approach to analyze the combined data set to draw a conservative inference about the treatment effect (TE) on the target outcome in the phase 3 study population. The observational study enrolls untreated individuals and collects baseline covariates, surrogate endpoints, and the target outcome, and is used to estimate the surrogate index-the regression of the target outcome on the surrogate endpoints and baseline covariates. The phase 3 trial randomizes participants to treated vs. untreated and collects the same data but is much smaller and hence very underpowered to directly assess TE, such that inference on TE is based on the surrogate index. This inference is made conservative by specifying 2 bias functions: one that expresses an imperfection of the surrogate index as a surrogate endpoint in the phase 3 study, and the other that expresses imperfect transport of the surrogate index in the untreated from the observational to the phase 3 study. Plug-in and nonparametric efficient one-step estimators of TE, with inferential procedures, are developed. The finite-sample performance of the estimators is evaluated in simulation studies. The causal roadmap is motivated by and illustrated with contemporary Group B Streptococcus vaccine development.}, }
@article {pmid40545000, year = {2025}, author = {Farhan, S and Kennedy, VE and Espinoza-Gutarra, MR and Lust, H and Bobillo, MSO and Lin, AY and Olin, RL and Lin, RJ and Rentscher, KE and Taylor, MR and Mohanraj, L and Wood, WA and Murthy, HS and Ahmed, N and Dueck, AC and Phelan, R and Kelly, DL and Yuen, C and Munshi, PN and Schoemans, H and Hamilton, BK and Lee, C and Sung, AD}, title = {Assessing physical function in transplantation and CAR-T recipients: expert recommendations from the survivorship, aging and biobehavioral special interest groups of ASTCT.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {10}, pages = {742-755}, doi = {10.1016/j.jtct.2025.06.017}, pmid = {40545000}, issn = {2666-6367}, support = {K12 TR004930/TR/NCATS NIH HHS/United States ; }, mesh = {*Stem Cell Transplantation/methods ; Humans ; Survivorship ; Aging/physiology ; *Physical Functional Performance ; *Immunotherapy, Adoptive ; Graft vs Host Disease/prevention &amp; control ; }, abstract = {The past few decades have witnessed significant advancements in stem cell transplantation and cell therapy (TCT). This has allowed their expanded use in older patients and those with comorbidities with favorable outcomes. However, these procedures carry significant risks, such as graft-versus-host disease, infection, cytokine release syndrome, and immune effector cell-associated neurotoxicity. Therefore, physical function assessment is crucial to assess patient fitness and potential optimization before and after TCT. The existence of diverse assessment tools makes implementation, comparison, and sharing knowledge among centers difficult. This paper proposes a tiered approach aiming to harmonize physical assessment in the TCT. This allows healthcare facilities to prioritize recommended assessments based on their current capabilities and resources. TCT patients should receive comprehensive physical assessments pre- and post-TCT using a combination of both patient-reported and objective measures. For patient-reported measures, the Patient-Reported Outcomes Measurement Information System should be considered. For objective measures, we recommend considering a physical performance assessment (eg, gait speed) or muscle strength assessment (eg, hand grip), if feasible. Albumin and C reactive protein are also informative in predicting the risk of nonrelapse mortality. Other composite tools, questionnaire libraries, biomarkers, imaging, and wearables can be added according to research and clinical needs. A care workflow needs to be in place in case any impairment is found during the evaluation with goals of increasing physiologic reserve and mitigating stressors. This tiered approach will increase awareness and adoption of these tools and hence improve patient care, facilitate data sharing, and enhance collaboration in this field.}, }
@article {pmid40545567, year = {2025}, author = {Gupta, M and Schoettler, ML and Orozco, G and Brazauskas, R and Bo-Subait, S and Battiwalla, M and Buchbinder, D and Hamilton, BK and Savani, BN and Schoemans, H and Sorror, ML and Ahmed, S and Badawy, SM and Bhushan, V and Birdsey, K and Couriel, D and Doherty, EE and Donato, M and Farag, SS and Gutman, J and Horwitz, M and El Jurdi, N and Maakaron, JE and Maziarz, RT and Pineiro, L and Schiller, G and Weisdorf, DJ and William, BM and Shaw, BE and Phelan, R and Porter, DL and Levine, M and Abt, PL}, title = {Risk Factors for Solid Organ Graft Failure and Death in Solid Organ Transplant Recipients Undergoing Hematopoietic Cell Transplantation: A Retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) and Organ Procurement and Transplantation Network (OPTN) Study.}, journal = {Transplantation}, volume = {109}, number = {10}, pages = {1611-1625}, pmid = {40545567}, issn = {1534-6080}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Retrospective Studies ; Male ; Risk Factors ; Female ; *Hematopoietic Stem Cell Transplantation/adverse effects/mortality ; Middle Aged ; Adult ; *Organ Transplantation/adverse effects/mortality ; Young Adult ; *Graft Rejection/mortality/etiology/epidemiology ; Adolescent ; Risk Assessment ; Aged ; Graft Survival ; Treatment Outcome ; Tissue and Organ Procurement ; Time Factors ; Child ; }, abstract = {BACKGROUND: There is a growing population of solid organ transplant (SOT) survivors who subsequently require a hematopoietic cell transplant (HCT), although there are limited data on survival, risk factors for SOT graft loss, and death in this cohort.<br><br>METHODS: This retrospective Center for International Blood and Marrow Transplant Research study included recipients of SOT followed by HCT between 1989 and 2017. HCT data were merged with organ transplant data from the Organ Procurement and Transplantation Network.<br><br>RESULTS: Eighty-three patients with an SOT underwent an HCT. Organs transplanted included heart/lung (thoracic, n&#x2005;=&#x2005;15), kidney (n&#x2005;=&#x2005;42), and liver (n&#x2005;=&#x2005;26); 24 patients (29%) received a living donor graft and 59 (71%) a deceased graft. Forty-one patients (49.4%) received an allogeneic HCT and 42 (50.6%) an autologous HCT. Three-year overall survival (OS) from HCT in the entire cohort was 38.6%. There were no significant differences in OS by SOT type, although 3-y OS appeared lowest in the kidney SOT group at 29.9%, compared with liver SOT at 40.6% and thoracic SOT at 58.2%. The incidence of SOT graft failure 3 y post-HCT was 59.1%. There were no significant differences in SOT graft failure by organ type: 3-y failure probability 67.2% for kidney, 56.5% for liver, and 46.2% for thoracic. Shared risk factors for death and graft failure included HCT indication (leukemia, lymphoma, and nonmalignant diseases), HCT type (allogeneic), and SOT type (kidney).<br><br>CONCLUSIONS: Although some SOT recipients may benefit from HCT, the incidence of SOT graft failure was high and OS was poor, particularly after allogeneic HCT.}, }
@article {pmid40545568, year = {2025}, author = {Gupta, M and Schoettler, ML and Brazauskas, R and Bo-Subait, S and Orozco, G and Battiwalla, M and Buchbinder, D and Hamilton, BK and Savani, BN and Schoemans, H and Sorror, ML and Ahmed, S and Badawy, SM and Bhushan, V and Birdsey, K and Couriel, D and Doherty, EE and Donato, M and Farag, SS and Gutman, J and Horwitz, M and El Jurdi, N and Maakaron, JE and Maziarz, RT and Pineiro, L and Schiller, G and Weisdorf, DJ and William, BM and Shaw, BE and Phelan, R and Porter, DL and Abt, PL and Levine, M}, title = {Risk Factors for Solid Organ Graft Failure and Death in Hematopoietic Cell Transplant Recipients Undergoing Solid Organ Transplantation: A Retrospective Center for International Blood and Marrow Transplant Research and Organ Procurement and Transplantation Network Study.}, journal = {Transplantation}, volume = {109}, number = {10}, pages = {1626-1638}, pmid = {40545568}, issn = {1534-6080}, support = {27305C0011/ES/NIEHS NIH HHS/United States ; 27307C0011/ES/NIEHS NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Retrospective Studies ; Female ; Male ; *Hematopoietic Stem Cell Transplantation/adverse effects/mortality ; Middle Aged ; Risk Factors ; Adult ; *Organ Transplantation/adverse effects/mortality ; Young Adult ; Aged ; Adolescent ; *Graft Rejection/mortality/etiology ; Risk Assessment ; Time Factors ; Treatment Outcome ; Tissue and Organ Procurement ; Graft Survival ; }, abstract = {BACKGROUND: There is a growing population of hematopoietic cell transplantation (HCT) survivors who later require a solid organ transplant (SOT). However, there are limited data on survival, risk factors (RFs) for SOT graft loss, and death.<br><br>METHODS: This is a retrospective Center for International Blood and Marrow Transplant Research study that included recipients of HCT followed by SOT between 2001 and 2017. HCT data were merged with data from the Organ Procurement and Transplantation Network.<br><br>RESULTS: Eighty patients underwent autologous (45%) or allogeneic (55%) HCT followed by single SOT. Common indications for HCT included leukemia/myelodysplastic syndrome (45%) and plasma cell disorders (38.8%). The median time from HCT to SOT was 47.7 mo. There were 49 kidney, 26 thoracic, and 5 liver transplants. Overall survival from SOT was significantly different by organ (P &#x2005;=&#x2005;0.01). Three-year overall survival by organ type was 85% among kidney, 70.7% among thoracic, and 30% among liver SOT recipients. Significant RFs for death included lymphoma versus plasma cell disorders and SOT type; thoracic and liver SOT carried a greater risk of death than kidney SOT. There was no significant difference in SOT failure incidence by SOT type; 3-y overall incidence was 27.8%. RFs for SOT graft loss included lymphoma, liver SOT, and positive recipient cytomegalovirus status at SOT.<br><br>CONCLUSIONS: In this study, liver SOT recipients had inferior outcomes. However, renal and thoracic SOT recipients after HCT have acceptable outcomes compared with those of the general SOT population, and thus, SOT should be considered a viable treatment option in these patients.}, }
@article {pmid40546723, year = {2025}, author = {Davids, MS and Ambrose, J and de Nigris, E and Prescott, J and Leng, S and Farooqui, MZH and Gandra, SR and Zettler, CM and Fernandes, LL and Wang, CK and Shadman, M}, title = {Real-world characteristics, treatment patterns, and outcomes of patients with 2 or more LOTs for CLL/SLL in the United States.}, journal = {Blood neoplasia}, volume = {2}, number = {1}, pages = {100047}, pmid = {40546723}, issn = {2950-3280}, abstract = {The development of targeted agents for chronic lymphocytic leukemia (CLL) has transformed the treatment paradigm for patients with CLL. Because of this evolving treatment landscape, contemporaneous evidence was needed related to US treatment patterns and outcomes among patients treated in the real-world. Using COTA's electronic health records-based database, we examined characteristics, treatment patterns, and outcomes of patients receiving ≥2 lines of therapy (LOTs). A total of 1283 adult patients with CLL were identified who initiated second LOT (2L) between 1 January 2014 and 30 June 2022. Of those patients, 542 (42.2%) later received third-line (3L) therapy, of whom 228 (42.1%) went on to receive fourth-line (4L) therapy. Overall, >18% of patients died after 2L initiation and before 3L initiation, and more than a quarter died before 4L initiation. Most patients were White (77.7%), male (60.6%), aged ≥65 years (68.8%), and treated in a community practice setting (87.8%). From 2014 to 2023, the use of chemoimmunotherapy in any ≥2L LOT decreased, whereas use of Bruton tyrosine kinase inhibitor and B-cell lymphoma 2 inhibitor therapy increased. Across endpoints, median times to event(s) were generally shorter with each subsequent LOT received, both in the overall population and among patients receiving a given therapy in different LOTs. With a median follow-up time from 2L initiation of 38.0 months, median real-world time to next treatment, progression-free survival, and overall survival was 31.9, 33.8, and 80.1 months, respectively. Despite great advancements in CLL treatments since 2014, unmet need persists for patients receiving late LOT.}, }
@article {pmid40546726, year = {2025}, author = {Iyer, SP and Dakhil, S and Shinohara, MM and Zain, J and Acosta, M and Foss, F}, title = {Pralatrexate injection combined with oral leucovorin for mucositis management in PTCL/CTCL treatment: a multicenter phase 2 trial.}, journal = {Blood neoplasia}, volume = {2}, number = {1}, pages = {100055}, pmid = {40546726}, issn = {2950-3280}, abstract = {Pralatrexate (Folotyn) is an antifolate indicated for the treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL), and although durable clinical benefit has been demonstrated, oral and gastrointestinal mucositis and/or skin reactions are frequent toxicity complications associated with pralatrexate treatment. Leucovorin (d,l-folinic acid) administration has been used as a standard rescue for patients receiving high-dose methotrexate therapy and has recently been studied in patients with PTCL and cutaneous T-cell lymphoma receiving pralatrexate. We describe results from a multicenter, phase 2, single-arm, open-label trial, conducted with the primary objective of evaluating the effect of leucovorin in preventing or reducing the incidence of grade 2 or higher oral mucositis associated with pralatrexate treatment in cycle 1. Patients were administered pralatrexate, 30 mg/m[2] as an IV push, once weekly for 6 weeks in each cycle, followed by a week of rest (no treatment). Leucovorin 25 mg tablets were administered 3 times daily for 2 days (a total of 6 doses [150 mg cumulative weekly dose]), initiated 24 hours (±2 hours) after each pralatrexate dose. The evaluable population included 34 patients, with a mean age of 63.7 years and 60% males, of whom 2 (5.9%) developed grade 2 oral mucositis during the study period (P < .0001) and there were no reports of grade 3 or higher oral mucositis. Dose modifications, including omissions, delays, or reductions, due to oral mucositis were limited to 1 patient. Coadministration of leucovorin resulted in a significant reduction in mucositis and can be considered a prophylactic therapy in patients receiving pralatrexate treatment. This trial was registered at www.clinicaltrials.gov as #NCT02106650.}, }
@article {pmid40546794, year = {2025}, author = {Unger, JM and Andrews, HS and Levit, LA and McKelvey, BA and Stewart, M and Canin, B and Flaherty, K and Kimball, D and Miller, T and Onitilo, A and Bruinooge, S and Garrett-Mayer, E and Schenkel, C}, title = {Impact of the COVID-19 Pandemic Mitigation Strategies on Cancer Treatment Trials: A Meta-Analysis of Industry and National Cancer Institute Studies.}, journal = {JCO oncology advances}, volume = {2}, number = {1}, pages = {e2500021}, pmid = {40546794}, issn = {2994-9750}, abstract = {PURPOSE: The onset of the COVID-19 pandemic in early 2020 disrupted the conduct of cancer clinical trials. In response, federal agencies allowed more flexibility for trial recruitment and patient follow-up. A key question is whether the benefits of adopting these strategies outweigh the potential detriments to quality metrics.<br><br>METHODS: A joint ASCO and Friends of Cancer Research task force invited industry and National Cancer Institute trial sponsors to contribute deidentified trial-level aggregate data on enrollment, major protocol deviations, dropouts, and severe adverse events (Common Terminology Criteria for Adverse Events grade 3-5). These quality metrics were examined as proportions of participants at risk during the pre-COVID-19 (January 2017-February, 2020), initial wave (March-April, 2020), initial recovery (May-December, 2020), and secondary recovery (January 2021-December 2022) periods. Multilevel beta-regression was used, adjusting for phase; study and sponsor were treated as random effects. Indicator variables were used with pre-COVID-19 as the reference.<br><br>RESULTS: Ten sponsors contributed 67 analyzable trials with N = 12,000 US-based participants. Enrollment odds decreased 49% in the initial wave (odds ratio [OR], 0.51 [95% CI, 0.30 to 0.86], P = .01) but recovered to pre-COVID-19 levels by 2021-2022 (OR, 1.01 [95% CI, 0.56 to 1.81], P = .97). Major protocol deviations, dropouts, and severe toxicity all had a lower incidence in the initial wave compared with pre-COVID-19; these outcomes were also less frequent (P < .05) in the initial recovery period but returned to pre-COVID-19 levels by 2021-2022.<br><br>CONCLUSION: In this multicollaborator evaluation, large declines in enrollment, major protocol deviations, dropouts, and severe toxicity during the acute phase of the pandemic all returned to pre-COVID-19 levels by 2021-2022. These findings highlight the impact of the temporary disruption to trial conduct during the pandemic's peak, but suggest that pandemic-related procedural flexibility did not result in long-term reduced data quality. Sponsors and regulators should consider broader adaptation of trial flexibilities moving forward.}, }
@article {pmid40548549, year = {2026}, author = {Chao, ST and Berkowitz, A and Harris, EER and Henderson, MA and Lo, SS and Pacella, M and Palmer, J and Saeed, H and Simone, CB and Ziemer, BP and Small, W and Schechter, NR}, title = {ACR-ARS Practice Parameter for the Performance of Stereotactic Body Radiation Therapy.}, journal = {American journal of clinical oncology}, volume = {49}, number = {1}, pages = {1-9}, doi = {10.1097/COC.0000000000001224}, pmid = {40548549}, issn = {1537-453X}, mesh = {*Radiosurgery/standards/methods ; Humans ; *Radiation Oncology/standards ; *Neoplasms/radiotherapy ; Radiotherapy Planning, Computer-Assisted/standards/methods ; Societies, Medical ; United States ; }, abstract = {OBJECTIVES: This practice parameter was revised collaboratively by the American College of Radiology (ACR) and American Radium Society (ARS). Stereotactic body radiation therapy (SBRT) precisely delivers higher dose(s) of radiation in 5 of fewer fractions, compared with conventional radiation. Given the complexity and technical nature of this treatment technique, practice parameters are needed to provide guidance to physicians and physicists.<br><br>METHODS: This practice parameter was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ARS.<br><br>RESULTS: Workflow, qualifications/responsibilities of personnel, quality control, and treatment delivery/verification are reviewed. Notable elements of SBRT include image guidance, immobilization, and motion management, with the treatment planning goal of minimizing the volume of normal tissue exposed to medium and high dose levels and maximizing dose safely to the target. Specialized training is encouraged, as some technologies are not used in standard treatments.<br><br>CONCLUSIONS: This practice parameter provides direction on key components recommended for SBRT and may be used as a guide to physicians and physicists wanting to provide this treatment to their patients.}, }
@article {pmid40548935, year = {2025}, author = {Readshaw, JJ and Doyle, LA and Puiu, M and Kelly, A and Nelson, A and Kaiser, AJ and McGuire, SF and Peralta Acosta, J and Smith, DL and Stoddard, BL and Kaiser, BK and Blower, TR}, title = {PglZ from Type I BREX phage defence systems is a metal-dependent nuclease that forms a sub-complex with BrxB.}, journal = {Nucleic acids research}, volume = {53}, number = {12}, pages = {}, pmid = {40548935}, issn = {1362-4962}, support = {BB/T008695/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; //Lister Institute Prize Fellowship to A.K. and T.R.B./ ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 GM105691/GM/NIGMS NIH HHS/United States ; R35GM148166/GF/NIH HHS/United States ; R15GM140375//BKK/ ; R15 GM140375/GM/NIGMS NIH HHS/United States ; R01GM105691/GF/NIH HHS/United States ; //New England Biolabs/ ; BB/Y003659/1//responsive mode/ ; //Fred Hutchinson Cancer Center/ ; R35 GM148166/GM/NIGMS NIH HHS/United States ; R01 GM129325/GM/NIGMS NIH HHS/United States ; }, mesh = {*Bacteriophages/genetics ; *Bacterial Proteins/metabolism/chemistry/genetics ; Models, Molecular ; *Viral Proteins/metabolism/chemistry ; Metals/metabolism ; *DNA-Binding Proteins/metabolism/chemistry/genetics ; }, abstract = {BREX (Bacteriophage Exclusion) systems, identified through shared identity with Pgl (Phage Growth Limitation) systems, are a widespread, highly diverse group of phage defence systems found throughout bacteria and archaea. The varied BREX Types harbour multiple protein subunits (between four and eight) and all encode a conserved putative phosphatase, PglZ, and an equally conserved, putative ATPase, BrxC. Almost all BREX systems also contain a site-specific methyltransferase, PglX. Despite having determined the structure and fundamental biophysical and biochemical behaviours of several BREX factors (including the PglX methyltransferase, the BrxL effector, the BrxA DNA-binding protein, and a commonly-associated transcriptional regulator, BrxR), the mechanism by which BREX impedes phage replication remains largely undetermined. In this study, we identified a stable BREX sub-complex of PglZ:BrxB, generated and validated a structural model of that protein complex, and assessed the biochemical activity of PglZ from BREX, revealing it to be a metal-dependent nuclease. PglZ can cleave cyclic oligonucleotides, linear oligonucleotides, plasmid DNA and both non-modified and modified linear phage genomes. PglZ nuclease activity has no obvious role in BREX-dependent methylation, but does contribute to BREX phage defence. BrxB binding does not impact PglZ nuclease activity. These data contribute to our growing understanding of BREX phage defence.}, }
@article {pmid40549085, year = {2025}, author = {Goodsell, KE and Sham, JG}, title = {ASO Author Reflections: Reasonable Doubt: The Case for Somatostatin Analogs in Pancreas Surgery Remains Unsettled.}, journal = {Annals of surgical oncology}, volume = {32}, number = {10}, pages = {7459-7460}, pmid = {40549085}, issn = {1534-4681}, }
@article {pmid40549281, year = {2025}, author = {Yi, JC and Walsh, CA and Chow, EJ and Baker, KS and Mendoza, JA and Cole, A}, title = {Primary care providers and their needs caring for cancer survivors: a qualitative study.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {40549281}, issn = {1932-2267}, support = {UL1 TR002319/TR/NCATS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: To enhance survivorship care, we explored primary care providers' (PCPs) preferences and needs related to treatment summary and survivorship care plans (TS/SCPs) as a communication tool and PCPs' general thoughts related to barriers in managing the care of cancer survivors.<br><br>METHODS: We conducted semi-structured qualitative interviews via video with PCPs within primary care practice networks in the Pacific Northwest. A codebook was developed with the interview guide as a template. Directed content analysis was used to analyze PCP reported challenges, supports needed, and TS/SCP feedback.<br><br>RESULTS: Qualitative interviews were conducted with 18 PCPs. The majority were female (72%) and non-Hispanic White (94%), with 56% from urban areas and with varied amounts of time in clinical practice (median 4.5&#xa0;years, range 0.5-47). PCPs reported common challenges caring for cancer survivors (e.g., unsure what surveillance is needed) and supports needed to improve care (e.g., further PCP education). PCPs also described preferred information to include in TS/SCPs (e.g., surveillance schedule) and format (e.g., in the electronic health record). They also reported that e-consultation could be useful in communication with other health care providers about any questions, CONCLUSIONS: PCPs want further education and support about cancer surveillance guidelines and managing long-term effects in survivors. Having TS/SCP information easy to find in the EHR was mentioned by the PCPs as something that would improve their care of cancer survivors.<br><br>Providing PCPs with more education and tools in the EHR could lead to improved care of cancer survivors.}, }
@article {pmid40549387, year = {2025}, author = {Marrero, RJ and Shastri, VM and Nicolet, D and Mrózek, K and Walker, CJ and Blum, WG and Powell, BL and Kolitz, JE and Moore, JO and Uy, GL and Stock, W and Carroll, AJ and Byrd, JC and Aplenc, R and Cooper, TM and Gamis, AS and Wu, H and Pounds, S and Wang, YC and Alonzo, TA and Meshinchi, S and Eisfeld, AK and Kolb, EA and Lamba, JK}, title = {Cytarabine Pharmacogenomics and Outcomes Among Children and Young Adults With Acute Myeloid Leukemia.}, journal = {JAMA network open}, volume = {8}, number = {6}, pages = {e2516296}, pmid = {40549387}, issn = {2574-3805}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; R01 CA132946/CA/NCI NIH HHS/United States ; R01 CA270120/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180882/CA/NCI NIH HHS/United States ; UG1 CA189850/CA/NCI NIH HHS/United States ; UG1 CA189824/CA/NCI NIH HHS/United States ; UG1 CA233247/CA/NCI NIH HHS/United States ; UG1 CA233253/CA/NCI NIH HHS/United States ; UG1 CA233327/CA/NCI NIH HHS/United States ; UG1 CA233328/CA/NCI NIH HHS/United States ; UG1 CA233331/CA/NCI NIH HHS/United States ; UG1 CA233339/CA/NCI NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U10 CA180882/CA/NCI NIH HHS/United States ; U24 CA196171/CA/NCI NIH HHS/United States ; R01 CA262496/CA/NCI NIH HHS/United States ; R01 CA284595/CA/NCI NIH HHS/United States ; R01 CA283574/CA/NCI NIH HHS/United States ; U10 CA180886/LM/NLM NIH HHS/United States ; T32 HG008958/HG/NHGRI NIH HHS/United States ; P30 CA247796/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/drug therapy/mortality ; Adolescent ; Male ; Female ; Child ; Young Adult ; Adult ; Child, Preschool ; *Cytarabine/therapeutic use ; *Antimetabolites, Antineoplastic/therapeutic use ; Infant ; *Pharmacogenetics ; Treatment Outcome ; Cohort Studies ; Infant, Newborn ; }, abstract = {IMPORTANCE: Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior survival outcomes compared with their White counterparts.<br><br>OBJECTIVE: To validate the association of the previously reported 10 single nucleotide variant (SNV)-based ara-C pharmacogenomics score (ACS10) with survival outcomes in a large cohort of pediatric AML patients; to evaluate whether ACS10 remains relevant in an adolescent and young adult (AYA) population of patients with AML treated with similar intensive induction chemotherapy protocols; and to assess the association of ACS10 with race and treatment outcomes in both cohorts.<br><br>This cohort study included patients from the Children's Oncology Group's AAML1031 trial, a multicenter, open-label randomized clinical trial that enrolled pediatric patients with newly diagnosed, treatment-naive primary AML from June 2011 to July 2017 (aged 0 to 29.5 years) and from the Alliance for Clinical Trials in Oncology frontline protocols, which included AYA patients from 9 different trials that enrolled patients with newly diagnosed AML from 1992 to 2010. Data were analyzed from September 2022 to March 2025.<br><br>EXPOSURES: Patients in the AAML1031 trial were randomized to 2 arms, standard chemotherapy alone or standard chemotherapy with the addition of bortezomib. Patients in the Alliance for Clinical Trials in Oncology cohorts were treated with similar intensive induction chemotherapy protocols.<br><br>MAIN OUTCOMES AND MEASURES: ACS10 scores were evaluated for association with outcomes according to race, treatment arm, and hematopoietic stem cell transplant (HSCT) status.<br><br>RESULTS: The study included 1086 patients with AML. There were 717 patients from the pediatric AML cohort (median [range] age, 9.6 [0.04-29.2 years]; 379 [53%] male; 33 [5%] Asian, 84 [12%] Black, and 522 [73%] White) and 369 AYA patients with AML from the Alliance for Clinical Trials in Oncology group (median [range] age, 30 [17-39] years; 196 [53%] male; 7 [2%] Asian, 32 [9%] Black, and 288 [78%] White). Within the standard treatment arm of AAML1031, patients in the low ACS10 group had significantly worse event-free survival (EFS) compared with those in the high ACS10 group (all patients: hazard ratio [HR], 1.42; 95% CI, 1.05-1.95; P&#x2009;=&#x2009;.02; non-HSCT cohort: HR, 1.48; 95% CI, 1.06-2.07; P&#x2009;=&#x2009;.02). The ACS10 score remained significantly associated with EFS in multivariable analysis after adjusting for age, race, risk group and white blood cell count, within the standard treatment arm (HR, 1.44; 95% CI, 1.03-2.02; P&#x2009;=&#x2009;.03). In the Alliance for Clinical Trials in Oncology AYA non-HSCT cohort, the low ACS10 score group had significantly inferior overall survival (OS) and a higher point estimate for EFS compared with patients with a high ACS10 score (OS: HR, 1.50; 95% CI, 1.05-2.14; P&#x2009;=&#x2009;.03; EFS: HR, 1.32; 95% CI, 0.95-1.83; P&#x2009;=&#x2009;.10). A higher number of early deaths was observed in the low ACS10 group compared with the high ACS10 group, but the difference was not statistically significant (death within 30 days of treatment initiation: 6 of 112 [5%] vs 2 of 257 [1%]; P&#x2009;=&#x2009;.07). Across both cohorts, a low ACS10 score was significantly more abundant in Black patients compared with White patients (eg, in Alliance for Clinical Trials in Oncology cohort, 27 of 32 Black patients [84%] had low ACS10 scores compared with 64 of 288 White patients [22%]; P&#x2009;<&#x2009;.001) and inferior survival was observed in Black patients (eg, OS of Black compared with White patients in AAML1031 cohort: HR, 1.47; 95% CI, 1.02-2.13; P&#x2009;=&#x2009;.04). In the AAML1031 cohort, there were no significant differences in EFS or OS between Black and White patients receiving augmented treatment, suggesting that the addition of bortezomib was associated with benefit for Black patients.<br><br>CONCLUSIONS AND RELEVANCE: In this study of 717 pediatric and 369 AYA patients with AML, the ACS10 score was associated with EFS in pediatric and AYA patients when treated with a standard induction regimen. There was a higher abundance of low ACS10 scores in Black patients, and Black patients treated with augmented therapy (ie, the addition of bortezomib) seemed to have improved outcomes. Integrating the ACS10 score into a prospective clinical trial to personalize induction therapy based on an individual's genetic profile has the potential to improve treatment outcomes.}, }
@article {pmid40549982, year = {2025}, author = {El-Jawahri, A and LeBlanc, TW and Kavanaugh, A and Webb, J and Fausto, J and Traeger, L and Greer, JA and Jackson, V and Horick, N and Rabideau, DJ and Fenech, A and Newcomb, R and Ufere, NN and Caruso, E and Pepper, J and DeFilipp, Z and Chen, YB and Lee, SJ and Temel, JS}, title = {Multisite Randomized Trial of Inpatient Palliative Care Intervention for Patients Undergoing Hematopoietic Stem Cell Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {24}, pages = {2700-2711}, pmid = {40549982}, issn = {1527-7755}, support = {R01 CA222014/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/psychology/adverse effects/methods ; Male ; Female ; *Palliative Care/methods ; Middle Aged ; Quality of Life ; Adult ; Inpatients/psychology ; Stress Disorders, Post-Traumatic/etiology ; Depression/etiology ; Anxiety ; Hospitalization ; Aged ; Patient Reported Outcome Measures ; Caregivers/psychology ; }, abstract = {PURPOSE: Patients undergoing hematopoietic stem cell transplantation (HSCT) and their caregivers endure immense physical and psychological symptoms, which result in quality-of-life (QOL) impairments during HSCT.<br><br>METHODS: We conducted a multisite randomized trial among adults undergoing autologous or allogeneic HSCT at three academic institutions. Patients were randomly assigned to an inpatient palliative care (PC) intervention or usual care. Intervention patients met with PC clinicians twice weekly during the HSCT hospitalization. Patients assigned to usual care could be referred to PC as per standard of care. We assessed QOL (patient: Functional Assessment of Cancer Therapy-Bone Marrow Transplant; caregiver: Caregiver-Oncology-QOL), depression and anxiety symptoms (Hospital-Anxiety-and-Depression-Scale), and patients' post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist) at baseline, week 2, and 3 and 6 months post-HSCT. The primary end point was patients' QOL at week 2 during hospitalization when patients experience their QOL nadir. We used linear regression, adjusting for baseline scores, to evaluate the effect of the intervention on patient-reported outcomes at week 2. We used linear mixed-effect models to assess the effect of the intervention on study outcomes longitudinally.<br><br>RESULTS: We enrolled 68.7% (360/524) of eligible patients between October 2018 and July 2022. Compared with those receiving usual care, patients receiving the intervention reported better QOL (adjusted mean difference [B], 6.3; SE, 0.1; P < .001), lower depression (B, -1; SE, 0.4; P = .026), and fewer PTSD symptoms (B, -1.9; SE, 0.9; P = .046) at week 2. Patient-reported anxiety did not differ significantly between groups at week 2. In longitudinal analyses, patients receiving the intervention reported a steeper decline in PTSD symptoms over 6 months post-HSCT (slope difference, -0.9; SE, 0.7; P = .012). All other patient-reported outcomes did not differ longitudinally between the groups.<br><br>CONCLUSION: PC led to substantial improvements in patients' QOL, depression, and PTSD symptoms with sustained effects on PTSD symptoms up to 6 months post-HSCT.}, }
@article {pmid40550509, year = {2025}, author = {Munoz, FM and Parameswaran, L and Gundacker, H and Posavad, CM and Badell, ML and Bunge, K and Mulligan, MJ and Olson-Chen, C and Novak, RM and Brady, RC and DeFranco, E and Gerber, JS and Pasetti, M and Shriver, MC and Coler, RN and Larsen, SE and Suthar, MS and Moreno, A and Miedema, J and Sui, Y and Richardson, BA and Piper, J and Beigi, R and Neuzil, KM and Brown, ER and Cardemil, CV and , }, title = {Infant Antibodies After Maternal COVID-19 Vaccination During Pregnancy or Postpartum.}, journal = {Pediatrics}, volume = {156}, number = {1}, pages = {}, doi = {10.1542/peds.2024-070175}, pmid = {40550509}, issn = {1098-4275}, mesh = {Humans ; Female ; Pregnancy ; Prospective Studies ; *Antibodies, Viral/blood ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; *COVID-19/prevention &amp; control/immunology ; Infant ; *Postpartum Period/immunology ; Infant, Newborn ; *Immunity, Maternally-Acquired ; *Antibodies, Neutralizing/blood ; Adult ; SARS-CoV-2/immunology ; Male ; Vaccination ; }, abstract = {BACKGROUND AND OBJECTIVE: We describe the kinetics of maternally derived antibodies in infants in the first 6 months of life following 2- or 3-dose maternal vaccination during pregnancy or postpartum.<br><br>METHODS: This prospective, multicenter cohort study enrolled infants born to mothers vaccinated with 2- (n&#x2009;=&#x2009;280) or 3-dose (boosted) monovalent messenger RNA vaccines in pregnancy (n&#x2009;=&#x2009;202) or to mothers vaccinated postpartum (n&#x2009;=&#x2009;36) from July 2021 to January 2022. Binding (immunoglobulin G to S and receptor-binding domain), pseudovirus, and live neutralizing antibody (nAb) geometric mean titers (GMTs) to vaccine and Omicron BA.1/BA.5 strains were measured at birth and 2 and 6&#xa0;months of age. Antibody half-life and the effect of maternal or infant COVID-19 infection were assessed.<br><br>RESULTS: Significantly higher GMTs of binding antibody and nAb to all antigens were present at birth and 2&#xa0;months in infants of boosted mothers (P&#x2009;<&#x2009;.01) and higher titers to the vaccine strain, but not Omicron BA.1 and BA.5, persisted up to 6&#xa0;months of age in infants of boosted mothers compared with the other groups (P&#x2009;<&#x2009;.01). Higher infant antibody titers at delivery and 6&#xa0;months of age were associated with a booster dose during pregnancy and maternal prenatal and infant COVID-19 infection. Maternal infection status or vaccine regimen did not influence the half-life of infant antibodies.<br><br>CONCLUSIONS: A maternal COVID-19 booster in pregnancy results in significantly higher functional antibody titers in infants compared with 2 doses in pregnancy or postpartum. High titers at birth and maternal hybrid immunity result in persistently elevated titers in infants for 6&#xa0;months.}, }
@article {pmid40553813, year = {2025}, author = {Barta, JA and Arenberg, D and Backhus, L and Detterbeck, F and Gould, MK and Nair, VS and Pasquinelli, M and Powell, CA and Sandler, K and Silvestri, G and Triplette, M and Vachani, A and Wiener, RS and Mazzone, PJ}, title = {Components Necessary for High-Quality Lung Cancer Screening: A 10-Year Update.}, journal = {Chest}, volume = {168}, number = {5}, pages = {1257-1270}, pmid = {40553813}, issn = {1931-3543}, mesh = {*Lung Neoplasms/diagnosis/prevention &amp; control ; *Mass Screening/organization &amp; administration/standards ; *Early Detection of Cancer/standards ; *Health Policy ; Societies, Medical ; Humans ; United States ; Health Plan Implementation ; Quality of Health Care ; Review Literature as Topic ; Practice Guidelines as Topic ; Tomography, X-Ray Computed/adverse effects/methods/standards ; }, abstract = {Lung cancer screening (LCS) has evolved over the past decade with research advances and clinical experience helping to define target populations for screening, improve lung nodule detection and management, and identify structural components of programs that improve the quality of screening delivery. The 2015 American College of Chest Physicians and American Thoracic Society policy statement "Components Necessary for High-Quality Lung Cancer Screening" identified 9 essential components for high-quality LCS. Ten years later, optimizing the balance between the benefits and harms of LCS and ensuring equitable screening among all population groups remain fundamental objectives. In this 2025 update, we aimed to summarize new knowledge and highlight critical components that are needed for providing high-quality LCS. A multidisciplinary group of LCS experts was assembled to review evidence from the past 10 years. The original components were reviewed and updated to develop 8 refined components that should be considered essential structural elements of screening programs. Each component recommended by the authors is supported by an evidence update. Applying this framework will allow screening programs across the country to ensure implementation of high-quality, net-benefit LCS.}, }
@article {pmid40554417, year = {2025}, author = {Sharifi, H and Moss, CT and Musa, Z and Bell, A and O'Donnell, C and Borges, CH and Matthaiou, EI and Johnston, L and Galban, CJ and Sheshadri, A and Yanik, G and Cheng, GS and Hsu, JL}, title = {Pirfenidone for the treatment of bronchiolitis obliterans syndrome related to chronic graft-versus-host disease.}, journal = {Blood advances}, volume = {9}, number = {19}, pages = {5024-5037}, pmid = {40554417}, issn = {2473-9537}, support = {R21 TR005507/TR/NCATS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01 HL075462/HL/NHLBI NIH HHS/United States ; P01 CA049605/CA/NCI NIH HHS/United States ; R01 HL157414/HL/NHLBI NIH HHS/United States ; R01 HL161037/HL/NHLBI NIH HHS/United States ; K08 HL122528/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Pyridones/therapeutic use/adverse effects/administration &amp; dosage ; *Bronchiolitis Obliterans/drug therapy/etiology/diagnosis ; *Graft vs Host Disease/complications/drug therapy/etiology ; Female ; Male ; Middle Aged ; Adult ; Hematopoietic Stem Cell Transplantation/adverse effects ; Chronic Disease ; Treatment Outcome ; Respiratory Function Tests ; Bronchiolitis Obliterans Syndrome ; }, abstract = {Bronchiolitis obliterans syndrome (BOS) is a severe form of chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic cell transplant (HCT), with a 5-year survival rate of 40%. Currently, there is no curative therapy for BOS. Preclinical data suggest that pirfenidone, an antifibrotic drug, may benefit small airway fibrosis in HCT-associated BOS. A single-arm, open-label, 56-week phase 1 trial with 56-month extension evaluated pirfenidone's tolerability, safety, and efficacy in patients with BOS. Efficacy was measured using pulmonary function tests (PFTs), quantitative computed tomography (qCT) scans, patient-reported outcomes (PROs), cGVHD indices, and laboratory tests. Lung function trajectory was assessed by change in regression slopes before and during treatment. Baseline qCT metrics, including percentage normal lung, air trapping, volume change (Jacobian), and heterogeneity of volume change (Jacobian variance), were analyzed by participant response. Of 30 participants, 25 completed the 56-week trial, and 10 continued into the extension. Overall, 63% tolerated the recommended dose without safety concerns. There was significant improvement in the percent predicted forced expiratory volume in 1 second (P = .00267) when analyzing all participants, and improvement in individual PFT trend for 41.3% of participants. qCT analysis by lobe showed healthier lungs in the upper lobes of responders. Significant improvements were noted in liver function tests, PROs related to physical functioning and shortness of breath, and cGVHD skin indices. These findings indicate that pirfenidone is safe and tolerable in patients with BOS after HCT and may improve lung function and symptoms. Further trials are warranted to evaluate the efficacy of pirfenidone as a treatment for BOS after HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03315741.}, }
@article {pmid40554428, year = {2025}, author = {Bhatt, NS and Borogovac, A and Efebera, YA and DeSalvo, A and Devine, SM and Foley, A and Greco-Stewart, V and Hamilton, BK and Heuer, M and Molfenter, T and Plastaras, JP and Ragon, BK and Wall, SA and Broglie, L and Juckett, MB and Khera, N and Horowitz, MM and DeZern, AE}, title = {Up-front alternative donor HCT in severe aplastic anemia: gaps and opportunities to translate evidence into practice.}, journal = {Blood advances}, volume = {9}, number = {17}, pages = {4448-4457}, pmid = {40554428}, issn = {2473-9537}, support = {UG1 HL069246/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Anemia, Aplastic/therapy/diagnosis ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; Graft vs Host Disease/prevention &amp; control/etiology ; *Tissue Donors ; Transplantation, Homologous ; Transplantation Conditioning/methods ; Unrelated Donors ; Treatment Outcome ; }, abstract = {Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder. Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporine has long been a frontline treatment option in SAA; however, its limited durability and risk of long-term complications such as secondary malignancies remain a drawback in this treatment modality. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative option with significantly improved outcomes over the long term, particularly with HLA-matched related donors. However, the use of alternative donors, such as haploidentical, mismatched, or matched unrelated donors, has previously been limited due to increased transplant-related morbidity, particularly graft-versus-host disease (GVHD). HCTs have therefore been limited to young recipients and those with HLA-matched related donors, creating significant disparity for older adults and those who lack matched donor options. Nevertheless, more recent advances in HCT, such as posttransplant cyclophosphamide for GVHD prophylaxis, have led to improved outcomes of HCT with alternative donors; however, alternative donor HCT remains underused as up-front therapy, in part because of limited multicenter trial data. This review discusses current SAA treatment approaches, including both IST and HCT, and highlights remaining gaps. It also discusses how ongoing clinical trials such as CureAA and TransIT could help address these gaps. Furthermore, we discuss the importance of stakeholder engagement and implementation science in the integration of research-based evidence into clinical practice. Bridging these gaps is necessary for achieving equitable access for patients historically excluded from frontline HCT, including older adults and racially or ethnically diverse populations.}, }
@article {pmid40554677, year = {2025}, author = {Venkataraman, V and Abrams, HR and Shulman, DS and Loggers, ET and Pollack, SM and Paulson, KG and Wagner, MJ}, title = {Effect of HLA restriction on racial and ethnic disparities in access to immune therapies for advanced synovial sarcoma.}, journal = {The oncologist}, volume = {30}, number = {7}, pages = {}, pmid = {40554677}, issn = {1549-490X}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Ethnicity ; *Healthcare Disparities/ethnology ; *Immunotherapy/methods ; *Sarcoma, Synovial/therapy/immunology/pathology/epidemiology ; United States/epidemiology ; Racial Groups ; }, abstract = {PURPOSE: Synovial sarcoma (SS) is aggressive with poor outcomes. Cellular therapies are now FDA-approved for advanced disease, but are restricted to certain HLA-A*02 alleles. We estimate eligibility for cellular therapies by race and ethnicity.<br><br>MATERIALS AND METHODS: Demographic and clinical features of SS cases from 2001 to 2020 were obtained from the United States Cancer Statistics (USCS; NPCR-SEER). Survival analyses were performed overall and by race/ethnicity. The proportion eligible for cellular therapy was estimated by race/ethnicity using previously published data on HLA-A*02 status and MAGE-A4 positivity.<br><br>RESULTS: From 2001 to 2020, 10&#xa0;605 patients (48% female, 64% Non-Hispanic White, 17% Hispanic) with SS were identified. The incidence rate was 1.5-1.8/million/person-years and was stable over time, corresponding to an average of 530 new cases annually. The most common primary site was the extremity (n&#x2005;=&#x2005;5877; 58%), and most patients presented with localized disease (n&#x2005;=&#x2005;5753; 54%). The 5-year cause-specific survival was 60% across all races/ethnicities and 79% for localized, 57% for regional, and 12% for distant disease. Differences by race and ethnicity were found in the proportions of patients expected to be eligible for HLA-restricted cellular therapies targeting MAGE-A4. People of European/European descent had the highest estimated proportion (25%-39%), and people of Asian/Pacific Islander descent had the lowest (11%-17%).<br><br>CONCLUSION: Engineered T-cells targeting MAGE-A4 have shown encouraging safety and efficacy in advanced SS; however, eligibility restrictions will lead to racial and ethnic disparities. HLA-independent solutions must be developed to counter disparities and ensure all patients have access.}, }
@article {pmid40555394, year = {2025}, author = {Iqbal, M and Kumar, A and Dreger, P and Chavez, J and Sauter, CS and Sureda, AM and Bachanova, V and Maziarz, RT and Dreyling, M and Smith, SM and Jacobson, C and Glass, B and Casulo, C and Oluwole, OO and Montoto, S and Advani, R and Cohen, J and Salles, G and Hamad, N and Kuruvilla, J and Kahl, BS and Shadman, M and Kanate, AS and Budde, LE and Kamdar, M and Flowers, C and Hamadani, M and Kharfan-Dabaja, MA}, title = {Corrigendum to 'Clinical Practice Recommendations for Hematopoietic Cell Transplantation.' Transplant Cell Ther. 2024 Sep;30(9):832-843.}, journal = {Transplantation and cellular therapy}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.jtct.2025.05.022}, pmid = {40555394}, issn = {2666-6367}, }
@article {pmid40556953, year = {2025}, author = {Mda, P and Mngadi, K and Zhang, B and Burnham, R and Juraska, M and Hyrien, O and Garrett, N and Dubula, T and Toni, S and Joseph, S and Kotze, P and Buchbinder, S and Takalani, A and Tomaka, F and Luedtke, A and Willems, W and Swann, E and Hutter, J and Gelderblom, H and McElrath, MJ and Lavreys, L and Stranix-Chibanda, L and Roxby, AC and Bekker, LG and Gray, GE}, title = {Pregnancy and contraceptive use among participants of childbearing potential in the HVTN 705 HIV vaccine trial in Southern Africa.}, journal = {Frontiers in reproductive health}, volume = {7}, number = {}, pages = {1565933}, pmid = {40556953}, issn = {2673-3153}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI154463/AI/NIAID NIH HHS/United States ; UM1 AI069496/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI069436/AI/NIAID NIH HHS/United States ; }, abstract = {BACKGROUND: HIV vaccine trial participants include sexually active cisgender females who agree to avoid pregnancy during the active vaccination period. Nevertheless, some pregnancies occur in almost all studies. We examined contraceptive use, pregnancy incidence, and the relationship between pregnancy and HIV seroconversion in one HIV vaccine trial.<br><br>METHODS: We performed an exploratory analysis of data collected for HVTN 705/HPX2008, a phase IIb HIV vaccine trial enrolling cisgender women across 23 sites in five southern African countries. Baseline characteristics and contraceptive use were assessed among participants who became pregnant and those who did not during the active vaccination phase (months 0-15). Pregnancy incidence rates were calculated for this phase and the duration of follow up (36 months). Cox regression analysis was used to assess factors associated with incident pregnancy.<br><br>RESULTS: There were 2,636 participants who received at least one vaccine or placebo dose (mean age: 23 years, standard deviation: 3 years). At enrolment, when contraception was required, 62.9% reported using injectable contraceptives. Overall pregnancy rate was 2.95 per 100 person-years (95% CI: 2.40, 3.58), with 101 pregnancies reported by month 15. Cumulative incidence of pregnancy at month 15 was similar between trial arms (log-rank p&#x2009;=&#x2009;0.688). Each additional year of age was associated with an 8% decrease in pregnancy incidence (p&#x2009;=&#x2009;0.014). Women aged 31-35 years had the lowest pregnancy incidence [1.75 (0.48, 4.48) per 100 person-years]. In a Cox regression analysis covering months 0-15, all contraceptive methods significantly reduced the incidence of pregnancy compared to no contraceptive use. Oral contraception was associated with the least reduction in pregnancy risk; implants were associated with the most reduction in pregnancy risk (p&#x2009;<&#x2009;0.001).<br><br>CONCLUSIONS: In HVTN 705/HPX2008, higher incidence of pregnancy was associated with younger age and oral contraception (compared to other methods). These data may inform future designs of HIV prevention or vaccine trials.}, }
@article {pmid40558267, year = {2025}, author = {Terashima, M and Nakayama, K and Ugai, S and Lee, HY and Tsukumo, Y and Suzuki, E and Mizuno, H and Song, M and Sasamoto, N and Kawachi, I and Ugai, T}, title = {Global Incidence Trend of Early-Onset Obesity-Related and Non-Obesity-Related Cancers.}, journal = {Current oncology (Toronto, Ont.)}, volume = {32}, number = {6}, pages = {}, pmid = {40558267}, issn = {1718-7729}, support = {R50 CA274122/CA/NCI NIH HHS/United States ; R50 CA274122/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/epidemiology/etiology ; *Obesity/complications/epidemiology ; Incidence ; Female ; Male ; Adult ; Age of Onset ; Middle Aged ; Global Health ; Young Adult ; }, abstract = {The global rise in obesity prevalence and the incidence of early-onset cancer (diagnosed between 20 and 49 years of age) is a serious public health concern. We, therefore, evaluated the recent global trends in the incidence of early-onset obesity-related cancers and compared them to those of non-obesity-related cancers. We obtained age-standardized incidence rates of early-onset cancers diagnosed between 2000 and 2012 in 44 countries from the Cancer Incidence in Five Continents database. Using joinpoint regression models, we calculated the average annual percentage changes (AAPCs) and their corresponding 95% confidence intervals (95% CIs) for combined and individual categories of obesity-related cancers (11 and 9 cancer types in females and males, respectively) and non-obesity-related cancers (12 cancer types in both females and males). Differences in the AAPC were assessed by comparing 95% CIs, where nonoverlapping 95% CIs were considered statistically significantly different. We observed statistically significant positive AAPCs for early-onset obesity-related cancers in all available countries combined among females (global AAPC, 4.3%; 95% CI, 4.1-4.6%) and males (global AAPC, 1.4%; 95% CI, 1.2-1.7%). When analyzed by countries, we observed statistically significant positive AAPCs in 26 countries among females and 11 countries among males. AAPCs for early-onset obesity-related cancers were statistically significantly higher than those of non-obesity-related cancers in several regions, especially North America and Oceania. In conclusion, this study indicates that the incidence of early-onset obesity-related cancers exhibited a more pronounced increasing trend than non-obesity-related cancers among both sexes in many countries and regions.}, }
@article {pmid40561372, year = {2025}, author = {Calverley, DC and Leader, A and Cheong, MA and Sanfilippo, KM and Mason, G and Lyman, GH and Kuderer, NM}, title = {Inconsistent and Inaccurate Cancer Clinical Trial Reporting of Venous and Arterial Thrombotic Events: An Urgent Call to Action.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {26}, pages = {2851-2855}, pmid = {40561372}, issn = {1527-7755}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, }
@article {pmid40561376, year = {2025}, author = {Bardia, A and Rugo, HS and Sedrak, MS and Loibl, S and Tolaney, SM and Punie, K and Hurvitz, SA and Kalinsky, KM and Cortés, J and O'Shaughnessy, JA and Dieras, V and Piccart-Gebhart, MJ and Dasgupta, A and Kaushik, A and Lai, C and Shi, L and Brufsky, A}, title = {Q-TWiST Analysis to Assess Benefit-Risk of Sacituzumab Govitecan in Previously Treated Patients With Metastatic Triple-Negative Breast Cancer.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2400806}, doi = {10.1200/OP-24-00806}, pmid = {40561376}, issn = {2688-1535}, abstract = {PURPOSE: In ASCENT, sacituzumab govitecan (SG) showed significantly longer overall survival and progression-free survival than chemotherapy of physician's choice with similar rates of treatment-emergent adverse events (TEAEs) in previously treated patients with metastatic triple-negative breast cancer (mTNBC). We assessed the benefit-risk of SG versus chemotherapy by integrating patient preferences (health utilities) with clinical benefits in this analysis.<br><br>METHODS: Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) methodology was used to compare treatments where survival was partitioned into three health states using the intention-to-treat ASCENT population: (1) toxicity (grade &#x2265;3 TEAE after random assignment and before disease progression), (2) TWiST (progression-free period without grade &#x2265;3 TEAE), and (3) relapse (disease progression until death or end of follow-up, whichever came first). Health state utilities were derived from published literature. Q-TWiST was calculated as utility-weighted sum of mean health state durations. The established threshold for relative Q-TWiST improvement considered clinically important is 10% and clearly clinically important is 15%.<br><br>RESULTS: SG had significantly longer Q-TWiST (8.3 months; 95% CI, 7.6 to 9.1 months) than chemotherapy (4.8 months; 95% CI, 4.3 to 5.4 months) in patients with mTNBC, a difference of 3.5 months (95% CI, 2.6 to 4.4 months; P < .0001). Relative Q-TWiST improvement with SG was 39.5%, exceeding the clearly clinically important threshold. Q-TWiST benefits of SG over chemotherapy increased over the available 31-month follow-up. Restricted mean time with toxicity was numerically higher with SG versus chemotherapy; this difference stabilized with longer follow-up.<br><br>CONCLUSION: The Q-TWiST analysis supports a positive benefit-risk ratio for SG versus chemotherapy in patients with previously treated mTNBC. Net benefits of SG continued to accrue over time.}, }
@article {pmid40561385, year = {2025}, author = {Zeiser, R and Russo, D and Ram, R and Hashmi, SK and Chakraverty, R and Middeke, JM and Musso, M and Giebel, S and Uzay, A and Langmuir, P and Hamad, N and Burock, K and Gowda, M and Stefanelli, T and Lee, SJ and Teshima, T and Locatelli, F}, title = {Ruxolitinib in Patients With Corticosteroid-Refractory or Corticosteroid-Dependent Chronic Graft-Versus-Host Disease: 3-Year Final Analysis of the Phase III REACH3 Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {23}, pages = {2566-2571}, pmid = {40561385}, issn = {1527-7755}, mesh = {Humans ; Nitriles ; *Graft vs Host Disease/drug therapy/mortality ; Pyrimidines ; *Pyrazoles/therapeutic use/adverse effects ; Female ; Male ; Middle Aged ; Adult ; Chronic Disease ; *Adrenal Cortex Hormones/therapeutic use ; Aged ; Young Adult ; Cross-Over Studies ; }, abstract = {In REACH3 (ClinicalTrials.gov identifier: NCT03112603), ruxolitinib was investigated versus best available therapy (BAT) for 3 years in patients with steroid-refractory/dependent chronic graft-versus-host-disease (SR/D-cGVHD). Patients received ruxolitinib (10 mg twice daily) or BAT for 24 weeks; thereafter (weeks 24-156), patients continued randomized treatment, entered long-term survival follow-up, or crossed over from BAT to ruxolitinib. In 329 randomly assigned patients (ruxolitinib: 165; BAT: 164), the median failure-free survival (FFS) was 38.4 months for ruxolitinib versus 5.7 months for BAT (hazard ratio, 0.36 [95% CI, 0.27 to 0.49]). Median duration of response (DOR) was not reached for ruxolitinib versus 6.4 months for BAT. Ruxolitinib-treated patients had a higher probability of FFS (ruxolitinib: 56.5%; BAT: 18.2%) and maintaining a response (ruxolitinib: 59.6%; BAT: 26.7%) at 36 months. Median overall survival was not reached. Nonrelapse mortality and malignancy relapse/recurrence events were low. In 70 patients who crossed over to ruxolitinib, the overall response rate (50.0%) at week 24 and best overall response (81.4%) during the crossover period were consistent with the primary analysis of randomly assigned patients. No new safety signals were observed. Ruxolitinib provided longer FFS and DOR than BAT, demonstrating sustained efficacy and manageable safety over 3 years of follow-up in patients with SR/D-cGVHD.}, }
@article {pmid40561681, year = {2025}, author = {Coleman, RL and Fleming, GF and Brady, MF and Swisher, EM and Steffensen, KD and Friedlander, M and Okamoto, A and Moore, KN and Leath, CA and Cella, D and Sun, Z and Patel, S and Tang, Z and Ratajczak, CK and Aghajanian, C and Bookman, MA}, title = {Veliparib concomitant with first-line chemotherapy and as maintenance therapy in ovarian cancer: Final overall survival and disease-related symptoms results.}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {225}, number = {}, pages = {115587}, doi = {10.1016/j.ejca.2025.115587}, pmid = {40561681}, issn = {1879-0852}, mesh = {Humans ; Female ; *Benzimidazoles/administration &amp; dosage/adverse effects/therapeutic use ; *Ovarian Neoplasms/drug therapy/mortality/pathology ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Double-Blind Method ; Aged ; Adult ; Maintenance Chemotherapy ; Carboplatin/administration &amp; dosage ; Paclitaxel/administration &amp; dosage ; Progression-Free Survival ; }, abstract = {INTRODUCTION: In the VELIA trial, the addition of veliparib to standard first-line platinum-based chemotherapy and continued as maintenance resulted in significantly longer median progression-free survival (PFS) compared with carboplatin plus paclitaxel induction therapy alone (23.5 vs 17.3 months; p < 0.001) in patients with ovarian cancer. We now report final overall survival (OS) and updated safety and disease-related symptoms (DRS) from patient-reported outcomes of the trial.<br><br>METHODS: This randomized, placebo-controlled, double-blind, multicenter, phase 3 study enrolled adult women with an initial diagnosis of stage III/IV high-grade serous ovarian cancer undergoing primary or interval cytoreductive surgery. Patients were randomized 1:1:1 to chemotherapy plus veliparib followed by veliparib maintenance (veliparib-throughout), chemotherapy plus veliparib followed by placebo maintenance (veliparib-combination-only), or chemotherapy plus placebo followed by placebo maintenance (placebo-throughout). PFS was the primary endpoint; OS and DRS were secondary endpoints.<br><br>RESULTS: In the intention-to-treat population (N&#x202f;=&#x202f;1140), median OS was 59.2 months (95&#x202f;% confidence interval: 52.1, 68.2) for the veliparib-throughout group, 58.0 (50.6, 64.1) months for veliparib-combination-only, and 57.8 (52.3, 63.8) months for placebo-throughout. OS outcomes were not significantly different between arms overall or in the BRCA-deficient and homologous recombination-deficient cohorts. No new safety signals were identified during the longer follow-up period and DRS analyses indicated there was no significant additional symptom-related burden overall when veliparib was added to chemotherapy or used for maintenance.<br><br>CONCLUSION: No OS or DRS benefit of addition of veliparib to platinum-based chemotherapy and continued as maintenance therapy was detected in this study, despite an observed benefit over chemotherapy alone in PFS.}, }
@article {pmid40562030, year = {2025}, author = {Banerjee, R and Yamshon, S}, title = {Double trouble: Non-relapse mortality with bispecific antibodies in lymphoma and myeloma.}, journal = {Molecular therapy : the journal of the American Society of Gene Therapy}, volume = {33}, number = {7}, pages = {2966-2967}, pmid = {40562030}, issn = {1525-0024}, }
@article {pmid40562770, year = {2025}, author = {Dima, D and Vazquez-Martinez, MA and Davis, JA and Goel, U and Afrough, A and Sannareddy, A and Pasvolsky, O and Razzo, B and Banerjee, R and Khouri, J and Grajales-Cruz, A and Lieberman-Cribbin, A and Rana, MS and Julian, K and DeJarnette, S and Portuguese, AJ and Gaballa, MR and De Avila, G and Susaniba Adaniya, S and Raza, S and Herr, MM and Ouchveridze, E and Richards, T and Hosoya, H and Mikkilineni, L and Kaur, G and Castaneda Puglianini, O and Rossi, A and Lin, Y and Atrash, S and Sborov, D and Shain, KH and Voorhees, PM and Richard, S and Garfall, AL and Hansen, DK and Sidana, S and Patel, KK and Cowan, AJ and Anderson, LD and Lee, HC and Anwer, F and Ferreri, CJ and Shune, L}, title = {Outcomes of teclistamab in patients with relapsed/refractory multiple myeloma with prior exposure to BCMA-directed therapy: a multicenter study from the U.S. Multiple Myeloma Immunotherapy Consortium.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {111}, pmid = {40562770}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality/pathology ; Male ; Female ; Middle Aged ; Aged ; *B-Cell Maturation Antigen/antagonists &amp; inhibitors ; Retrospective Studies ; Adult ; Aged, 80 and over ; Treatment Outcome ; United States ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; }, abstract = {Data describing outcomes of teclistamab in multiple myeloma patients with prior exposure to BCMA-directed therapy (BCMA-DT) are limited. The goal of this multicenter retrospective analysis was to report the efficacy and safety of standard-of-care teclistamab in patients with prior BCMA-DT. A total of 385 patients were included, of whom 193 (50%) had received prior BCMA-DT, including 47 (24%) patients with prior antibody-drug conjugate (ADC)-only, 99 (51%) with chimeric antigen receptor T-cell therapy (CAR T)-only, 36 (19%) with both ADC and CAR T, 6 (3%) with bispecific antibody-only, and 5 (3%) with other combinations. Most safety parameters between cohorts were comparable. The prior BCMA-DT cohort had a lower overall response rate (ORR: 48.7% versus 61.5%; p = 0.012), and median progression-free survival (PFS: 4.6 versus 8.2 months; p = 0.017) compared to the cohort without prior BCMA-DT. However, in multivariable analysis, despite a clear trend, ultimately receipt of a prior BCMA-DT was not independently associated with ORR or PFS (p = 0.057 and p = 0.1, respectively). No significant differences in PFS were noted when stratifying patients by number of prior BCMA-DTs, types of all prior BCMA-DTs received, type of most recent prior BCMA-DT, or depth of response to most recent BCMA-DT. Using the maximally selected rank statistics method, the optimal cut-off for time from the last BCMA-DT exposure to teclistamab initiation was identified as 8.7 months. Patients with >8.7 months between their last exposure to prior BCMA-DT and teclistamab initiation had a significantly improved median PFS with teclistamab (8.1 months, 95% CI: 4.6-11.7) compared to patients with <8.7 months (2.5 months, 95% CI: 1.1-5.7), p = 0.001. Altogether, our findings support the use of teclistamab as a viable treatment option in patients previously exposed to BCMA-DT.}, }
@article {pmid40564099, year = {2025}, author = {Wang, H and Wang, C and Qin, R and He, J and Zhang, X and Ma, C and Li, S and Fan, L and Wang, L and Cao, L}, title = {Integrative Analysis of Plasma Proteomics and Transcriptomics Reveals Potential Therapeutic Targets for Psoriasis.}, journal = {Biomedicines}, volume = {13}, number = {6}, pages = {}, pmid = {40564099}, issn = {2227-9059}, support = {82304250//National Natural Science Foundation of China/ ; 82273734//National Natural Science Foundation of China/ ; YQ2022H005//Heilongjiang Province Natural Science Foundation/ ; }, abstract = {Background Psoriasis (PsO): is an immune-mediated inflammatory disease that imposes a significant burden on patients. Many patients experience relapse or inadequate responses, and PsO subtypes also lack effective therapies, highlighting the need for new therapeutic targets. Methods: We performed a proteome-wide Mendelian randomization (MR) to explore potential therapeutic targets for PsO. Protein quantitative trait loci (pQTLs) data were obtained from the Pharma Proteomics Project (54,219 UK Biobank participants, 2923 proteins), and PsO phenotype and subtype data were sourced from FinnGen (10,312 cases; 397,564 controls) for discovery. Replication MR utilized integrated protein data (Iceland and Norfolk) and phenotype data from multiple databases (UK Biobank and GWAS Catalog). Reverse MR and colocalization were used to support causal relationships. Single-cell RNA-seq analysis revealed distinct expression patterns of protein-coding genes across different cell types in PsO biopsy samples and normal skin tissues. Protein-protein interactions (PPI) and molecular docking were used to evaluate druggability. Results: MR analysis identified 13 proteins significantly associated with PsO risk (p < 2.56×10-5), including 10 proteins associated with PsO subtypes. Decreased levels of eight proteins (IFNLR1, APOF, TDRKH, DDR1, HLA-E, LTA, MOG, and ICAM3) and increased levels of five proteins (IFNGR2, HCG22, IL12B, BTN3A2, and TRIM40) showed protective effects against PsO progression. Robust colocalization (PPH4 > 0.9) identified IFNLR1, IFNGR2, APOF, and TDRKH as top candidates. Single-cell RNA sequencing analysis revealed that IFNLR1, IFNGR2, LTA, TDRKH, and DDR1 were specifically expressed in T cells of psoriatic biopsy specimens compared to healthy controls. Molecular docking indicated the druggability of IFNLR1 and IFNGR2. Conclusions: We identified several potential therapeutic targets for PsO, with IFNLR1, IFNGR2, APOF, and TDRKH emerging as promising candidates, particularly IFNLR1 and IFNGR2, which are associated with the IFN family. These findings may provide new perspectives on PsO therapy and pathogenesis.}, }
@article {pmid40568668, year = {2025}, author = {Mendez, JS and Queme, B and Fu, Y and Morrison, J and Lewinger, JP and Kawaguchi, E and Mi, H and Obón-Santacana, M and Moratalla-Navarro, F and Martín, V and Moreno, V and Lin, Y and Bien, SA and Qu, C and Su, YR and White, E and Harrison, TA and Huyghe, JR and Tangen, CM and Newcomb, PA and Phipps, AI and Thomas, CE and Conti, DV and Wang, J and Platz, EA and Keku, TO and Newton, CC and Um, CY and Kundaje, A and Shcherbina, A and Murphy, N and Gunter, MJ and Dimou, N and Papadimitriou, N and Bézieau, S and van Duijnhoven, FJ and Männistö, S and Rennert, G and Wolk, A and Hoffmeister, M and Brenner, H and Chang-Claude, J and Tian, Y and Le Marchand, L and Cotterchio, M and Tsilidis, KK and Bishop, DT and Melaku, YA and Lynch, BM and Buchanan, DD and Ulrich, CM and Ose, J and Peoples, AR and Pellatt, AJ and Li, L and Devall, MA and Campbell, PT and Albanes, D and Weinstein, SJ and Berndt, SI and Gruber, SB and Ruiz-Narvaez, E and Song, M and Joshi, AD and Drew, DA and Petrick, JL and Chan, AT and Giannakis, M and Hsu, L and Peters, U and Gauderman, WJ and Stern, MC}, title = {Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40568668}, support = {U01 HG004438/HG/NHGRI NIH HHS/United States ; U01 HG004446/HG/NHGRI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U01 CA261961/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; U2C CA252971/CA/NCI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; U54 CA233465/CA/NCI NIH HHS/United States ; R01 CA285851/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, abstract = {BACKGROUND: High intake of red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported 204 variants (G) associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways and constructed pathway-based Polygenic Risk Scores (pPRS) to model pPRS x environment (E) interactions.<br><br>METHODS: A pooled sample of 30,812 cases and 40,504 CRC controls of European ancestry from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. The 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red or processed meat intake in relation to CRC risk.<br><br>RESULTS: A total of 30 variants were overrepresented in four pathways: Alzheimer disease-presenilin, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-&#x3b2; signaling. We found a significant interaction between TGF-&#x3b2;-pPRS and red meat intake (p = 0.003). When variants in the TGF-&#x3b2; pathway were assessed, significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.013 &amp; 0.011, respectively) were observed. We did not find evidence of pPRS x red meat interactions for other pathways or with processed meat.<br><br>CONCLUSIONS: This pathway-based interaction analysis revealed a significant interaction between variants in the TGF-&#x3b2; pathway and red meat consumption that impacts CRC risk.<br><br>IMPACT: These findings shed light into the possible mechanistic link between CRC risk and red meat consumption.}, }
@article {pmid40568722, year = {2025}, author = {Hogan, LE and Bhatla, T and Xu, X and Gore, L and Raetz, EA and Bhojwani, D and Teachey, DT and Hunger, SP and Loh, ML and Brown, PA and Ji, L}, title = {Severe toxicity and poor efficacy of reinduction chemotherapy are associated with overall poor outcomes in relapsed B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group AALL1331 trial.}, journal = {Haematologica}, volume = {110}, number = {12}, pages = {2930-2941}, pmid = {40568722}, issn = {1592-8721}, support = {P30 CA046934/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; Child ; Female ; Male ; Child, Preschool ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality/therapy/drug therapy/pathology ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; Young Adult ; Treatment Outcome ; Adult ; Recurrence ; Antibodies, Bispecific/administration &amp; dosage/adverse effects/therapeutic use ; Induction Chemotherapy/adverse effects ; Hematopoietic Stem Cell Transplantation ; Infant ; }, abstract = {Children's Oncology Group AALL1331 utilized an intensive chemotherapy induction (Block 1) based on UK ALLR3 induction for children, adolescents, and young adults with acute lymphoblastic leukemia in first relapse, followed by risk-stratified therapy. High/intermediate-risk patients were subsequently randomized to receive two blocks of chemotherapy or two blocks of blinatumomab followed by a hematopoietic stem cell transplant. Low-risk patients were randomized to chemotherapy or chemotherapy cycles intercalated with three blinatumomab blocks. Patients who had early treatment failure were eligible to receive blinatumomab for up to two salvage cycles. We reviewed Block 1 responses, risk stratification, randomization rates, adverse events, event-free survival and overall survival for all enrolled patients. AALL1331 enrolled 661 patients: 24 died during Block 1 and 42 experienced early treatment failure. Overall, 531/661 (80.3%) attained complete remission with 586 risk-assigned and only 471 were randomized. Of 532 patients with bone marrow involvement, 290 (54.5%) were positive for minimal residual disease (≥0.01%) after Block 1. Grade 3, 4 or 5 adverse events occurred in Block 1 in 44.9%, 24.1%, and 3.6% of patients, respectively, with febrile neutropenia, infections, and sepsis being most frequent. Notably, 190 enrolled patients (28.7%) did not proceed with post-induction therapy, including 115 (17.4%) risk-stratified but not randomized. These patients had dismal survival. More effective and less toxic reinduction strategies are needed for B-cell acute lymphoblastic leukemia in first relapse. Trial registration number: NCT02101853.}, }
@article {pmid40569290, year = {2025}, author = {Biernacki, MA and Lok, J and Foster, KA and Cummings, C and Busch, S and Black, RG and Ray, S and Baquero Galvis, L and Monahan, T and Oh, ST and Oehler, VG and Stirewalt, DL and Wu, D and Deeg, HJ and Doulatov, S and Bleakley, M}, title = {SF3B1K700E Neoantigen Is a CD8+ T-cell Target Shared across Human Myeloid Neoplasms.}, journal = {Cancer immunology research}, volume = {13}, number = {9}, pages = {1391-1404}, pmid = {40569290}, issn = {2326-6074}, support = {RC2 DK127989/DK/NIDDK NIH HHS/United States ; R01 HL169156/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; Challenge Grant//MPN Research Foundation (MPNRF)/ ; 5 RC2 DK127989//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; Amy Strelzer Manasevit Research Program//National Marrow Donor Program (NMDP)/ ; R01 HL151651/HL/NHLBI NIH HHS/United States ; P30 CA015704-46//Center for Cancer Research (CCR)/ ; }, mesh = {Humans ; *RNA Splicing Factors/genetics/immunology ; *CD8-Positive T-Lymphocytes/immunology/metabolism ; *Antigens, Neoplasm/immunology/genetics ; Animals ; *Myelodysplastic Syndromes/immunology/genetics ; *Phosphoproteins/genetics/immunology ; Mice ; Cell Line, Tumor ; Mutation ; }, abstract = {Acquired mutations in spliceosome genes in early hematopoietic stem/progenitor cells are common events in myelodysplastic neoplasms (MDS) and related myeloid malignancies. Mutations in the spliceosome factor subunit B1 (SF3B1) gene occur in ≥20% of MDS cases at conserved hotspots and in early neoplastic clones as driver events. Neoantigens from aberrant SF3B1 proteins could serve as shared T-cell therapy targets for SF3B1-mutated myeloid neoplasms. We identified a candidate neoantigen from the prevalent SF3B1K700E variant using in silico predictions of epitope processing and presentation and then validated presentation and immunogenicity in vitro. CD8+ T cells recognizing SF3B1K700E demonstrated high functional avidity and killed neoplastic myeloid cell lines and primary cells in an antigen-specific manner. We then sequenced, cloned, and transduced an SF3B1K700E-specific T-cell receptor into third-party T cells and confirmed that T-cell receptor transfer conferred antigen specificity and killing of neoplastic myeloid cells in vitro and in vivo. The data indicate that the SF3B1K700E neoantigen represents a promising T-cell target for patients with SF3B1-mutated MDS and acute myeloid leukemia.}, }
@article {pmid40569643, year = {2025}, author = {Rashidi, A}, title = {Microbiota and chronic GVHD: a plasmablast link.}, journal = {Blood}, volume = {145}, number = {26}, pages = {3073-3075}, doi = {10.1182/blood.2025029521}, pmid = {40569643}, issn = {1528-0020}, }
@article {pmid40569864, year = {2025}, author = {Kiptinness, C and Naik, P and Kareithi, T and Thuo, N and Okello, P and Culquichicon, C and Rafferty, M and Abdulrashid, S and Jomo, E and Nyamasyo, N and Wood, T and Mendonca, R and Malen, RC and Dettinger, JC and Pintye, J and Mwangi, J and Stergachis, A and Onentia, J and Curran, K and Mugambi, ML and Were, D and Ngure, K and Sharma, M and Ortblad, KF and , }, title = {Online delivery of oral HIV pre- and post-exposure prophylaxis: findings from the ePrEP Kenya pilot.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 1}, number = {Suppl 1}, pages = {e26468}, pmid = {40569864}, issn = {1758-2652}, support = {K01 MH115789/MH/NIMH NIH HHS/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; INV-037646/GATES/Gates Foundation/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Administration, Oral ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; *HIV Infections/prevention &amp; control ; Kenya ; Pilot Projects ; *Post-Exposure Prophylaxis/methods ; *Pre-Exposure Prophylaxis/methods ; *Telemedicine ; }, abstract = {INTRODUCTION: The expansion of telecommunication networks and smartphones in many African countries could be leveraged to deliver HIV prevention products directly to consumers. In collaboration with a private e-commerce platform and online pharmacy in Kenya, MYDAWA, we piloted a new model of HIV pre- and post-exposure prophylaxis (PrEP/PEP) delivery.<br><br>METHODS: In the ePrEP Kenya pilot (NCT05377138), individuals living in Nairobi and Mombasa Counties could complete a free telehealth visit with a remote clinician to assess eligibility for online PrEP/PEP (i.e. &#x2265;18 years; no medical contraindications). Eligible individuals could order HIV testing services-courier delivered to clients' choice location-for a fee of 250 KES (&#x223c;$2 USD) for self-testing or 150 KES (&#x223c;$1 USD) for provider-administered rapid diagnostic testing. Following confirmation of clients' HIV-negative status (via an uploaded test result image), free PrEP/PEP drugs from government supply were courier delivered with or separately from HIV testing services. Clients paid a delivery fee &#x2264;149 KES (&#x223c;$1 USD) per courier visit.<br><br>RESULTS: From October 2022 to December 2023, we screened 2257 individuals and enrolled 1915. Most PrEP/PEP clients were men (63%, 1428/1915), &#x2265;25 years (72%, 1631/1915) and never married (80%, 1796/1915); few had ever used PrEP (3%, 48/1915) or PEP (14%, 263/1915). At enrolment, 227 (12%) were preliminarily eligible for PrEP and 1688 (88%) for PEP. Among PrEP-eligible clients, 89% (203/227) completed HIV testing and 92% (208/227) received PrEP; among PEP-eligible clients, 92% (1551/1688) completed HIV testing and 92% (1549/1688) received PEP. Most PrEP/PEP clients completed HIV testing within 6 hours of their telehealth visit (53%, 927/1757) and had drugs delivered with testing services (88%, 1546/1757). Among PrEP clients eligible for follow-up, 47% (120/256) continued PrEP and 4% (10/256) initiated PEP following PrEP discontinuation. Among PEP clients eligible for follow-up, 7% (99/1428) repeated PEP use and 6% (83/1428) transitioned from PEP to PrEP.).<br><br>CONCLUSIONS: Online PrEP/PEP delivery could expand access to prevention services by reaching individuals not engaged in existing delivery platforms. The uptake of online PEP was five times greater than PrEP, underscoring an unmet demand for PEP and highlighting the potential for online pharmacies to deliver time-sensitive PEP services.}, }
@article {pmid40569884, year = {2025}, author = {Roche, SD and Omollo, V and Mogere, P and Asewe, M and Gakuo, S and Banerjee, P and Harkey, K and Sharma, M and Pintye, J and Mugambi, ML and Shah, P and Odoyo, J and Ong'wen, P and Were, D and Bukusi, EA and Ngure, K and Ortblad, KF}, title = {A modified pharmacy provider-led delivery model of oral HIV pre- and post-exposure prophylaxis in Kenya: a pilot study extension.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 1}, number = {Suppl 1}, pages = {e26467}, pmid = {40569884}, issn = {1758-2652}, support = {INV-033052/GATES/Gates Foundation/United States ; R01HD108041//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R34 MH120106/MH/NIMH NIH HHS/United States ; R00MH121166/MH/NIMH NIH HHS/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; R01 HD108041/HD/NICHD NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; *HIV Infections/prevention &amp; control ; Kenya/epidemiology ; Pharmacies ; Pilot Projects ; *Post-Exposure Prophylaxis/methods ; *Pre-Exposure Prophylaxis/methods ; }, abstract = {INTRODUCTION: Private pharmacies in Africa reach individuals with ongoing and periodic HIV risk, yet few countries currently leverage pharmacies as an HIV service delivery platform. We conducted a 6-month pilot to evaluate a model for pharmacy provider-led delivery of HIV pre- and post-exposure prophylaxis (PrEP and PEP) in Kenya.<br><br>METHODS: At 12 private pharmacies in Kisumu and Kiambu Counties, licensed pharmacy providers initiated and managed eligible clients &#x2265;18 years on PrEP and PEP under remote clinician supervision (NCT04558554); four of these pharmacies additionally offered sextually transmitted infection (STI) testing. PrEP/PEP clients were scheduled for follow-up 1 month later and then quarterly (PrEP clients only). Primary outcomes included PrEP and PEP initiation and continuation during the pilot period. Client and providers rated the model across multiple constructs of acceptability and feasibility from established frameworks.<br><br>RESULTS: From January to July 2022, 1028 clients interested in PrEP, PEP and/or STI testing were screened and 829 initiated one or more service: 661 PrEP, 162 PEP and 52 STI testing. About half of clients (48%, 398/829) were male, most were unmarried (78%, 644/829) and PrEP-na&#xef;ve (89%, 737/829), and the median age was 25 years (IQR 22-31). Most PrEP clients reported inconsistent condom use (88%, 581/661) or sex with partners of unknown HIV status (70%, 460/661) in the past 6 months. Most PEP clients reported condomless sex (48%, 78/162) or a condom break (46%, 75/162) in the past 72 hours; 4% (6/162) reported sexual assault. Among PrEP clients eligible for a refill, 73% (479/658) refilled at least once and 60% (197/328) twice. Among PEP clients eligible for follow-up, 44% (65/148) completed follow-up HIV testing and 20% (30/148) transitioned to PrEP. Among STI clients, 19% (10/52) tested positive for gonorrhoea (n = 7) and/or chlamydia (n = 5). Most clients and providers (&#x2265;92%) found the delivery model and its implementation strategies acceptable. All providers (n = 12) thought it was possible to deliver PrEP and PEP at pharmacies in Kenya.<br><br>CONCLUSIONS: Pharmacy PrEP/PEP delivery achieved high uptake, continuation and acceptability among eligible clients that could benefit, highlighting the potential of pharmacies to expand HIV prevention service coverage in Kenya, particularly to individuals not accessing these services at clinics.}, }
@article {pmid40569916, year = {2025}, author = {Ortblad, KF and Brown, ER and Heffron, R and Ngure, K and Mujugira, A and Donnell, D}, title = {Research designs to generate evidence of HIV post-exposure prophylaxis effectiveness for new long-acting agents.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 1}, number = {Suppl 1}, pages = {e26475}, pmid = {40569916}, issn = {1758-2652}, support = {K24 MH123371/MH/NIMH NIH HHS/United States ; R00 MH121166/NH/NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; K24 MH123371/NH/NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/drug therapy ; *Post-Exposure Prophylaxis/methods ; *Research Design ; *Anti-HIV Agents/administration &amp; dosage/therapeutic use ; Treatment Outcome ; Pre-Exposure Prophylaxis ; }, abstract = {INTRODUCTION: New longer-acting antiretroviral (ARV) drugs-that is single doses with antiviral activity for at least a month-are being utilized for HIV treatment and pre-exposure prophylaxis (PrEP) but have not been explored for post-exposure prophylaxis (PEP). A "one-and-done" simplification of PEP has the potential to serve the HIV prevention needs of individuals not being met with traditional services and expand overall biomedical HIV prevention coverage. We discuss challenges with the assessment of PEP effectiveness in human trials and potential study designs that could generate evidence needed to inform the use of new, single-administered, long-acting ARVs for PEP.<br><br>DISCUSSION: Challenges with determining the effectiveness of new long-acting PEP agents in human trials include the low likelihood of observing an HIV acquisition and the short period for outcome assessment (likely 1 month) following PEP administration. Additional challenges include recruiting individuals in the brief window in which they could benefit (<72 hours of a potential HIV exposure) and ethics of conducting informed consent during a period of high stress/vulnerability. Consequently, design approaches where the efficacy goal is to establish that the HIV incidence rate following PEP administration (of the standard or a novel agent) approaches zero should be considered. HIV RNA testing conducted within 5 days of a potential exposure could define prevention per exposure. Novel recruitment venues-such as community-based retail or online pharmacies-could be used to reach individuals after a potential exposure. Potential study designs include one- or two-arm individual-level product assignment aimed at demonstration of short-course efficacy or longer-term effectiveness compared to a background rate; cluster-randomized controlled trials of recruitment venues; and novel individual-level approaches that either do not or do utilize randomization in combination with choice, enabling assessment of preferences and effectiveness.<br><br>CONCLUSIONS: Over the past decade, multiple new HIV PrEP products-but no new PEP products-have been developed to meet the diverse needs of individuals seeking HIV prevention services. Challenges exist with generating PEP effectiveness evidence, but they are not insurmountable. Effectiveness research on new PEP products could advance the number of HIV prevention options available.}, }
@article {pmid40570746, year = {2025}, author = {Giacani, L and Romeis, E and Haynes, A and Molini, BJ and Tantalo, LC and Xu, LH and Trejos, AT and Keane, J and Mohamed, Z and Armstrong, TD and Wieland, BA and Phung, Q and Vyshenska, D and Campbell, VL and Godornes, C and Koelle, DM and Reid, TB and Wang, Y and Vorobieva, AA and Wald, A and Lieberman, NAP and Greninger, AL}, title = {Immunization with full-length TprC variants induces a broad response to surface-exposed epitopes of the Treponema pallidum repeat protein family and is partially protective in the rabbit model of syphilis.}, journal = {Vaccine}, volume = {61}, number = {}, pages = {127406}, pmid = {40570746}, issn = {1873-2518}, support = {T32 AI007140/AI/NIAID NIH HHS/United States ; T32 AI007509/AI/NIAID NIH HHS/United States ; U19 AI144133/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Rabbits ; *Syphilis/prevention &amp; control/immunology ; *Treponema pallidum/immunology ; Antibodies, Bacterial/blood/immunology ; *Bacterial Vaccines/immunology/administration &amp; dosage ; Disease Models, Animal ; *Epitopes/immunology ; *Porins/immunology ; *Antigens, Bacterial/immunology ; Immunization ; *Bacterial Proteins/immunology ; Female ; }, abstract = {An effective vaccine against syphilis could aid current control measures to reduce the incidence of infection. Protective immunity from the syphilis agent, Treponema pallidum subsp. pallidum (T. pallidum), is associated with pathogen clearance by phagocytosis, supporting that immunization with an effective vaccine candidate should elicit opsonic antibodies to key epitopes at the host-pathogen interface. The T. pallidumrepeat (Tpr) proteins are putative β-barrel outer membrane porins with ten predicted extracellular loops. Here, we immunized three groups of eight rabbits with either a combination of three recombinant variants of the full-length TprC antigen, the TprD2 protein, or the conserved NH2-terminal region of TprK, with the latter antigen already known to induce incomplete protection in immunized rabbits. Compared to unimmunized controls, rabbits immunized with the three TprC variants or the TprK fragment exhibited attenuated primary chancres, reduced treponemal burden at the challenge sites, and limited pathogen dissemination to lymph nodes. Immunization with TprD2, alone did not produce comparable results. Strong humoral and cellular responses against TprC and TprK were elicited by immunization, and functional analyses supported the induction of opsonizing antibodies. Epitope mapping performed using TprC- and TprK-specific synthetic peptides and phage immunoprecipitation-sequencing identified a subset of highly reactive sequences and demonstrated immunity to predicted surface-exposed epitopes across multiple Tpr paralogs, which explained the significant, albeit incomplete protection measured post-challenge. These data advance TprC and TprK as syphilis vaccine candidates and highlight several correlates of their protection that deserve further examination.}, }
@article {pmid40571676, year = {2025}, author = {Muskara, A and Parthasarathy, PB and Oyarbide, U and Ma, Y and Ganguly, S and Imamura, J and Liao, R and Rubin, BP and Macaskill, A and Murphy, ES and Anderson, PM and Gryder, BE and Scott, JG and Zahler, SG and Mian, OY}, title = {Transcriptomic Profiling of Relapsed Rhabdomyosarcoma: Pre- and Post-Treatment Tissue Analysis Reveals Molecular Characteristics of Treatment Failure.}, journal = {Pediatric blood &amp; cancer}, volume = {72}, number = {9}, pages = {e31864}, pmid = {40571676}, issn = {1545-5017}, support = {L30CA220908//NIH/NCI/ ; P30CA043703//Case Comprehensive Cancer Center NIH/ ; //VeloSano Foundation Research/ ; L30 CA220908/CA/NCI NIH HHS/United States ; P30 CA043703/CA/NCI NIH HHS/United States ; //Case Comprehensive Cancer Center, Case Western Reserve University/ ; }, mesh = {Humans ; *Rhabdomyosarcoma/genetics/pathology/therapy ; Male ; Child ; Female ; *Gene Expression Profiling ; *Neoplasm Recurrence, Local/genetics/pathology/therapy ; Child, Preschool ; Treatment Failure ; *Oncogene Proteins, Fusion/genetics ; Infant ; *Transcriptome ; Adolescent ; *Biomarkers, Tumor/genetics ; PAX3 Transcription Factor/genetics ; Prognosis ; Forkhead Box Protein O1/genetics ; Follow-Up Studies ; }, abstract = {BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. Historically classified based on histology, advances in molecular profiling have allowed further sub-classification, which has improved risk stratification. Although molecular profiling has improved our understanding of disease progression and risk, the molecular evolution of therapy resistance in RMS remains poorly characterized. Transcriptomic profiling of patients with high-risk, relapsed RMS was undertaken with the goal of uncovering insights into the biology of RMS treatment failure.<br><br>PROCEDURE: Formalin-fixed, paraffin-embedded (FFPE) tissue samples from patients with relapsed RMS who had samples archived at diagnosis and relapse were obtained. Histologic subtype and PAX3/7::FOXO1 fusion status were confirmed. Transcriptomic profiling of the FFPE tissue samples was performed using the high-throughput genomics (HTG) whole transcriptome panel.<br><br>RESULTS: We identified 11 patients with relapsed RMS who had FFPE tissue samples archived at diagnosis and relapse following multimodality therapy. All patients were stratified as high risk, including five with PAX3/7::FOXO1 fusion-positive RMS (FP-RMS) and six with PAX3/7::FOXO1 fusion-negative RMS (FN-RMS). The transcriptomic analysis revealed that the myogenesis pathway and markers associated with myogenic differentiation were enriched pre-treatment in patients with FP-RMS and enriched post-treatment in patients with FN-RMS. Post-treatment enrichment of the inflammatory response pathway was observed in both FP-RMS and FN-RMS samples.<br><br>CONCLUSIONS: Using a probe-based transcriptome panel to characterize matched pre- and post-treatment tissue samples from patients with RMS, we report that relapsed RMS follows a fusion status-dependent evolutionary trajectory, marked by differential expression of myogenesis-associated genes, myogenic differentiation markers, and inflammatory response pathways.}, }
@article {pmid40575114, year = {2023}, author = {Vannier, D and Torok-Storb, B and Stromholt, S and Chowning, JT}, title = {The Pathways Undergraduate Researchers Program: Fostering Career Interests, Sense of Belonging, and Student Confidence in Pursuing Science.}, journal = {Journal of STEM outreach}, volume = {6}, number = {2}, pages = {}, pmid = {40575114}, issn = {2576-6767}, support = {R25 CA221770/CA/NCI NIH HHS/United States ; }, abstract = {The Pathways Undergraduate Researchers Program is a paid, nine-week summer internship at the Fred Hutchinson Cancer Center. It targets rising first-, second-, and third-year college students from backgrounds underrepresented in biomedical research. This paper describes how the internship impacted students' awareness of biomedical careers, scientific identification, and sense of belonging in research. Interns reported an increased awareness of biomedical careers and how to attain them. The experience also challenged interns' career ideas. Interns described a mix of feelings on sense of belonging. All felt welcomed and confident in their abilities. Nonetheless, some noted they were different from the other researchers. A number were motivated by being in the minority and ready to become leaders in diversifying the workforce. Data gathered during the COVID-19 pandemic shed a different light on the internship's impact. The interns reported becoming 'credible resources' on public health issues for their families and communities. The program supported this by building their confidence to understand and communicate science. This undergraduate program developed out of a longer running high school internship effort and many of the strategies described herein are used in both. These findings have implications for programs for underrepresented students at the high school and college level.}, }
@article {pmid40576334, year = {2025}, author = {Lee, EM and Srinivasan, S and Purvine, SO and Fiedler, TL and Leiser, OP and Proll, SC and Minot, SS and Djukovic, D and Raftery, D and Johnston, C and Fredricks, DN and Deatherage Kaiser, BL}, title = {Syntrophic bacterial and host-microbe interactions in bacterial vaginosis.}, journal = {The ISME journal}, volume = {19}, number = {1}, pages = {}, pmid = {40576334}, issn = {1751-7370}, support = {P41 GM103493/GM/NIGMS NIH HHS/United States ; S10 OD021562/OD/NIH HHS/United States ; R01 AI061628/AI/NIAID NIH HHS/United States ; U19 AI113173/AI/NIAID NIH HHS/United States ; S10OD021562/RI/ORIP NIH HHS/United States ; R01AI061628/NH/NIH HHS/United States ; GM103493/GM/NIGMS NIH HHS/United States ; U19 AI113173/NH/NIH HHS/United States ; }, mesh = {Female ; *Vaginosis, Bacterial/microbiology ; Humans ; Vagina/microbiology ; *Host Microbial Interactions ; *Bacteria/metabolism/classification/genetics/isolation &amp; purification ; Formates/metabolism ; Adult ; Putrescine/metabolism ; Proteomics ; Microbiota ; Bacterial Proteins/metabolism ; }, abstract = {Bacterial vaginosis (BV) is a common, polymicrobial condition of the vaginal microbiota that is associated with symptoms such as malodor and excessive discharge, along with increased risk of various adverse sequelae. Host-bacteria and bacteria-bacteria interactions are thought to contribute to the condition, but many of these functions have yet to be elucidated. Using untargeted metaproteomics, we identified 1068 host and 1418 bacterial proteins in a set of cervicovaginal lavage samples collected from 20 participants with BV and 9 who were negative for the condition. We identified Dialister micraerophilus as a major producer of malodorous polyamines and identified a syntrophic interaction between this organism and Fannyhessea vaginae that leads to increased production of putrescine, a metabolite characteristic of BV. Although formate synthesis has not previously been noted in BV, we discovered diverse bacteria associated with the condition express pyruvate formate-lyase enzymes in vivo and confirm these organisms secrete formic acid in vitro. Sodium hypophosphite efficiently inhibited this function in multiple taxa. We also found that the fastidious organism Coriobacteriales bacterium DNF00809 can metabolize formic acid secreted by Gardnerella vaginalis, representing another syntrophic interaction. We noted an increased abundance of the host epithelial repair protein transglutaminase 3 in the metaproteomic data, which we confirmed by enzyme-linked immunosorbent assay. Other proteins identified in our samples implicate Finegoldia magna and Parvimonas micra in the production of malodorous trimethylamine. Some bacterial proteins identified represent novel targets for future therapeutics to disrupt BV communities and promote vaginal colonization by commensal lactobacilli.}, }
@article {pmid40576634, year = {2025}, author = {Figueiredo, JC and Redwood, D and Li, L and Donato, E and Fort, D and Fox, EE and Grady, WM and Green, H and Harrison, TA and Haupt, C and Hsu, L and Hullar, MAJ and Huyghe, JR and Johnson, W and Koehne, AL and LaBrie, SD and Lakey, MA and Lin, M and Loroña, NC and Maresh, GA and Matrana, M and Mizrahi, JD and Nash, SH and Nguyen, NT and Paruch, JL and Phipps, AI and Qu, C and Randolph, TW and Romo, S and Thomas, CE and Thomas, S and Tiesinga, J and Whitlow, C and Yeung, CCS and Yin, H and Zibilich, CM and Li, CI and Thomas, TK and Peters, U}, title = {The Translational Research Program in Cancer Differences across Populations.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {9}, pages = {1472-1482}, pmid = {40576634}, issn = {1538-7755}, support = {R01CA155101//National Cancer Institute (NCI)/ ; P20CA252733//National Cancer Institute (NCI)/ ; U01 CA290673/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA238087/CA/NCI NIH HHS/United States ; P50 CA285275/CA/NCI NIH HHS/United States ; R01 CA155101/CA/NCI NIH HHS/United States ; R01CA238087//National Cancer Institute (NCI)/ ; R01 CA248931/CA/NCI NIH HHS/United States ; P30CA015704//Fred Hutchinson Cancer Center (FHCRC)/ ; R01CA284732//National Cancer Institute (NCI)/ ; //Goldman Sachs Foundation/ ; //V Foundation/ ; P20 CA252733/CA/NCI NIH HHS/United States ; R01 CA217970/CA/NCI NIH HHS/United States ; R01 CA280639/CA/NCI NIH HHS/United States ; R01 CA284732/CA/NCI NIH HHS/United States ; R01CA280639//National Cancer Institute (NCI)/ ; U01CA290673//National Cancer Institute (NCI)/ ; P50CA285275//National Cancer Institute (NCI)/ ; R01CA248931//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Translational Research, Biomedical ; Female ; Male ; Case-Control Studies ; *Colorectal Neoplasms/epidemiology ; United States/epidemiology ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: Cancer incidence and mortality vary substantially across populations. The Translational Research Program in Cancer Differences across Populations (TRPCDP) was established in 2020 to address differences in cancer incidence and mortality rates within the United States, with a particular focus on colorectal cancer.<br><br>METHODS: The TRPCDP centralized data acquisition and harmonization across three sites in the United States to create a well-annotated resource of colorectal cancer tumors across four populations: African American/Black, Alaska Native, Hispanic/Latino/Latina, and non-Hispanic White. Using a case-control framework, patients with lethal colorectal cancer were matched to two controls with nonlethal colorectal cancer. Formalin-fixed, paraffin-embedded tumor and normal tissue were retrieved and sent for centralized pathology review, followed by DNA and RNA extraction and tissue microarray development. Multiomics and spatial profiling are underway to evaluate the transcriptome, proteome, and microbiome. Patient demographic and clinical data were obtained by medical record review, patient self-report, or linkage to cancer registries. Additional health-related factors were assessed using geospatial linkage.<br><br>RESULTS: The virtual biorepository includes 7,181 patients [African American (n = 1,345), Alaska Native (n = 1,640), Hispanic (n = 1,659), and non-Hispanic White (n = 2,537)]. Tissue blocks (1,594 tumor and 728 normal colon samples) were selected for 938 patients. To date, DNA and RNA have been extracted (n = 831), and tissue microarrays have been constructed (n = 414). Transcriptomic analysis, spatial tumor profiling (multiplex immunofluorescence, PhenoCycler, and GeoMx), and microbiome data (16S rRNA sequencing and digital droplet PCR) are available.<br><br>CONCLUSIONS: The TRPCDP has developed a clinically annotated biorepository for future molecular epidemiology studies.<br><br>IMPACT: The TRPCDP is a unique program that supports collaborative research, community engagement, and pipeline development for the next generation of scientists.}, }
@article {pmid40576840, year = {2025}, author = {Mayer, J and Blanco-Melo, D and Coffin, JM and Gifford, RJ and Johnson, WE and Lindemann, D and Peeters, M and Sato, K and Stoye, J and Tachedjian, G and Hatziioannou, T}, title = {2024 taxonomy update for the family Retroviridae.}, journal = {Archives of virology}, volume = {170}, number = {8}, pages = {164}, pmid = {40576840}, issn = {1432-8798}, support = {R01 AI184043/AI/NIAID NIH HHS/United States ; }, mesh = {*Retroviridae/classification/genetics ; Genome, Viral ; Phylogeny ; Terminology as Topic ; Humans ; }, abstract = {The Retroviridae are a family of viruses that reverse transcribe their RNA genome and integrate the resulting double-stranded DNA copy into the genome of the host cell. Retroviruses are well-documented pathogens that have been associated with a variety of diseases. The International Committee on Taxonomy of Viruses (ICTV) currently lists 65 species of retroviruses. As required by the ICTV, we have converted the species nomenclature to a binomial format comprised of the genus and a freeform epithet. Assigning binomial species names to classify new retroviruses will be facilitated when following the epithet rules described herein.}, }
@article {pmid40576898, year = {2025}, author = {Goodsell, KE and Chauhan, SSB and Pillarisetty, VG and Sham, JG}, title = {Somatostatin Analogs for Preventing Postoperative Pancreatic Fistula: Past Evidence Reveals New Opportunities.}, journal = {Annals of surgical oncology}, volume = {32}, number = {10}, pages = {7382-7392}, pmid = {40576898}, issn = {1534-4681}, support = {R38 AI181011/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Fistula/prevention &amp; control/etiology ; *Somatostatin/analogs &amp; derivatives/therapeutic use ; *Pancreatectomy/adverse effects ; *Postoperative Complications/prevention &amp; control ; *Pancreatic Neoplasms/surgery ; Octreotide/therapeutic use ; Peptides, Cyclic ; }, abstract = {Postoperative pancreatic fistula (POPF) is the defining complication following pancreatectomy. The incidence of POPF after pancreatic resection remains high even at experienced centers, with associated patient morbidity, increased healthcare costs, and poorer oncologic outcomes. There is evidence that POPF is more frequent after distal pancreatectomy. On the basis of the premise that reduction in pancreatic exocrine secretion reduces the risk of fistula formation, somatostatin analogs (SSA) to prevent POPF and its sequelae have been studied for more than 30 years. However, evidence regarding their efficacy remains mixed. Early multicenter randomized control trials demonstrated a benefit of octreotide in reducing POPF, although subsequent single-center studies failed to confirm these results. Despite additional studies demonstrating a significant reduction in POPF with the use of newer SSAs including pasireotide and lanreotide, surgical practices in the use of somatostatin analogs in preventing POPF are highly variable. Herein, we review three decades of available data on SSA for POPF prophylaxis and highlight the need for pragmatic, focused, and data-driven design for future trials with modern agents.}, }
@article {pmid40577227, year = {2025}, author = {Perazzolo, S and Flexner, CW and Stephen, ZR and Acosta, EP and Bender Ignacio, RA and Ho, RJY}, title = {Long-acting Injectable Containing Lopinavir Eliminates Reliance on Ritonavir Pharmacokinetic Enhancement.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {3}, pages = {607-611}, pmid = {40577227}, issn = {1537-6613}, support = {UM1 AI120176/NH/NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; R01 AI052663/AI/NIAID NIH HHS/United States ; U01 AI148055/AI/NIAID NIH HHS/United States ; U01 AI148055/NH/NIH HHS/United States ; AI149665/NH/NIH HHS/United States ; R24 AI118397)/NH/NIH HHS/United States ; 2020-39-GLAD)//World Health Organization// ; }, mesh = {*Ritonavir/pharmacokinetics/administration &amp; dosage/blood ; *Lopinavir/pharmacokinetics/administration &amp; dosage/blood ; Humans ; COVID-19 Drug Treatment ; Drug Interactions ; *HIV Protease Inhibitors/pharmacokinetics/administration &amp; dosage ; SARS-CoV-2 ; Delayed-Action Preparations/pharmacokinetics/administration &amp; dosage ; HIV Infections/drug therapy ; Male ; Injections, Subcutaneous ; Female ; }, abstract = {High-extraction protease inhibitors (eg, for human immunodeficiency virus and severe acute respiratory syndrome coronavirus 2) typically require ritonavir to enhance bioavailability by overcoming first-pass metabolism. However, in the long-acting subcutaneous injectable dosage form TLC-ART 101, lopinavir persisted in plasma for 57 days, while ritonavir was detectable for only 3-7 days. The remarkable duration of lopinavir suggests that ritonavir may be unnecessary in long-acting injectable products, potentially reducing side effects and drug-drug interactions.}, }
@article {pmid40578047, year = {2025}, author = {Ssenyonga, N and Stiller, CA and Marcos-Gragera, R and Kuehni, CE and Saint-Jacques, N and Bulliard, JL and Redaniel, MT and Nakata, K and Schwartz, S and De, P and Ragusa, R and Troussard, X and Curado, MP and Girardi, F and Maynadié, M and Valkov, M and Guilloteau, A and Lima, C and Coleman, MP and Allemani, C and , }, title = {Conditional survival of children, adolescents and young adults (0-24 years) diagnosed with leukaemia during 2000-2014 world-wide: (CONCORD-3).}, journal = {European journal of cancer (Oxford, England : 1990)}, volume = {225}, number = {}, pages = {115445}, doi = {10.1016/j.ejca.2025.115445}, pmid = {40578047}, issn = {1879-0852}, mesh = {Humans ; Adolescent ; Child ; Infant ; Child, Preschool ; Young Adult ; Male ; Female ; Infant, Newborn ; *Leukemia/mortality/diagnosis/therapy ; Registries ; Global Health ; Survival Rate ; }, abstract = {BACKGROUND: Population-based survival estimates provide valuable insights into cancer care patterns world-wide. Access to optimal treatment leads to better outcomes, however, treatment pathways vary globally. Conditional survival is the probability that patients who have already survived for a given number of years since diagnosis will live for an additional number of years. It is a useful proxy to assess the success of initial treatment or remission of leukaemia.<br><br>METHODS: We analysed data for 164,563 patients aged 0-24 years diagnosed during 2000-2014, from 258 population-based cancer registries in 61 countries. Using the Pohar-Perme estimator, we estimated net survival at five years, conditional on surviving at least one year, and at 10 years conditional on surviving five years. To control for background mortality, we used life tables of all-cause mortality by single year of age, sex, country and calendar year. All-ages survival estimates were standardised to the marginal age distribution.<br><br>FINDINGS: During 2010-2014, age-standardised five-year conditional net survival ranged from 61.8&#x202f;% in Mexico to 90&#x202f;% or more in 20 countries. By 2010-2014, five-year conditional survival in most high-income countries exceeded 90&#x202f;% for children, but not for older patients, and for acute myeloid leukaemia it was typically 5-10&#x202f;% lower than for lymphoid leukaemia. Ten-year conditional survival was 90&#x202f;% or higher in most countries, with less variation world-wide.<br><br>INTERPRETATION: World-wide variation in survival was less marked for patients who survived the first year(s) after diagnosis. Notable gains occurred in countries with initially lower five-year survival (e.g., China or Mexico), where legislative changes contributed to improved access to treatment for young patients with cancer. Nonetheless, inequalities persisted between high-income and low- and middle-income countries. Population-based cancer registry data remain essential to monitor further improvements.<br><br>FUNDING: Children with Cancer UK; the Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, US National Cancer Institute and the American Cancer Society.}, }
@article {pmid40578660, year = {2025}, author = {Mitsunami, M and Soria-Contreras, DC and Ortiz-Panozo, E and Harris, HR and Missmer, SA and Chavarro, JE}, title = {Soy consumption and the risk of laparoscopically confirmed endometriosis in a prospective cohort study.}, journal = {Fertility and sterility}, volume = {124}, number = {5 Pt 2}, pages = {1061-1070}, doi = {10.1016/j.fertnstert.2025.06.028}, pmid = {40578660}, issn = {1556-5653}, mesh = {Humans ; Female ; *Endometriosis/epidemiology/diagnosis/prevention &amp; control ; Adult ; Prospective Studies ; *Laparoscopy ; Risk Factors ; *Isoflavones/administration &amp; dosage ; *Soy Foods ; Incidence ; United States/epidemiology ; Risk Assessment ; }, abstract = {OBJECTIVE: To investigate the association of soy and isoflavone intake with the risk of laparoscopically confirmed endometriosis.<br><br>DESIGN: The Nurses' Health Study II, a prospective cohort study from 1991-2021.<br><br>SUBJECTS: A total of 82,084 premenopausal participants aged 27-44 years in 1991.<br><br>EXPOSURE: Soy and isoflavone intake was evaluated from 1991 and every 4 years using a Food Frequency Questionnaire.<br><br>MAIN OUTCOME MEASURES: Self-reported laparoscopically confirmed endometriosis in biennial follow-up questionnaires. Cox proportional hazard models with age in months were used to calculate hazard ratios and 95% confidence intervals for laparoscopically confirmed endometriosis. Restricted cubic splines were used to examine the possibility of nonlinear relations between isoflavone intake and the risk of endometriosis.<br><br>RESULTS: A total of 3,829 incident cases of laparoscopically confirmed endometriosis were reported over 1,038,888 person-years of follow-up (incidence rate = 369 per 100,000 person-years). Increasing soy intake by one serving per week was associated with an 8% lower risk of laparoscopically confirmed endometriosis (Hazard ratio, 0.92, 95% confidence interval, [0.87-0.98]). This association was present among participants without a concurrent report of infertility (hazard ratio, 0.92, 95% confidence interval, 0.86-0.99), although not among participants with a concurrent infertility diagnosis (hazard ratio, 0.97, 95% confidence interval, 0.83-1.13, and test for heterogeneity 1.00). There was evidence of a nonlinear inverse association of isoflavones intake with the risk of laparoscopically confirmed endometriosis, in which the inverse association between isoflavones and endometriosis was approximately linear up until an intake of 4 mg/d (approximately 95th percentile of intake), which plateaued thereafter.<br><br>CONCLUSION: In a population with a modest intake of soy products, consistent with levels seen in other Western populations, soy intake is associated with a lower risk of laparoscopically confirmed endometriosis.}, }
@article {pmid40578716, year = {2025}, author = {Morrell, ED and Cheng, GS}, title = {Lumpers vs. splitters: The search for treatable traits in post-transplant BOS.}, journal = {The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation}, volume = {44}, number = {10}, pages = {1567-1568}, doi = {10.1016/j.healun.2025.06.010}, pmid = {40578716}, issn = {1557-3117}, }
@article {pmid40579877, year = {2025}, author = {Dudakov, JA and van den Brink, MRM}, title = {Burning Down the House: Thymic Repair and Regeneration After Acute Damage.}, journal = {Immunological reviews}, volume = {332}, number = {1}, pages = {e70050}, pmid = {40579877}, issn = {1600-065X}, support = {R01 HL145276/HL/NHLBI NIH HHS/United States ; P01-CA023766/CA/NCI NIH HHS/United States ; R01 CA228308/CA/NCI NIH HHS/United States ; R35 CA284024/CA/NCI NIH HHS/United States ; R01-CA228358/CA/NCI NIH HHS/United States ; R35 HL171556/HL/NHLBI NIH HHS/United States ; R01-HL147584/HL/NHLBI NIH HHS/United States ; R01 CA228358/CA/NCI NIH HHS/United States ; R01 HL123340/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01-CA228308/CA/NCI NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; R01-HL145276/HL/NHLBI NIH HHS/United States ; R01 HL165673/HL/NHLBI NIH HHS/United States ; R01 HL147584/HL/NHLBI NIH HHS/United States ; R01-HL165673/HL/NHLBI NIH HHS/United States ; U01-AI70035//National Institute of Allergy and Infectious Diseases/ ; P30 CA008748/CA/NCI NIH HHS/United States ; R35-HL-171556/HL/NHLBI NIH HHS/United States ; P01 AG052359/AG/NIA NIH HHS/United States ; P30 CA033572/CA/NCI NIH HHS/United States ; P01-AG052359/AG/NIA NIH HHS/United States ; R01-HL123340/HL/NHLBI NIH HHS/United States ; U01 AI170035/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Thymus Gland/physiology/immunology/radiation effects ; *Regeneration ; Animals ; Signal Transduction ; Cytokines/metabolism ; }, abstract = {The thymus is extremely sensitive to insult but also has a remarkable capacity for endogenous repair. However, even though there is continual thymic involution and regeneration in response to everyday insults like stress and infection, profound thymic damage such as ionizing radiation leads to prolonged T cell lymphopenia for which there is currently no therapeutic treatment. We and others have been focusing in recent years on untangling the cellular and molecular mechanisms underlying endogenous thymic regeneration in the hope of being able to exploit them for clinical benefit. To date, multiple molecular mechanisms have been identified that are centered on several distinct cell axes, including interleukin-22 produced by innate lymphoid cells, BMP4 by endothelial cells, and type 2 cytokines from eosinophils, ILCs, and Tregs. Notably, one of the uniting triggers for these pathways of repair centers on the balance of cell death detection. In this review, we will highlight the current state of play with regard to cellular and molecular pathways of regeneration as well as the mechanisms triggering them. We will also highlight recent work that sheds light on the limitations of thymus repair and speculate as to what will be needed for an effective thymus-boosting therapy.}, }
@article {pmid40580948, year = {2025}, author = {Khor, S and Carlson, JJ and Basu, A and Bansal, A and Yu, K and Fedorenko, CR and Ramsey, S and Shankaran, V}, title = {The association between new cancer therapy innovations and financial toxicity.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {10}, pages = {2021-2028}, doi = {10.1093/jnci/djaf152}, pmid = {40580948}, issn = {1460-2105}, support = {//Predoctoral Fellowship in Health Outcomes Research/ ; //PhRMA Foundation/ ; //American Foundation for Pharmaceutical Education/ ; //Predoctoral Fellowship in Health Outcomes Disparities/ ; //Kathryn Butler Memorial Foundation and Texas 4000 for Cancer/ ; }, mesh = {Humans ; Female ; Male ; Aged ; Retrospective Studies ; Middle Aged ; SEER Program ; *Carcinoma, Non-Small-Cell Lung/economics/mortality/therapy ; *Lung Neoplasms/economics/mortality/therapy ; *Neoplasms/economics/therapy/mortality ; Adult ; Aged, 80 and over ; United States/epidemiology ; }, abstract = {BACKGROUND: Recent advancements in cancer treatments have improved survival rates, but rising costs associated with these innovations raise concerns about their financial impact on patients. This study investigates the trade-off between improved survival and the financial toxicity over time in advanced non-small cell lung cancer (NSCLC).<br><br>METHODS: We conducted a retrospective cohort study using linked data from the Western Washington SEER cancer registry and TransUnion credit records, focusing on adults diagnosed with advanced NSCLC, bladder, uterine, head and neck, and liver cancers between 2013 and 2017. Financial toxicity was assessed through major adverse financial events (AFEs), including collections, charge offs, liens, delinquent payments, foreclosures, repossessions, and bankruptcies. Multivariable multinomial logistic regression evaluated trends in a composite outcome of survival and AFEs for NSCLC patients within 2 years post-diagnosis. A falsification test evaluated a negative control group of advanced cancers lacking new therapies.<br><br>RESULTS: Our study included 6548 patients (mean age 69; 42% female; 86% non-Hispanic White). Two-year survival for NSCLC patients increased from 15.2% to 19.2% between 2013 and 2017 (mean change 4.0%pt, 95% CI = 0.7 to 7.3). The proportion of survivors without AFEs increased by 2.2%pt (95% CI = -0.6 to 5.1), while those alive with major AFEs increased by 1.9%pt (95% CI = 0.02 to 3.6). This trend was absent in the negative control group.<br><br>CONCLUSIONS: The trade-off between survival gains and increased economic hardships linked to treatment innovations underscores the need to expand our focus beyond clinical outcomes and implement protective measures that ensure healthcare advancements promote population health without inducing financial distress.}, }
@article {pmid40581305, year = {2025}, author = {Khawaja, F and Zamora, D and Yong, MK and Hakki, M and Goscicki, BK and Danziger-Isakov, L and Lin, A and Carpenter, PA and Boeckh, M and Papanicolaou, GA and Dadwal, SS and Chemaly, RF}, title = {American Society for Transplantation and Cellular Therapy Series #11: Updated Cytomegalovirus Guidelines in Hematopoietic Cell Transplant and Cellular Therapy Recipients.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {10}, pages = {727-741}, doi = {10.1016/j.jtct.2025.06.025}, pmid = {40581305}, issn = {2666-6367}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; *Cytomegalovirus Infections/prevention &amp; control/etiology/drug therapy ; *Cytomegalovirus ; *Cell- and Tissue-Based Therapy/methods ; Antiviral Agents/therapeutic use ; Societies, Medical ; United States ; Transplant Recipients ; }, abstract = {The Practice Guidelines Committee of the American Society of Transplantation and Cellular Therapy partnered with the society's Transplant Infectious Diseases Special Interest Group to update its previous infectious disease guidelines for the prevention and management of cytomegalovirus (CMV) infection and disease following hematopoietic cell transplantation (HCT). The two updates, published in 2021, focused on the prevention and management of CMV infection, respectively, including refractory and resistant CMV infections. To best serve clinical providers, each standalone topic in the infectious diseases series has been published in a concise format of frequently asked questions (FAQs). Adult and pediatric infectious diseases and HCT content experts developed the FAQs and the answers; recommendations were graded according to their strength (A-E) and the level of the supporting evidence (I-III). Several advances in CMV prevention and management since 2021 warranted an update to the original third and fourth topics in the series. This eleventh topic in the series focuses on new antiviral treatments for CMV, expanded indications of existing antiviral therapy for the prevention of CMV, and the treatment of CMV in special populations such as CAR T-cell therapy recipients and pediatric transplant recipients.}, }
@article {pmid40581329, year = {2025}, author = {Kalkeri, R and Zhu, M and Cloney-Clark, S and Parekh, A and Gorinson, D and Cai, Z and Cai, MR and Mahato, S and Chau, G and Babu, TM and Wald, A and Ramanathan, P and Aurelia, LC and Selva, KJ and Marchese, AM and Fries, L and Dunkle, LM and Chung, AW and Plested, JS}, title = {Anti-spike IgG4 and Fc effector responses: The impact of SARS-CoV-2 vaccine platform-specific priming and immune imprinting.}, journal = {The Journal of infection}, volume = {91}, number = {2}, pages = {106543}, doi = {10.1016/j.jinf.2025.106543}, pmid = {40581329}, issn = {1532-2742}, mesh = {*Immunoglobulin G/immunology/blood ; Humans ; *Spike Glycoprotein, Coronavirus/immunology ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; *SARS-CoV-2/immunology ; *Antibodies, Viral/immunology/blood ; Antibodies, Neutralizing/immunology/blood ; *COVID-19/immunology/prevention &amp; control ; *Immunoglobulin Fc Fragments/immunology ; Immunization, Secondary ; Female ; Vaccination ; }, abstract = {Proportional increases in anti-Spike (S) IgG4 associated with decreased Fc effector functions have been reported following repeated mRNA, but not recombinant protein-based (rS) (NVX-CoV2373, Novavax, Inc.), SARS-CoV-2 vaccination. We demonstrate the first evidence of a negative correlation between anti-S IgG4 and neutralizing antibody (nAb), as well as antibody-dependent surrogate Fc effector functions. Priming with two NVX-CoV2373 vaccines followed by a third dose was associated with higher IgG1 and IgG3, lower IgG4, higher nAb titers and surrogate Fc effector functions versus mRNA. Immune imprinting of anti-S IgG4 and nAbs, and Fc effector function imprinting after mRNA priming was observed. This effect was partially overcome by updated XBB.1.5 protein subunit vaccination, but not by ancestral vaccine strains. We establish correlation of anti-S IgG4 responses to reduced nAbs and surrogate Fc effector functions and demonstrate the impact of additional booster vaccination on subsequent immune response and Fc effector functions in the context of ancestral and XBB.1.5 strains.}, }
@article {pmid40581613, year = {2025}, author = {Maurice, NJ and Erickson, JR and DeJong, CS and Mair, F and Taber, AK and Frutoso, M and Islas, LV and Vigil, ALBG and Lawler, RL and McElrath, J and Newell, E and Sullivan, LB and Shree, R and McCartney, SA}, title = {Cytokine and metabolite networks shape T cell residency and functionality at the term human maternal-fetal interface.}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, volume = {214}, number = {9}, pages = {2221-2237}, pmid = {40581613}, issn = {1550-6606}, support = {//Andy Hill Endowment Distinguished Researcher/ ; F31 HD098769/NH/NIH HHS/United States ; //Doris Duke Foundation/ ; R01 CA264646/CA/NCI NIH HHS/United States ; F99 CA245735/CA/NCI NIH HHS/United States ; //Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; //Institute of Translational Health Sciences/ ; TL1 TR002318/TR/NCATS NIH HHS/United States ; //Burroughs Wellcome Fund/ ; R01 AI123323/AI/NIAID NIH HHS/United States ; K12 HD000849/HD/NICHD NIH HHS/United States ; R21 AI144677/AI/NIAID NIH HHS/United States ; //Andy Hill Endowment Distinguished Researcher CARE/ ; //Dr. Nancy Herrigel-Babienko Memorial Scholar/ ; F31 HD098769/HD/NICHD NIH HHS/United States ; R21 AI144677/NH/NIH HHS/United States ; 2023-0231//Doris Duke Clinical Scientist Development/ ; //Leslie and Pete Higgins Achievement Rewards for College Scientists Fellow/ ; }, mesh = {Humans ; Female ; Pregnancy ; *Cytokines/metabolism/immunology ; *T-Lymphocytes/immunology ; *Maternal-Fetal Exchange/immunology ; *Placenta/immunology ; Transforming Growth Factor beta1/immunology/metabolism ; }, abstract = {Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI), which affect T cell programming, but the identities (i.e. memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as proinflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of costimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although proinflammatory molecules elicit T cell effector functions, we show that additional cytokine (transforming growth factor β1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, these data demonstrate that T cells at the MFI are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments in which they are enriched.}, }
@article {pmid40581741, year = {2025}, author = {Harlass, M and Knudsen, AB and Nieboer, D and van Duuren, LA and Kuntz, KM and Rutter, CM and Nascimento de Lima, P and Collier, N and Ozik, J and Hahn, AI and Alarid-Escudero, F and Zauber, AG and Inadomi, JM and Meester, RGS and Lansdorp-Vogelaar, I}, title = {Benefits of colorectal cancer screening using fecal immunochemical testing with varying positivity thresholds by age and sex.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {11}, pages = {2219-2228}, pmid = {40581741}, issn = {1460-2105}, support = {//Laboratory Computing Resource Center at Argonne National Laboratory/ ; //National Energy Research Scientific Computing Center/ ; P30 CA008748/CA/NCI NIH HHS/United States ; ALCC-ERCAP0029912//National Energy Research Scientific Computing Center/ ; //Department of Energy Office of Science User Facility/ ; U01 CA253913/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; U01CA253913//Cancer Intervention and Surveillance Modelling Network/ ; DE-AC02-06CH11357//Department of Energy Office of Science User Facility/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Age Factors ; *Colorectal Neoplasms/diagnosis/economics/prevention &amp; control/epidemiology ; Cost-Benefit Analysis ; *Early Detection of Cancer/methods/economics ; *Feces/chemistry ; *Hemoglobins/analysis ; *Mass Screening/methods/economics ; *Occult Blood ; Quality-Adjusted Life Years ; Sensitivity and Specificity ; Sex Factors ; Cost-Effectiveness Analysis ; }, abstract = {BACKGROUND: Fecal immunochemical test (FIT) performance for colorectal cancer screening varies by age and sex, yet most FIT-based screening programs use uniform positivity thresholds. This study assessed the potential benefits of stratifying FIT thresholds based on age and sex.<br><br>METHODS: We conducted a meta-analysis of FIT sensitivity and specificity at various positivity thresholds by age and sex. We then used these estimates in 2 microsimulation models of colorectal cancer and projected lifetime clinical outcomes, incremental costs, and quality-adjusted life-years (QALYs) gained from age- and sex-stratified FIT strategies. FIT thresholds ranged from 10 to 50&#x2009;&#xb5;g hemoglobin per gram of feces.<br><br>RESULTS: For current uniform FIT screening (20&#x2009;&#xb5;g hemoglobin/gram of feces), models projected 85.67 to 122.15 QALYs gained at incremental costs of &#x2012;$982 to $504 per 1000 individuals compared with no screening. At equivalent costs to current uniform screening, only 1 model found stratified FIT approaches cost-effective, yielding a marginal increase of 1.04 and 1.10 QALYs gained/1000 female and male individuals, respectively. At a willingness-to-pay threshold of $100&#x200a;000/QALYs gained, both models found stratified FIT cutoffs to be the best strategy, with cutoffs being equal to or higher for males and lowest at older ages (70-75 years). Uniform strategies showed comparable effectiveness, falling within 1 quality-adjusted life-day per person of efficient strategies at up to $112 more per person. Results were sensitive to FIT test performance characteristics and 1-time setup costs.<br><br>CONCLUSION: Stratifying FIT thresholds by age and sex may be cost-effective compared to current screening. The gain in expected health benefits with stratified FIT screening, however, is likely small.}, }
@article {pmid40585005, year = {2025}, author = {Brittain, JS and Tsui, J and Inward, R and Gutierrez, B and Mwanyika, G and Tegally, H and Huynh, T and Githinji, G and Tessema, SK and McCrone, JT and Bhatt, S and Dasgupta, A and Ratcliffe, S and Kraemer, MUG}, title = {GRAPEVNE - Graphical Analytical Pipeline Development Environment for Infectious Diseases.}, journal = {Wellcome open research}, volume = {10}, number = {}, pages = {279}, pmid = {40585005}, issn = {2398-502X}, abstract = {The increase in volume and diversity of relevant data on infectious diseases and their drivers provides opportunities to generate new scientific insights that can support 'real-time' decision-making in public health across outbreak contexts and enhance pandemic preparedness. However, utilising the wide array of clinical, genomic, epidemiological, and spatial data collected globally is difficult due to differences in data preprocessing, data science capacity, and access to hardware and cloud resources. To facilitate large-scale and routine analyses of infectious disease data at the local level (i.e. without sharing data across borders), we developed GRAPEVNE (Graphical Analytical Pipeline Development Environment), a platform enabling the construction of modular pipelines designed for complex and repetitive data analysis workflows through an intuitive graphical interface. Built on the Snakemake workflow management system, GRAPEVNE streamlines the creation, execution, and sharing of analytical pipelines. Its modular approach already supports a diverse range of scientific applications, including genomic analysis, epidemiological modeling, and large-scale data processing. Each module in GRAPEVNE is a self-contained Snakemake workflow, complete with configurations, scripts, and metadata, enabling interoperability. The platform's open-source nature ensures ongoing community-driven development and scalability. GRAPEVNE empowers researchers and public health institutions by simplifying complex analytical workflows, fostering data-driven discovery, and enhancing reproducibility in computational research. Its user-driven ecosystem encourages continuous innovation in biomedical and epidemiological research but is applicable beyond that. Key use-cases include automated phylogenetic analysis of viral sequences, real-time outbreak monitoring, forecasting, and epidemiological data processing. For instance, our dengue virus pipeline demonstrates end-to-end automation from sequence retrieval to phylogeographic inference, leveraging established bioinformatics tools which can be deployed to any geographical context. For more details, see documentation at: https://grapevne.readthedocs.io.}, }
@article {pmid40586142, year = {2025}, author = {Glover, R and Yeboah, B and Vassallo, RR and Stolla, M and Panch, SR and Khan, J and Kogler, VJ and Luckey, CJ and Gorham, JD}, title = {It is time to eliminate the one-hour corrected count increment in the diagnostic workup of platelet transfusion refractoriness.}, journal = {Transfusion}, volume = {65}, number = {8}, pages = {1553-1555}, doi = {10.1111/trf.18327}, pmid = {40586142}, issn = {1537-2995}, }
@article {pmid40588371, year = {2025}, author = {Patel, SP and Fisher, J and Chae, YK and Soto, LS and Kasi, A and Konda, B and Walshauser, M and Parra, E and Zhang, J and Duault, C and Gonzalez-Kozlova, E and Manyam, G and Zhang, J and Chen, H and Duose, DY and Laberiano Fernandez, C and Luthra, R and Al-Atrash, G and Kim-Schulze, S and Maecker, HT and Wistuba, II and Gnjatic, S and Lee, JJ and Zhang, J and Magner, CM and Chen, HX and Sharon, E and Othus, M and Ryan, CW and Blanke, C and Haymaker, CL and Kurzrock, R}, title = {Phase II basket trial of Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: pancreatic neuroendocrine neoplasm (PNEN) cohort.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {6}, pages = {}, pmid = {40588371}, issn = {2051-1426}, support = {UG1 CA233331/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; UG1 CA233320/CA/NCI NIH HHS/United States ; U24 CA224319/CA/NCI NIH HHS/United States ; R33 CA263705/CA/NCI NIH HHS/United States ; U01 DK124165/DK/NIDDK NIH HHS/United States ; U10 CA180821/CA/NCI NIH HHS/United States ; U24 CA224316/CA/NCI NIH HHS/United States ; U24 CA224285/CA/NCI NIH HHS/United States ; U10 CA180828/CA/NCI NIH HHS/United States ; UG1 CA233198/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; U24 CA224309/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; P30 CA196521/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Pancreatic Neoplasms/drug therapy/mortality/pathology ; Female ; Middle Aged ; Aged ; Adult ; *CTLA-4 Antigen/antagonists &amp; inhibitors ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Nivolumab/therapeutic use/pharmacology ; *Neuroendocrine Tumors/drug therapy ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Ipilimumab/therapeutic use/pharmacology ; }, abstract = {PURPOSE: SWOG S1609 Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.<br><br>EXPERIMENTAL DESIGN: Treatment consisted of ipilimumab 1&#x2009;mg/kg intravenously every 6 weeks with nivolumab 240&#x2009;mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites.<br><br>RESULTS: 19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6&#x2009;months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). Peripheral effector memory T-cell activation (N=11 patients assessed by cytometry by time-of-flight with 5 having longitudinal analysis) was associated with response, though the number of patients evaluated was limited.<br><br>CONCLUSIONS: Low-dose ipilimumab plus nivolumab demonstrated an 11% ORR and 26% CBR (includes SD>6 months) in patients with refractory PNEN, with durable benefit (>2 years) in 3 (16%) patients.<br><br>TRIAL REGISTRATION NUMBER: NCT02834013.}, }
@article {pmid40588476, year = {2025}, author = {Banerjee, R and Hosoya, H and Mikkilineni, L and Hansen, DK and Wolf, JL and Lin, Y}, title = {Managing IEC-associated enterocolitis following CAR-T therapy in multiple myeloma.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {112}, pmid = {40588476}, issn = {2044-5385}, support = {P50 CA186781/CA/NCI NIH HHS/United States ; }, }
@article {pmid40589281, year = {2025}, author = {Wright, JD and Prest, MT and Ferris, JS and Chen, L and Xu, X and Rouse, KJ and Melamed, A and Hur, C and Heckman-Stoddard, BM and Samimi, G and Bickell, NA and Layne, TM and Myers, ER and Havrilesky, LJ and Blank, SV and Stout, NK and Hazelton, WD and Kong, CY and Elkin, EB}, title = {Projected Trends in the Incidence and Mortality of Uterine Cancer in the United States.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {7}, pages = {1156-1166}, pmid = {40589281}, issn = {1538-7755}, support = {U01 CA265739/CA/NCI NIH HHS/United States ; 1U01 CA265739//National Cancer Institute (NCI)/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Black or African American/statistics &amp; numerical data ; Incidence ; United States/epidemiology ; *Uterine Neoplasms/mortality/epidemiology ; White/statistics &amp; numerical data ; }, abstract = {BACKGROUND: To develop a natural history model for uterine cancer calibrated to population-based incidence and mortality data to project future trends in the disease through 2050.<br><br>METHODS: We developed a state-transition microsimulation model of uterine cancer. The model begins at 18 years of age and simulates Black and White patients, includes transition states for precursor lesions, and separately models endometrioid and nonendometrioid tumors. The model was calibrated to population-based incidence and mortality data using parameter extrapolation.<br><br>RESULTS: The model closely fit population-based incidence and mortality data of uterine cancer. From 2020 to 2050, the incidence of uterine cancer is projected to increase in White women to 74.2 cases per 100,000 (compared with 57.7 cases per 100,000 in 2018) and increase to 86.9 per 100,000 (compared with 56.8 cases per 100,000 in 2018) in Black women. Among White women, incidence-based mortality will increase from 6.1 per 100,000 in 2018 to 11.2 per 100,000 in 2050, whereas incidence-based mortality in Black women will increase from 14.1 per 100,000 to 27.9 per 100,000. Endometrioid tumors are expected to increase considerably in both White and Black women; White women will experience only a slight increase in nonendometrioid tumors, whereas the incidence of these tumors will increase substantially in Black women.<br><br>CONCLUSIONS: The incidence and mortality of uterine cancer are projected to increase substantially over the next three decades. Black women will experience a disproportionate increase in the disease.<br><br>IMPACT: Projecting the incidence and mortality of uterine cancer can facilitate future cancer control efforts.}, }
@article {pmid40590452, year = {2025}, author = {Brown, TT and Arao, RF and Warsi, M and Phanuphak, N and Vasconcelos, R and Oyedele, T and Sullivan, PA and Hanscom, B and Rooney, JF and Rinehart, AR and McCauley, M and Grinsztejn, B and Landovitz, RJ}, title = {Bone Changes With Long-Acting Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention in Cisgender Men and Transgender Women: HPTN 083.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {81}, number = {5}, pages = {983-986}, pmid = {40590452}, issn = {1537-6591}, support = {U01 AI069476/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; UM1 AI069476/AI/NIAID NIH HHS/United States ; UM1 AI069424/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control ; Female ; Male ; *Pre-Exposure Prophylaxis/methods ; Transgender Persons ; *Anti-HIV Agents/adverse effects/therapeutic use/administration &amp; dosage ; Adult ; *Tenofovir/adverse effects/therapeutic use/administration &amp; dosage ; *Emtricitabine/adverse effects/therapeutic use/administration &amp; dosage ; Bone Density/drug effects ; *Pyridones/adverse effects/therapeutic use/administration &amp; dosage ; Middle Aged ; *Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/adverse effects/therapeutic use ; Young Adult ; Diketopiperazines ; }, abstract = {In a randomized clinical trial, pre-exposure prophylaxis (PrEP) with long-acting cabotegravir (CAB-LA) had a better bone safety profile than tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) over 105 weeks. For individuals with low bone mineral density or other fracture risk factors, CAB-LA PrEP should be considered over TDF-based PrEP. Clinical Trials Registration. clinicaltrials.gov (NCT02720094).}, }
@article {pmid40590661, year = {2025}, author = {Søgaard, MT and Tseng, D and Gibbs, S and Wu, W and Nolan, LG and Yang, PY and Lai, M and Cao, J and Pipavath, S and Mayer-Blackwell, K and Newell, EW and Houghton, AM and Payne, KK and Chiou, SH and Nair, VS}, title = {T-cell Receptor Profiling of Blood to Detect Lung Cancer.}, journal = {Cancer immunology research}, volume = {13}, number = {9}, pages = {1405-1417}, pmid = {40590661}, issn = {2326-6074}, support = {PC115-24//New Jersey Health Foundation (NJHF)/ ; U01 CA253166/CA/NCI NIH HHS/United States ; CA253166//National Cancer Institute (NCI)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; P30CA015704//National Cancer Institute (NCI)/ ; R01 CA285774/CA/NCI NIH HHS/United States ; PC140-23//New Jersey Health Foundation (NJHF)/ ; UL1TR002319//National Center for Advancing Translational Sciences (NCATS)/ ; P30CA072720-6851//Rutgers Cancer Institute of New Jersey (CINJ)/ ; L30 CA284429/CA/NCI NIH HHS/United States ; 1R37CA295820-01//National Cancer Institute (NCI)/ ; UL1 TR002319/TR/NCATS NIH HHS/United States ; R37 CA295820/CA/NCI NIH HHS/United States ; R21 CA286389/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/diagnosis/blood/immunology/genetics ; Male ; Female ; *Receptors, Antigen, T-Cell/genetics/blood ; Middle Aged ; Case-Control Studies ; Early Detection of Cancer/methods ; Aged ; *Biomarkers, Tumor/blood ; Lymphocytes, Tumor-Infiltrating/immunology/metabolism ; }, abstract = {The blood T-cell receptor (TCR) repertoire broadly reflects current and lifetime immune responses against infectious pathogens and cancer, but the circulating T-cell repertoire remains a largely untapped resource for cancer biomarker studies due to repertoire complexity and limited profiling data. In this study, we investigated the use of blood TCR sequencing for the early detection of lung cancer. We sequenced the leukocyte fraction of peripheral blood from 633 individuals divided into a case-control cohort (n = 511) and a lung cancer screening cohort (n = 122), representing more than 12.6 million unique clonotypes. Based on the TCR repertoires in these individuals, we devised a Tumor Immune Lymphocyte Score (TILS) using either TCR specificity groups (TILS-A) or highly recurrent "public" TCR clonotypes (TILS-B) capable of detecting lung cancer. TILS-A consisted of 125 TCR specificity groups that outperformed the TILS-B classifier of 49 public, TCRβ-Vβ-defined clonotypes for cancer detection. TILS classifiers (TILS-A and TILS-B) provided predictive value after accounting for age, smoking status, and nodule size in the lung cancer screening cohort and improved cancer prediction for individuals with indeterminate lung cancer risk. In the subgroup analysis, TILS-A was associated with lung cancer in both early- and late-stage disease, had improved accuracy when accounting for HLA status, and was validated in an external dataset studying lung cancer initiation. Collectively, these data suggest that profiles of the circulating T-cell response can provide value for lung cancer detection and support its use as a diagnostic tool.}, }
@article {pmid40590852, year = {2025}, author = {Levis, MJ and Hamadani, M and Logan, BR and Jones, RJ and Singh, AK and Litzow, MR and Wingard, JR and Papadopoulos, EB and Perl, AE and Soiffer, RJ and Ustun, C and Oshima, MU and Uy, GL and Waller, EK and Vasu, S and Solh, M and Mishra, A and Muffly, LS and Kim, HJ and Stelljes, M and Najima, Y and Onozawa, M and Thomson, K and Chen, C and Hasabou, N and Rosales, M and Hill, JE and Gill, SC and Nuthethi, R and King, D and Mendizabal, A and Devine, SM and Horowitz, MM and Chen, YB}, title = {Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia.}, journal = {Blood advances}, volume = {9}, number = {20}, pages = {5123-5133}, pmid = {40590852}, issn = {2473-9537}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; UG1 HL138645/HL/NHLBI NIH HHS/United States ; UG1 HL108987/HL/NHLBI NIH HHS/United States ; UG1 HL069246/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; UG1 HL069291/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Nucleophosmin ; *Leukemia, Myeloid, Acute/therapy/genetics/mortality ; *fms-Like Tyrosine Kinase 3/genetics ; *Transplantation Conditioning/methods ; Neoplasm, Residual ; *Hematopoietic Stem Cell Transplantation/methods ; *Mutation ; *Nuclear Proteins/genetics ; Female ; Middle Aged ; Male ; Adult ; Transplantation, Homologous ; Aged ; Aniline Compounds ; Pyrazines ; }, abstract = {We conducted a post hoc analysis of data from Blood and Marrow Transplant Clinical Trials Network 1506 (MORPHO), a randomized trial of gilteritinib vs placebo as posttransplantation maintenance for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 comutation status reported from diagnosis. Comparing FLT3-ITD MRD before and after conditioning, there was no difference between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in eradication or reduction of FLT3-ITD MRD. For participants who were FLT3-ITD MRD negative before HCT, there was no difference in the cumulative incidence of relapse during follow-up between those receiving MAC vs RIC. NPM1 comutation was associated with the largest magnitude of relapse-free survival benefit from post-HCT gilteritinib, and in these participants, post-HCT gilteritinib in the setting of RIC appeared to be as effective as MAC at preventing relapse. MAC appeared superior to RIC in preventing relapse only in participants who were NPM1 wild type at diagnosis and FLT3-ITD MRD positive before HCT. Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from MAC and that, similar to AML therapy before HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. This trial was registered at www.clinicaltrials.gov as #NCT02997202.}, }
@article {pmid40592341, year = {2025}, author = {Clark, ML and Simeonov, KP and Mowel, WK and Michieletto, MF and Joannas, L and Wright, JM and Erickson, I and Johnson, LR and Krishnan, R and de la Fuente-Núñez, C and Minn, AJ and Henao-Mejia, J}, title = {Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity.}, journal = {Immunity}, volume = {58}, number = {7}, pages = {1670-1687.e12}, pmid = {40592341}, issn = {1097-4180}, support = {T32 DK007780/DK/NIDDK NIH HHS/United States ; T32 AI070077/AI/NIAID NIH HHS/United States ; F30 AI154694/AI/NIAID NIH HHS/United States ; R01 CA294364/CA/NCI NIH HHS/United States ; P30 DK019525/DK/NIDDK NIH HHS/United States ; R01 AI168240/AI/NIAID NIH HHS/United States ; R01 AI168136/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Mice ; *Tumor-Associated Macrophages/immunology/metabolism ; Signal Transduction/immunology ; MicroRNAs/genetics ; *Interferons/metabolism/immunology ; Mice, Inbred C57BL ; Humans ; Tumor Microenvironment/immunology ; *Mitochondria/metabolism ; *Melanoma, Experimental/immunology ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; }, abstract = {Tumor-associated macrophages (TAMs) influence tumor progression and immune checkpoint blockade (ICB) efficacy. Interferon (IFN)-TAMs predict better survival and ICB responses, yet the mechanisms governing IFN-TAMs remain unclear. Here, we identify NDUFA4, a complex IV subunit of the electron transport chain, as a functional switch controlling TAM function and anti-tumor immunity. NDUFA4 expression sustained pro-tumoral TAMs. However, intratumoral IFNs decreased NDUFA4 expression in TAMs via the cooperative action of NDUFA4L3 and miR-147, co-encoded by a conserved bifunctional transcript. Mechanistically, NDUFA4 repression increased mitochondrial DNA release into the cytoplasm and subsequent STING activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, we designed RNA-based therapeutics that leveraged the specificity of miR-147 for the Ndufa4 transcript to enhance ICB efficacy and inhibit B16 melanoma tumor growth. These findings uncover mitochondrial complex IV remodeling as a critical mechanism governing the functional adaptation of macrophages to distinct microenvironments with broad implications for immunotherapy.}, }
@article {pmid40593437, year = {2025}, author = {Grivas, P and Moon, HH}, title = {A Podcast on Real-World Evidence with Avelumab First-Line Maintenance and Treatment Sequencing in Locally Advanced or Metastatic Urothelial Carcinoma.}, journal = {Targeted oncology}, volume = {20}, number = {5}, pages = {743-754}, pmid = {40593437}, issn = {1776-260X}, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; *Carcinoma, Transitional Cell/drug therapy/pathology ; Neoplasm Metastasis ; *Urinary Bladder Neoplasms/drug therapy/pathology ; *Urologic Neoplasms/drug therapy/pathology ; }, abstract = {Avelumab first-line maintenance is an approved treatment for cisplatin-eligible or -ineligible patients with advanced urothelial carcinoma (UC) who are progression free following first-line platinum-based chemotherapy, based on the results of the JAVELIN Bladder 100 phase 3 trial. In recent years, an increasing number of real-world studies have examined the effectiveness and safety of avelumab first-line maintenance in heterogeneous populations from different countries, expanding the clinical evidence base. In this podcast, we discuss findings from these real-world studies, which have complemented clinical trials and provided additional insights about overall effectiveness, treatment sequencing involving second-line enfortumab vedotin monotherapy or other options, and healthcare resource utilization. We also briefly discuss the evolving treatment landscape in advanced UC in addition to benefits and limitations of real-world studies in general. Overall, across multiple studies involving more than 3000 patients worldwide, real-world outcomes with avelumab first-line maintenance treatment have been consistent with findings from the JAVELIN Bladder 100 trial, confirming the clinical benefits of this treatment approach for patients with advanced UC who are encountered in day-to-day practice.}, }
@article {pmid40593602, year = {2025}, author = {Cuénod, A and Chac, D and Khan, AI and Chowdhury, F and Hyppa, RW and Markiewicz, SM and Rice, A and Kholwadwala, A and Calderwood, SB and Ryan, ET and Harris, JB and LaRocque, RC and Bhuiyan, TR and Smith, GR and Qadri, F and Lypaczewski, P and Weil, AA and Shapiro, BJ}, title = {Prevalent chromosome fusion in Vibrio cholerae O1.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5830}, pmid = {40593602}, issn = {2041-1723}, support = {P500PB_214356//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; T32 HD007233/HD/NICHD NIH HHS/United States ; R01 AI106878/AI/NIAID NIH HHS/United States ; R35 GM118120/GM/NIGMS NIH HHS/United States ; K08 AI123494/AI/NIAID NIH HHS/United States ; R56 AI106878/AI/NIAID NIH HHS/United States ; R37 AI106878/AI/NIAID NIH HHS/United States ; }, mesh = {*Chromosomes, Bacterial/genetics ; *Vibrio cholerae O1/genetics/isolation &amp; purification/pathogenicity ; *Cholera/microbiology/transmission ; Humans ; Bangladesh ; Biofilms/growth &amp; development ; Virulence Factors/genetics ; Genome, Bacterial ; }, abstract = {Two circular chromosomes are a defining feature of the bacterial family Vibrionaceae, including the pathogen Vibrio cholerae, with rare reports of isolates with a single, fused chromosome. Here, we use long-read sequencing to analyse 467 V. cholerae O1 isolates from 47 cholera patients and household contacts in Bangladesh. We identify several independent chromosome fusion events that are likely transmissible within a household. Fusions occur in a 12 kilobase-pair homologous sequence shared between the two chromosomes and are stable for at least 200 generations under laboratory conditions. We find no detectable effect of fusion on V. cholerae growth, virulence factor expression, or biofilm formation. The factors promoting fusion, affecting chromosome stability, and subtle phenotypic or clinical consequences merit further investigation.}, }
@article {pmid40595413, year = {2025}, author = {Luecken, MD and Gigante, S and Burkhardt, DB and Cannoodt, R and Strobl, DC and Markov, NS and Zappia, L and Palla, G and Lewis, W and Dimitrov, D and Vinyard, ME and Magruder, DS and Mueller, MF and Andersson, A and Dann, E and Qin, Q and Otto, DJ and Klein, M and Botvinnik, OB and Deconinck, L and Waldrant, K and Yasa, SN and Szałata, A and Benz, A and Li, Z and ,  and Bloom, JM and Pisco, AO and Saez-Rodriguez, J and Wulsin, D and Pinello, L and Saeys, Y and Theis, FJ and Krishnaswamy, S}, title = {Defining and benchmarking open problems in single-cell analysis.}, journal = {Nature biotechnology}, volume = {43}, number = {7}, pages = {1035-1040}, pmid = {40595413}, issn = {1546-1696}, support = {T15//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; 860329 Marie-Curie ITN "STRATEGY-CKD"//EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)/ ; 1F31CA257625//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; 1SF3822N//Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)/ ; 101054957//European Commission (EC)/ ; }, }
@article {pmid40595741, year = {2025}, author = {Zheng, Y and Caron, DP and Kim, JY and Jun, SH and Tian, Y and Mair, F and Stuart, KD and Sims, PA and Gottardo, R}, title = {ADTnorm: robust integration of single-cell protein measurement across CITE-seq datasets.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {5852}, pmid = {40595741}, issn = {2041-1723}, support = {U19 AI128949/AI/NIAID NIH HHS/United States ; T32 AI106711/AI/NIAID NIH HHS/United States ; K99 HG012797/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R00 HG012797/HG/NHGRI NIH HHS/United States ; U19 AI128914/AI/NIAID NIH HHS/United States ; HG012797//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; }, mesh = {*Single-Cell Analysis/methods ; Humans ; Antibodies/immunology ; Transcriptome ; *Epitopes/genetics/immunology ; Gene Expression Profiling/methods ; *Membrane Proteins/genetics/metabolism ; High-Throughput Nucleotide Sequencing/methods ; COVID-19/virology ; }, abstract = {Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) enables paired measurement of surface protein and mRNA expression in single cells using antibodies conjugated to oligonucleotide tags. Due to the high copy number of surface protein molecules, sequencing antibody-derived tags (ADTs) allows for robust protein detection, improving cell-type identification. However, variability in antibody staining leads to batch effects in the ADT expression, obscuring biological variation, reducing interpretability, and obstructing cross-study analyses. Here, we present ADTnorm, a normalization and integration method designed explicitly for ADT abundance. Benchmarking against 14 existing scaling and normalization methods, we show that ADTnorm accurately aligns populations with negative- and positive-expression of surface protein markers across 13 public datasets, effectively removing technical variation across batches and improving cell-type separation. ADTnorm enables efficient integration of public CITE-seq datasets, each with unique experimental designs, paving the way for atlas-level analyses. Beyond normalization, ADTnorm includes built-in utilities to aid in automated threshold-gating as well as assessment of antibody staining quality for titration optimization and antibody panel selection. Applying ADTnorm to an antibody titration study, a published COVID-19 CITE-seq dataset, and a human hematopoietic progenitors study allowed for identifying previously undetected phenotype-associated markers, illustrating a broad utility in biological applications.}, }
@article {pmid40598383, year = {2025}, author = {Mangale, DI and Heitner, J and Ortblad, KF and Mogere, P and Kiptinness, C and Mugo, NR and Baeten, JM and Ngure, K and Barnabas, R}, title = {Opportunity for cost savings with a novel differentiated model of PrEP delivery: a comparative costing analysis of six-month PrEP supported by interim HIV self-testing and standard of care PrEP dispensing in Kenya.}, journal = {BMC health services research}, volume = {25}, number = {1}, pages = {865}, pmid = {40598383}, issn = {1472-6963}, support = {R00 MH121166/MH/NIMH NIH HHS/United States ; R01 MH113572/MH/NIMH NIH HHS/United States ; R01MH113572/MH/NIMH NIH HHS/United States ; }, mesh = {Humans ; Kenya ; *Pre-Exposure Prophylaxis/economics/methods ; *HIV Infections/prevention &amp; control/diagnosis/economics ; *Cost Savings ; *Anti-HIV Agents/economics/therapeutic use/administration &amp; dosage ; Male ; *Self-Testing ; Female ; }, abstract = {BACKGROUND: Cost remains an important barrier to HIV pre-exposure prophlyaxis (PrEP) delivery in Africa. Simplified delivery models that reduce costs without compromising PrEP outcomes are needed. The JiPime-JiPrEP trial tested a model of six-month PrEP dispensing supported with interim HIV self-testing (HIVST) and found non-inferior HIV testing, PrEP refilling, and adherence compared to three-month PrEP dispensing and quarterly clinic visits, the standard-of-care (SOC). We estimated the cost of this novel differentiated PrEP delivery model compared to SOC in Kenya.<br><br>METHODS: Using activity-based micro-costing (payer perspective) and time-and-motion observations, we estimated the cost of PrEP delivery (per client-month) in the intervention and SOC between May 2018 to December 2019. Data from budgets and expense reports, published documents, and interviews informed our estimates. We calculated costs over a one-year horizon for: 1) the trial scenario (i.e., costs within the trial), and 2) the Ministy of Health (MOH) scenario (i.e., hypothetical costs at public clinics). Estimates were in 2019 US dollars and excluded research-related costs.<br><br>RESULTS: The mean personnel time attributable to PrEP delivery was 76 minutes per visit and 152 minutes projected over a year in the intervention and 54 minutes per visit and 282 minutes per year in the SOC. In the trial scenario, PrEP delivery cost $17.73 per client-month in the intervention (n=2039 PrEP-months) and $25.50 in the SOC (n=913 PrEP-months). The projected cost of PrEP delivery in the MOH scenario was $11.94 in the intervention and $14.76 in the SOC, with the addition of HIVST kits in the intervention more than offset by personnel savings. In this scenario, personnel (intervention: 55%; SOC: 44%) and medication (intervention: 16%; SOC: 32%) were the primary cost drivers. Including serum creatine testing twice a year in the MOH scenario resulted in a slight increase in the cost of PrEP delivery in the intervention ($12.88 per client-month) versus SOC ($16.17 per client-month).<br><br>CONCLUSIONS: Six-month PrEP with interim HIVST demonstrated lower costs than three-month dispensing, with decreased personnel time. Scale-up of PrEP delivery requires efficient use of limited resources; the savings in this model of PrEP delivery could be redirected towards currently unmet medical needs.<br><br>CLINIAL TRIAL NUMBER: NCT03593629|| https://www.<br><br>CLINICALTRIALS: gov/ with the Clinical Trial Registry (Registration date: 2018-07-20).}, }
@article {pmid40598755, year = {2025}, author = {Grinsztejn, B and Appay, V and Bekker, LG and Beyrer, C and Donnell, D and Sanchez, J and Canagasabey, D and Coutinho, C and Ganor, Y and Muturi-Kioi, V and Ortblad, KF and Cooney, E and Devisich, G and Ellenberg, P and Ghiglione, Y and K'Orimba, K and Ssemambo, PK and Ludwig-Barron, NT and Mielke, DK and Mullick, R and Muthui, MK and Radusky, PD and Sendaula, E and Tirmizi, SRH and Sanchez, AVM and Vega, J and Pebody, R}, title = {The science at HIVR4P 2024: The era of choice in biomedical HIV prevention.}, journal = {Journal of the International AIDS Society}, volume = {28}, number = {7}, pages = {e70001}, pmid = {40598755}, issn = {1758-2652}, support = {T32 MH019105/MH/NIMH NIH HHS/United States ; UM1 AI069530/AI/NIAID NIH HHS/United States ; //International AIDS Society/ ; R00 MH121166/MH/NIMH NIH HHS/United States ; //Roger Pebody and Dr Wendy Smith/ ; }, mesh = {Humans ; AIDS Vaccines/administration &amp; dosage/immunology ; Anti-HIV Agents/therapeutic use ; *HIV Infections/prevention &amp; control ; Peru ; *Pre-Exposure Prophylaxis/methods ; Congresses as Topic ; }, abstract = {INTRODUCTION: HIVR4P 2024, the 5th HIV Research for Prevention Conference, took place in Lima, Peru, 6-10 October 2024. The conference focused on new developments in HIV prevention from basic research to new product development and implementation science.<br><br>METHODS: Sessions were assigned to one of five tracks: basic science; pre-exposure prophylaxis (PrEP) and antiretroviral (ARV)-based prevention; vaccines and broadly neutralizing antibodies (bNAbs); applied and implementation science; and other prevention modalities and cross-cutting issues. A team of rapporteurs covered each track and identified conference highlights.<br><br>RESULTS: Strategies to elicit bNAb responses by vaccination are advancing to clinical trials, while combination bNAbs show promise as an alternative to ARV-based products. There is promising diversity in the PrEP product pipeline and twice-yearly lenacapavir has demonstrated exceptional efficacy, but barriers to widespread access and implementation remain, compounded by new challenges from the significant policy changes and funding reductions of the new US administration. Innovative ways of delivering PrEP to vulnerable communities that could benefit are being explored and, in some cases, have been successfully implemented.<br><br>DISCUSSION: Choice in HIV prevention products and differentiated delivery models that enable clients to select options that meet their preferences and changing needs is essential. Additionally, the involvement of the community throughout the design, implementation and dissemination process is necessary to maximize the impact of HIV prevention. Ensuring equitable access in a rapidly changing context will involve policy changes, partnerships with local organizations and addressing social determinants that impact health outcomes.<br><br>CONCLUSIONS: We are in an era with more tools than ever before to prevent HIV acquisition; now, we need to facilitate collaborations between diverse stakeholders, including researchers, community members, policymakers, healthcare providers and funders. The future of HIV prevention should lie in a holistic approach that respects individual choice, enhances service accessibility and is flexible to meet evolving challenges and opportunities. However, policy changes since the conference ended have profoundly altered the HIV prevention landscape and threaten the advances described in this report.}, }
@article {pmid40600473, year = {2025}, author = {Noller, K and Botsis, T and Camara, PG and Ciotti, L and Cooper, LAD and Goecks, J and Griffith, M and Haas, BJ and Ideker, T and Karchin, R and Kontos, D and Lai, J and Marcus, D and Meyer, CA and Naegle, K and Pati, S and Peters, B and Pratt, D and Raphael, BJ and Reich, M and Savova, GK and Wright, C and Fertig, EJ and Bakas, S}, title = {Informatics at the Frontier of Cancer Research.}, journal = {Cancer research}, volume = {85}, number = {16}, pages = {2967-2986}, pmid = {40600473}, issn = {1538-7445}, support = {5R01CA161749-09 and 5R01CA223816-05//National Institutes of Health (NIH)/ ; UE5 CA254170/CA/NCI NIH HHS/United States ; R01 CA223816/CA/NCI NIH HHS/United States ; U24 CA284167/CA/NCI NIH HHS/United States ; U24 CA253531/CA/NCI NIH HHS/United States ; 5P41GM103504-12//National Institutes of Health (NIH)/ ; U24CA231877//National Institutes of Health (NIH)/ ; U01CA220401//National Institutes of Health (NIH)/ ; U24 CA237719/CA/NCI NIH HHS/United States ; U2CCA233280//National Institutes of Health (NIH)/ ; T32 CA154274/CA/NCI NIH HHS/United States ; 5U24CA258482//National Institutes of Health (NIH)/ ; U24CA279629//National Institutes of Health (NIH)/ ; U24 HG010263/HG/NHGRI NIH HHS/United States ; U01 CA220401/CA/NCI NIH HHS/United States ; U24 CA248138/CA/NCI NIH HHS/United States ; and U01CA248235//National Institutes of Health (NIH)/ ; U01CA269409//National Institutes of Health (NIH)/ ; U24 CA258393/CA/NCI NIH HHS/United States ; U24 CA258115/CA/NCI NIH HHS/United States ; U01CA242871//National Institutes of Health (NIH)/ ; R01 CA161749/CA/NCI NIH HHS/United States ; U24CA258115//National Institutes of Health (NIH)/ ; U24CA237719//National Institutes of Health (NIH)/ ; U01 CA248235/CA/NCI NIH HHS/United States ; 5U24CA189523-05//National Institutes of Health (NIH)/ ; 1OT2OD032742-01//National Institutes of Health (NIH)/ ; U24 CA231877/CA/NCI NIH HHS/United States ; P41 GM103504/GM/NIGMS NIH HHS/United States ; U24 CA248457/CA/NCI NIH HHS/United States ; U24CA237617//National Institutes of Health (NIH)/ ; U24 CA269436/CA/NCI NIH HHS/United States ; 5R01EB009352 and 5U24CA253531//National Institutes of Health (NIH)/ ; and U24HG010263//National Institutes of Health (NIH)/ ; U01 CA242871/CA/NCI NIH HHS/United States ; U24CA248010//National Institutes of Health (NIH)/ ; U2C CA233280/CA/NCI NIH HHS/United States ; R01 EB009352/EB/NIBIB NIH HHS/United States ; U24CA258393//National Institutes of Health (NIH)/ ; U54 CA274502/CA/NCI NIH HHS/United States ; 1U24CA269436-01A1//National Institutes of Health (NIH)/ ; U24 CA279629/CA/NCI NIH HHS/United States ; 1U54CA274502-01//National Institutes of Health (NIH)/ ; U01CA271273 and U54CA253403//National Institutes of Health (NIH)/ ; U01 CA269409/CA/NCI NIH HHS/United States ; UE5CA254170//National Institutes of Health (NIH)/ ; U24 CA248453/CA/NCI NIH HHS/United States ; U24 CA275783/CA/NCI NIH HHS/United States ; U24CA248453//National Institutes of Health (NIH)/ ; U24CA248138//National Institutes of Health (NIH)/ ; U24 CA237617/CA/NCI NIH HHS/United States ; U01 CA253403/CA/NCI NIH HHS/United States ; U24 HG012107/HG/NHGRI NIH HHS/United States ; U24 CA189523/CA/NCI NIH HHS/United States ; U24CA248457//National Institutes of Health (NIH)/ ; U24CA275783//National Institutes of Health (NIH)/ ; OT2 OD032742/OD/NIH HHS/United States ; 5U24HG012107-02//National Institutes of Health (NIH)/ ; U24CA19436201//National Institutes of Health (NIH)/ ; U24 CA248010/CA/NCI NIH HHS/United States ; U24 CA258483/CA/NCI NIH HHS/United States ; U01 CA271273/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/therapy/diagnosis/genetics ; *Computational Biology/methods ; *Biomedical Research/methods ; *Medical Informatics/methods ; Artificial Intelligence ; Machine Learning ; }, abstract = {Digitized healthcare data, high-throughput profiling technologies, and data repositories have facilitated the emergence of a new era of cancer research. Each data stream requires specialized analysis methods for interpretation. The data-driven era of cancer research requires the development, enhancement, and sustainment of informatics technology software infrastructure, including fundamental methodology development in artificial intelligence and data science. We review current and emerging informatics technology developments for cancer research and discovery, spanning molecular and cellular characterizations, image analysis, informatics, and therapeutics. Summarizing the diverse methods and applications of informatics throughout cancer research identifies themes and emerging areas for the next generation of cancer research. This article is part of a special series: Driving Cancer Discoveries with Computational Research, Data Science, and Machine Learning/AI.}, }
@article {pmid40600502, year = {2025}, author = {Stansfield, SE and Moore, M and Jamieson, L and Meyer-Rath, G and Johnson, LF and Kaftan, D and Bershteyn, A and Smith, J and Cambiano, V and Bansi-Matharu, L and Phillips, A and Heitner, J and Barnabas, RV and Hanscom, B and Donnell, DJ and Boily, MC and Dimitrov, D}, title = {Estimated impact of long-acting injectable PrEP in South Africa: a model comparison analysis.}, journal = {Journal of the International AIDS Society}, volume = {28 Suppl 2}, number = {Suppl 2}, pages = {e26453}, pmid = {40600502}, issn = {1758-2652}, support = {MR/X020258/1//MRC Centre for Global Infectious Disease Analysis/ ; //UK Medical Research Council/ ; 019496//Bill and Melinda Gates Foundation/ ; //Global Health EDCTP3 Joint Undertaking/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; MR/T042796/1/MRC_/Medical Research Council/United Kingdom ; R01 AI179417/AI/NIAID NIH HHS/United States ; UM1 068617//the NIH NIAID/ ; INV-007145/GATES/Gates Foundation/United States ; }, mesh = {South Africa/epidemiology ; *Pre-Exposure Prophylaxis/methods ; *HIV Infections/prevention &amp; control/epidemiology/transmission ; Humans ; *Anti-HIV Agents/administration &amp; dosage ; Male ; Female ; *Pyridones/administration &amp; dosage ; Tenofovir/administration &amp; dosage ; Adult ; Injections ; Emtricitabine/administration &amp; dosage ; Diketopiperazines ; }, abstract = {INTRODUCTION: Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) in two clinical trials. This analysis projects the impact of expanding PrEP coverage with CAB-LA in South Africa between 2022 and 2042.<br><br>METHODS: Three independently calibrated models of HIV transmission in South Africa (Synthesis, EMOD-HIV, Thembisa) projected HIV acquisitions and effective coverage (average PrEP coverage across exposure groups, weighted by HIV incidence in the absence of PrEP in each group) over 20 years under multiple scenarios of PrEP expansion compared to no PrEP expansion. PrEP expansion scenarios differed in targeted overall coverage, speed of expansion, coverage of high-exposure groups, and relative coverage of women and men.<br><br>RESULTS: Achieving 5% PrEP coverage with CAB-LA by 2032 prioritizing high-exposure groups resulted in 49% (Synthesis), 18% (EMOD-HIV), and 8% (Thembisa) effective coverage and averted a median of 43%, 29% and 10% of new HIV acquisitions, respectively. Similar expansion with TDF/FTC resulted in lower impact by 19 percentage points (pp), 18pp and 3pp, respectively. Increasing CAB-LA coverage to 15% led to an additional 7pp, 12pp and 16pp, respectively, of HIV acquisitions averted. Achieving 5% CAB-LA coverage expanding to women only resulted in a lower impact by 16pp (Synthesis) and 13pp (EMOD-HIV), and a higher impact by 2pp (Thembisa). Scenarios with similar effective coverage resulted in comparable impact estimates across models.<br><br>CONCLUSIONS: Offering CAB-LA in South Africa may substantially impact the HIV epidemic based on these projections. Effective coverage proved to be a good predictor of intervention effectiveness.}, }
@article {pmid40601110, year = {2025}, author = {Hyde, ET and Evenson, KR and Howard, AG and Parada, H and Di, C and LaMonte, MJ and Bellettiere, J and Cuthbertson, CC and Lee, IM and LaCroix, AZ}, title = {Sitting time and risk of cancer incidence and cancer mortality in postmenopausal women: the Women's Health Accelerometry Collaboration.}, journal = {Cancer causes &amp; control : CCC}, volume = {36}, number = {11}, pages = {1417-1430}, pmid = {40601110}, issn = {1573-7225}, support = {R61 HL151885/HL/NHLBI NIH HHS/United States ; P30 AG059299/AG/NIA NIH HHS/United States ; R01 HL130591/HL/NHLBI NIH HHS/United States ; T32HL07989/HL/NHLBI NIH HHS/United States ; U54 CA285117/CA/NCI NIH HHS/United States ; U54 CA285115/CA/NCI NIH HHS/United States ; R33 HL151885/HL/NHLBI NIH HHS/United States ; R01 HL153462/HL/NHLBI NIH HHS/United States ; R01 HL150170/HL/NHLBI NIH HHS/United States ; 75N92021D00002, HL153462, HL151885, HL150170, and HL130591/HL/NHLBI NIH HHS/United States ; 31KT1501//Tobacco-Related Disease Research Program/ ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; K01 CA234317/CA/NCI NIH HHS/United States ; U54 CA285117 &amp; U54 CA285115//SDSU/UCSD Cancer Center Comprehensive Partnership/ ; }, mesh = {Humans ; Female ; Accelerometry/methods ; Aged ; *Postmenopause ; Incidence ; *Neoplasms/epidemiology/mortality/etiology ; *Sedentary Behavior ; Risk Factors ; Women's Health ; *Sitting Position ; Exercise ; Middle Aged ; United States/epidemiology ; Cohort Studies ; }, abstract = {PURPOSE: Few studies have explored whether accelerometer-measured sedentary behavior increases cancer risk. We examined the associations of accelerometer-measured daily sitting time and mean sitting bout duration classified by the Convolutional Neural Network Hip Accelerometer Posture (CHAP) machine-learned algorithm with incidence of any cancer, incidence of 13 physical activity-related cancers, and cancer mortality among postmenopausal women.<br><br>METHODS: We used data from 22,097 women (mean age&#x2009;=&#x2009;73.3&#xa0;years, standard deviation [SD]&#x2009;=&#x2009;6.7) in the Women's Health Accelerometry Collaboration, a consortium of two US-based cohort studies of postmenopausal women: the Women's Health Study and the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study. Women who completed hip-worn triaxial accelerometry for&#x2009;&#x2265;&#x2009;4 of 7 consecutive days were included. Associations between sedentary behaviors and physician-adjudicated invasive cancer incidence and mortality were tested using Cox regression.<br><br>RESULTS: Women were followed on average 8.0&#xa0;years to identify cancer cases (n&#x2009;=&#x2009;1,861) and deaths (n&#x2009;=&#x2009;601). Overall, mean sitting time was 567 (SD&#x2009;=&#x2009;113) min/day and mean sitting bout duration was 12.8 (SD&#x2009;=&#x2009;4) min/bout. In covariate-adjusted models, one-SD increment higher in sitting time was associated with a 6% increased risk of incident cancer (hazard ratio [HR]&#x2009;=&#x2009;1.06, 95% CI: 1.01-1.11); associations were similar for bout duration (HR&#x2009;=&#x2009;1.05, 95% CI: 1.00-1.10). Estimates were similar for the 13 physical activity-related cancers (sitting time: HR&#x2009;=&#x2009;1.10, 95% CI: 1.04-1.17; bout duration: HR&#x2009;=&#x2009;1.08, 95% CI: 1.02-1.14) and for cancer mortality (sitting time: 1.06, 95% CI: 0.98-1.16; bout duration: HR&#x2009;=&#x2009;1.05, 95% CI: 0.97-1.13).<br><br>CONCLUSION: Among postmenopausal women, sedentary behavior was associated with increased cancer risk, particularly for physical activity-related cancers and cancer mortality.}, }
@article {pmid40603473, year = {2025}, author = {Banjoko, AW and Ng'uni, T and Naidoo, N and Ramsuran, V and Hyrien, O and Ndhlovu, ZM}, title = {High resolution class I HLA-A, -B, and -C diversity in Eastern and Southern African populations.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {23667}, pmid = {40603473}, issn = {2045-2322}, support = {SANTHE COL018//Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE)/ ; INV-027499/GATES/Gates Foundation/United States ; INV-032929/GATES/Gates Foundation/United States ; INV-032929/GATES/Gates Foundation/United States ; INV-048833//Bill and Melinda Gates Foundation/ ; R01A1181690//National Institutes of Health, NIH/NIAID/ ; INV-027090/GATES/Gates Foundation/United States ; }, mesh = {Humans ; *Genetic Variation ; Gene Frequency ; Haplotypes ; *Black People/genetics ; *HLA-A Antigens/genetics ; *HLA-B Antigens/genetics ; Alleles ; *HLA-C Antigens/genetics ; Linkage Disequilibrium ; Africa, Southern ; Genetics, Population ; Africa, Eastern ; }, abstract = {Africa, being one of the most genetically diverse regions in the world, remains significantly underrepresented in high-resolution Human Leukocyte Antigen (HLA) data. The extensive genetic variation in HLA alleles across the region underscores the need for population-specific immunogenetic data to guide T-cell vaccine development. This study analysed Class I HLA data from Eastern and Southern African populations to assess regional genetic diversity. Analyses included allele and haplotype frequency distributions, deviations from Hardy-Weinberg equilibrium, linkage disequilibrium, and homozygosity test of neutrality across various populations. To further contextualise African HLA diversity, comparisons were made among African populations and also with African American and European American populations using the Hellinger diversity index and multidimensional scaling methods. The results revealed that South African populations exhibited an estimated average of 34.1% genetic diversity with respect to other African populations. Rwanda demonstrated an estimated 26.9% genetic diversity, Kenya (26.5%), Zambia (26.5%), and Uganda (24.7%). Additionally, in-country analyses revealed variations in HLA diversity among different tribes within each country. The estimated average in-country diversity was 51% in Kenya, 35.8% in Uganda, and 33.2% in Zambia. These results reveal various levels of genetic diversity among African populations. The highlighted differences in HLA Class I allele frequencies between Eastern and Southern African populations compared to US populations, demonstrate that it is inappropriate to extrapolate HLA data from US populations including that of African Americans when designing T-cell-inducing vaccines tailored to African populations. Our findings underscore the urgent need to generate high-resolution HLA data to guide vaccine development tailored to African populations.}, }
@article {pmid40605619, year = {2025}, author = {Pearson, RA and Krish, KN and Whatney, WE and Jaoko, W and Mandaliya, K and Overbaugh, J and Graham, SM and McClelland, RS and Hicks, SL and Maurer, J and Scharer, CD and Day, CL}, title = {Single-Cell Transcriptomics Reveals Depletion and Dysregulation of Mycobacterium tuberculosis-Specific Th1 and Th17 Cells Early After Acquisition of Human Immunodeficiency Virus.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {4}, pages = {835-846}, pmid = {40605619}, issn = {1537-6613}, support = {P51OD011132//Emory National Primate Research Center/ ; //NIAID T32 Training Program/ ; P30AI168386//Emory/Georgia TB Research Advancement Center/ ; T32 AI138952/AI/NIAID NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; P51 OD011132/OD/NIH HHS/United States ; R21 AI155221/AI/NIAID NIH HHS/United States ; R21AI155221/NH/NIH HHS/United States ; }, mesh = {Humans ; *Mycobacterium tuberculosis/immunology ; *Th1 Cells/immunology ; *HIV Infections/immunology/complications ; *Th17 Cells/immunology ; Single-Cell Analysis ; *Tuberculosis/immunology ; *Transcriptome ; Male ; Female ; Adult ; Cytokines/metabolism ; CD4-Positive T-Lymphocytes/immunology ; Gene Expression Profiling ; Middle Aged ; }, abstract = {Human immunodeficiency virus (HIV) significantly increases the risk of developing tuberculosis (TB) and is associated with impaired CD4 T-cell responses to Mycobacterium tuberculosis (Mtb). We evaluated the frequency and functional capacity of Mtb-specific CD4 T cells in individuals with and without HIV using flow cytometry and performed single-cell RNA sequencing on these cells longitudinally in a subset of individuals before and after acquisition of HIV. Our findings reveal preferential depletion and functional impairment of Mtb-specific CD4 T cells early after acquisition of HIV, characterized by reduced cytokine production, loss of effector functions, and transcriptional dysregulation. Mtb-specific T-helper 1 (Th1) and T-helper 17 (Th17) cells decreased, whereas TCF7+ stem-like cells were enriched following acquisition of HIV. Pathway analysis revealed upregulation of hypoxia and Wnt signaling, and downregulation of cell adhesion, migration, antigen processing, and cytokine signaling pathways. These findings provide novel insights into HIV-mediated dysregulation of CD4 T-cell responses to Mtb.}, }
@article {pmid40605713, year = {2025}, author = {Danilov, AV and Li, H and Shadman, M and Rimsza, L and Zebari, A and Smith, SM and LeBlanc, M and Friedberg, JW and Carlson, C and Song, JY}, title = {Minimal residual disease status predicts outcomes in patients with follicular lymphoma treated with chemoimmunotherapy on the SWOG S0016 trial.}, journal = {Haematologica}, volume = {110}, number = {12}, pages = {3145-3149}, pmid = {40605713}, issn = {1592-8721}, }
@article {pmid40605797, year = {2025}, author = {Orozco, JJ and Matesan, MC and Lundberg, SJ and Haaf, RL and Miyaoka, RS and Fisher, DR and Gooley, TA and Green, DJ and Sandmaier, BM and Martin, PS and Gopal, AK}, title = {Pretargeted Anti-CD20 Radioimmunotherapy with scFv Fusion Protein Safely Combines with BEAM and ASCT in Patients with High-risk B-cell Lymphomas.}, journal = {Molecular cancer therapeutics}, volume = {24}, number = {12}, pages = {1928-1937}, pmid = {40605797}, issn = {1538-8514}, support = {P01 CA044991/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P01CA044991//National Cancer Institute (NCI)/ ; P01CA078902//National Cancer Institute (NCI)/ ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Antigens, CD20/immunology ; Combined Modality Therapy ; *Lymphoma, B-Cell/therapy/pathology ; *Radioimmunotherapy/methods ; *Recombinant Fusion Proteins ; *Single-Chain Antibodies/administration &amp; dosage ; *Stem Cell Transplantation ; Transplantation, Autologous ; Treatment Outcome ; Yttrium Radioisotopes ; }, abstract = {Despite new therapies, many patients with non-Hodgkin lymphoma (NHL) relapse and need more effective salvage therapies. This study (NCT02483000) evaluated the safety of B9E9-FP, a tetrameric single-chain anti-CD20-streptavidin fusion protein used in pretargeted radioimmunotherapy, when combined with BEAM and autologous stem cell transplantation (ASCT) for patients with NHL. Patients with high-risk NHL received B9E9-FP on day -17, clearing agent on day -15, and DOTA-biotin (DOTA-Bt) equally divided and labeled with dose-escalated yttrium-90 (90Y) or with indium-111 (for imaging) on day -14. BEAM chemotherapy started at day -7 before stem cell infusion. Three patients with NHL (mantle cell lymphoma, transformed diffuse large B-cell lymphoma, and de novo diffuse large B-cell lymphoma), ages 52 to 62 years, were treated with 30, 50, or 70 mCi (1,110, 1,850, or 2,590 MBq) 90Y/m2 before ASCT without any dose-limiting toxicity. One case of diarrhea (grade 2) and one case of rash (grade 1) were possibly associated with B9E9-FP or DOTA-Bt, respectively. Pharmacokinetic studies showed peak blood biological percent injected dose per gram blood (% ID/g) of 90Y-DOTA-Bt at 15 minutes after infusion (14.8%-49.4% ID), with only 0.82% to 2.59% ID after 72 hours. Uptake was preferential at bone marrow (1.73-5.96 cGy/mCi injected) and spleen (2.4-4.17 cGy/mCi injected) compared with lungs (0.19-0.48 cGy/mCi). Unbound 90Y-DOTA-Bt was excreted renally without any renal dysfunction noted up to 2 years later. Two of the three enrolled patients are alive and in remission 3.5 to 4.9 years after transplant. Pharmacokinetic, dosimetry, and outcome data support that B9E9-FP pretargeted radioimmunotherapy combined with 90Y-augmented ASCT DOTA-Bt is feasible.}, }
@article {pmid40607811, year = {2025}, author = {Simonich, CAL and McMahon, TE and Ju, X and Yu, TC and Brunette, N and Stevens-Ayers, T and Boeckh, MJ and King, NP and Greninger, AL and Bloom, JD}, title = {RSV F evolution escapes some monoclonal antibodies but does not strongly erode neutralization by human polyclonal sera.}, journal = {Journal of virology}, volume = {99}, number = {7}, pages = {e0053125}, pmid = {40607811}, issn = {1098-5514}, support = {K12-HD000850/NH/NIH HHS/United States ; DGE-2140004//National Science Foundation/ ; INV-072143//Bill and Melinda Gates Foundation/ ; U19 AI181767/AI/NIAID NIH HHS/United States ; K12 HD000850/HD/NICHD NIH HHS/United States ; Investigator/HHMI/Howard Hughes Medical Institute/United States ; R01AI141707/NH/NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; 1U19AI181767/NH/NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology ; *Antibodies, Monoclonal/immunology ; *Respiratory Syncytial Virus, Human/immunology/genetics ; *Viral Fusion Proteins/immunology/genetics ; *Antibodies, Viral/immunology ; *Respiratory Syncytial Virus Infections/immunology/virology ; Neutralization Tests ; Evolution, Molecular ; Animals ; }, abstract = {Vaccines and monoclonal antibodies targeting the respiratory syncytial virus (RSV) fusion protein (F) have recently begun to be widely used to protect infants and high-risk adults. Some other viral proteins evolve to erode polyclonal antibody neutralization and escape individual monoclonal antibodies. However, the impact of RSV F evolution on antibody neutralization is not yet thoroughly understood. Here, we develop an experimental system for measuring neutralization titers against RSV F using pseudotyped lentiviral particles. This system is easily adaptable to evaluate neutralization of relevant clinical strains. We apply this system to demonstrate that the natural evolution of RSV F leads to escape from some monoclonal antibodies, but at most modestly affects neutralization by polyclonal serum antibodies. Overall, our work sheds light on RSV antigenic evolution and describes a tool to measure the ability of antibodies and sera to neutralize contemporary RSV strains.IMPORTANCEWe describe an efficient approach to measure how antibodies inhibit infection by historical and recent human strains of respiratory syncytial virus (RSV). This approach is useful for understanding how viral evolution affects antibody immunity. We apply this approach to demonstrate that RSV evolution can escape some monoclonal antibodies, but polyclonal serum antibodies are less impacted by viral evolution. This information is relevant given the recent development of RSV preventative measures, including monoclonal antibodies and vaccines.}, }
@article {pmid40608157, year = {2025}, author = {Barrero, DJ and Hedouin, S and Mao, Y and Asbury, CL and Stergachis, AB and O'Toole, E and Biggins, S}, title = {Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.}, journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology}, volume = {33}, number = {1}, pages = {14}, pmid = {40608157}, issn = {1573-6849}, support = {R35 GM149357/NH/NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; DP5 OD029630/OD/NIH HHS/United States ; DP5-OD029630/NH/NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35GM134842/NH/NIH HHS/United States ; }, mesh = {*Centromere/metabolism/genetics ; *Microtubules/metabolism ; Kinetochores/metabolism ; *Kluyveromyces/genetics/metabolism ; Nucleosomes/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Chromosome Segregation ; Centromere Protein A ; Thermotolerance ; }, abstract = {Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast, which have short, sequenced-defined point centromeres. In S. cerevisiae, a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere, but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.}, }
@article {pmid40609469, year = {2025}, author = {Chen, J and Hart, JE and VoPham, T and Elliott, EG and Jones, RR and Ward, MH and Laden, F and Birmann, BM}, title = {Ambient dioxin exposure and incidence of lymphoid malignancies in large prospective US cohorts of female nurses.}, journal = {Journal of hazardous materials}, volume = {495}, number = {}, pages = {139115}, pmid = {40609469}, issn = {1873-3336}, support = {U01 HL145386/HL/NHLBI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 ES034079/ES/NIEHS NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; ZIA CP010125/ImNIH/Intramural NIH HHS/United States ; R01 CA149445/CA/NCI NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; U01 CA176726/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; United States/epidemiology ; *Lymphoma, Non-Hodgkin/epidemiology/chemically induced ; Incidence ; *Dioxins/toxicity/analysis ; Middle Aged ; *Multiple Myeloma/epidemiology/chemically induced ; Prospective Studies ; Nurses/statistics &amp; numerical data ; Adult ; *Environmental Exposure/adverse effects ; *Air Pollutants/toxicity/analysis ; }, abstract = {BACKGROUND: Limited evidence exists from prospective cohorts on residential dioxin exposure and incident non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). We assessed the associations in two US nationwide cohorts - the Nurses' Health Study (NHS, 1986-2012) and NHSII (1989-2019).<br><br>METHODS: We estimated residential proximity, duration of residence and emissions from industrial dioxin-emitting facilities within 3&#x202f;km, 5&#x202f;km, and 10&#x202f;km radii. Outcomes included overall NHL, major NHL subtypes, and MM. Using time-varying Cox proportional hazards models, we estimated hazard ratios (HRs) with 95&#x202f;% confidence intervals (CIs) and meta-analyzed cohort-specific results.<br><br>RESULTS: We observed 984 NHL and 227 MM cases in NHS (1,921,802 person-years), and 396 NHL and 61 MM cases in NHSII (2,845,710 person-years). We did not observe consistent associations between dioxin exposure and overall NHL or MM incidence. Results were heterogeneous across major NHL subtypes. Increased follicular lymphoma incidence was suggestively associated with residential proximity to dioxin-emitting facilities (HRyes vs. no and 95&#x202f;% CI: 1.26, 0.95&#x202f;-1.68) and duration of residence near these facilities (HR&#x2264;median vs. non-exposed and 95&#x202f;% CI: 1.44, 0.98&#x202f;-2.12) and significantly with dioxin emission levels (HR&#x2264;median vs. non-exposed and 95&#x202f;% CI: 1.52, 1.07&#x202f;-2.16) within 3&#x202f;km. These positive associations remained suggestive for up to 10&#x202f;km.<br><br>CONCLUSION: Dioxin exposure showed no consistent association with overall NHL or MM, but a positive association with follicular lymphoma was suggested.}, }
@article {pmid40609538, year = {2025}, author = {Severson, TM and Minnee, E and Zhu, Y and Schuurman, K and Nguyen, HM and Brown, LG and Hakkola, S and Menezes, R and Gregoricchio, S and Kim, Y and Kneppers, J and Linder, S and Stelloo, S and Lieftink, C and van der Heijden, MS and Nykter, M and van der Noort, V and Sanders, J and Morris, B and Jenster, G and van Leenders, GJ and Pomerantz, M and Freedman, ML and Beijersbergen, RL and Urbanucci, A and Wessels, L and Nelson, PS and Corey, E and Prekovic, S and Zwart, W and Bergman, AM}, title = {Epigenetic profiling identifies markers of endocrine resistance and therapeutic options for metastatic castration-resistant prostate cancer.}, journal = {Cell reports. Medicine}, volume = {6}, number = {7}, pages = {102215}, pmid = {40609538}, issn = {2666-3791}, support = {R01 CA234715/CA/NCI NIH HHS/United States ; }, mesh = {Male ; *Prostatic Neoplasms, Castration-Resistant/genetics/drug therapy/pathology ; Humans ; *Epigenesis, Genetic/drug effects ; Animals ; Histone Deacetylases/metabolism/genetics ; Vorinostat/pharmacology/therapeutic use ; Histone Deacetylase Inhibitors/pharmacology/therapeutic use ; Cell Line, Tumor ; *Drug Resistance, Neoplasm/genetics/drug effects ; Receptors, Androgen/metabolism/genetics ; Phenylthiohydantoin/analogs &amp; derivatives/therapeutic use/pharmacology ; Mice ; Xenograft Model Antitumor Assays ; Benzamides ; Neoplasm Metastasis ; Receptors, Glucocorticoid/metabolism ; Histones/metabolism ; Cell Proliferation/drug effects ; *Biomarkers, Tumor/genetics/metabolism ; Nitriles ; Gene Expression Regulation, Neoplastic/drug effects ; Acetylation ; Histone Deacetylase 3 ; }, abstract = {Androgen receptor (AR) signaling inhibitors, including enzalutamide, are treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC), but resistance inevitably develops. Using metastatic samples from a prospective phase 2 clinical trial, we epigenetically profile enhancer/promoter activities with acetylation of lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation followed by sequencing, before and after AR-targeted therapy. We identify a distinct subset of H3K27ac-differentially marked regions that are associated with treatment responsiveness, which we successfully validate in mCRPC patient-derived xenograft (PDX) models. In silico analyses reveal histone deacetylase (HDAC)3 to critically drive resistance to hormonal interventions, which we validate in vitro. Critically, we identify the pan-HDAC inhibitor vorinostat to be effective in decreasing tumor cell proliferation, both in vitro and in vivo. Moreover, we uncover evidence for HDAC3 working together with glucocorticoid receptor (GR) as a potential mechanism for this therapeutic effect. These findings demonstrate the rationale for therapeutic strategies including HDAC inhibitors to improve patient outcome in advanced stages of mCRPC.}, }
@article {pmid40609573, year = {2025}, author = {Layman, RM and Han, HS and Rugo, HS and Stringer-Reasor, EM and Specht, JM and Dees, EC and Kabos, P and Suzuki, S and Mutka, SC and Sullivan, BF and Gorbatchevsky, I and Wesolowski, R}, title = {Overall survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer treated in a phase 1b trial evaluating gedatolisib in combination with palbociclib and endocrine therapy.}, journal = {The Lancet. Oncology}, volume = {26}, number = {7}, pages = {e332-e333}, doi = {10.1016/S1470-2045(25)00236-0}, pmid = {40609573}, issn = {1474-5488}, }
@article {pmid40609744, year = {2025}, author = {Banerjee, R and Amonoo, HL and Barata, A and Bhatt, NS and Espinoza-Gutarra, MR and Jayani-Kosarzycki, RV and Katz, H and Kennedy, VE and Nawas, M and Steineck, A and Wanjiku, C and Costanzo, E and Cusatis, RN and Knight, JM and Schoemans, H and Sidana, S and Wood, WA and Sung, AD and Lee, CJ and Hamilton, BK}, title = {Assessing Quality of Life and Symptoms in Transplantation and CAR-T Recipients: Expert Panel Recommendations from the Survivorship Special Interest Group of ASTCT.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {10}, pages = {774-788}, pmid = {40609744}, issn = {2666-6367}, support = {K08 CA251654/CA/NCI NIH HHS/United States ; K12 TR004930/TR/NCATS NIH HHS/United States ; R03 CA259489/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Quality of Life ; *Hematopoietic Stem Cell Transplantation ; Patient Reported Outcome Measures ; *Immunotherapy, Adoptive/methods ; Survivorship ; Surveys and Questionnaires ; }, abstract = {Patient-reported outcomes (PROs) to measure quality of life (QOL) and other symptoms play an increasingly important role in clinical trials and regulatory approvals for hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy. However, their adoption has been hindered by wide heterogeneity in the choice of PRO measures for clinical research, including the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT) and the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) inventories. In addition, the potential for PRO integration into routine standard-of-care (SOC) practice for patients undergoing HCT or CAR-T therapy has not yet been realized. As part of a coordinated effort by 3 American Society for Transplantation and Cellular Therapy Special Interest Groups, we developed best practices for PRO integration in adult and pediatric recipients of HCT and CAR-T therapy. We strongly encourage the use of the Patient-Reported Outcomes Measurement Information System (PROMIS) or the PRO version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) instruments as the primary PRO measures for most HCT and CAR-T trials. Measures such as the PROMIS-29 inventory can be used for QOL assessments, while PRO-CTCAE item banks can be used for specific symptoms. Rationales for our strong recommendation to move from FACT-BMT and EORTC QLQ-C30 to PROMIS/PRO-CTCAE instruments include: (1) free licensing and ease of implementation, including in electronic medical records; (2) psychometric validation in a variety of oncologic settings, including during inpatient hospitalizations; (3) translation into multiple languages, with validation in both adult and pediatric settings; and (4) adoption into centrally collected PRO protocols from the Center for International Blood and Marrow Transplant Research for both HCT and CAR-T recipients. Steps to operationalize these PRO measures are discussed, as are methods to migrate existing data from legacy PRO instruments. We similarly recommend the consideration of PRO integration into SOC clinical practice, including the development of threshold-based workflows to both personalize and standardize care in this setting. Other panel recommendations include the use of standardized timepoints for longitudinal PRO assessments and the inclusion of patient advocates when implementing PRO measures. Implementing these steps will improve the ability of PROs to improve outcomes for patients undergoing HCT or CAR-T therapy, both in trials and-more importantly-in SOC practice.}, }
@article {pmid40610289, year = {2025}, author = {Keyes, M and Sturdza, AE and Crook, J and Anderson, B and Boldrini, L and Chino, J and Corradini, S and Deufel, C and Farach, A and Folkert, MR and Frank, SJ and Hannoun-Levi, JM and Hoskin, P and Jurgenliemk-Schulz, I and Kamrava, M and Kollmeier, M and McKee, MM and Iii, POF and Rossi, P and Pieters, BR and Strnad, V and Shah, C and Siebert, FA and Stewart, A and Taggar, AS and Tagliaferri, L and Morton, G}, title = {Joint ABS/GEC-ESTRO Consensus Statement on the objectives of training in brachytherapy for physicians.}, journal = {Brachytherapy}, volume = {24}, number = {5}, pages = {631-643}, doi = {10.1016/j.brachy.2025.05.006}, pmid = {40610289}, issn = {1873-1449}, mesh = {*Brachytherapy/standards ; Humans ; *Radiation Oncology/education ; Clinical Competence ; Curriculum ; Canada ; United States ; *Education, Medical, Graduate/standards ; }, abstract = {Brachytherapy is an essential skill in the practice of radiation oncology and is an important component of high-quality, full-service radiation oncology departments. With rapidly changing technology, the role of brachytherapy is constantly evolving, but it remains critically important for optimal patient care in several disease sites. As a procedural aspect of radiation oncology practice, brachytherapy requires a fundamentally different and more focused training approach, with specific training objectives, a unique knowledge base, and specialized training environment. The existing gap in brachytherapy training and experience is compounded with a lack of standardized training objectives. Consensus statement objectives were in part adapted with permission from the Royal College of Physician and Surgeons of Canada, and then further reviewed, modified and enriched with expert knowledge by all authors. Training objectives were further synchronized with the US Accreditation Council for Graduate Medical Education (ACGME). This ABS/GEC-ESTRO Consensus Statement of training objectives will facilitate brachytherapy training by outlining the necessary knowledge and procedural skills for successful practice in brachytherapy. The final brachytherapy curriculum development for any individual program, country and regions, is the responsibility of the individual programs and licensing jurisdictions and should be tailored to their patient population, available equipment and facilities.}, }
@article {pmid40613577, year = {2026}, author = {Fourment, M and Macaulay, M and Swanepoel, CJ and Ji, X and Suchard, MA and Matsen Iv, FA}, title = {torchtree: Flexible Phylogenetic Model Development and Inference Using PyTorch.}, journal = {Systematic biology}, volume = {75}, number = {1}, pages = {39-51}, pmid = {40613577}, issn = {1076-836X}, support = {R01 AI153044/NH/NIH HHS/United States ; R01 AI162611/NH/NIH HHS/United States ; R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; //Louisiana Board of Regents/ ; DEB1754142//NSF/ ; LP180100593//Australian Research Council/ ; S10OD028685//Fred Hutch/ ; S10 OD028685/OD/NIH HHS/United States ; }, mesh = {*Phylogeny ; *Classification/methods ; *Software ; Algorithms ; Markov Chains ; }, abstract = {Bayesian inference has predominantly relied on the Markov chain Monte Carlo (MCMC) algorithm for many years. However, MCMC is computationally laborious, especially for complex phylogenetic models of time trees. This bottleneck has led to the search for alternatives, such as variational Bayes, which can scale better to large data sets. In this paper, we introduce torchtree, a framework written in Python that allows developers to easily implement rich phylogenetic models and algorithms using a fixed tree topology. One can either use automatic differentiation or leverage torchtree's plug-in system to compute gradients analytically for model components for which automatic differentiation is slow. We demonstrate that the torchtree variational inference framework performs similarly to BEAST in terms of speed, and delivers promising approximation results, though accuracy varies across scenarios. Furthermore, we explore the use of the forward Kullback-Leibler (KL) divergence as an optimizing criterion for variational inference, which can handle discontinuous and nondifferentiable models. Our experiments show that inference using the forward KL divergence is frequently faster per iteration compared with the evidence lower bound (ELBO) criterion, although the ELBO-based inference may converge faster in some cases. Overall, torchtree provides a flexible and efficient framework for phylogenetic model development and inference using PyTorch.}, }
@article {pmid40613977, year = {2025}, author = {Mezzanotte-Sharpe, J and Hsu, CY and Choi, D and Sheffield, H and Zelinskas, S and Proskuriakova, E and Montalvo, M and Lee, DS and Whisenant, JG and Gaffney, K and Thompson, MS and Blenman, K and Tawagi, K and Symonds, L and Santa-Maria, C and Unni, N and Quiroga, D and Shyr, Y and Kennedy, LC}, title = {Adverse events in patients treated with neoadjuvant chemo/immunotherapy for triple negative breast cancer: results from seven academic medical centers.}, journal = {Breast cancer research and treatment}, volume = {213}, number = {1}, pages = {71-80}, pmid = {40613977}, issn = {1573-7217}, support = {K12 CA090625/CA/NCI NIH HHS/United States ; T32 CA217834/CA/NCI NIH HHS/United States ; 2T32CA217834-07//VOLT T32/ ; }, mesh = {Humans ; *Triple Negative Breast Neoplasms/drug therapy/pathology/mortality ; Female ; Middle Aged ; *Neoadjuvant Therapy/adverse effects ; Academic Medical Centers ; Retrospective Studies ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ; Adult ; Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects ; *Immunotherapy/adverse effects/methods ; Treatment Outcome ; Chemotherapy, Adjuvant/adverse effects ; }, abstract = {PURPOSE: The standard-of-care neoadjuvant treatment for early-stage or locally advanced triple negative breast cancer (TNBC) is the KEYNOTE-522 regimen that combines pembrolizumab and chemotherapy. Although this approach has superior response and survival rates, high-grade adverse events (AEs) are common. Real-world data from a diverse patient population is needed to better understand practice patterns and the impact of immunotherapy in TNBC patients.<br><br>METHODS: Medical records from TNBC patients were retrospectively reviewed during neoadjuvant and adjuvant treatment with pembrolizumab and chemotherapy. CTCAE version 5.0 was used to grade AEs. Variables were reported with descriptive statistics, and AE, pCR and hospitalization rates were estimated with 95% confidence intervals.<br><br>RESULTS: We identified 415 patients from seven academic medical centers; 60% identified as White and 21% as Black. pCR rate was 52%. 88% of patients experienced an AE, 38% experienced a grade 3+&#x2009;AE, and 31% stopped pembrolizumab early. Hospitalization rate was 26%. There were no statistically significant differences in AE, pCR or hospitalization rates between White and Black patients. Obese patients had a statistically significant higher hospitalization rate (p&#x2009;=&#x2009;0.014). There were 18 deaths during treatment, mainly from progressive TNBC.<br><br>CONCLUSION: This is one of the largest real-world, diverse patient cohorts for TNBC patients treated with chemotherapy and pembrolizumab. pCR rate was lower than that reported in the KEYNOTE-522 study and in smaller real-world studies, potentially due to high rates of pembrolizumab and chemotherapy discontinuation. AEs and hospitalizations were common, with obese patients more likely to be hospitalized than patients with a normal BMI.}, }
@article {pmid40614134, year = {2025}, author = {Marchak, JG and Seidel, KD and Cherven, BO and Klosky, JL and Ritenour, CWM and Leisenring, WM and Sklar, CA and Ford, JS and Krull, KR and Robison, LL and Armstrong, GT and Meacham, LR}, title = {Comprehensive assessment of sexual function in male survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {131}, number = {14}, pages = {e35967}, pmid = {40614134}, issn = {1097-0142}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; CA21765/CA/NCI NIH HHS/United States ; //American Lebanese Syrian Associated Charities/ ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; //Lance Armstrong Foundation/ ; CA55727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Adult ; Middle Aged ; Young Adult ; *Neoplasms/complications ; *Sexual Dysfunction, Physiological/epidemiology/etiology ; Surveys and Questionnaires ; *Survivors ; *Cancer Survivors ; Child ; Risk Factors ; *Sexual Dysfunctions, Psychological/epidemiology/etiology ; Sexual Behavior ; }, abstract = {BACKGROUND: Assessment of sexual dysfunction among adult male survivors of childhood cancer has primarily been limited to erectile dysfunction. This study aimed to characterize sexual functioning more comprehensively among a large population of male survivors of childhood cancer.<br><br>METHODS: Male survivors (N&#xa0;=&#xa0;1595, 22.0-59.4 years, median age, 37.8 years) and siblings (N&#xa0;=&#xa0;269, 21.5-60.8 years, median age, 38.9 years) from the Childhood Cancer Survivor Study completed the Sexual Functioning Questionnaire (SFQ) to assess interest, desire, arousal, satisfaction, activity, orgasm, masturbation, relationship, and problems. Poor sexual functioning was defined as SFQ Total scores >2 standard deviations below siblings' mean. Multivariable logistic regression identified risk factors for poor sexual function.<br><br>RESULTS: Survivors (8.3%) were more likely to report poor sexual functioning as compared to siblings (4.9%, odds ratio [OR], 1.9; 95% confidence interval [CI], 1.1-3.4) and reported lower SFQ total scores (p&#xa0;<&#xa0;.001) and lower means on seven subscales. Poor sexual functioning among survivors was associated with older age (40-49 years: OR, 3.81; 95% CI, 1.78-8.18; 50-59 years: OR, 6.45; 95% CI, 2.28-18.30), not being married (OR,&#xa0;4.39; 95% CI, 2.66-7.26), lower education (OR, 3.07; 95% CI, 1.32-7.14), learning/memory problems (OR,&#xa0;1.83; 95% CI, 1.02-3.27), and high-dose cranial (&#x2265;40 Gy: OR, 3.45; 95% CI, 1.58-7.51) or high-dose testicular (&#x2265;10 Gy: OR,&#xa0;4.16; 95% CI, 1.66-10.39) radiation.<br><br>CONCLUSIONS: Adult male survivors report poor sexual functioning at twice the rate expected before age 60 years. High-dose cranial or testicular radiation, as well as social and cognitive factors, contributes to risk. Improved awareness of sexual dysfunction prevalence and risk factors in male childhood cancer survivors can help clinicians better assess and treat those at highest risk.}, }
@article {pmid40614783, year = {2025}, author = {Corn, BW and Paulus, R and Gondi, V and Mehta, MP and Fogh, S and Wefel, JS and Videtic, GM and Sun, A and Yoon, H and Heinzerling, JH and McGarry, RC and Kundapur, V and Devisetty, K and Wu, A and McCarron, EC and Pollock, J and Kanner, AA and Feldman, DB and Pugh, SL and Kachnic, LA and Movsas, B}, title = {"Hope" Drives Quality of Life in Patients With Brain Metastases, But, the "Hope Center" Remains Elusive: An Analysis of NRG-CC003.}, journal = {International journal of radiation oncology, biology, physics}, volume = {123}, number = {3}, pages = {642-652}, pmid = {40614783}, issn = {1879-355X}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; UG1 CA189867/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Quality of Life/psychology ; *Brain Neoplasms/secondary/psychology/radiotherapy/prevention &amp; control ; *Cranial Irradiation/psychology/methods ; *Lung Neoplasms/pathology/psychology ; *Hippocampus/radiation effects/physiology ; Female ; Male ; Middle Aged ; *Hope ; *Small Cell Lung Carcinoma/psychology/radiotherapy/secondary ; Aged ; Patient Reported Outcome Measures ; Cognition ; Adult ; }, abstract = {PURPOSE: NRG-CC003 randomized 393 patients with small cell lung cancer to prophylactic cranial irradiation (PCI) with or without hippocampal avoidance (HA). "Hopefulness" is a cognitive construct with 3 components: goals, pathways, and agency. Hope is measurable with validated instruments. Since hope is cognitive in nature, the existence of a "hope center" in the brain-most likely in the hippocampus-has been hypothesized. One exploratory objective of NRG-CC003 posited that if hope levels were better maintained in patients randomized to PCI + HA, then the hippocampus would be implicated in the mechanism of hopefulness.<br><br>METHODS AND MATERIALS: PCI consisted of 10 fractions of 2.5 Gy. The Adult Hope Scale (AHS) was administered at time-zero and at 6 months. Regarding patient-reported outcome measures, the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 was administered at baseline and at 3, 6-, 12-, 18- and 24-month intervals. Comparisons of AHS scores by arm were made using Wilcoxon-Mann-Whitney tests, and correlation of AHS with EORTC QLQ-C30 by Pearson correlation coefficients.<br><br>RESULTS: Approximately 95% completed the AHS at baseline and 67% filled out the questionnaire at 6 months paralleling the completion rates of the conventional tools for QOL and neurocognition. When comparing hope levels (change from baseline to 6 months) there was no significant difference (P > .05) between the 2 arms of the trial. There was a correlation for the components of hopefulness with QOL; specifically, between change in agency score and QLQ-C30 global health status (&#x3c1; = 0.27, P < .0001) as well as between change in pathways score and QLQ-C30 global health status (&#x3c1; = 0.16, P = .022).<br><br>CONCLUSIONS: It is feasible to study hopefulness in the context of prospective trials conducted within the National Clinical Trials Network. The hippocampus could not be implicated as a critical structure in a central pathway that coordinates hopefulness. For the first time, validated tools established a relationship between hope and quality of life among cancer patients.}, }
@article {pmid40614969, year = {2025}, author = {Kennedy, VE and Ahmed, N and Artz, A and Bhatt, NS and Custatis, R and Espinoza-Gutarra, MR and Farhan, S and Ferguson, RJ and Hamilton, B and Katz, H and Kelly, DL and Knight, JM and Lee, C and Lin, A and Lin, R and Mohanraj, L and Munshi, P and Nawas, M and Nelson, AM and Odstracil, S and Olin, R and Phelan, R and Rentscher, KE and Schoemans, H and Sung, A and Taylor, MR and Wood, W and Yuen, CH and Jayani-Kosarzycki, RV}, title = {Assessing cognitive function in transplantation and chimeric antigen receptor t cell therapy recipients: Expert recommendations from the survivorship, aging and biobehavioral special interest groups of the American Society for Transplantation and Cellular Therapy.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {10}, pages = {756-773}, doi = {10.1016/j.jtct.2025.06.026}, pmid = {40614969}, issn = {2666-6367}, support = {K12 TR004930/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Cognitive Dysfunction/etiology/diagnosis ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Immunotherapy, Adoptive/adverse effects/methods ; *Cognition/physiology ; Quality of Life ; *Receptors, Chimeric Antigen ; Survivorship ; }, abstract = {Cognitive impairment is a prevalent yet underexplored comorbidity and complication in hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy. Affecting up to one-half of patients, cognitive impairment may include acute phases, manifesting as transplantation-associated altered mentation and encephalopathy or immune effector cell-associated neurotoxicity syndrome, and may persist for years post-treatment as cancer-related cognitive impairment (CRCI). Such dysfunction undermines autonomy, healthcare management, work reintegration, and quality of life. This consensus review synthesizes current evidence on CRCI across the timeline of transplantation and cellular therapy (TCT), organized into pre-TCT, peri-TCT, and post-TCT phases, with additional focus on specific populations, including older adults and pediatric patients. It highlights gaps in the understanding of cognitive impairment risks, trajectory, and impact alongside the challenges of standardizing assessments in diverse practice settings. Key recommendations, endorsed by the American Society for Transplantation and Cellular Therapy's Aging, Biobehavioral Research, and Survivorship Special Interest Groups, advocate for cognitive assessment pretherapy and post-therapy using validated instruments such as the Montreal Cognitive Assessment or Blessed Orientation-Memory-Concentration Test. We also recommend supplementation with patient-reported outcome measures for comprehensive evaluation. We recommend action items for cases in which cognitive impairment is identified, including exclusion of alternative etiologies, reconsideration of therapy or caregiving plans, and referrals for additional evaluation and rehabilitation, among others. Practical guidance for implementation across clinical and research settings is provided, emphasizing the need for multidisciplinary strategies to address identified impairments. This work aims to establish a framework for systematic cognitive monitoring, improving patient outcomes and quality of life while guiding future research to address significant knowledge and implementation gaps.}, }
@article {pmid40616382, year = {2025}, author = {Lakkaraja, M and Baker, KS}, title = {Precision transplant and cell therapies for non-malignant disorders-The path forward.}, journal = {British journal of haematology}, volume = {207}, number = {4}, pages = {1222-1226}, pmid = {40616382}, issn = {1365-2141}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; //American Society of Hematology/ ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods ; *Precision Medicine/methods ; *Cell- and Tissue-Based Therapy/methods ; *Transplantation Conditioning/methods ; Genetic Therapy/methods ; }, abstract = {The number of patients undergoing haematopoietic stem cell transplant (HCT) and cell therapies for non-malignant disorders is steadily increasing with more genetic diseases being identified and newer gene therapy products being introduced for various indications. By combining individualized conditioning, novel graft manipulation techniques, using cutting edge methods to monitor post HCT response and offering exceptional survivorship care, one can achieve excellent survival and improved quality of life for these patients.}, }
@article {pmid40616435, year = {2025}, author = {Huang, Y and Zhang, B and Zhang, L and Mayer, BT and Martin, T and Hahn, W and Hyrien, O and Gelderblom, HC}, title = {Dose finding in early-phase human immunodeficiency virus type 1 prevention monoclonal antibody clinical trials.}, journal = {Clinical trials (London, England)}, volume = {22}, number = {4}, pages = {442-451}, pmid = {40616435}, issn = {1740-7753}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control ; *HIV-1/immunology ; *Antibodies, Monoclonal/administration &amp; dosage ; Antibodies, Neutralizing/administration &amp; dosage/immunology ; *HIV Antibodies/administration &amp; dosage/immunology ; Immunization, Passive/methods ; Clinical Trials as Topic ; }, abstract = {Human immunodeficiency virus type 1 remains a major public health burden with 39 million people living with human immunodeficiency virus type 1 and 1.3 million new diagnoses in 2023, despite the recent approval of multiple antiretroviral-based prevention products. While the development of a safe and effective human immunodeficiency virus type 1 vaccine remains the ultimate goal for controlling the worldwide pandemic, progress has been hindered by unprecedented challenges, including the extraordinary genetic diversity of human immunodeficiency virus type 1, the inability of current vaccines to induce broadly reactive antibody responses, and the lack of clear immune correlates of protection to serve as benchmarks for vaccine development. Passive administration of broadly neutralizing monoclonal antibodies that are engineered versions of naturally occurring antibodies has emerged as a potential complement to current human immunodeficiency virus type 1 prevention modalities. These antibodies are isolated from people with human immunodeficiency virus type 1 and can neutralize a broad range of human immunodeficiency virus type 1 viruses. Importantly, advances in antibody engineering have improved the pharmacokinetics of these monoclonal antibodies, offering potential for lower levels and/or less frequent monoclonal antibody dosing with greater feasibility and accessibility for human immunodeficiency virus type 1 prevention. Evaluating monoclonal antibody candidates in human immunodeficiency virus type 1 prevention trials, dose-finding and optimization requires a careful balance between virus-neutralization coverage, cost considerations, and practical constraints. To achieve this, pharmacokinetic modeling of antibody concentrations over time, combined with pharmacodynamics modeling of the relationship between neuralization titers and prevention efficacy, serves as a core of the statistical framework. In addition, for human immunodeficiency virus type 1 monoclonal antibodies administered to individuals without human immunodeficiency virus type, neutralization titers can be reliably predicted from antibody concentrations, owning to the preservation of neutralization function post-administration of these monoclonal antibodies. Within this framework, the antibody-mediated prevention efficacy trials of VRC01, an human immunodeficiency virus type 1 monoclonal antibody, and a meta-analysis of 16 different monoclonal antibodies in non-human primates provided consistent evidence that neutralization titer is a potential pharmacodynamics biomarker of monoclonal antibody prevention efficacy. These findings support the use of integrated pharmacokinetics/pharmacodynamics modeling as a foundation for dose finding of human immunodeficiency virus type 1 monoclonal antibodies. However, in the context of combination monoclonal antibody regimens, additional challenges arise. The total dose cost, operational feasibility, and the influence of dosing ratios on neutralization breadth and potency across diverse human immunodeficiency virus type 1 viral strains are important areas for further research. While monoclonal antibody clinical trials share some common design features with therapeutic small molecule drug trials, monoclonal antibodies possess unique safety, pharmacokinetics and pharmacodynamics profiles that require dedicated statistical and clinical considerations, particularly when used for prevention of viral infections. In this article, we highlight dose-finding efforts particularly for combination monoclonal antibodies regimens, including the selection of optimal dosing ratio and total dose amount in the context of human immunodeficiency virus type 1 prevention. Looking ahead, future directions in monoclonal antibody-based human immunodeficiency virus type 1 prevention include efforts to enhance dose-associated cost-effectiveness, and the identification and validation of robust pharmacokinetic and pharmacodynamic markers that are predictive of the prevention efficacy of combination monoclonal antibodies.}, }
@article {pmid40617294, year = {2025}, author = {Te, C and Elahi, T and Samples, K and Onstad, L and Lee, SJ}, title = {Serositis Associated with Chronic Graft-Versus-Host Disease.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {11}, pages = {902.e1-902.e6}, pmid = {40617294}, issn = {2666-6367}, support = {P01 CA018029/CA/NCI NIH HHS/United States ; R01 CA118953/CA/NCI NIH HHS/United States ; U01 CA118953/CA/NCI NIH HHS/United States ; U01 CA236229/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/complications/etiology ; Male ; Female ; Middle Aged ; *Serositis/etiology/pathology ; Adult ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Retrospective Studies ; Chronic Disease ; Aged ; Risk Factors ; Young Adult ; }, abstract = {Serositis is a recognized complication associated with chronic graft-versus-host disease (cGVHD) in patients who undergo allogeneic hematopoietic cell transplantation (HCT). Although it is uncommon, serositis after HCT can have significant negative clinical impacts. There are limited data describing the patient population, incidence, risk factors, and management strategies of cGVHD-associated serositis. We retrospectively identified 50 adult patients who underwent HCT at the Fred Hutchinson Cancer Center between 1998 and 2021 and developed serositis attributed to cGVHD. Most patients developed pericardial effusions (n = 31) and/or pleural effusions (n = 38). Overall, 94% of patients with pleural effusion and 87% of patients with pericardial effusion received medical management for their serositis. Eleven patients experienced at least one recurrence of serositis. The median overall survival for all serositis types at 1-year postserositis diagnosis was 86%, and 69% for 3-year postserositis diagnosis. Serositis is a serious atypical cGVHD manifestation, and prospective data collected from a larger cohort of patients is required to better understand favorable treatment strategies and outcomes of this complication.}, }
@article {pmid40617679, year = {2025}, author = {Petersdorf, EW}, title = {Semper Progrediens.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {7}, pages = {399-400}, doi = {10.1016/j.jtct.2025.06.005}, pmid = {40617679}, issn = {2666-6367}, }
@article {pmid40618773, year = {2025}, author = {White, RG and Churchyard, GJ and Horton, KC and Fiore-Gartland, A and Behr, MA and Clark, RA and Cobelens, F and Ernst, JD and Esmail, H and Garcia-Basteiro, AL and Hadinegoro, SR and Hanekom, WA and Hatherill, M and Hill, PC and Muloiwa, R and Pelzer, PT and Rangaka, L and Rees, H and Schrager, L and Stanley, M and Tufet, M and Wong, EB and Houben, RMGJ}, title = {Evidence required to evaluate the use of bacteriologically confirmed asymptomatic tuberculosis disease as a primary endpoint in prevention of tuberculosis disease vaccine licensure trials.}, journal = {The Lancet. Respiratory medicine}, volume = {13}, number = {10}, pages = {933-942}, pmid = {40618773}, issn = {2213-2619}, support = {INV-035506/GATES/Gates Foundation/United States ; 75N93019C00070/AI/NIAID NIH HHS/United States ; INV-001754/GATES/Gates Foundation/United States ; P30 AI168034/AI/NIAID NIH HHS/United States ; R01 AI175555/AI/NIAID NIH HHS/United States ; R01 AI147321/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Tuberculosis Vaccines/therapeutic use ; *Tuberculosis/prevention &amp; control/diagnosis ; Clinical Trials as Topic ; *Endpoint Determination ; Mycobacterium tuberculosis/isolation &amp; purification/immunology ; *Asymptomatic Infections ; }, abstract = {Current licensure trials of new vaccines to prevent tuberculosis disease use bacteriologically confirmed symptomatic tuberculosis disease as the primary endpoint. Globally, the incidence of symptomatic tuberculosis disease is low, making licensure trials large, long, and expensive. New data suggest that bacteriologically confirmed asymptomatic tuberculosis disease might occur more frequently than symptomatic tuberculosis disease. Therefore, if vaccines have efficacy against asymptomatic disease, tuberculosis vaccine licensure trials could include it in the primary endpoint, potentially leading to smaller or shorter trials. We describe the potential benefits and risks of this inclusion in the primary endpoint of tuberculosis vaccine licensure trials. We also simulate licensure trial endpoint accrual and summarise feedback from anonymous regulators and policy makers on the knowledge needed to consider this proposal and research studies needed to fill these evidence gaps. If bacteriologically confirmed asymptomatic tuberculosis disease could be included in the primary endpoint of tuberculosis disease licensure trials, it could lead to cheaper and more rapid tuberculosis vaccine development.}, }
@article {pmid40619005, year = {2025}, author = {Hullar, MA and Kahsai, O and Curtis, KR and Navarro, SL and Zhang, Y and Randolph, TW and Levy, L and Shojaie, A and Kratz, M and Neuhouser, ML and Lampe, PD and Raftery, D and Lampe, JW}, title = {Metabolic plasticity of the gut microbiome in response to diets differing in glycemic load in a randomized, crossover, controlled feeding study.}, journal = {The American journal of clinical nutrition}, volume = {122}, number = {3}, pages = {780-792}, pmid = {40619005}, issn = {1938-3207}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA192222/CA/NCI NIH HHS/United States ; U54 CA116847/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Gastrointestinal Microbiome ; Male ; Cross-Over Studies ; Female ; Adult ; *Glycemic Load ; *Diet ; Feces/microbiology ; *Bacteria/classification/genetics/metabolism ; Young Adult ; Middle Aged ; RNA, Ribosomal, 16S/genetics ; }, abstract = {BACKGROUND: Dietary patterns characterized by low glycemic, minimally processed plant foods are associated with lower risk of several chronic diseases.<br><br>OBJECTIVES: Evaluate the effects of a low glycemic load (LGL) compared with a high glycemic load (HGL) dietary pattern on stool bacterial community structure and metabolism.<br><br>METHODS: Participants in this crossover-controlled feeding study were healthy men and women (n = 69). We identified genera, species, and genes and transcripts of metabolic pathways and bacterial enzymes using 16S rRNA gene, metagenomic and metatranscriptomic sequencing, and bioinformatic analysis.<br><br>RESULTS: Overall community structure measured by alpha and beta diversity was not significantly different across the diets, although diet did significantly increase the abundance of 13 of 161 genera (Padj < 0.05) and 5 species in the LGL diet and 7 species in the HGL diet. Gene expression in the hexitol fermentation pathway (&#x3b2; = -1.15; SE = 0.24; 95% confidence interval [CI]: -1.63, -0.67; Padj = 0.002) was significantly higher in the HGL diet, whereas expression in the L-lysine biosynthesis pathway (&#x3b2; = 0.20; SE = 0.05; 95% CI: 0.09, 0.30; Padj = 0.03) was enriched in the LGL diet. The beta diversity of expressed carbohydrate-active enzymes (CAZymes) was significantly different between the diets (MiRKAT, P < 0.001). CAZymes enriched in the HGL diet reflected dietary additives, whereas CAZymes enriched in the LGL diet reflected diverse phytochemical intake. There was a significant interaction between homeostasis model assessment of insulin resistance (HOMA-IR) and the coenzyme A biosynthesis I pathway involved in bacterial fatty acid biosynthesis (Padj = 0.035), which was positive in the HGL diet (b = 0.20; SE = 0.09; 95% CI: 0.02, 0.39) and negative in the LGL diet (&#x3b2; = -0.23; SE = 0.09; 95% CI: -0.40, -0.06).<br><br>CONCLUSIONS: In healthy humans, diet impacts microbial metabolism and enzymatic activity but not the overall diversity of the gut microbiome. This emphasizes the relevance of dietary components in activating expression of specific bacterial genes and their impact on host metabolism. This trial was registered at clinicaltrials.gov as NCT00622661.}, }
@article {pmid40619101, year = {2025}, author = {Jimenez Jimenez, AM and Spellman, SR and Politikos, I and McCurdy, SR and Devine, SM and Malki, MMA and Bolon, YT and Lee, SJ and Dehn, J and Pidala, J and Maiers, M and Askar, M and Malmberg, C and Auletta, JJ and Stefanski, H and Broglie, L and Qayed, M and Horwitz, M and Wilder, JS and Gooptu, M and Mehta, RS and Fernandez-Viña, M and Shaw, BE and Shaffer, BC}, title = {Allogeneic Hematopoietic Cell Donor Selection: Contemporary Guidelines from the NMDP/CIBMTR.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {12}, pages = {973-988}, pmid = {40619101}, issn = {2666-6367}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects ; *Donor Selection/methods/standards ; Graft vs Host Disease/prevention &amp; control ; Transplantation, Homologous ; Tissue Donors ; }, abstract = {Allogeneic hematopoietic cell transplantation (HCT) remains a curative therapy for many patients with hematologic malignancies, bone marrow failure syndromes, inborn errors of immunity and metabolic disorders. Current donor selection strategies typically prioritize the selection of an HLA-matched donor over HLA mismatched ("alternative") donor sources, with a hierarchical approach to the donor search. More recent data challenge this rubric, particularly in the context of novel graft-versus-host disease (GVHD) prophylaxis strategies that demonstrate improved outcomes in alternative donor HCT recipients. In this setting, an increased emphasis on non-HLA factors (both donor characteristics and systemic factors) in determining donor selection is now feasible. In this guideline, we review recent evidence from prospective clinical trials as well as high-quality observational studies and provide expert panel recommendations on donor selection algorithms and prioritization in the era of novel GVHD prophylaxis. We then highlight important questions still to be answered in our field.}, }
@article {pmid40620045, year = {2025}, author = {Kauffman, ZJ and Koesser, K and Helzer, KT and Sharifi, MN and Heninger, E and Li, C and Juang, DS and Jarrard, DF and Zhao, SG and Haffner, MC and Beebe, DJ and Lang, JM and Sperger, JM}, title = {Lossless Altered Histone Modification Analysis System (LAHMAS).}, journal = {Lab on a chip}, volume = {25}, number = {16}, pages = {4059-4070}, pmid = {40620045}, issn = {1473-0189}, support = {P30 CA014520/CA/NCI NIH HHS/United States ; P50 CA269011/CA/NCI NIH HHS/United States ; R01 CA247479/CA/NCI NIH HHS/United States ; R50 CA293840/CA/NCI NIH HHS/United States ; }, mesh = {*Histones/metabolism/analysis/chemistry ; Humans ; *Microfluidic Analytical Techniques/instrumentation/methods ; *Lab-On-A-Chip Devices ; Dimethylpolysiloxanes/chemistry ; Equipment Design ; }, abstract = {Miniaturized biological assays using microfluidics have the potential to enhance assay sensitivity, reduce reagent consumption, and increase throughput. However, challenges to miniaturization include increased platform complexity and increased surface to volume ratios leading to risk of evaporation and analyte loss through surface binding. Exclusive Liquid Repellency (ELR) enables open microfluidic systems that minimize these challenges through an oil phase that protects small aqueous volumes from temperature fluctuation and evaporation while eliminating surface fouling that leads to sample loss. Here we report a novel microfluidic platform leveraging ELR and Exclusion-based Sample Preparation (ESP) for the miniaturization of CUT&amp;Tag, a complex multistep biological assay. The resultant Lossless Altered Histone Modification Analysis System (LAHMAS) employs a PDMS-silane treated glass surface immersed in silicone oil to facilitate lossless liquid handling and prevent sample evaporation. The device design, compatible with standard laboratory equipment, allows effective processing of cell inputs as low as 100 cells with higher specificity than macroscale CUT&amp;Tag facilitating accurate chromatin profiling of low input and rare cell samples.}, }
@article {pmid40622009, year = {2025}, author = {Chen, W and Majovski, J and Bhatia, S and Chan, A and Grivas, P and Lee, S and Shah, S and Thompson, JA and Tykodi, SS and Veatch, JR and Schapira, L and Hall, ET}, title = {A mixed-method analysis of oncologist-patient communications about immune checkpoint inhibitors (COACH).}, journal = {The oncologist}, volume = {30}, number = {7}, pages = {}, pmid = {40622009}, issn = {1549-490X}, mesh = {Humans ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Female ; *Oncologists/psychology ; Male ; *Physician-Patient Relations ; Middle Aged ; *Communication ; *Neoplasms/drug therapy/immunology ; Aged ; Adult ; Surveys and Questionnaires ; }, abstract = {BACKGROUND: Despite significant attention in the media and oncology community about improved outcomes associated with immune checkpoint inhibitors (ICIs), there remains a gap in our understanding of how oncologists describe ICIs to their patients. Communication around ICIs represents a challenge as some patients have durable, remarkable benefits while others experience severe toxicities. We investigated oncologist-patient communication practices by performing a mixed-methods study of in-clinic discussions about ICIs.<br><br>MATERIALS AND METHODS: This was a mixed-method study in which in-clinic conversations between oncologists and their patients with advanced cancers about ICIs as potential treatments were audio-recorded. Patients were asked to complete a post-discussion survey. Qualitative data was derived from a general inductive thematic approach while descriptive statistics were used to analyze the survey responses.<br><br>RESULTS: We recorded and analyzed 13 in-clinic conversations involving 8 oncologists and 13 patients. Twelve patients completed the post-discussion surveys. The conversations involved sophisticated discussions of immune function, cancer and ICI mechanisms, and&#xa0;trade-offs&#xa0;between anticancer benefits and toxicities. Oncologists incorporated metaphors and probabilistic information in their explanations. In the post-discussion surveys, patients indicated a preference for detailed information about ICIs and reported that they received the right depth of information in these discussions.<br><br>CONCLUSIONS: During in-clinic discussions of ICI therapy, oncologists provided detailed information about immunology and cancer, often aided by metaphors. Probabilities were commonly used to describe the likelihood of toxicities and benefits. The amount of information provided by the oncologists aligned with the patients' preference for detailed information about their cancer treatments.}, }
@article {pmid40622392, year = {2026}, author = {Naidoo, N and Bell-Brown, A and Kimura, A and Akinsoto, N and Fang, V and Peck, A and Wood, J and Issaka, RB}, title = {Fecal Immunochemical Test Completion by Instruction Type: A Randomized Clinical Trial Comparing Quick Response Code-Linked Video to Pictorial Instructions.}, journal = {The American journal of gastroenterology}, volume = {121}, number = {3}, pages = {785-791}, pmid = {40622392}, issn = {1572-0241}, support = {K08 CA241296/CA/NCI NIH HHS/United States ; K08 CA241296/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Colorectal Neoplasms/diagnosis ; Female ; *Early Detection of Cancer/methods ; Middle Aged ; *Occult Blood ; Aged ; *Patient Education as Topic/methods ; *Health Literacy ; Language ; Quality Improvement ; Video Recording ; }, abstract = {INTRODUCTION: Low-literacy, pictorial instructions improve fecal immunochemical test (FIT) completion and might enhance colorectal cancer (CRC) screening. The aim of this study was to compare FIT completion among English-speaking and Spanish-speaking patients in an organized CRC screening program based on the type of instructions received (quick response [QR] code linked to video vs pictorial instructions).<br><br>METHODS: In this randomized controlled quality improvement study, English-speaking and Spanish-speaking patients eligible for mailed outreach through an organized CRC screening program were randomized 1:1 to receive a FIT kit with either a QR code-linked video or pictorial instructions in their preferred language. Patient demographics (sex, age, race, ethnicity, and insurance type) and clinical outcomes (FIT completion and time to completion) were abstracted from electronic health records.<br><br>RESULTS: Thirteen thousand four hundred seventy-one English-speaking patients and 508 Spanish-speaking patients were included. Overall, 31.9% of patients who received mailed outreach completed CRC screening by FIT. However, FIT completion was higher among patients who received QR code instructions vs pictorial instructions (33.5% vs 30.4%, absolute difference 3.1%, 95% confidence interval 1.5%-4.6%). These findings were similar among English-speaking and Spanish-speaking patients. The median time to FIT completion was 2 days longer (24 days, 95% confidence interval 23-25) for patients who received QR code instructions versus pictorial instructions; however there was no difference in time to FIT completion by the language group.<br><br>DISCUSSION: Providing QR code-based education offers a promising format for delivering low literacy instructions, which might be a practical strategy to improve FIT completion for CRC screening.}, }
@article {pmid40623045, year = {2025}, author = {Dhodapkar, MV and Paiva, B}, title = {Immune alterations in myeloma evolution and outcomes: quo vadis?.}, journal = {Blood}, volume = {146}, number = {9}, pages = {1041-1050}, pmid = {40623045}, issn = {1528-0020}, mesh = {Humans ; *Multiple Myeloma/immunology/pathology/therapy ; *Monoclonal Gammopathy of Undetermined Significance/immunology/pathology/therapy ; Tumor Microenvironment/immunology ; Animals ; Plasma Cells/immunology/pathology ; Disease Progression ; }, abstract = {The pathogenesis of multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS) is linked to an aging immune system. Chronic activation of B/plasma cells may contribute to the origin of MGUS, which is frequent in the older individuals. However, only 1% of individuals with MGUS annually experience progression to MM. The immune system can specifically recognize MGUS lesions, and preclinical MM models provide evidence for both innate and adaptive immune surveillance. Multiomic studies have identified several systemic alterations at the MGUS stage, suggesting accelerated immune aging prior to evolution into clinical malignancy. MM is further associated with spatial alterations in patterns of tumor growth and in situ regulation of regional immunity. Both tumor and microenvironment-related factors contribute to immune paresis, which facilitates the dissemination of clonal plasma cells, and increases the risk of infections in patients with MM. Immune profiles in blood or marrow exhibit considerable heterogeneity, and have been linked to outcomes following immune therapies, including T-cell redirection. Understanding how underlying systemic immune changes impact in vivo function and durability of natural or synthetic tumor/antigen-specific immunity needs further study. Preserving or restoring immune function may be critical for long-term outcomes both in the context of prevention of clinical MM and of treating active disease. Benchmarking of immune biomarkers followed by its prospective integration into current risk models, together with improved understanding of mechanisms underlying tumor immunity in vivo, are needed to optimize immune approaches and improve outcomes in MM.}, }
@article {pmid40623049, year = {2025}, author = {Perales, MA and Awan, FT and Boumendil, A and Patel, J and Castagna, L and Angelucci, E and Finel, H and Kulagin, A and Glass, B and Corradini, P and Herrera, AF and Blaise, D and Kharfan-Dabaja, MA and Halahleh, K and Ahmed, S and Martínez, C and Giebel, S and Montoto, S and Jones, RJ and Ahmed, N and Lynch, RC and De Lima, MJ and Shadman, M and Sauter, CS and Ahn, KW and Hamadani, M and Bazarbachi, A and Sureda, A}, title = {Outcomes of allogeneic HCT in Hodgkin lymphoma in the era of checkpoint inhibitors: a joint CIBMTR and EBMT analysis.}, journal = {Blood}, volume = {146}, number = {8}, pages = {1011-1029}, pmid = {40623049}, issn = {1528-0020}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hodgkin Disease/therapy/mortality ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods ; Female ; Male ; Middle Aged ; Adult ; Graft vs Host Disease/etiology/prevention &amp; control ; *Immune Checkpoint Inhibitors/therapeutic use ; Transplantation, Homologous ; Aged ; Young Adult ; Adolescent ; Treatment Outcome ; Cyclophosphamide/therapeutic use ; }, abstract = {Checkpoint inhibitors (CPIs) have shown remarkable efficacy in Hodgkin lymphoma (HL), and are now used routinely. While allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for HL, there are concerns prior CPIs may exacerbate post-allo-HCT complications, particularly graft-versus-host disease (GVHD), and lead to worse outcomes. Given the relative paucity of data, we performed a Center for International Blood and Marrow Transplant Research/European Society for Blood and Marrow Transplantation study to examine the impact of prior CPIs in allo-HCT. We included 2186 adult patients aged >18 years who received a first allo-HCT using a matched related, unrelated, or haploidentical donor from 2008 to 2023. Twenty-seven percent of patients received prior CPIs. GVHD prophylaxis was posttransplant cyclophosphamide (PTCy) in 55.8% of patients in the CPI cohort, and 35% in the non-CPI cohort. Median follow-up among survivors was longer for the non-CPI (39 months) than CPI cohort (16.5 months). In multivariate analysis, prior CPI exposure did not affect overall survival (OS) or nonrelapse mortality, but resulted in improved progression-free survival (non-CPI vs CPI hazard ratio [HR], 0.81; 0.67-0.98; P = .03) and lower relapse incidence (HR, 0.58; 0.45-0.76; P < 001). While grade 2 to 4 (HR, 1.26; 1.04-1.53; P = .02) and 3 to 4 (HR, 1.41; 1.04-1.92; P = .03) acute GVHD (aGVHD) were increased, differences in chronic GVHD (cGVHD) were not significant. PTCy-based GVHD prophylaxis resulted in improved OS, lower grade 2 to 4 aGVHD, and cGVHD in patients with prior CPI exposure. In summary, allo-HCT should still be considered a curative option for patients with HL in the era of CPIs.}, }
@article {pmid40623109, year = {2025}, author = {Jochim, B and Topalidou, I and Lehrbach, N}, title = {Protein sequence editing defines distinct and overlapping functions of SKN-1A/Nrf1 and SKN-1C/Nrf2.}, journal = {PLoS genetics}, volume = {21}, number = {7}, pages = {e1011780}, pmid = {40623109}, issn = {1553-7404}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; R35 GM142728/GM/NIGMS NIH HHS/United States ; }, mesh = {*Caenorhabditis elegans Proteins/genetics/metabolism ; Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Transcription Factors/genetics/metabolism ; *DNA-Binding Proteins/genetics/metabolism ; Oxidative Stress/genetics ; *NF-E2-Related Factor 2/genetics/metabolism ; Proteasome Endopeptidase Complex/genetics/metabolism ; *NF-E2-Related Factor 1/genetics/metabolism ; }, abstract = {The Nrf/NFE2L family of transcription factors regulates redox balance, xenobiotic detoxification, metabolism, proteostasis, and aging. Nrf1/NFE2L1 is primarily responsible for stress-responsive upregulation of proteasome subunit genes and is essential for adaptation to proteotoxic stress. Nrf2/NFE2L2 is mainly involved in activating oxidative stress responses and promoting xenobiotic detoxification. Nrf1 and Nrf2 contain very similar DNA binding domains and can drive similar transcriptional responses. In C. elegans, a single gene, skn-1, encodes distinct protein isoforms, SKN-1A and SKN-1C, that function analogously to mammalian Nrf1 and Nrf2, respectively, and share an identical DNA binding domain. Thus, the extent to which SKN-1A/Nrf1 and SKN-1C/Nrf2 functions are distinct or overlapping has been unclear. Regulation of the proteasome by SKN-1A/Nrf1 requires post-translational conversion of N-glycosylated asparagine residues to aspartate by the PNG-1/NGLY1 peptide:N-glycanase, a process we term 'sequence editing'. Here, we reveal the consequences of sequence editing for the transcriptomic output of activated SKN-1A. We confirm that activation of proteasome subunit genes is strictly dependent on sequence editing. In addition, we find that sequence edited SKN-1A can also activate genes linked to redox homeostasis and xenobiotic detoxification that are also regulated by SKN-1C, but the extent of these genes' activation is antagonized by sequence editing. Using mutant alleles that selectively inactivate either SKN-1A or SKN-1C, we show that both isoforms promote optimal oxidative stress resistance, acting as effectors for distinct signaling pathways. These findings suggest that sequence editing governs SKN-1/Nrf functions by tuning the SKN-1A/Nrf1 regulated transcriptome.}, }
@article {pmid40623281, year = {2025}, author = {Montano-Campos, JF and Hahn, E and Haupt, E and Radich, J and Bansal, A}, title = {Using Early Biomarker Change and Treatment Adherence to Predict Risk of Relapse Among Patients With Chronic Myeloid Leukemia Who Are in Remission.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500003}, pmid = {40623281}, issn = {2473-4276}, support = {R37 CA218413/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/pathology/genetics/diagnosis ; Male ; Female ; Middle Aged ; *Biomarkers, Tumor ; Adult ; Aged ; *Neoplasm Recurrence, Local/epidemiology ; *Fusion Proteins, bcr-abl/genetics ; Remission Induction ; Prognosis ; *Treatment Adherence and Compliance ; Risk Assessment ; }, abstract = {PURPOSE: There is little guidance for decision making in chronic myeloid leukemia (CML) after patients achieve molecular remission. Our study addresses this gap by developing a risk prediction model for molecular relapse using early longitudinal factors, such as BCR::ABL1 biomarker-level changes and treatment adherence.<br><br>METHODS: We analyzed electronic health record data of patients with CML diagnosed between 2007 and 2019 from an integrated health system. We used a time-to-event modeling framework using a Cox proportional hazards approach where we evaluated time from molecular remission to molecular relapse. The main predictors were early changes in BCR::ABL1 levels from treatment initiation to the first follow-up measurement (typically around 3 months) and treatment adherence in the first 6 months, categorized as perfect (&#x2265;0.98) or less-than-perfect (<0.98). Model performance was assessed through five-fold cross-validation combined with 100 Monte Carlo bootstrapping iterations to ensure robustness and minimize bias.<br><br>RESULTS: Patients with early improvement in BCR::ABL1 levels had a 70% lower risk relapse (hazard ratio [HR], 0.30 [95% CI, 0.15 to 0.59]) compared with those without early molecular response. Perfect adherence during this critical early phase of treatment was associated with a 56% lower relapse risk (HR, 0.44 [95% CI, 0.22 to 0.85]). Predictive accuracy was high at 6 months (AUC, 0.90; 95% CI, 0.87 to 0.95) and 1-year postremission (AUC, 0.78; 95% CI, 0.74 to 0.81). Relapse risk was significantly higher among Black, Asian, and Hispanic patients compared with non-Hispanic White patients.<br><br>CONCLUSION: Early biomarker trends and adherence after treatment initiation are critical for accurately predicting relapse among patients who achieve molecular remission. The proposed model addresses a gap in guidance after molecular remission and has the potential to enable personalized monitoring and optimize surveillance strategies, offering transformative potential for CML care.}, }
@article {pmid40623313, year = {2025}, author = {Aragaki, AK and Manson, JE and LeBlanc, ES and Chlebowski, RT and Tinker, LF and Allison, MA and Haring, B and Odegaard, AO and Wassertheil-Smoller, S and Saquib, N and Masaki, K and Harris, HR and Jager, LR and Bea, JW and Wactawski-Wende, J and Anderson, GL}, title = {Development and Validation of Body Mass Index-Specific Waist Circumference Thresholds in Postmenopausal Women : A Prospective Cohort Study.}, journal = {Annals of internal medicine}, volume = {178}, number = {8}, pages = {1073-1084}, pmid = {40623313}, issn = {1539-3704}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Body Mass Index ; *Waist Circumference ; Prospective Studies ; *Postmenopause ; Middle Aged ; Aged ; Obesity/mortality ; United States/epidemiology ; Overweight ; Risk Assessment ; Risk Factors ; }, abstract = {BACKGROUND: A 2020 consensus statement proposed body mass index (BMI)-specific waist circumference (WC) thresholds to improve patient care.<br><br>OBJECTIVE: To determine whether stratifying BMI categories by BMI-specific WC thresholds improves mortality risk prediction.<br><br>DESIGN: Prospective cohort study.<br><br>SETTING: Women's Health Initiative multicenter, population-based U.S. study, with enrollment from 1993 to 1998 and follow-up through 2021.<br><br>PARTICIPANTS: 139&#x2009;213 postmenopausal women aged 50 to 79 years were included in a development cohort (n = 67&#x2009;774) and 2 external validation cohorts. Validation Cohort 1 had high prevalence of overweight or obesity (n = 48&#x2009;335), and Validation Cohort 2 included diverse, geographically separate centers (n = 23&#x2009;104).<br><br>MEASUREMENTS: Height, weight, and WC measured at enrollment. BMI categories were normal weight (18.5 to <25 kg/m[2]), overweight (25 to <30 kg/m[2]), obesity-1 (30 to <35 kg/m[2]), obesity-2 (35 to <40 kg/m[2]), and obesity-3 (&#x2265;40 kg/m[2]), with further stratification by prespecified WC thresholds (&#x2265;80, &#x2265;90, &#x2265;105, &#x2265;115, and &#x2265;115 cm, respectively). Mortality was ascertained annually and was supplemented with serial National Death Index queries. Ten- and 20-year mortality prediction models that included BMI categories were compared to models with BMI categories stratified by WC thresholds using c-statistics and continuous net reclassification improvement (NRI).<br><br>RESULTS: Over a median of 24 years of follow-up, 69&#x2009;297 participants died. Multivariable-adjusted mortality risk was consistently greater for BMI categories with large WC than those with normal WC. Compared with women with normal weight and normal WC, women with normal or overweight BMI but large WC (hazard ratios [HRs], 1.17 [95% CI, 1.12 to 1.21] and 1.19 [CI, 1.15 to 1.24], respectively) had risk similar to those with obesity-1 but normal WC (HR, 1.12 [CI, 1.08 to 1.16]). Mortality associated with obesity-1 and large WC (HR, 1.45 [CI, 1.35 to 1.55]) was similar to that with obesity-3 and normal WC (HR, 1.40 [CI, 1.28 to 1.54]). Models with BMI-specific WC thresholds improved discrimination and risk stratification at 10 years for Validation Cohort 1; c-statistics improved by 0.7% (CI, 0.3% to 1.0%) to 61.3% (CI, 60.2% to 62.5%), and continuous NRI was 20.4% (CI, 17.3% to 23.6%). Results were mixed for Validation Cohort 2; risk stratification improved (continuous NRI, 12.3% [CI, 8.5% to 16.0%]), but not discrimination. Results were similar at 20 years.<br><br>LIMITATION: The study did not include men or younger women.<br><br>CONCLUSION: Further stratifying BMI categories by WC thresholds modestly improved mortality risk stratification, with larger WC predicting greater mortality, although the degree of improvement varied by cohort. Discrimination did not improve consistently.<br><br>PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.}, }
@article {pmid40624264, year = {2025}, author = {Templin, T and Fort, S and Padmanabham, P and Seshadri, P and Rimal, R and Oliva, J and Hassmiller Lich, K and Sylvia, S and Sinnott-Armstrong, N}, title = {Framework for bias evaluation in large language models in healthcare settings.}, journal = {NPJ digital medicine}, volume = {8}, number = {1}, pages = {414}, pmid = {40624264}, issn = {2398-6352}, support = {K01 AI159233/AI/NIAID NIH HHS/United States ; N/A//Public Health Sciences Klorfine Pilot Award/ ; K01AI159233/AI/NIAID NIH HHS/United States ; 2026498//National Science Foundation/ ; }, abstract = {A critical gap in the adoption of large language models for AI-assisted clinical decisions is the lack of a standardized audit framework to evaluate models for accuracy and bias. Our framework introduces a five-step framework that guides practitioners through stakeholder engagement, model calibration to specific patient populations, and rigorous testing through clinically relevant scenarios. We provide open-access tools for stakeholder engagement and an example of an audit. As the regulation of models becomes more critical, we believe adoption of an audit framework that tests model outputs, rather than regulating specific hyperparameters or inputs, will encourage the responsible use of AI in clinical settings.}, }
@article {pmid40624354, year = {2025}, author = {Baele, G and Ji, X and Hassler, GW and McCrone, JT and Shao, Y and Zhang, Z and Holbrook, AJ and Lemey, P and Drummond, AJ and Rambaut, A and Suchard, MA}, title = {BEAST X for Bayesian phylogenetic, phylogeographic and phylodynamic inference.}, journal = {Nature methods}, volume = {22}, number = {8}, pages = {1653-1656}, pmid = {40624354}, issn = {1548-7105}, support = {U19 AI135995/AI/NIAID NIH HHS/United States ; R01 AI153044/AI/NIAID NIH HHS/United States ; R01 HG006139/HG/NHGRI NIH HHS/United States ; K25 AI153816/AI/NIAID NIH HHS/United States ; T32 HG002536/HG/NHGRI NIH HHS/United States ; R01 GM072562/GM/NIGMS NIH HHS/United States ; F31 AI154824/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {*Phylogeny ; Bayes Theorem ; Phylogeography/methods ; *Software ; Models, Genetic ; Evolution, Molecular ; Algorithms ; Computer Simulation ; }, abstract = {Here we present the open-source and cross-platform BEAST X software that combines molecular phylogenetic reconstruction with complex trait evolution, divergence-time dating and coalescent demographics in an efficient statistical inference engine. BEAST X significantly advances the flexibility and scalability of evolutionary models supported. Novel clock and substitution models leverage a large variety of evolutionary processes; discrete, continuous and mixed traits with missingness and measurement errors; and fast, gradient-informed integration techniques that rapidly traverse high-dimensional parameter spaces.}, }
@article {pmid40627379, year = {2025}, author = {Chatterjee, S and Rückert, T and Martin, I and Michaeli, E and Buescher, J and Apostolova, P and Erny, D and Lalioti, ME and Biavasco, F and Hartmann, A and Runge, S and Braun, LM and Talvard-Balland, N and Adams, RC and Schmitt-Graeff, A and Cook, J and Wenger, V and Athanassopoulos, D and Hasavci, D and Vallejo-Janeta, AP and Blank, T and Schaible, P and Vinnakota, JM and Zähringer, A and Ganal-Vonarburg, SC and Melchinger, W and Pfeifer, D and Köhler, N and Rosshart, SP and Michonneau, D and Socié, G and Andrieux, G and Cabezas-Wallscheid, N and Boerries, M and Prinz, M and Zeiser, R}, title = {Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {9}, pages = {}, doi = {10.1084/jem.20242180}, pmid = {40627379}, issn = {1540-9538}, support = {2021/A2-Fol//University of Freiburg/ ; 2021/B3-Fol//University of Freiburg/ ; 450392965//Deutsche Forschungsgemeinschaft/ ; 259373024//Deutsche Forschungsgemeinschaft/ ; 441891347//Deutsche Forschungsgemeinschaft/ ; 256073931//Deutsche Forschungsgemeinschaft/ ; 431984000//Deutsche Forschungsgemeinschaft/ ; 491676693//Deutsche Forschungsgemeinschaft/ ; 471011418//Deutsche Forschungsgemeinschaft/ ; 493802833//Deutsche Forschungsgemeinschaft/ ; 872/4-1//Deutsche Forschungsgemeinschaft/ ; ZE 872/7-1//Deutsche Forschungsgemeinschaft/ ; ZE 872/8-1//Deutsche Forschungsgemeinschaft/ ; RO 6247/1-1//Deutsche Forschungsgemeinschaft/ ; 446316360//Deutsche Forschungsgemeinschaft/ ; 256073931//Deutsche Forschungsgemeinschaft/ ; 491676693//Deutsche Forschungsgemeinschaft/ ; 101094168/ERC_/European Research Council/International ; 70114655//Deutsche Krebshilfe/ ; 70116490//Deutsche Krebshilfe/ ; DJCLS 09R/2022//Jose-Carreras Leukemia Foundation/ ; 7030-23//Leukemia and Lymphoma Society/ ; 390939984//Germany's Excellence Strategy/ ; 560868983//Germany's Excellence Strategy/ ; 10.001.317/SNSF_/Swiss National Science Foundation/Switzerland ; //European Hematology Association/ ; 24C246//Novartis Foundation for Biomedical Research/ ; 2015_A147//Else Kr&#xf6;ner-Fresenius-Stiftung/ ; //Albert-Ludwigs-University of Freiburg/ ; 01ZZ2322A//German Federal Ministry of Education and Research/ ; 01ZZ2015//German Federal Ministry of Education and Research/ ; 101119855//Deutschen Konsortium f&#xfc;r Translationale Krebsforschung/ ; }, mesh = {Animals ; *Gastrointestinal Microbiome/drug effects ; Microglia/metabolism/drug effects ; *Graft vs Host Disease/microbiology/metabolism/pathology/etiology ; Mice ; Toll-Like Receptor 4/metabolism ; Mice, Inbred C57BL ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Anti-Bacterial Agents/pharmacology ; Male ; p38 Mitogen-Activated Protein Kinases/metabolism ; Acute Disease ; *Central Nervous System/pathology ; T-Lymphocytes/immunology ; Female ; Specific Pathogen-Free Organisms ; }, abstract = {Acute graft-versus-host disease (aGVHD) can affect the central nervous system (CNS) through microglial activation and T cell infiltration, but the role of gut microbiota in CNS-aGVHD remains unclear. Here, we investigated the role of microbiota in microglial activation during aGVHD using antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice. Antibiotic-mediated microbiota depletion led to infiltration of IFN-γ-producing T cells in the brain, activation of microglia via the TLR4/p38 MAPK pathway, and neurocognitive deficits in SPF aGVHD mice. Microglial depletion reversed the neurocognitive deficits. GF and wildling mice treated with antibiotics exhibited similar microglial activation after allogeneic hematopoietic cell transplantation (allo-HCT). Mechanistically, the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA) was decreased in microglia following antibiotic treatment. TMAVA administration suppressed TLR4/p38 MAPK pathway activity in microglia and alleviated gut microbiota depletion-mediated neurocognitive deficits. Additionally, TMAVA abundance decreased in patient blood after allo-HCT and after GVHD onset. In summary, we identify TMAVA loss as a central causative factor for CNS-aGVHD, opening new perspectives for a metabolite-based therapy.}, }
@article {pmid40627547, year = {2025}, author = {Paatela, EM and St Amant, FG and Hamm, DC and Bennett, SR and Gujral, TS and van der Maarel, SM and Tapscott, SJ}, title = {A discrete region of the D4Z4 is sufficient to initiate epigenetic silencing.}, journal = {Human molecular genetics}, volume = {34}, number = {18}, pages = {1526-1540}, pmid = {40627547}, issn = {1460-2083}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01AR066248/NH/NIH HHS/United States ; R01 AR066248/AR/NIAMS NIH HHS/United States ; P50AR065139/NH/NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; }, mesh = {Humans ; *Homeodomain Proteins/genetics/metabolism ; *Gene Silencing ; Muscular Dystrophy, Facioscapulohumeral/genetics ; *Epigenesis, Genetic ; Promoter Regions, Genetic ; Animals ; Repressor Proteins/metabolism/genetics ; Muscle, Skeletal/metabolism ; Mice ; }, abstract = {The DUX4 transcription factor is briefly expressed in the early embryo and is epigenetically repressed in somatic tissues. Loss of epigenetic repression can result in the aberrant expression of DUX4 in skeletal muscle and can cause facioscapulohumeral dystrophy (FSHD). Multiple factors have been identified as necessary to maintain epigenetic silencing of DUX4 in skeletal muscle, but whether specific sequences at the DUX4 locus are sufficient for initiating epigenetic silencing has not been known. We cloned fragments of the D4Z4 macrosatellite repeat, the DNA region that encompasses the DUX4 retrogene, adjacent to a reporter driven by a constitutive promoter and identified a single fragment sufficient to epigenetically repress reporter gene expression. Previously identified repressors of DUX4 expression-SETDB1, ATF7IP, SIN3A/B, and LRIF1-were necessary for silencing activity and p38 inhibitors enhanced suppression. These findings identify a key regulatory sequence for D4Z4 epigenetic repression and establish a model system for mechanistic and discovery studies.}, }
@article {pmid40628395, year = {2025}, author = {Farrell-Sherman, A and de la Force, N and Prator, CA and Valieris, R and Azam, W and Da Silva, I and Deeks, SG and Thanh, C and Bosch, RJ and Henrich, TJ and Cohn, LB}, title = {Antiviral Monocytes Increase Prior to Detectable HIV-1 Rebound Viremia.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {5}, pages = {1061-1066}, pmid = {40628395}, issn = {1537-6613}, support = {INV-002707/GATES/Gates Foundation/United States ; UM1AI068636//National Institute of Allergy and Infectious Diseases/ ; P30 CA015704/CA/NCI NIH HHS/United States ; K24 AI174971/AI/NIAID NIH HHS/United States ; UM1 AI068634/AI/NIAID NIH HHS/United States ; UM1AI106701//National Institute of Allergy and Infectious Diseases/ ; UM1 AI164560/AI/NIAID NIH HHS/United States ; INV-002707/GATES/Gates Foundation/United States ; UM1 AI106701/AI/NIAID NIH HHS/United States ; R01 AI141003/AI/NIAID NIH HHS/United States ; R01AI141003//National Institute of Allergy and Infectious Diseases/ ; UM1AI068634//National Institute of Allergy and Infectious Diseases/ ; K24AI174971//National Institute of Allergy and Infectious Diseases/ ; UM1AI164560//National Institute of Allergy and Infectious Diseases/ ; U01 AI068634/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Viremia/immunology/virology ; *Monocytes/immunology/virology ; *HIV-1/immunology ; *HIV Infections/immunology/virology ; Viral Load ; Leukocytes, Mononuclear/immunology/virology ; Receptors, IgG ; Proteomics ; Male ; Single-Cell Analysis ; }, abstract = {The persistence of human immunodeficiency virus 1 (HIV-1) proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compared plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells before, during, and after detectable plasma viremia. We observed unique transcriptional signatures prior to viral rebound, including a significant increase in CD16++ monocytes with increased antiviral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.}, }
@article {pmid40628699, year = {2025}, author = {Li, Z and Yang, W and Wu, G and Chang, TC and Cheng, Z and Devidas, M and Shago, M and Carroll, AJ and Heerema, NA and Gastier-Foster, JM and Wood, BL and Sanclemente, L and Raetz, EA and Hunger, SP and Loh, ML and Feingold, E and Rosser, TC and Allen, EG and Sherman, SL and Rabin, KR and Lupo, PJ and Yang, JJ}, title = {Inferring chromosome segregation error stage and crossover in trisomic disorders with application to Down syndrome.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6316}, pmid = {40628699}, issn = {2041-1723}, support = {U24 CA196173/CA/NCI NIH HHS/United States ; R01 CA249867/CA/NCI NIH HHS/United States ; P30 CA125123/CA/NCI NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; R03 HD103908/HD/NICHD NIH HHS/United States ; U24 CA114766/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Down Syndrome/genetics ; *Chromosome Segregation/genetics ; *Crossing Over, Genetic ; Meiosis/genetics ; *Nondisjunction, Genetic/genetics ; Female ; Markov Chains ; *Trisomy/genetics ; Male ; Child ; }, abstract = {Errors in chromosome segregation during gametogenesis, such as nondisjunction (NDJ) errors, have severe consequences in human reproduction, and a better understanding of their etiology is of fundamental interest in genetics. Mapping NDJ errors to meiotic/mitotic stages typically requires proband-parent comparison, limiting its applicability. Herein, we develop Mis-segregation Error Identification through Hidden Markov Models (MeiHMM), a method for inferring NDJ error stage and crossover events based on only genomic data of trisomic probands. Guided by triallelic genotype/haplotype configurations, MeiHMM discerns the allelic origin at each locus, which informs NDJ error during gamete formation, without identifying the parental origin of the trisomy. In 152 Down syndrome (DS) cases, MeiHMM achieved an accuracy of 96.1% in classifying NDJ errors, with a sensitivity of 91.6% in crossover identification, compared to proband-parents trio analysis. 17% of Meiosis II errors were misclassified as Meiosis I, mainly due to small proximal crossover events. Applying MeiHMM to 509 children with DS-associated childhood leukemia, we demonstrate that NDJ error is associated with the age of disease onset, somatic genomic abnormalities, and prognosis. Thus, MeiHMM is an effective method for trisomic NDJ error classification and crossover identification that can be applied broadly to study the etiology of congenital aneuploidy conditions.}, }
@article {pmid40629152, year = {2025}, author = {Simar, SR and Tran, TT and Rydell, KB and Atterstrom, RL and Sahasrabhojane, PV and Dinh, AQ and Schettino, MG and Slanis, HS and Deyanov, AE and DeTranaltes, AM and Axell-House, DB and Miller, WR and Munita, JM and Tobys, D and Seifert, H and Biehl, LM and Zervos, M and Suleyman, G and Kaur, J and Warzocha, V and Rosa, R and Cifuentes, RO and Abbo, LM and Shimose, L and Liu, C and Nguyen, K and Miller, A and Shelburne, SA and Hanson, BM and Arias, CA}, title = {Clinical and Genomic Characterization of Recalcitrant Enterococcal Bacteremia: A Multicenter Prospective Cohort Study (VENOUS).}, journal = {The Journal of infectious diseases}, volume = {232}, number = {6}, pages = {1351-1364}, pmid = {40629152}, issn = {1537-6613}, support = {P01 AI152999/AI/NIAID NIH HHS/United States ; T32 AI141349/AI/NIAID NIH HHS/United States ; P01AI152999-01//National Institute of Allergy and Infectious Disease/ ; R01 AI134637/AI/NIAID NIH HHS/United States ; K01AI148593-01//National Institute of Allergy and Infectious Disease/ ; K24 AI121296/AI/NIAID NIH HHS/United States ; K01 AI148593/AI/NIAID NIH HHS/United States ; R01 AI148342/AI/NIAID NIH HHS/United States ; K24AI121296//National Institute of Allergy and Infectious Disease/ ; 5T32AI055449-15/NH/NIH HHS/United States ; R01AI134637//National Institute of Allergy and Infectious Disease/ ; R01AI148342-01//National Institute of Allergy and Infectious Disease/ ; T32 AI055449/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Bacteremia/microbiology/drug therapy ; Male ; Female ; *Gram-Positive Bacterial Infections/microbiology/drug therapy ; Prospective Studies ; Middle Aged ; Aged ; Whole Genome Sequencing ; Anti-Bacterial Agents/therapeutic use/pharmacology ; Genomics ; Enterococcus faecium/genetics/drug effects/isolation &amp; purification ; *Vancomycin-Resistant Enterococci/genetics ; Enterococcus faecalis/genetics/drug effects/isolation &amp; purification ; Genome, Bacterial ; Adult ; }, abstract = {BACKGROUND: Patients with recalcitrant enterococcal bloodstream infections are at greater risk of adverse outcomes. We identified patients in the 2016-2022 Vancomycin-Resistant Enterococcal Bacteremia Outcomes Study (VENOUS) cohort experiencing recalcitrant bloodstream infections for further clinical and genomic characterization.<br><br>METHODS: Bacteremia episodes were considered persistent if there was a lack of clearance on day 4 while receiving &#x2265; 48&#x2005;hours of active therapy and recurrent if there was clearance during hospitalization with a subsequent positive culture (collectively, recalcitrant bacteremia). A matched comparison group of nonrecalcitrant bacteremia patients was chosen in a 2:1 control to case ratio. Isolates were subjected to short- and long-read whole-genome sequencing. Hybrid assemblies were created using a custom pipeline.<br><br>RESULTS: A total of 46 recalcitrant infections from 41 patients were identified. Patients with persistent bacteremia were more often admitted to the intensive care unit upon admission relative to controls. Enterococcus faecalis strains causing persistent infections had a significantly higher proportion of genes associated with carbohydrate utilization relative to controls. Representation of functional groups associated with mutated genes was disparate between Enterococcus faecium and E. faecalis index and persistent isolates, suggesting species-specific adaptation.<br><br>DISCUSSION: Enterococcal isolates causing recalcitrant bacteremia were genomically diverse, indicating that strain-specific signatures are not drivers of persistence. However, comparisons of index versus persistent isolates revealed that E. faecium may be genetically preadapted to cause persistent infection, and site-specific structural variation during infection suggests the role of differential gene expression in adaptation and persistence. These data lay groundwork for future studies to define signatures of enterococcal adaptation during bacteremia.}, }
@article {pmid40629516, year = {2025}, author = {Razzo, BM and Midha, S and Portuguese, AJ and Grajales-Cruz, AF and De Menezes Silva Corraes, A and Costello, P and Liu, Y and Sperling, AS and Nadeem, O and Dima, D and Banerjee, R and Cowan, AJ and Afrough, A and Anderson, LD and Lieberman-Cribbin, A and Kaur, G and Goyal, A and Atrash, S and Ferreri, CJ and Voorhees, PM and Pasvolsky, O and Lee, HC and Patel, KK and Julian, KL and Forsberg, PA and Herr, MM and Chhabra, S and Parrondo, RD and Lin, Y and Chen, A and Susanibar-Adaniya, SP and Khouri, J and Raza, S and Anwer, F and Vazquez-Martinez, M and Castaneda Puglianini, O and Sborov, DW and Davis, JA and Rossi, A and Shune, L and Bhurtel, J and Hwang, WT and Hansen, DK and Sidana, S and Garfall, AL and Richard, S}, title = {Real-World Experience with Teclistamab for Relapsed/Refractory Multiple Myeloma from the US Myeloma Immunotherapy Consortium.}, journal = {Blood cancer discovery}, volume = {6}, number = {6}, pages = {561-571}, doi = {10.1158/2643-3230.BCD-24-0354}, pmid = {40629516}, issn = {2643-3249}, support = {T32CA009615//Center for Cancer Research (CCR)/ ; //Leukemia and Lymphoma Society (LLS)/ ; }, mesh = {Humans ; *Multiple Myeloma/drug therapy/mortality/pathology ; Male ; Female ; Aged ; Middle Aged ; *Antibodies, Bispecific/therapeutic use/adverse effects/administration &amp; dosage ; Retrospective Studies ; Aged, 80 and over ; Adult ; United States ; Immunotherapy ; *Antineoplastic Agents, Immunological/therapeutic use/adverse effects ; Treatment Outcome ; B-Cell Maturation Antigen ; }, abstract = {UNLABELLED: Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin.<br><br>SIGNIFICANCE: T cell-engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542.}, }
@article {pmid40631121, year = {2025}, author = {Kenaston, MW and Cherkashchenko, L and Skawinski, CLS and Fishburn, AT and Peddamallu, V and Florio, CJ and Robertson, AE and Bhattacharya, T and Young, JM and Malik, HS and Shah, PS}, title = {Yellow Fever Virus Interactomes Reveal Common and Divergent Strategies of Replication and Evolution for Mosquito-borne Flaviviruses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40631121}, issn = {2692-8205}, support = {R01 AI170857/AI/NIAID NIH HHS/United States ; R21 AI168716/AI/NIAID NIH HHS/United States ; S10 OD026702/OD/NIH HHS/United States ; U54 AI170792/AI/NIAID NIH HHS/United States ; }, abstract = {Pathogenic mosquito-borne flaviviruses infect mosquito and human hosts, relying on host protein interactions to replicate, evade immunity, and mediate pathogenesis. Prior proteomic studies mapped such interactions for some flaviviruses, but yellow fever virus (YFV)-a pathogen of resurgent concern-remains understudied. Here, we map YFV interactomes in human and mosquito cells to identify interactions common among divergent flaviviruses or unique to YFV. Functional assays reveal a previously unrecognized YFV restriction factor: RBBP6 inhibits YFV genome replication by interacting with the viral polymerase NS5. We enhance the identification of dual-host interactions using structural modeling and holistic network integration. Extending our holistic approach to other flavivirus interactomes, we distinguish conserved mechanisms of host targeting from those unique to YFV. Contrary to expectations that conserved viral proteins lead to conserved protein interactions, we find that Capsid, a divergent structural protein, shares more host interactions than NS5, a conserved enzyme. Integrating proteomics with complementary analyses defines new principles of host-targeting strategies across flavivirus and host evolution, offering a versatile resource for navigating the complex landscape of flavivirus biology.}, }
@article {pmid40632085, year = {2025}, author = {Han, C and Zhang, Z and Crosse, EI and Sajedi, S and Lu, B and Wang, X and Karma, S and Kostich, M and Rajendran, SH and Udy, DB and Chen, S and Arnuk, A and Lawal, AE and Koenig, KR and McKenna, M and Reville, PK and Abbas, HA and Abdel-Wahab, O and Miura, P and Bradley, RK and Wang, E}, title = {An Isoform-Specific RUNX1C-BTG2 Axis Governs AML Quiescence and Chemoresistance.}, journal = {Blood cancer discovery}, volume = {6}, number = {5}, pages = {464-483}, pmid = {40632085}, issn = {2643-3249}, support = {CA254838-01//Foundation for the National Institutes of Health (FNIH)/ ; //Butler Family Foundation/ ; P30 CA034196/CA/NCI NIH HHS/United States ; P50 CA254838/CA/NCI NIH HHS/United States ; R01 HL128239/HL/NHLBI NIH HHS/United States ; HL128239//Foundation for the National Institutes of Health (FNIH)/ ; CA242020//Foundation for the National Institutes of Health (FNIH)/ ; R35GM138319//National Institute of General Medical Sciences (NIGMS)/ ; R01 CA251138/CA/NCI NIH HHS/United States ; R01 CA242020/CA/NCI NIH HHS/United States ; R35 GM138319/GM/NIGMS NIH HHS/United States ; CA283364//Foundation for the National Institutes of Health (FNIH)/ ; //Leukemia Research Foundation (LRF)/ ; R25 CA233420/CA/NCI NIH HHS/United States ; P30CA034196//Foundation for the National Institutes of Health (FNIH)/ ; CA251138//Foundation for the National Institutes of Health (FNIH)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA283364/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/drug therapy/metabolism/pathology ; *Drug Resistance, Neoplasm/genetics ; *Core Binding Factor Alpha 2 Subunit/genetics/metabolism ; *Tumor Suppressor Proteins/metabolism/genetics ; Protein Isoforms/genetics/metabolism ; *Immediate-Early Proteins/metabolism/genetics ; Cell Line, Tumor ; Gene Expression Regulation, Leukemic ; }, abstract = {UNLABELLED: Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted rRNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of rRNAs increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineated an isoform-specific transcriptional circuit that governed chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.<br><br>SIGNIFICANCE: This study identifies RUNX1C as a contributor to AML chemoresistance and an inducer of quiescence through BTG2. Targeting RUNX1C with RNA-based approaches disrupts this state and improves chemotherapy response, highlighting RUNX1C inhibition as a promising strategy to overcome resistance and enhance treatment efficacy in AML.}, }
@article {pmid40632513, year = {2025}, author = {Raychaudhuri, R and Lin, DW and Montgomery, RB}, title = {Complexity of Prostate Cancer-Reply.}, journal = {JAMA}, volume = {334}, number = {6}, pages = {544-545}, doi = {10.1001/jama.2025.7193}, pmid = {40632513}, issn = {1538-3598}, }
@article {pmid40632975, year = {2025}, author = {Anbil, S and Seewald, NJ and Chiorean, EG and Hussein, M and Kasi, PM and Laux, DE and Schwartz, GK and Shapiro, GI and Lin, KK and Craib, M and Maloney, L and McLachlan, K and Tukachinsky, H and Schrock, AB and Wang, S and Sokol, ES and Decker, B and Nathanson, KL and Domchek, SM and Reiss, KA}, title = {LODESTAR: A Single-Arm Phase II Study of Rucaparib in Solid Tumors With Pathogenic Germline or Somatic Variants in Homologous Recombination Repair Genes.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500090}, doi = {10.1200/PO-25-00090}, pmid = {40632975}, issn = {2473-4284}, mesh = {Humans ; Female ; Male ; Middle Aged ; *Neoplasms/drug therapy/genetics ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Aged ; Adult ; *Indoles/therapeutic use ; *Recombinational DNA Repair/genetics ; Germ-Line Mutation ; }, abstract = {PURPOSE: To explore poly (ADP-ribose) polymerase inhibitor utility across solid tumors and identify biomarkers that predict sensitivity.<br><br>PATIENTS AND METHODS: This single-arm phase II study assessed rucaparib monotherapy in patients with solid tumors and pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, and RAD51D (cohort A) or BARD1, BRIP1, FANCA, NBN, and RAD51B (cohort B). The primary end point was overall response rate (ORR) in cohort A. Secondary end points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. A scar-based homologous recombination deficiency signature (HRDsig) and platinum sensitivity status were explored post hoc.<br><br>RESULTS: Fifty-one patients in cohort A and 12 in cohort B were evaluable for efficacy. ORR of cohort A was 18% (95% CI, 10 to 30). A significantly higher ORR was observed with HRDsig+ tumors compared with HRDsig- tumors (32%; 95% CI, 15 to 54 v 0%; 95% CI, 0 to 14; P < .01). In the entire study population, DCR was 65% (95% CI, 53 to 76), median PFS (mPFS) 5.5 months (95% CI, 3.68 to 7.82), and median OS 12.1 months (95% CI, 10.6 to inferred). PFS and hazard of death from any cause was significantly better for platinum-sensitive tumors (mPFS: 7.8 months v 3.5 months; P = .02; hazard ratio, 0.11 [95% CI, 0.02 to 0.55]). Tumor histology was not independently predictive of outcome. Tumors with PVs in cohort A genes were more likely to be HRDsig+ than tumors with PVs in cohort B genes. Analysis of a large commercial database showed that in noncanonical tumors with BRCA PVs, 30.2% were HRDsig+.<br><br>CONCLUSION: Rucaparib has activity in HRDsig+ solid tumors with PVs in homologous recombination repair genes, regardless of histology. Platinum sensitivity correlated with improved outcomes.}, }
@article {pmid40633141, year = {2025}, author = {Ramachandran, D and Wang, X and Laisk, T and Zheng, Y and Ingold, N and Canson, DM and Kho, PF and Naumann, BJ and Chapman, CJ and Bousset, K and Krause, AV and Schürmann, P and Wieland, B and Hanel, P and Hülse, F and Häfner, N and Runnebaum, I and Dubrowinskaja, N and Turmanov, N and Yugay, T and Yessimsiitova, ZB and Amant, F and Annibali, D and Beckmann, MW and Bodelon, C and Buchanan, DD and Chen, C and Clarke, MA and Cook, LS and De Vivo, I and De Wispelaere, W and Du, M and Easton, DF and Emons, J and Fasching, PA and Friedenreich, CM and Gallagher, G and Giles, GG and Goode, EL and Harris, HR and Hunter, DJ and Kolin, DL and Kraft, P and Lacey, JV and Lambrechts, D and Lu, L and Mutter, GL and Naduparambil, J and O'Connell, K and Patel, AV and Pharoah, PDP and Rebbeck, TR and Ricceri, F and Risch, HA and Ruebner, M and Sacerdote, C and Scott, RJ and Setiawan, VW and Shu, XO and Southey, MC and Tham, E and Tomlinson, I and Turman, C and Wentzensen, N and Xu, W and Yu, H and Zheng, W and Spurdle, AB and Yarden, Y and ,  and Mägi, R and Hillemanns, P and Glubb, DM and Dörk, T and O'Mara, TA}, title = {GWAS meta-analysis identifies five susceptibility loci for endometrial cancer.}, journal = {EBioMedicine}, volume = {118}, number = {}, pages = {105830}, pmid = {40633141}, issn = {2352-3964}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Endometrial Neoplasms/genetics ; Female ; *Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Polymorphism, Single Nucleotide ; *Genetic Loci ; Case-Control Studies ; Genotype ; Nerve Tissue Proteins/genetics ; }, abstract = {BACKGROUND: Endometrial cancer is the most common gynaecological cancer in high-income countries. In addition to environmental risk factors, genetic predisposition contributes towards endometrial cancer development but is still incompletely defined.<br><br>METHODS: Building on genome-wide association studies (GWASs) by the Endometrial Cancer Association Consortium, we conducted a GWAS meta-analysis of 17,278 endometrial cancer cases and 289,180 controls, incorporating biobank samples from the UK, Finland, Estonia and Japan.<br><br>FINDINGS: GWAS analysis identified five additional risk loci (3p25.2, 3q25.2, 6q22.31, 12q21.2, and 17q24.2). Corresponding gene-based analyses supported findings for three of the five loci, at NAV3 (12q21.2), PPARG (3p25.2), and BPTF (17q24.2), as well as two additional candidate risk regions at ATF7IP2 (16p13.2-p13.13) and RPP21 (6p22.1). Validation genotyping in further independent case-control series replicated the most significant locus at 12q21.2 and corroborated risk variants located intronic to NAV3, the gene for Neuron Navigator 3. Downregulation of NAV3 in endometrial cell lines accelerated cell division and wound healing capacity whereas NAV3 overexpression reduced cell survival and increased cell death, indicating that NAV3 acts as a tumour suppressor in endometrial cells.<br><br>INTERPRETATION: Our large study extends the number of genome-wide significant risk loci identified for endometrial carcinoma by about one-third and proposes a role of NAV3 as a tumour suppressor in this common cancer.<br><br>FUNDING: This study was mainly supported by funding from the Wilhelm Sander Foundation, Germany, and the National Health and Medical Research Council (NHMRC) of Australia. A complete list of funding organisations is provided in the acknowledgements.}, }
@article {pmid40633624, year = {2026}, author = {Chari, ST and Wu, B and Lopez, C and Lustigova, E and Chen, Q and Van Den Eeden, SK and Leimpeter, AD and Fisher, W and Wood, A and Alexander, AS and Valenta, J and Vege, SS and Carlson, EE and Rabe, KG and Hart, PA and Qian, L and Zhao, YQ and Yosuf, N and Matrisian, L and Kenner, B and Rinaudo, JA and Maitra, A and Feng, Z}, title = {Risk of Pancreatic Cancer in Glycemically Defined New-Onset Diabetes: A Prospective Cohort Study.}, journal = {Gastroenterology}, volume = {170}, number = {1}, pages = {106-117}, pmid = {40633624}, issn = {1528-0012}, support = {U01 DK108288/DK/NIDDK NIH HHS/United States ; P50 CA221707/CA/NCI NIH HHS/United States ; U01 DK108326/DK/NIDDK NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; U01 DK108327/DK/NIDDK NIH HHS/United States ; U01 DK126365/DK/NIDDK NIH HHS/United States ; U01 DK108328/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Pancreatic Neoplasms/epidemiology/ethnology/diagnosis ; Male ; Female ; Aged ; Middle Aged ; Prospective Studies ; Incidence ; United States/epidemiology ; Risk Factors ; *Diabetes Mellitus/blood/ethnology/diagnosis/epidemiology ; Risk Assessment ; Aged, 80 and over ; Time Factors ; }, abstract = {BACKGROUND &amp; AIMS: The increased 3-year incidence of pancreatic cancer after new-onset diabetes observed in retrospective studies needs prospective validation. It is unknown whether incidence varies by race and ethnicity.<br><br>METHODS: In a prospective, observational study using active real-time surveillance of electronic health records, we identified 18,838 adults 50 years or older with glycemically defined new-onset diabetes (GNOD). In this interim analysis, we report 3-year Kaplan-Meier estimates of the proportion diagnosed with pancreatic cancer after GNOD (absolute incidence [95% CI]) and associated standardized incidence ratio (SIR) by race and ethnicity, overall 3-year incidence of pancreatic cancer adjusting for racial distribution of incident diabetes in the United States, and interval between GNOD and pancreatic cancer diagnosis.<br><br>RESULTS: During median follow-up of 2.3 years, 82 pancreatic cancers were diagnosed (60% in men; mean [SD] age, 71 [8] years). The 3-year estimates for the proportion diagnosed with pancreatic cancer and associated SIR by race and ethnicity were as follows: non-Hispanic White patients (n = 6518): 0.84% (95% CI, 0.60%-1.07%) and 6.4 (95% CI, 4.8-8.4); Hispanic patients (n = 5984): 0.40% (95% CI, 0.20%-0.60%) and 4.2 (95% CI, 2.6-6.3); African American patients (n = 2192): 0.37% (95% CI, 0.07%-0.67%) and 2.4 (95% CI, 1.0-5.0), and Asian/Pacific Islander patients (n = 3360): 0.22% (95% CI, 0.06%-0.39%) and 3.0 (95% CI, 1.4-6.0). Overall, race-adjusted 3-year pancreatic cancer incidence was 0.62%. On average, GNOD occurred 8 months before clinical diagnosis (0-4 months in 30.5%, 4-12 months in 31.3%, 12-24 months in 19.5%, and 24-36 months in 18.7%).<br><br>CONCLUSIONS: GNOD, identifiable in real time using active surveillance of electronic health records, is associated with a high 3-year incidence of pancreatic cancer with marked racial and ethnic differences. Longer-term risk needs further study.}, }
@article {pmid40634609, year = {2025}, author = {Tortorici, MA and Choi, A and Gibson, CA and Lee, J and Brown, JT and Stewart, C and Joshi, A and Harari, S and Willoughby, I and Treichel, C and Leaf, EM and Bloom, JD and King, NP and Tait-Burkard, C and Whittaker, GR and Veesler, D}, title = {Loss of FCoV-23 spike domain 0 enhances fusogenicity and entry kinetics.}, journal = {Nature}, volume = {645}, number = {8079}, pages = {235-243}, pmid = {40634609}, issn = {1476-4687}, support = {75N93022C00036/AI/NIAID NIH HHS/United States ; DP1 AI158186/AI/NIAID NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; }, mesh = {*Spike Glycoprotein, Coronavirus/chemistry/ultrastructure/metabolism/genetics/immunology ; Animals ; Humans ; *Virus Internalization ; Kinetics ; Protein Domains/genetics ; Cryoelectron Microscopy ; Models, Molecular ; CD13 Antigens/metabolism/chemistry ; Cats ; *Coronavirus/chemistry/pathogenicity/immunology/ultrastructure/genetics/classification ; Cross Reactions/immunology ; Antibodies, Monoclonal/immunology ; Receptors, Virus/metabolism/chemistry ; Polysaccharides/metabolism/chemistry ; }, abstract = {The ability of coronaviruses to recombine and cross species barriers affects human and animal health globally and is a pandemic threat[1,2]. FCoV-23 is a recently emerged, highly pathogenic recombinant coronavirus responsible for a widespread outbreak of feline infectious peritonitis. Here we report cryogenic electron microscopy structures of two FCoV-23 spike isoforms that correspond to the in-host loss of domain 0 observed in clinical samples. The loss of domain 0 markedly enhances the fusogenicity and kinetics of entry into cells and possibly enables biotype switching and lethality. We show that FCoV-23 can use several aminopeptidase N orthologues as receptors and reveal the molecular determinants of receptor species tropism, including a glycan that modulates human receptor engagement. We define antigenic relationships among alphacoronaviruses that infect humans and other mammalian species and identify a cross-reactive alphacoronavirus monoclonal antibody that inhibits FCoV-23 entry. Our results pave the way for the development of vaccines and therapeutics that target this highly pathogenic virus.}, }
@article {pmid40635049, year = {2025}, author = {Rosenthal, EA and Wei, WQ and Luo, Y and Namjou-Khales, B and Schaid, DJ and Esplin, ED and Lape, M and Kottyan, L and Pacheco, JA and Weng, C and Gordon, AS and Kullo, IJ and Crosslin, DR and Grady, WM and Hsu, L and Peters, U and Jarvik, GP}, title = {Phenome-wide association study identifies multiple traits associated with a polygenic risk score for colorectal cancer.}, journal = {Human genomics}, volume = {19}, number = {1}, pages = {77}, pmid = {40635049}, issn = {1479-7364}, support = {U01 HG008676/HG/NHGRI NIH HHS/United States ; U01HG008657, U01HG008685, U01HG008672, U01HG008666, U01HG006379, U01HG008679 , U01HG008680 , U01HG008684 , U01HG008673 , U01HG008701 , U01HG008676 , U01HG008664 , U54MD007593/HG/NHGRI NIH HHS/United States ; U01 HG008657/HG/NHGRI NIH HHS/United States ; U01 HG008672/HG/NHGRI NIH HHS/United States ; U01 HG008684/HG/NHGRI NIH HHS/United States ; U01 HG008679/HG/NHGRI NIH HHS/United States ; U01 HG008666/HG/NHGRI NIH HHS/United States ; U01 HG008680/HG/NHGRI NIH HHS/United States ; U01 HG008673/HG/NHGRI NIH HHS/United States ; U01 HG008685/HG/NHGRI NIH HHS/United States ; U01 HG006379/HG/NHGRI NIH HHS/United States ; U01 HG008664/HG/NHGRI NIH HHS/United States ; U01 HG008701/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/pathology/epidemiology ; Male ; *Multifactorial Inheritance/genetics ; Female ; *Genetic Predisposition to Disease ; Genome-Wide Association Study ; Risk Factors ; Middle Aged ; Phenotype ; Aged ; Polymorphism, Single Nucleotide/genetics ; United Kingdom/epidemiology ; Phenomics ; Genetic Risk Score ; }, abstract = {BACKGROUND: Many factors, including environmental and genetic variables, contribute to Colorectal Cancer (CRC) risk. The genetic components of risk can be divided into monogenic and polygenic factors. Just as monogenic factors can increase risk for more than one condition, polygenic factors may also underlie multiple phenotypes, including behavioral traits. In order to understand the biology of CRC risk better, it is important to understand the shared polygenic genetic architecture contributing to CRC risk and other phenotypes, including CRC associated risk factors.<br><br>METHODS: We investigated potential shared genetics by performing a Phenome-wide association study (PheWAS) with a multi-ancestry CRC polygenic risk score (PRS). The discovery cohort (N&#x2009;=&#x2009;426,464) consisted of ancestrally diverse participants from the United Kingdom Biobank. The replication cohort (N&#x2009;=&#x2009;87,271) consisted of ancestrally diverse participants from the electronic Medical Records and Genomics Network phase 3. We used a mixed-effects model to adjust for the presence of related individuals. To preserve power, we limited the number of tests by restricting analysis to ancestor phecodes derived from the electronic health record&#xa0;(EHR) that were not likely to be a result of CRC or its treatment.<br><br>RESULTS: We discovered and replicated associations between the CRC PRS and breast cancer, prostate cancer, obesity, smoking and alcohol use (discovery p&#x2009;<&#x2009;1.1e-4; replication p&#x2009;<&#x2009;0.0019). The association between CRC risk and prostate cancer may be a novel finding, whereas the association with breast cancer has been previously observed using orthogonal methods. The association between CRC risk and behavioral risk factors corroborate previous studies, also using orthogonal methods, and may reveal potential prevention or treatment strategies.<br><br>CONCLUSIONS: As these results corroborate findings from other studies using orthogonal methods, we demonstrate that a CRC PRS can be used as a proxy for genetic risk for CRC when investigating shared genetics between CRC and other phenotypes. Further study of the relationship between PRS from multiple traits with EHR data may reveal additional shared genetic factors. Ultimately, understanding these underlying genetic correlations may identify prevention and treatment strategies for CRC.}, }
@article {pmid40637727, year = {2026}, author = {Dima, D and Logue, JM and Waqar, SHB and Peres, LC and Colin-Leitzinger, CM and De Avila, G and Smith, EC and Skelson, L and Matte, KL and Blue, B and Hovanky, VN and Gaballa, M and Pasvolsky, O and Oswald, LB and Fortuna, GGM and Wagner, CB and DeJarnette, S and Dillard, C and Perna, F and Mikkilineni, L and Hosoya, H and Freeman, CL and Shain, KH and Baz, RC and Grajales-Cruz, A and Puglianini, OC and Alsina, M and Locke, FL and Shune, LO and Sborov, DW and Patel, KK and Sidana, S and Hansen, DK}, title = {Cytopenias and infections following ciltacabtagene autoleucel in heavily pretreated relapsed or refractory multiple myeloma.}, journal = {Haematologica}, volume = {111}, number = {1}, pages = {184-195}, pmid = {40637727}, issn = {1592-8721}, support = {KL2 TR003143/TR/NCATS NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA281756/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Multiple Myeloma/therapy/complications/pathology ; Male ; Female ; Middle Aged ; Aged ; Retrospective Studies ; *Infections/etiology/diagnosis ; *Immunotherapy, Adoptive/adverse effects ; Adult ; *Antigens, CD19/therapeutic use ; Aged, 80 and over ; Cytopenia ; }, abstract = {Ciltacabtagene autoleucel (cilta-cel) was approved by the Food and Drug Administration in February 2022 for the treatment of relapsed/refractory multiple myeloma after four lines of therapy. On the CARTITUDE-1 trial, grade ≥3 cytopenias and infections were common. Herein, we sought to characterize cytopenias and infections after cilta-cel infusion in the standardof- care setting. This multicenter, retrospective study included 105 patients who received cilta-cel; 91 reached day 90 and 49 reached day 180 of follow-up. Grade ≥3 cytopenia was present among 52% of patients on day 30, and 24% of patients on day 90. Based on the newer immune effector cell-associated hematotoxicity (ICAHT) grading for neutropenia severity, 11 patients (10%) experienced grade ≥3 early ICAHT in the first 30 days, while only three (3.3%) experienced grade ≥3 late ICAHT after day 30. On univariate analysis, any grade thrombocytopenia at apheresis was associated with grade ≥3 cytopenia at both days 30 and 90. Granulocyte colony-stimulating factor was administered to 65%, transfusion support to 38%, thrombopoietin agonists to 10%, intravenous immunoglobulins to 52%, and CD34+ stem cell boosts to 9.5% of patients. Infections occurred in 49% of patients and were severe in 32%. Earlier infections in the first 30 days were equally bacterial (42%) and viral (42%). Later infections between days 31-100 and after day 100 were mostly viral (59% and 60%, respectively), with only 32% and 12% being grade ≥3 in each time period. On univariate analysis, worse Eastern Cooperative Oncology Group performance status at lymphodepletion, higher maximum grade of cytokine-release syndrome, delayed neurotoxicity, steroid and anakinra use, and lower IgA levels at day 90 were associated with severe infections.}, }
@article {pmid40639796, year = {2025}, author = {Parnes, M and Gonzalez, E and Tran, N and Stein, MA and Mendoza, J and Tandon, P}, title = {Adherence to 24-Hour Movement Guidelines and Behavioral Health in Children With Attention Deficit Hyperactivity Disorder in the United States.}, journal = {Journal of physical activity &amp; health}, volume = {22}, number = {9}, pages = {1143-1152}, pmid = {40639796}, issn = {1543-5474}, support = {R21 AT010041/AT/NCCIH NIH HHS/United States ; }, mesh = {Humans ; *Attention Deficit Disorder with Hyperactivity/psychology/physiopathology ; Male ; Female ; Child ; *Exercise ; United States ; Accelerometry ; Sleep/physiology ; Sedentary Behavior ; Screen Time ; *Guideline Adherence ; Sleep Wake Disorders ; }, abstract = {BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a 24-hour disorder that both impacts, and, is impacted by, daily activity and sleep. Children with ADHD are less likely to meet recommended 24-hour movement guidelines (ie, on average 60 min of moderate to vigorous physical activity and several hours of light activity per day, less than 2 h of screen time, and 9-11 h of sleep). The current study examined associations between meeting 24-hour movement guidelines with ADHD symptoms, sleep problems, and media use.<br><br>METHODS: Accelerometer data measured physical activity and sleep among a sample of 93 children with ADHD (mean age = 8.10, SDage = 1.37, 58.9% male). Parent-report measures assessed ADHD symptoms, sleep difficulties, and media use. Multivariate analysis of covariance analyses explored associations between meeting 24-hour movement guidelines and outcomes. Latent class analysis (LCA) identified unique combinations of 24-hour movement guideline adherence. Associations were examined between classes and outcomes.<br><br>RESULTS: Overall, 41.5% of children met physical activity guidelines, 23.4% met sedentary behavior guidelines, and 45.7% met sleep guidelines. Multivariate analysis of covariance analyses found that meeting more guidelines was associated with less sleep difficulties and problematic media use. LCA revealed 2 classes: Hypoactive children who were unlikely to meet activity guidelines and Work Hard, Play Hard children who were likely to meet activity and sleep guidelines. Children in the Work Hard, Play Hard class had less bedtime resistance compared with the Hypoactive class.<br><br>CONCLUSION: Findings have implications for clinicians and caregivers supporting children with ADHD to take a holistic approach to improve health behaviors throughout the whole day.}, }
@article {pmid40639916, year = {2025}, author = {Zheng, C and Casjens, SR and Davidson, AR and Amundsen, SK and Smith, GR}, title = {Lambdoid phages with abundant Chi recombination hotspots reflect diverse viral strategies for recombination-dependent growth.}, journal = {Genome research}, volume = {35}, number = {8}, pages = {1767-1780}, pmid = {40639916}, issn = {1549-5469}, support = {R35 GM118120/GM/NIGMS NIH HHS/United States ; }, mesh = {*Recombination, Genetic ; Genome, Viral ; Escherichia coli/virology/genetics ; Exodeoxyribonuclease V/genetics/metabolism ; *Bacteriophages/genetics/growth &amp; development ; Bacteriophage lambda/genetics ; Viral Proteins/genetics ; }, abstract = {Many phages encode recombination-mediating enzymes, but characterization of their roles in phage lifecycles is limited, and their impact on phage replication is controversial. To address these issues, we have searched for phages whose growth is impacted by the major recombination-promoting helicase-nuclease of Escherichia coli, the RecBCD enzyme. Although no phages inhibited by RecBCD are identified, growth of a newly isolated phage, named LLS, is enhanced by RecBCD. LLS's genome sequence reveals it is related to bacteriophage λ but encodes no recombination-promoting (Rec) proteins or associated RecBCD inhibitor. However, it contains an unexpectedly high number of Chi sites, activators of RecBCD-dependent recombination. Through analysis of 325 genomes of phages related to λ (lambdoid phages), we have found 71 other phage genomes that encode no Rec proteins but mostly possess large numbers of Chi sites. Conversely, phages encoding Rec proteins and a RecBCD inhibitor (collectively a Rec module) mostly lack Chi sites. Lambdoid phages of both diverse enteric bacteria and a pseudomonad have these properties. For this study, we thoroughly analyze the Rec modules of 246 lambdoid phage genomes. These analyses reveal a remarkable heterogeneity of Rec module protein types, both in sequence and in function, and allow us to identify phages that do not contain Rec modules. We conclude that phages lacking their own recombination systems have compensated by becoming enriched in Chi sites, enabling them to use the host's RecBCD to fulfill the requirement for recombination to efficiently replicate. This study highlights the importance of recombination for phage survival and the diversity of strategies to achieve it.}, }
@article {pmid40640959, year = {2025}, author = {Cai, Y and Johnson, M and Haessler, J and Molstad, AJ and Hwang, SJ and Joehanes, R and Murabito, JM and Tahir, UA and Franceschini, N and Gerszten, RE and Sun, W and Levy, D and Raffield, LM and Kooperberg, C and Hsu, L and Reiner, AP}, title = {Protein quantitative trait locus analysis in African American and non-Hispanic White individuals.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {200}, pmid = {40640959}, issn = {1474-760X}, support = {R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; R01 HL152439/HL/NHLBI NIH HHS/United States ; K08 HL161445-01A1/GF/NIH HHS/United States ; HHSN268201600034I, HL133870/GF/NIH HHS/United States ; U01-HG011720/HG/NHGRI NIH HHS/United States ; U01-HG011720/HG/NHGRI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Black or African American/genetics ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; *White/genetics ; }, abstract = {BACKGROUND: Substantial efforts have been dedicated to exploring the link between genetic regulation and the proteome, informing studies of complex trait mechanisms. Most of these efforts have been limited to populations of European ancestry.<br><br>RESULTS: We conduct an Olink protein quantitative trait locus (pQTL) analysis on 1245 proteins involving 1033 self-identified African American (AA) and 1764 non-Hispanic White (NHW) participants from the Women's Health Initiative and Framingham Heart Study. For replication of candidate pQTLs, we use data from 534 self-identified AA adults from the Jackson Heart Study and protein genome-wide association analysis statistics from the UK Biobank Pharma Proteomics Project, including 54,219 participants, of whom 931 are of African ancestry. In total, we identify and validate 5103 pQTLs (4496 or 88% cis- and 602 or 12% trans-pQTLs) for 983 proteins. Among these, 195 are previously unreported, with most (166 or 85%) identified in our AA sample, many of which were essentially monomorphic in European reference populations. Several of these newly identified African ancestry-specific pQTLs have been reported in ClinVar; our results suggest impact on circulating protein levels, potentially bolstering evidence for clinical significance. We identify a "cis pQTL hotspot" within the leukocyte receptor gene cluster on human chromosome 19q13.4. We also provide examples where a particular cis-pQTL, identified through conditional analysis, offers biological insights into an overlapping GWAS signal for disease susceptibility.<br><br>CONCLUSIONS: The identification of previously undescribed African ancestry-specific pQTLs contributes to understanding protein genetic regulation and highlights the significance of proteomic analysis in diverse populations.}, }
@article {pmid40641655, year = {2025}, author = {Chakraborty, H and Sun, Q and Bhupathiraju, SN and Schenk, JM and Mishchuk, DO and Bain, JR and He, X and Sun, J and Harnly, J and Simmons, W and Raftery, D and Liang, L and Newman, JW and Fiehn, O and Clish, CB and Lampe, JW and Bennett, BJ and Navarro, SL and Wang, Y and Zheng, C and Mossavar-Rahmani, Y and McCullough, ML and Huang, Y and Shojaie, A and Zhu, W and Djukovic, D and Sacks, F and Williams, J and Steinberg, FM and Adams, SH and Hu, FB and Neuhouser, ML and Slupsky, CM and Maruvada, P}, title = {The Dietary Biomarkers Development Consortium: An Initiative for Discovery and Validation of Dietary Biomarkers for Precision Nutrition.}, journal = {Current developments in nutrition}, volume = {9}, number = {5}, pages = {107435}, pmid = {40641655}, issn = {2475-2991}, support = {P30 DK035816/DK/NIDDK NIH HHS/United States ; P30 ES007033/ES/NIEHS NIH HHS/United States ; R01 AG055527/AG/NIA NIH HHS/United States ; }, abstract = {UNLABELLED: Diet is a complex exposure that affects health across the lifespan. Objective biomarkers that can reliably reflect intake of nutrients, foods, and dietary patterns with sufficient accuracy are an important tool for assessing associations of diet with health outcomes. Advances in metabolomics, coupled with feeding trials and high-dimensional bioinformatics analyses, pave the way for discovering compounds that can serve as sensitive and specific biomarkers of dietary exposures. The Dietary Biomarkers Development Consortium (DBDC) is leading the first major effort to improve dietary assessment through the discovery and validation of biomarkers for foods commonly consumed in the United States diet. To achieve this goal, a 3-phase approach will be implemented to identify, evaluate, and validate food biomarkers. In phase 1, 3 controlled feeding trial designs will be implemented by administering test foods in prespecified amounts to healthy participants, followed by metabolomic profiling of blood and urine specimens collected during the feeding trials to identify candidate compounds. Data from these studies will characterize the pharmacokinetic parameters of candidate biomarkers associated with specific foods. In phase 2, the ability of candidate biomarkers to identify individuals eating the biomarker-associated foods will be evaluated using controlled feeding studies of various dietary patterns. In phase 3, the validity of candidate biomarkers to predict recent and habitual consumption of specific test foods will be evaluated in independent observational settings. Data generated during all study phases will be archived in a publicly accessible database as a resource for the research community. The DBDC aims to significantly expand the list of validated biomarkers of intake for foods consumed in the United States diet, which can help advance understanding of how diet influences human health. This manuscript discusses the DBDC's organizational infrastructure, study design, laboratory methods, and strategies for dietary biomarker discovery and validation.<br><br>TRIAL REGISTRATION NUMBER: This trial was registered at Phase 1 Seattle Dietary Biomarkers Development Center (P1-SDBDC) as NCT05580653, at Fruit and Vegetable Biomarker Discovery (UCD-DBDC) as NCT05621863, and at Dietary Biomarkers Intervention Core as NCT05616585.}, }
@article {pmid40644338, year = {2025}, author = {Koric, A and Chang, CE and Lee, YA and Wei, M and Lee, C and Wang, J and Hashibe, M}, title = {Incident depression after breast cancer among older Asian, Native Hawaiian, and Pacific Islander women.}, journal = {JNCI cancer spectrum}, volume = {9}, number = {4}, pages = {}, pmid = {40644338}, issn = {2515-5091}, support = {T32 CA190194/CA/NCI NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; *Asian American Native Hawaiian and Pacific Islander/statistics &amp; numerical data/psychology ; *Breast Neoplasms/psychology/ethnology/mortality ; *Depression/epidemiology/ethnology/etiology ; Incidence ; Proportional Hazards Models ; Risk Factors ; SEER Program ; United States/epidemiology ; White/psychology/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Longitudinal studies examining mental health outcomes among older (≥66 years) Asian, Native Hawaiian, and Pacific Islander (ANHPI) women diagnosed with breast cancer are limited. We evaluated incident depression after breast cancer among specific groups of older ANHPI compared with older non-Hispanic White (NHW) women. Predictors of depression and the risk of death following early onset of depression after breast cancer were also evaluated.<br><br>METHODS: A cohort of 26&#xa0;776 older ANHPI women in the United States diagnosed with breast cancer between 2000 and 2017 was identified from the SEER-Medicare linked claims. There were 6694 older ANHPI and 20&#xa0;082 older NHW women diagnosed with breast cancer. Adjusted hazard ratios (HRs) were calculated with the Cox proportional hazards regression and 99% confidence intervals (CI) to evaluate incident depression and death among older ANHPI compared with age-matched NHW counterparts.<br><br>RESULTS: Compared with older NHW women with breast cancer, older Japanese (HR&#x2009;=&#x2009;0.43, 99% CI = 0.31 to 0.66), Chinese (HR&#x2009;=&#x2009;0.46, 99% CI = 0.31 to 0.67), Filipino (HR&#x2009;=&#x2009;0.43, 99% CI = 0.30 to 0.60), and Asian Indian/Pakistani women (HR&#x2009;=&#x2009;0.49, 99% CI = 0.28 to 0.84) had a lower risk of depression overall and within 5&#x2009;years of follow-up; lower risk persisted for Japanese and Chinese women >5&#x2009;years. ANHPI breast cancer patients with early onset of depression had a higher risk of death (HR&#x2009;=&#x2009;1.46, 99% CI = 1.30 to 1.65) compared to those without depression.<br><br>CONCLUSION: Compared with older NHW women, older ANHPI women had a lower incidence of depression, although disentangling the stigma surrounding depression by race and ethnicity remains challenging.}, }
@article {pmid40645186, year = {2025}, author = {Chiou, SH and Tseng, D}, title = {Blood TCRs go to town with early NPC detection.}, journal = {Cancer cell}, volume = {43}, number = {8}, pages = {1396-1398}, doi = {10.1016/j.ccell.2025.06.016}, pmid = {40645186}, issn = {1878-3686}, mesh = {Humans ; *Early Detection of Cancer/methods ; *Receptors, Antigen, T-Cell/blood ; *Nasopharyngeal Neoplasms/diagnosis/blood/virology/immunology ; *Biomarkers, Tumor/blood ; }, abstract = {In this issue of Cancer Cell, Zhang et al. report an innovative approach utilizing patients' blood T cell receptor (TCR) sequences for the early detection of nasopharyngeal cancer. This study highlights the potential of harnessing highly public TCRs in the peripheral blood as biomarkers for virally associated malignancies.}, }
@article {pmid40645851, year = {2025}, author = {Huang, J and Shadman, M}, title = {First-line Therapy: Time-Limited Venetoclax Doublet Therapy.}, journal = {Hematology/oncology clinics of North America}, volume = {39}, number = {5}, pages = {885-901}, doi = {10.1016/j.hoc.2025.05.007}, pmid = {40645851}, issn = {1558-1977}, mesh = {Humans ; *Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/administration &amp; dosage ; *Sulfonamides/therapeutic use/administration &amp; dosage ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/mortality ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-bcl-2/antagonists &amp; inhibitors ; Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; }, abstract = {Studies examining venetoclax in combination with anti-CD20 monoclonal antibodies and covalent Bruton tyrosine kinase inhibitors (BTKi) demonstrated a progression-free survival and in some cases overall survival benefit over chemoimmunotherapy. It is currently unclear what is the most optimal combination partner for a B-cell leukemia/lymphoma 2 inhibitor (BCL2i). We are eagerly awaiting results from studies to determine the most effective BCL2i and BTKi combination for the first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma given the development of second-generation drugs.}, }
@article {pmid40646132, year = {2025}, author = {Apperley, JF and Milojkovic, D and Cross, NCP and Hjorth-Hansen, H and Hochhaus, A and Kantarjian, H and Lipton, JH and Malhotra, H and Niederwieser, D and Radich, J and Rousselot, P and Saussele, S and Schiffer, CA and Silver, R and Soverini, S and Stenke, L and Turkina, A and Casado, LF and Castagnetti, F and Cervantes, F and Clark, RE and Cortes, J and Deininger, M and Hughes, TP and Janssen, J and Jiang, Q and Kim, DW and Larson, RA and Mahon, FX and Mauro, M and Mayer, J and Nicolini, FE and Pane, F and Rea, D and Richter, J and Rosti, G and Saglio, G and Hehlmann, R}, title = {2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia.}, journal = {Leukemia}, volume = {39}, number = {8}, pages = {1797-1813}, pmid = {40646132}, issn = {1476-5551}, mesh = {Humans ; Disease Management ; Europe ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy/drug therapy/diagnosis ; *Protein Kinase Inhibitors/therapeutic use ; }, abstract = {In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate on dose reduction rather than drug switching to manage toxicities and discuss treatment sequencing. Data have matured for the outcome of treatment discontinuation and for management of parenting for both men and women. We acknowledge that most patients will remain on treatment for many years and emphasize the needs to minimize side effects, manage co-morbidities and optimize quality of life. Recent advances in allogeneic stem cell transplantation have broadened access to alternative donors, and lessened limitations of age and co-morbidities such that transplant remains a valuable option for patients for whom long-term disease control is not achieved through TKI therapy.}, }
@article {pmid40650496, year = {2025}, author = {Smith, D and Fleming, T and Gianella, S and Halloran, E and Hillier, S and Longini, I and Smeaton, L and DeGruttola, V}, title = {Salvaging information from paused or stopped clinical studies.}, journal = {Clinical trials (London, England)}, volume = {22}, number = {6}, pages = {761-762}, pmid = {40650496}, issn = {1740-7753}, support = {P30 AI036214/AI/NIAID NIH HHS/United States ; UL1 TR001442/TR/NCATS NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068634/AI/NIAID NIH HHS/United States ; }, }
@article {pmid40655537, year = {2025}, author = {Krawczuk, P and Fox, ZR and Petkov, V and Negoita, S and Doherty, J and Stroup, A and Schwartz, S and Penberthy, L and Hsu, E and Gounley, J and Hanson, HA}, title = {Large-scale deep learning for metastasis detection in pathology reports.}, journal = {JAMIA open}, volume = {8}, number = {4}, pages = {ooaf070}, pmid = {40655537}, issn = {2574-2531}, abstract = {OBJECTIVES: No existing algorithm can reliably identify metastasis from pathology reports across multiple cancer types and the entire US population. In this study, we develop a deep learning model that automatically detects patients with metastatic cancer by using pathology reports from many laboratories and of multiple cancer types.<br><br>MATERIALS AND METHODS: We use 60&#xa0;471 unstructured pathology reports from 4 Surveillance, Epidemiology, and End Results (SEER) registries. The reports were coded into 1 of 3 labels: metastasis negative, metastases positive, or metastasis undetermined. We utilize a task-specific deep neural network trained from scratch and compare its performance with a widely used large language model (LLM).<br><br>RESULTS: Our deep learning architecture trained on task-specific data outperforms a general-purpose LLM, with a recall of 0.894 compared to 0.824. We quantified model uncertainty and used it to defer reports for human review. We found that retaining 72.9% of reports increased recall from 0.894 to 0.969.<br><br>DISCUSSION: A smaller deep learning architecture trained on task-specific data outperforms a general LLM. Equally critical to model performance is the incorporation of uncertainty quantification, achieved here through an abstention mechanism.<br><br>CONCLUSIONS: This study's finding demonstrate the feasibility of developing algorithms to automatically identify metastatic cancer cases from unstructured pathology reports.}, }
@article {pmid40656459, year = {2025}, author = {Zhang, T and Ameen, S and Ghosh, S and Kim, K and Pandey, M and Cheung, BCH and Thanh, M and Patteson, AE and Wu, M and Schwarz, JM}, title = {Enhanced extracellular matrix remodeling due to embedded spheroid fluidization.}, journal = {New journal of physics}, volume = {27}, number = {7}, pages = {073301}, pmid = {40656459}, issn = {1367-2630}, support = {R01 CA221346/CA/NCI NIH HHS/United States ; R35 GM142963/GM/NIGMS NIH HHS/United States ; S10 OD010605/OD/NIH HHS/United States ; }, abstract = {Embedding a collective of tumor cells, i.e. a tumor spheroid, in a fibrous environment, such as a collagen network, provides an essential in vitro platform to investigate the biophysical mechanisms of tumor invasion. To predict new mechanisms, we develop a three-dimensional computational model of an embedded spheroid using a vertex model, with cells represented as deformable polyhedrons, mechanically coupled to a fiber network via active linker springs. As the linker springs actively contract, the fiber network remodels. As we tune the rheology of the spheroid and the fiber network stiffness, we find that both factors affect the remodeling of the fiber network with fluid-like spheroids densifying and radially realigning the fiber network more on average than solid-like spheroids but only for a range of intermediate fiber network stiffnesses. Our predictions are supported by experimental studies comparing non-tumorigenic MCF10A spheroids and malignant MDA-MB-231 spheroids embedded in collagen networks. The spheroid rheology-dependent effects are the result of cellular motility generating spheroid shape fluctuations. These shape fluctuations lead to emergent feedback between the spheroid and the fiber network to further remodel the fiber network. This emergent feedback occurs only at intermediate fiber network stiffness since at low fiber network stiffness, the mechanical response of the coupled system is dominated by the spheroid and for high fiber network stiffness, the mechanical response is dominated by the fiber network. We are therefore able to quantify the regime of optimal spheroid-fiber network mechanical reciprocity. Our results uncover intricate morphological-mechanical interplay between an embedded spheroid and its surrounding fiber network with both spheroid contractile strength and spheroid shape fluctuations playing important roles in the pre-invasion stages of tumor invasion.}, }
@article {pmid40656602, year = {2025}, author = {Shadman, M and Brown, JR and Williams, R and Mohseninejad, L and Yang, K and Rakonczai, P and Lamanna, N and Xu, S and Cleary Cohen, A and O'Brien, SM and Tedeschi, A and Tam, CS}, title = {Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC).}, journal = {Therapeutic advances in medical oncology}, volume = {17}, number = {}, pages = {17588359251340554}, pmid = {40656602}, issn = {1758-8340}, abstract = {BACKGROUND: There are no head-to-head studies comparing the efficacy of the Bruton tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, in relapsed or refractory chronic lymphocytic leukemia (R/R CLL).<br><br>OBJECTIVE: To compare the relative efficacy of zanubrutinib and acalabrutinib in R/R CLL using indirect treatment comparison.<br><br>DESIGN: An unanchored matching-adjusted indirect comparison (MAIC) was performed.<br><br>METHODS: Individual patient-level data from ALPINE (zanubrutinib) were reweighted using prognostic/effect-modifying variables to match aggregate data from ASCEND (acalabrutinib). MAIC outcomes included investigator-assessed progression-free survival (PFS-INV), overall survival (OS), and complete response (CR).<br><br>RESULTS: Post-matching, PFS-INV was improved significantly for zanubrutinib versus acalabrutinib (hazard ratio (HR)&#x2009;=&#x2009;0.68 (95% confidence interval (CI): 0.46-0.99); p&#x2009;=&#x2009;0.0448) and OS showed a trend toward improvement for zanubrutinib (HR&#x2009;=&#x2009;0.60; 95% CI: 0.35-1.02, p&#x2009;=&#x2009;0.0575). CR was significantly higher for zanubrutinib versus acalabrutinib (odds ratio&#x2009;=&#x2009;2.90 (95% CI: 1.13-7.43); p&#x2009;=&#x2009;0.0270).<br><br>CONCLUSION: Zanubrutinib was associated with a significant PFS-INV and CR advantage over acalabrutinib, with a trend toward improvement in OS.}, }
@article {pmid40658414, year = {2025}, author = {Kanaya, AM and Anderson, GL}, title = {MOSAAIC to Capture Key Measures of Aging Across the Lifespan.}, journal = {JAMA internal medicine}, volume = {185}, number = {9}, pages = {1174}, doi = {10.1001/jamainternmed.2025.2908}, pmid = {40658414}, issn = {2168-6114}, }
@article {pmid40658837, year = {2025}, author = {McGrosky, A and Luke, A and Arab, L and Bedu-Addo, K and Bonomi, AG and Bovet, P and Brage, S and Buchowski, MS and Butte, N and Camps, SG and Casper, R and Cummings, DK and Krupa Das, S and Deb, S and Dugas, LR and Ekelund, U and Forrester, T and Fudge, BW and Gillingham, M and Goris, AH and Gurven, M and Hambly, C and Joosen, A and Katzmarzyk, PT and Kempen, KP and Kraus, WE and Kriengsinyos, W and Kuriyan, R and Kushner, RF and Lambert, EV and Larsson, CL and Leonard, WR and Lessan, N and Löf, M and Martin, CK and Medin, AC and Neuhouser, ML and Pietilainen, KH and Plasqui, G and Prentice, RL and Racette, SB and Raichlen, DA and Ravussin, E and Redman, L and Reynolds, RM and Rimm, EB and Roberts, S and Rosinger, AY and Samuels, MH and Sinha, S and Snodgrass, JJ and Stice, E and Uauy, R and Urlacher, SS and Verbunt, JA and Wolfe, B and Wood, B and Zhang, X and Murphy-Alford, AJ and Loechl, CJ and Rood, J and Sagayama, H and Schoeller, DA and Westerterp, KR and Wong, WW and Yamada, Y and Speakman, JR and Pontzer, H and , }, title = {Energy expenditure and obesity across the economic spectrum.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {29}, pages = {e2420902122}, pmid = {40658837}, issn = {1091-6490}, support = {P2C HD065563/HD/NICHD NIH HHS/United States ; UL1 TR002369/TR/NCATS NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; CAS 153E11KYSB20190045//Chinese Academy of Sciences (CAS)/ ; BCS-1824466//National Science Foundation (NSF)/ ; }, mesh = {Humans ; *Obesity/epidemiology/metabolism/economics ; *Energy Metabolism/physiology ; Body Mass Index ; Adult ; Male ; Female ; Middle Aged ; Energy Intake ; Life Style ; }, abstract = {Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size-adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size-adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development.}, }
@article {pmid40658949, year = {2025}, author = {Tsai, CS and Szewczyk, W and Drerup, M and Liao, J and Vasbinder, A and Greenlee, H and Heffner, JL and Yung, R and Reding, KW}, title = {A Personalized, Texting-Based Conversational Agent to Address Sleep Disturbance in Individuals Who Have Survived Breast Cancer: Protocol for a Pilot Waitlist Randomized Controlled Trial.}, journal = {JMIR research protocols}, volume = {14}, number = {}, pages = {e62712}, pmid = {40658949}, issn = {1929-0748}, mesh = {Humans ; *Text Messaging ; *Breast Neoplasms/complications/psychology ; Female ; Pilot Projects ; *Cancer Survivors/psychology ; Quality of Life ; *Cognitive Behavioral Therapy/methods ; Adult ; *Sleep Initiation and Maintenance Disorders/therapy/etiology ; *Sleep Wake Disorders/therapy/etiology ; Randomized Controlled Trials as Topic ; Middle Aged ; }, abstract = {BACKGROUND: Sleep disturbance is one of the most common health concerns reported by individuals who have survived breast cancer (BC) and is associated with poor quality of life (QoL) and greater mortality after treatment. Cognitive behavioral therapy for insomnia (CBTi) has shown efficacy for improving sleep and QoL for this population. Considered the gold standard for insomnia treatment, CBTi can be delivered remotely, including via digital intervention. Despite the potential for wider dissemination of CBTi via digital means, these modalities have unique challenges, including technology barriers and poor adherence. We developed a conversational agent (CA) to deliver CBTi via a SMS text messaging intervention, supported by mobile-ready web content. Named "Cecebot," this CA delivers sleep education, implements sleep compression, provides just-in-time interventions for sleep-disrupting behaviors, and includes enhanced support for physical activity (PA) beyond what is typically included in CBTi. This represents a novel modality for a CBTi and PA intervention among individuals who have survived BC.<br><br>OBJECTIVE: We aim to examine the safety and acceptability of the Cecebot intervention, developed by an academic partnership between Dr Reding's research team and Moby Inc, for individuals who have survived BC and experience symptoms of insomnia, and to explore its efficacy.<br><br>METHODS: This trial will recruit 60 individuals who have survived BC and are experiencing moderate to severe sleep disturbance. Participants will be assigned to the Cecebot intervention or waitlist control group at a 1:1 ratio. The treatment group will receive the Cecebot intervention during weeks 1-6 of the study, while the waitlist control condition will receive the Cecebot intervention during weeks 6-12. The Cecebot intervention uses SMS text messaging technology paired with a Fitbit. Participants will be assessed at baseline, week 6, and week 12. Measurements will include feasibility and acceptability and will explore the effect of the Cecebot intervention. Feasibility will be assessed through recruitment, enrollment, and retention rates. Acceptability will be evaluated using a satisfaction survey and open-ended responses. Quantitative analysis, such as t test, Fisher exact tests, and generalized linear models, will be used to assess feasibility, baseline group differences, and the outcomes of the intervention.<br><br>RESULTS: Recruitment of participants began in Fall 2024. The completion of data collection is anticipated to be by Fall 2025.<br><br>CONCLUSIONS: The study results will give insight into the potential for an SMS text messaging-based CA to improve sleep in individuals who have survived BC and experience sleep disturbances.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov NCT06392789; https://clinicaltrials.gov/study/NCT06392789.<br><br>DERR1-10.2196/62712.}, }
@article {pmid40659309, year = {2025}, author = {Ehret, F and Ebner, DK and Kutuk, T and Shakeri, A and Shrestha, S and Skalina, KA and Fekrmandi, F and Lo, SS and Gore, JL and Kotecha, R and Lee, P and Slotman, BJ and Fürweger, C and Muacevic, A and Siva, S and Reddy, K}, title = {Stereotactic Body Radiation Therapy for the Treatment of Adrenal Metastases - A Case-Based Radiosurgery Society Practice Guide and Review.}, journal = {Practical radiation oncology}, volume = {15}, number = {6}, pages = {597-609}, doi = {10.1016/j.prro.2025.06.011}, pmid = {40659309}, issn = {1879-8519}, mesh = {Humans ; *Adrenal Gland Neoplasms/secondary/radiotherapy ; Case Reports as Topic ; *Radiosurgery/methods ; }, abstract = {PURPOSE: Adrenal metastases are frequently diagnosed in patients with common solid tumors. Surgical adrenalectomy has historically been used for their management. However, stereotactic body radiation therapy (SBRT) has emerged as a safe and effective alternative. Careful treatment planning is essential, considering multiple factors such as tumor size and location, motion management, dose and fractionation, and proximity to adjacent organs at risk. This case-based practice guide and review provides an overview of SBRT for the management of adrenal tumors, with a particular focus on adrenal metastases.<br><br>METHODS AND MATERIALS: Three clinical scenarios were selected to illustrate the use of SBRT in managing adrenal tumors. These include a small right-sided metastasis treated with single-fraction, fiducial-based SBRT, a large left-sided metastasis treated with fractionated SBRT under magnetic resonance imaging guidance, and a case of bilateral metastases, which emphasizes the potential risk of adrenal insufficiency. We also address the limited evidence available regarding the management of primary adrenal gland tumors with SBRT.<br><br>RESULTS: SBRT is an effective treatment modality for most adrenal tumors, demonstrating a favorable safety profile. Thoughtful treatment planning and an understanding of potential pitfalls, limitations, and risks are essential to ensure the appropriate use of SBRT.<br><br>CONCLUSIONS: This case-based guide and review provides a comprehensive overview of SBRT for treating adrenal tumors, specifically metastases. We present and discuss clinical cases and relevant literature, highlighting key considerations specific to adrenal SBRT.}, }
@article {pmid40660865, year = {2025}, author = {Hope, A and Mundis, M and Sonke, JJ and Kang, J and Korreman, S and Napolitano, B and Elguindi, S and Joiner, MC and Burmeister, J and Dominello, MM}, title = {Three discipline collaborative radiation therapy (3DCRT) special debate: AI structure segmentation is better than clinician contouring for both OARs and targets.}, journal = {Journal of applied clinical medical physics}, volume = {26}, number = {7}, pages = {e70183}, pmid = {40660865}, issn = {1526-9914}, }
@article {pmid40661112, year = {2025}, author = {Read, C and Bhatia, S and Totonchy, M}, title = {Programmed cell death 1 blockade in the setting of severe ocular sarcoidosis: Cancer immunotherapy in a patient with autoimmunity.}, journal = {JAAD case reports}, volume = {62}, number = {}, pages = {43-45}, pmid = {40661112}, issn = {2352-5126}, }
@article {pmid40661279, year = {2025}, author = {Bulstra, CA and Dai, X and Ngure, K and Rosenberg, MS and Wamuti, BM and Hontelez, JAC and Salomon, JA and Ortblad, KF and Bärnighausen, T}, title = {The real-world association between male circumcision and risk of HIV infection in sub-Saharan Africa: a household fixed-effects analysis of 279,351 men from 29 countries.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40661279}, support = {K99 MH121166/MH/NIMH NIH HHS/United States ; R00 MH121166/MH/NIMH NIH HHS/United States ; }, abstract = {INTRODUCTION: While voluntary medical male circumcision (VMMC) reduces the individual-level risk of HIV acquisition by approximately 60% in randomised-controlled trials, little is known about the 'real-world' long-term effect of medical and traditional male circumcision on the cumulative risk of HIV infection. We estimate the association between these for the first time using a quasi-experimental study design-a household fixed-effects analysis-for sub-Saharan Africa, the global region with the largest HIV burden.<br><br>METHODS: We pooled individual-level cross-sectional data from the nationally-representative Demographic and Health Surveys and AIDS Indicator Surveys across all sub-Saharan African countries in which the surveys included data on both male circumcision and HIV status. We estimated the association between male circumcision and HIV status using modified Poisson regression models with household fixed-effects-which control for unobserved and observed confounding shared by men living in the same household-and included additional individual-level controls for demographic characteristics, socio-economic factors, and sexual behaviour.<br><br>RESULTS: We included individual data from 279,351 male participants in 48 nationally-representative surveys conducted in 29 countries between 2003-2018. The mean survey-level prevalence of male circumcision was 65.9% (median 84.5%, IQR 28.8%-68.1%) and HIV was 5.6% (median 2.5%, IQR 1.2%-10.2%). We estimated that male circumcision was significantly associated with a nearly one-fifth reduction in the cumulative risk of HIV infection (adjusted risk ratio 0.81, 95% CI 0.73-0.89).<br><br>CONCLUSIONS: Male circumcision was associated with a significant reduction in the risk of HIV infection in sub-Saharan Africa over the past two decades. Increased political and financial commitment to VMMC could likely lead to further reductions in HIV prevalence, especially when rolled out as a HIV prevention option in combination with other interventions.}, }
@article {pmid40661527, year = {2025}, author = {Cao, J and Ferguson, M and Sun, J and Shen, M and Small, R and Hippe, DS and Zhao, X and Zhang, D and Watase, H and Yuan, C and Gao, P and DeMarco, JK and Nicosia, RF and Wang, Y and Li, H and Li, Z and Wang, Y and Kohler, T and Hatsukami, T and Sui, B}, title = {Composition of Carotid Plaques Differs Between Chinese and United States Patients: A Histology Study.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661527}, issn = {2692-8205}, support = {R01 HL073401/HL/NHLBI NIH HHS/United States ; R01 HL103609/HL/NHLBI NIH HHS/United States ; R01 NS083503/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: The clinical manifestations of cerebrovascular disease are known to differ between the Chinese and United States (U.S.) populations as do the plaque features on imaging.<br><br>OBJECTIVES: The aim of this study was to investigate and compare the histological features of excised carotid plaques from Chinese and U.S. patients.<br><br>METHODS: Carotid endarterectomy specimens collected from two prospective studies were included. The entire plaque was serially sectioned (10 &#x3bc;m thickness) at 0.5-1 mm intervals. Hematoxylin and eosin staining and Mallory's trichrome staining were performed. The morphology and components of the plaques were measured and compared between the two groups.<br><br>RESULTS: A total of 1,152 histological sections from 75 Chinese patients and 1,843 sections from 111 U.S. patients were analyzed. The Chinese group had significantly smaller minimum lumen diameters (median: 1.1 vs. 1.3 mm, p=0.046) and a larger percent wall volume (median: 74% vs. 70%, p=0.018) than the U.S. group. After adjusting for confounding factors, carotid plaques in the Chinese population were more likely to have more lipid pools (&#x3b2;=10.0%, 95%CI: 4.9 to 15.9%), more recent intraplaque hemorrhage (IPH; &#x3b2;=8.4%, 95%CI: 4.5 to 12.7%), and less late IPH (&#x3b2;=-8.2%, 95%CI: -11.3 to -5.4), and fewer fibrous cap disruptions (45% vs. 67%, p=0.061). Chinese plaques were more homogeneous and had a higher percentage of plaques with features of xanthomas than did U.S. plaques (20% vs 2.7%, p<0.001).<br><br>CONCLUSIONS: The histology of Chinese plaques differs significantly from that of U.S. plaques, suggesting substantial differences in the pathophysiology of atherosclerotic cerebrovascular disease between Chinese and North American populations, which could enhance the gap in racial pathology comparison, indicating a need for a different management approach.}, }
@article {pmid40661569, year = {2025}, author = {Risse-Adams, OS and Liquori, JL and Sinnott-Armstrong, N and Musharoff, SA}, title = {Examining the Effect of Social Determinants of Health on Human Trait Heritability.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661569}, issn = {2692-8205}, support = {RM1 HG010461/HG/NHGRI NIH HHS/United States ; U54 CA267738/CA/NCI NIH HHS/United States ; }, abstract = {Social determinants of health (SDOH) data are often excluded from genetic models of human traits. We use individual-level data from the All of Us Research Program to assess whether SDOH survey variables alter heritability estimates. Incorporating SDOH summaries decreases heritability significantly for 4 of 18 anthropometric and metabolic traits in individuals whose self-reported race is "White" (n=67,545). There are no such significant changes in individuals whose self-reported race is "Black or African American" (n=6,538), likely reflecting reduced statistical power. Incorporating genetic principal components consistently lowers heritability estimates in both groups, whether or not SDOH summaries are included. These findings demonstrate that survey-derived SDOH summaries can change heritability estimates and should be considered along with genetic summaries.}, }
@article {pmid40661619, year = {2025}, author = {DeWitt, WS and Vora, AA and Araki, T and Galloway, JG and Alkutkar, T and Bortolatto, J and Castro, TBR and Dumm, W and Jennings-Shaffer, C and Jia, T and Mesin, L and Ozorowski, G and Pae, J and Ralph, DK and Bloom, JD and Nourmohammad, A and Song, YS and Ward, AB and Starr, TN and Matsen, FA and Victora, GD}, title = {Replaying germinal center evolution on a quantified affinity landscape.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661619}, issn = {2692-8205}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; R01 AI139117/AI/NIAID NIH HHS/United States ; R01 AI180451/AI/NIAID NIH HHS/United States ; DP2 AI177890/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; R01 AI119006/AI/NIAID NIH HHS/United States ; R01 HG013117/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Darwinian evolution of immunoglobulin genes within germinal centers (GC) underlies the progressive increase in antibody affinity following antigen exposure. Whereas the mechanics of how competition between GC B cells drives increased affinity are well established, the dynamical evolutionary features of this process remain poorly characterized. We devised an experimental evolution model in which we "replay" over one hundred instances of a clonally homogenous GC reaction and follow the selective process by assigning affinities to all cells using deep mutational scanning. Our data reveal how GCs achieve predictable evolutionary outcomes through the cumulative effects of many rounds of imperfect selection, acting on a landscape shaped heavily by somatic hypermutation (SHM) targeting biases. Using time-calibrated models, we show that apparent features of GC evolution such as permissiveness to low-affinity lineages and early plateauing of affinity are best explained by survivorship biases that distort our view of how affinity progresses over time.}, }
@article {pmid40661642, year = {2025}, author = {Gao, J and Brusselmans, M and Carvalho, LM and Suchard, MA and Baele, G and Matsen, FA}, title = {Biological causes and impacts of rugged tree landscapes in phylodynamic inference.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40661642}, issn = {2692-8205}, support = {R01 AI153044/AI/NIAID NIH HHS/United States ; R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Phylodynamic analysis has been instrumental in elucidating the epidemiological and evolutionary dynamics of pathogens. The Bayesian approach to phylodynamics integrates out phylogenetic uncertainty, which is typically substantial in phylodynamic datasets due to low genetic diversity. Bayesian phylodynamic analysis does not, however, scale with modern datasets, partly due to difficulties in traversing tree space. Here, we set out to characterize tree space of phylodynamic inference and assess its impacts on analysis difficulty and key biological estimates. By running extensive Bayesian analyses of 15 classic large phylodynamic datasets and carefully analyzing the posterior samples, we find that the posterior landscape in tree space ("tree landscape") is diffuse yet rugged, leading to widespread tree sampling problems that usually stem from the sequences in a small part of the tree. We develop clade-specific diagnostics to show that a few sequences-including putative recombinants and recurrent mutants-frequently drive tree space ruggedness and sampling problems, although existing data-quality tests show limited power to detect such sequences. The sampling problems can significantly impact phylodynamic inferences or even distort major biological conclusions; the impact is usually stronger on "local" estimates (e.g., introduction history) that are associated with particular clades than on "global" parameters (e.g., demographic trajectory) that are governed by the general tree shape. We evaluate existing and newly-developed MCMC diagnostics, and offer strategies for optimizing MCMC settings and mitigating impacts of the sampling problems. Our findings highlight the need for and directions to develop efficient traversal over the rugged tree landscape, ultimately advancing scalable and reliable phylodynamics.}, }
@article {pmid40662973, year = {2025}, author = {Oviedo, F and Kazerouni, AS and Liznerski, P and Xu, Y and Hirano, M and Vandermeulen, RA and Kloft, M and Blum, E and Alessio, AM and Li, CI and Weeks, WB and Dodhia, R and Lavista Ferres, JM and Rahbar, H and Partridge, SC}, title = {Cancer Detection in Breast MRI Screening via Explainable AI Anomaly Detection.}, journal = {Radiology}, volume = {316}, number = {1}, pages = {e241629}, pmid = {40662973}, issn = {1527-1315}, support = {K99 CA293004/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; U01 CA152637/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/diagnostic imaging ; *Magnetic Resonance Imaging/methods ; Retrospective Studies ; Middle Aged ; *Artificial Intelligence ; Breast/diagnostic imaging ; Adult ; Aged ; *Image Interpretation, Computer-Assisted/methods ; Early Detection of Cancer/methods ; Sensitivity and Specificity ; }, abstract = {Background Artificial intelligence (AI) models hold potential to increase the accuracy and efficiency of breast MRI screening; however, existing models have not been rigorously evaluated in populations with low cancer prevalence and lack interpretability, both of which are essential for clinical adoption. Purpose To develop an explainable AI model for cancer detection at breast MRI that is effective in both high- and low-cancer-prevalence settings. Materials and Methods This retrospective study included 9738 breast MRI examinations from a single institution (2005-2022), with external testing in a publicly available multicenter dataset (221 examinations). In total, 9567 consecutive examinations were used to develop an explainable fully convolutional data description (FCDD) anomaly detection model to detect malignancies on contrast-enhanced MRI scans. Performance was evaluated in three cohorts: grouped cross-validation (for both balanced [20.0% malignant] and imbalanced [1.85% malignant] detection tasks), an internal independent test set (171 examinations), and an external dataset. Explainability was assessed through pixelwise comparisons with reference-standard malignancy annotations. Statistical significance was assessed using the Wilcoxon signed rank test. Results FCDD outperformed the benchmark binary cross-entropy (BCE) model in cross-validation for both balanced (mean area under the receiver operating characteristic curve [AUC] = 0.84 ± 0.01 [SD] vs 0.81 ± 0.01; P < .001) and imbalanced (mean AUC = 0.72 ± 0.03 vs 0.69 ± 0.03; P < .001) detection tasks. At a fixed 97% sensitivity in the imbalanced setting, mean specificity across folds was 13% for FCDD and 9% for BCE (P = .02). In the internal test set, FCDD outperformed BCE for balanced (mean AUC = 0.81 ± 0.02 vs 0.72 ± 0.02; P < .001) and imbalanced (mean AUC = 0.78 ± 0.05 vs 0.76 ± 0.01; P < .02) detection tasks. For model explainability, FCDD demonstrated better spatial agreement with reference-standard annotations than BCE (internal test set: mean pixelwise AUC = 0.92 ± 0.10 vs 0.81 ± 0.13; P < .001). External testing confirmed that FCDD performed well, and better than BCE, in the balanced detection task (AUC = 0.86 ± 0.01 vs 0.79 ± 0.01; P < .001). Conclusion The developed explainable AI model for cancer detection at breast MRI accurately depicted tumor location and outperformed commonly used models in both high- and low-cancer-prevalence scenarios. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Bae and Ham in this issue.}, }
@article {pmid40663785, year = {2025}, author = {Brooks, TR and Zabor, EC and Bedelu, YB and Yang, X and Karimi, YH and Nedved, AN and Wang, Y and Dave, N and Landsburg, DJ and Baron, K and Hu, B and Trotier, DC and Pophali, PA and Miller, J and Grover, N and Reinert, C and Major, A and Schwarz, T and Patel, K and Salafian, K and Ayers, E and Sundaram, S and Brody, JD and McKenna, M and Ryu Tiger, YK and Sears-Smith, M and Ghosh, N and Peterson, C and Khan, C and Bliven, SP and Narkhede, M and Gibson, A and Kline, J and Munoz, J and Garza-Morales, R and Ho, CI and Smith, SD and Niu, A and Hernandez-Ilizaliturri, F and Chinyengetere, F and Dave, S and Abdel-Razeq, N and Moustafa, MA and Caimi, PF and Hill, BT}, title = {Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab.}, journal = {Blood}, volume = {146}, number = {18}, pages = {2177-2188}, doi = {10.1182/blood.2025029117}, pmid = {40663785}, issn = {1528-0020}, mesh = {Humans ; Middle Aged ; Female ; Male ; Aged ; Adult ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/mortality/pathology ; *Antibodies, Bispecific/therapeutic use/adverse effects ; Aged, 80 and over ; Antigens, CD20/immunology ; Treatment Outcome ; *Antineoplastic Agents, Immunological/therapeutic use ; Young Adult ; }, abstract = {Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.}, }
@article {pmid40664448, year = {2025}, author = {Miller, NJ and Baik, C and Neal, JW and Sun, F and Santana-Davila, R and Lee, S and Eaton, KD and Martins, RG and Rodriguez, C and Wakelee, H and Padda, SK and Sotillo, E and Konnick, EQ and Camai, A and Pisarenko, T and Nair, VS and Mackall, C and Houghton, AM and Chiou, SH and Tseng, D}, title = {Napsin A-specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non-small cell lung cancer.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {7}, pages = {}, pmid = {40664448}, issn = {2051-1426}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA124435/CA/NCI NIH HHS/United States ; P50 CA228944/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/drug therapy/immunology/pathology/mortality ; *Lung Neoplasms/drug therapy/immunology/pathology/mortality ; Female ; *Aspartic Acid Endopeptidases/immunology/metabolism ; Male ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Middle Aged ; Aged ; *T-Lymphocytes/immunology ; *Immunotherapy/methods ; Aged, 80 and over ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: Napsin A is normally expressed in human lung pneumocytes and is a highly expressed cancer antigen in lung adenocarcinoma. We examined whether T cells specific for Napsin A may play a role in immune checkpoint inhibitor (ICI)-mediated responses. We used bulk T-cell receptor (TCR) repertoire data to assess whether the presence of Napsin A-specific clonotypes in the peripheral blood was associated with improved clinical responses to ICI.<br><br>METHODS: Patients with metastatic non-small cell lung cancer (NSCLC) receiving anti-programmed cell death protein 1 (PD-1) and/or programmed death-ligand 1 (PD-L1) were enrolled at Fred Hutchinson Cancer Center and Stanford University Medical Center (n=62; histology of adenocarcinoma n=48, squamous n=9, NSCLC/other n=5). Peripheral blood mononuclear cells were collected for genomic DNA isolation at one pretreatment and one post-treatment time point (range 3 weeks to 3 months). TCR&#x3b2; was bulk sequenced via the immunoSEQ platform (Adaptive Biotechnologies). Napsin A-specific TCR&#x3b2; sequences were identified from publicly available data and their frequencies were quantified in each patient sample. We examined whether overall survival (OS) and progression-free survival (PFS) outcomes differed in patients with or without detectable Napsin A-specific TCRs (herein Napsin TCRs). We used Cox proportional hazards regression to assess the association between detectable Napsin TCRs and PFS or OS in univariable and multivariable analyses.<br><br>RESULTS: Napsin TCRs were detectable in the blood in a large fraction of our cohort (n=25/62 (40%) pretreatment; n=21/42 (50%) post-treatment). Patients with detectable Napsin TCRs had a significant improvement in OS compared with patients without these TCRs (median OS 45.4 vs 14.8 months, p=0.0043 pretreatment; median OS 55.4 vs 18.9 months, p=0.0066 post-treatment). Among 27 HLA-A*02 carriers of 55 human leukocyte antigen-typed patients (49%), patients with detectable pretreatment Napsin TCRs had a significant improvement in OS (median 60.2 vs 16.5 months, p=0.0054) and PFS (median 21.5 vs 7.2 months, p=0.031) compared with patients without these TCRs. In univariate and multivariate analysis, the presence of Napsin TCRs pretreatment was associated with improved OS (p=0.0057, HR 0.40, 95%&#x2009;CI 0.21 to 0.76 univariate; p=0.033,&#x2009;HR 0.45, 95%&#x2009;CI 0.23 to 0.91 multivariate).<br><br>CONCLUSIONS: Napsin TCRs are frequently detected in patients with NSCLC and are associated with improved OS in patients with NSCLC receiving ICI.}, }
@article {pmid40664658, year = {2025}, author = {Thiele, K and Urbschat, C and Riquelme, JIA and Ahrendt, LS and Wöhrle, R and Schepanski, S and Eckert, JJ and Becht, E and Qi, M and Alawi, M and Becker, M and Gagliani, N and Mittrücker, HW and Diemert, A and Arck, PC}, title = {Pregnancy-acquired memory CD4[+] regulatory T cells improve pregnancy outcome in mice.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6522}, pmid = {40664658}, issn = {2041-1723}, support = {Scholarship from the IRTG of the CRC1192//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; iPRIME Scholarship//Else Kr&#xf6;ner-Fresenius-Stiftung (Else Kroner-Fresenius Foundation)/ ; 75N93022D00005/AI/NIAID NIH HHS/United States ; AR232/26-2, AR232/27-2, AR232/29-2//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 75N93023D00005/AI/NIAID NIH HHS/United States ; 01GL2404A//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/ ; 75N99020D00005/OF/ORFDO NIH HHS/United States ; 75N95020D00005/DA/NIDA NIH HHS/United States ; TH 2126/1-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; }, mesh = {Female ; Pregnancy ; Animals ; *T-Lymphocytes, Regulatory/immunology ; *Immunologic Memory/immunology ; Mice ; *Pregnancy Outcome ; Th17 Cells/immunology ; Mice, Inbred C57BL ; Receptors, CXCR4/metabolism/immunology ; }, abstract = {Subsequent pregnancies are generally less prone to obstetric complications. A successful pregnancy outcome requires pivotal immunological adaptation to ensure immune tolerance towards the foetus. Thus, the lower risk for pregnancy complication during subsequent pregnancies may be attributable to immune memory mounted during first pregnancies. Here we identify higher frequencies of fetal-antigen-specific CD4[+] regulatory T (Treg) cells both postpartum and in subsequent pregnancies in mice which are partly originating from trans-differentiated Th17 cells. Our functional experiments demonstrate that these CD4[+] Treg cells have memory functions (CD4[+] mTreg) and account for an improved fetal development and pregnancy outcome, also during adverse conditions, such as gestational sound stress. Using a high-throughput single-cell quantification method, we identify candidate markers for the detection of CD4[+] mTreg cells, which include CXCR4 and CD274. Our findings thus contribute to the improved understanding of pregnancy-induced immune memory and foster the identification of immune targets aiming to reduce the risk for immune-mediated pregnancy complications.}, }
@article {pmid40665019, year = {2025}, author = {Miller, NJ and Kwan, SW and Leary, JB and Hippe, DS and McCamy, W and Veatch, JR and Hall, ET and Monsky, WL and Bhatia, S}, title = {Concurrent treatment with transarterial immunoembolization of hepatic metastases and systemic immune checkpoint inhibitors to overcome immune evasion in patients with metastatic uveal melanoma.}, journal = {Cancer immunology, immunotherapy : CII}, volume = {74}, number = {8}, pages = {270}, pmid = {40665019}, issn = {1432-0851}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/therapy/immunology/pathology/mortality ; Middle Aged ; Male ; Female ; *Uveal Neoplasms/pathology/immunology/therapy/mortality ; *Liver Neoplasms/secondary/therapy/immunology ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Retrospective Studies ; Uveal Melanoma ; Aged ; Adult ; *Tumor Escape/drug effects ; Combined Modality Therapy ; Aged, 80 and over ; Immunotherapy/methods ; *Chemoembolization, Therapeutic/methods ; }, abstract = {BACKGROUND: Metastatic uveal melanoma (mUM) is an uncommon melanoma subtype, poorly immunogenic with low objective response rates (ORR) to immune checkpoint inhibitors (ICI). Liver-directed therapies (LDT) are commonly used given the strong predilection for hepatic metastases. Transarterial immunoembolization (TAIE) with granulocyte-macrophage colony stimulating factor (GM-CSF) can potentially synergize with concurrent systemic ICI to overcome immune evasion.<br><br>METHODS: This single-center, retrospective study includes mUM patients with liver-predominant metastases who received TAIE, with/without concurrent systemic&#xa0;ICI (&#x2264;&#x2009;3&#xa0;months before/during TAIE). Endpoints included ORR, progression-free survival (PFS), overall survival (OS), and adverse events (AEs).<br><br>RESULTS: Between 2016 and 2023, 18 mUM patients (median age 64&#xa0;years) received TAIE (median 4 procedures/patient). Fourteen patients (78%) received concurrent ICI. ORR was 17% (3/18), all in patients receiving ICI, with partial responses lasting 4.2, 35&#x2009;+&#x2009;and 46&#xa0;months. Disease control rate (stable disease or better) was 56% (10/18). Median time to next systemic therapy or death was 19.5&#xa0;months (range 1.6- 46). Median PFS and OS from first TAIE treatment were 4.9&#xa0;months (range 0.7-46) and 35&#xa0;months (range 1.7- 46). Immune-related AEs (IRAE) during concurrent therapy occurred in seven of 10 patients receiving anti-CTLA-4/PD-1 combination, including hepatitis (n&#x2009;=&#x2009;5; grade 2 in 1, grade 3 in 4). Four of seven patients resumed anti-PD-1 monotherapy without recurrent IRAE.<br><br>CONCLUSIONS: Concurrent LDT with GM-CSF TAIE and ICI, including anti-CTLA-4/PD-1 combination, is feasible, safe, and can lead to sustained clinical benefit in a subset of mUM patients. OS with this combination compares favorably to published outcomes for systemic therapy or LDT alone.}, }
@article {pmid40665521, year = {2025}, author = {Watt, GP and Reiner, AS and Shu, X and Malone, KE and Knight, JA and John, EM and Chow, EJ and Lynch, CF and Mellemkjær, L and Woods, M and Liang, X and Tran, AP and Oh, JH and Derkach, A and Bernstein, JL}, title = {Polygenic risk of coronary artery disease for long-term survivors of breast cancer.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {10}, pages = {2073-2081}, pmid = {40665521}, issn = {1460-2105}, support = {R01CA129639/CA/NCI NIH HHS/United States ; R21 CA234752/CA/NCI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; R21CA234752/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA083178/CA/NCI NIH HHS/United States ; R01 CA129639/CA/NCI NIH HHS/United States ; U01CA083178/CA/NCI NIH HHS/United States ; //Dutch Ministry of Health, Welfare, and Sport/ ; //Netherlands Cancer Institute/ ; R01 CA097397/CA/NCI NIH HHS/United States ; //Dutch Cancer Society/ ; R01CA097397/CA/NCI NIH HHS/United States ; P30CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Coronary Artery Disease/epidemiology/genetics/etiology ; *Cancer Survivors/statistics &amp; numerical data ; Middle Aged ; *Breast Neoplasms/complications/therapy/epidemiology/genetics ; Adult ; Risk Factors ; *Multifactorial Inheritance ; Genetic Predisposition to Disease ; Incidence ; Follow-Up Studies ; Anthracyclines/adverse effects ; }, abstract = {BACKGROUND: Cardiovascular disease is a leading cause of death for long-term breast cancer survivors. We evaluated whether a polygenic risk score for coronary artery disease (CAD-PRS) was associated with the risk of incident CAD for survivors of unilateral or contralateral breast cancer.<br><br>METHODS: The study included 1307 women with breast cancer first diagnosed at younger than 55&#x2009;years of age who participated in the Women's Environmental&#xa0;Cancer and Radiation Epidemiology Follow-up Study. The CAD-PRS was based on a PRS developed and validated in a separate population. We modeled the association between incident CAD and the CAD-PRS, adjusting for age, CAD risk factors, first (and second) breast cancer treatment, study recruitment phase, and genetic population stratification. We also explored whether the risk of CAD depended on interactions between the CAD-PRS and cardiotoxic cancer treatment.<br><br>RESULTS: There were 66 incident CAD diagnoses reported at a median of 16&#x2009;years after breast cancer diagnosis. Participants with CAD-PRS&#x2009;at or above the median had a 2.48-times increased risk of CAD (95% confidence interval [CI]&#x2009;=&#x2009;1.44 to 4.29) relative to participants with CAD-PRS&#x2009;below the&#x2009;median. Anthracycline-based chemotherapy was associated with increased CAD risk (hazard ratio [HR]&#x2009;=&#x2009;2.04, 95% CI&#x2009;=&#x2009;1.04 to 3.98), and the association was not modified by the CAD-PRS. The association between incident CAD and left-sided radiation therapy (RT) was increased for those with CAD-PRS&#x2009;at or above the median (HR&#x2009;=&#x2009;2.90, 95% CI&#x2009;=&#x2009;1.26 to 6.68) but not for those with CAD-PRS&#x2009;below the median (HR&#x2009;=&#x2009;0.96, 95% CI&#x2009;=&#x2009;0.32 to 2.88). There was evidence of super-additive interaction between the CAD-PRS and left-sided RT (relative excess risk due to interaction&#x2009;=&#x2009;2.06, 95% CI&#x2009;=&#x2009;0.05 to 4.06).<br><br>CONCLUSION: A genome-wide CAD-PRS was associated with nonfatal CAD risk for long-term breast cancer survivors, providing potential utility for personalized cardiovascular care, particularly after RT.}, }
@article {pmid40665795, year = {2025}, author = {Muchadeyi, MT and Hao, S and Hernandez-Villafuerte, K and Khan, SA and Becker, N and Krilaviciute, A and Seibold, P and Gulati, R and Albers, P and Schlander, M and Clements, M}, title = {Cost effectiveness analysis of prostate cancer screening strategies in Germany: A microsimulation study.}, journal = {International journal of cancer}, volume = {157}, number = {8}, pages = {1662-1679}, pmid = {40665795}, issn = {1097-0215}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/diagnosis/economics/epidemiology ; *Cost-Benefit Analysis ; Germany/epidemiology ; Middle Aged ; Aged ; *Early Detection of Cancer/economics/methods ; Prostate-Specific Antigen/blood ; Quality-Adjusted Life Years ; Magnetic Resonance Imaging/economics ; Digital Rectal Examination/economics ; Biopsy/economics ; *Mass Screening/economics/methods ; Overdiagnosis ; Cost-Effectiveness Analysis ; }, abstract = {Prostate cancer (PCa) represents a significant public health challenge in Germany, with increasing incidence and economic impact. This study assessed the cost-effectiveness of 10 screening strategies: prostate-specific antigen-based risk-adaptive screening (PSA-RAS), with or without magnetic resonance imaging (MRI), in men starting at age 45 or 50 and stopping at 60 or 70, digital rectal examination (DRE) for ages 45-75 years, and no screening. Using a well calibrated microsimulation model (Swedish Prostata) from a statutory health insurance perspective, lifetime outcomes were evaluated, including cancer incidence, mortality, overdiagnosis, biopsies, life-years, and quality-adjusted life-years (QALYs) discounted annually at 3%. Cost and utility inputs were derived from the German diagnostic-related group schedule, fee-for-service catalogues, literature, and expert opinion. DRE-only was the least cost-effective, yielding high biopsy and overdiagnosis rates with minimal QALY gains. PSA-RAS reduced overdiagnosis and biopsy rates, with PSA-RAS (50-60 years) without MRI emerging as the most cost-efficient strategy, saving approximately €1.2 million per 100,000 men compared with no screening. Extending the PSA-RAS to 70 years improved its effectiveness in terms of QALYs. PSA-RAS (50-70) with MRI could become cost-effective at an increasing willingness to pay threshold or decreasing MRI cost. This study suggests the potential of PSA-RAS to improve PCa screening in Germany. Incorporating MRI, reducing MRI cost within the screening setting, and extending screening to 70 to align with EU recommendations could improve the cost-effectiveness of PSA-RAS with MRI. Future research should explore the integration of MRI with ancillary tests, such as 4K-score or risk calculators, to reduce MRI use and associated costs.}, }
@article {pmid40665819, year = {2025}, author = {Corello, H and Pang, S and Bustillos, H and Velez, JW}, title = {Clinical considerations for pharmacists regarding the use of radiopharmaceuticals in oncology.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {31}, number = {7}, pages = {1165-1173}, doi = {10.1177/10781552251359187}, pmid = {40665819}, issn = {1477-092X}, mesh = {Humans ; *Radiopharmaceuticals/adverse effects/therapeutic use/administration &amp; dosage ; *Neoplasms/radiotherapy/drug therapy ; *Pharmacists/organization &amp; administration ; Antineoplastic Agents/therapeutic use/adverse effects/administration &amp; dosage ; Professional Role ; }, abstract = {BackgroundRadiopharmaceutical therapy encompasses the targeted delivery of radioactive atoms to sites of malignancy within the body and represent a rapidly growing area of drug development in oncology. In comparison to cytotoxic chemotherapy, radiopharmaceutical therapy has the potential for fewer adverse effects and is able to produce a strong anti-cancer response in a wide range of malignancies.ObjectiveThis article reviews radiopharmaceutical therapy mechanisms and discusses four well-established agents that are used in clinical practice, their place in therapy, safety, utilization of concomitant therapies, and contact precautions for each agent.SourcesInformation presented in this article is sourced from the available literature on radiopharmaceutical development, oncology clinical practice guidelines, clinical trial results, and package insert data.SummaryRadiopharmaceuticals possess significant differences in drug mechanism and design from that of traditional cytotoxic chemotherapy agents. The basic functional and structural variances in combination with isotope selection drive the clinical efficacy of radiopharmaceutical therapy and inform pharmacists of the important considerations of each therapy's distribution, off-target effects, clearance, and toxicities.ConclusionThe drug and safety information presented in this article pertaining to select radiopharmaceuticals is pertinent to an oncology pharmacist's role in patient care as radioactive therapies continue to expand the complexity of the oncology treatment landscape.}, }
@article {pmid40666860, year = {2025}, author = {Harris, ED and McGovern, M and Pernikoff, S and Ikeda, R and Kipnis, L and Hannon, W and Sobolik, EB and Gray, M and Greninger, AL and He, S and Chin, CN and Fu, TM and Pancera, M and Boonyaratanakornkit, J}, title = {DEVELOPMENT OF A POTENT MONOCLONAL ANTIBODY FOR TREATMENT OF HUMAN METAPNEUMOVIRUS INFECTIONS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40666860}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI171186/AI/NIAID NIH HHS/United States ; }, abstract = {Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for both treatment and prevention. Here, we describe the discovery and characterization of 4F11, a highly potent and broadly neutralizing mAb with demonstrated in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we defined a unique mechanism of binding HMPV employed by 4F11, which distinguishes it from previously characterized RSV and HMPV mAbs. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies, which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan, representing a unique glycan-dependent mode of recognition. In vitro, 4F11 displayed high potency and broad neutralization across diverse HMPV strains. It also showed a low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation had significantly decreased fitness in vitro compared to wild-type virus. In a hamster challenge model, 4F11 significantly reduced viral loads in both the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development, particularly for immunocompromised individuals and other high-risk groups.}, }
@article {pmid40666929, year = {2025}, author = {Kumar, S and Jiang, J and Donald-Paladino, MS and Chen, J and Gutierrez, A and Federation, AJ and Szulzewsky, F and Holland, EC and Ferguson, FM and Nabet, B}, title = {Development of PROTACs for targeted degradation of oncogenic TRK fusions.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40666929}, issn = {2692-8205}, support = {K22 CA258805/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R43 TR004221/TR/NCATS NIH HHS/United States ; U01 CA282109/CA/NCI NIH HHS/United States ; }, abstract = {Chromosomal translocations leading to the fusion of tropomyosin receptor kinases (TRK) with diverse partner proteins have been identified as oncogenic drivers in many adult and pediatric cancers. While first-generation TRK kinase inhibitors, such as entrectinib and larotrectinib, have shown positive responses in TRK fusion-positive cancers, resistance mutations against these inhibitors in the kinase domain limit their efficacy. Second-generation inhibitors are in clinical evaluation, highlighting a need for novel therapeutic modalities to achieve durable suppression of the oncogenic activity of TRK fusions. Here, we developed heterobifunctional small molecule degraders (PROTACs) to achieve targeted degradation of TRK fusions. By conjugating entrectinib to thalidomide, we identified JWJ-01-378 as a potent and selective CRBN-recruiting degrader of the TPM3-TRKA fusion. JWJ-01-378 induced TPM3-TRKA degradation through the ubiquitin-proteasome system and proteomics analysis confirmed the acute selectivity of JWJ-01-378 for achieving TPM3-TRKA degradation with minimal off-target effects. While JWJ-01-378 was also able to degrade wild-type TRK, it was unable to degrade TRK inhibitor resistant mutants and ALK fusions. Importantly, TPM3-TRKA degradation by JWJ-01-378 suppressed downstream signaling and reduced cancer cell viability, with improved responses compared to heterobifunctional control compounds that cannot degrade TPM3-TRKA. Together, our study expands the toolbox of compounds for evaluating targeted degradation of TRK fusions in cancer.}, }
@article {pmid40666976, year = {2025}, author = {Johnson, MM and Sung, K and Haddox, HK and Vora, AA and Araki, T and Victora, GD and Song, YS and Fukuyama, J and Matsen Iv, FA}, title = {Nucleotide context models outperform protein language models for predicting antibody affinity maturation.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40666976}, issn = {2692-8205}, support = {R01 AI146028/AI/NIAID NIH HHS/United States ; R01 HG013117/HG/NHGRI NIH HHS/United States ; R56 HG013117/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {Antibodies play a crucial role in adaptive immunity. They develop as B cell receptors (BCRs): membrane-bound forms of antibodies that are expressed on the surfaces of B cells. BCRs are refined through affinity maturation, a process of somatic hypermutation (SHM) and natural selection, to improve binding to an antigen. Computational models of affinity maturation have developed from two main perspectives: molecular evolution and language modeling. The molecular evolution perspective focuses on nucleotide sequence context to describe mutation and selection; the language modeling perspective involves learning patterns from large data sets of protein sequences. In this paper, we compared models from both perspectives on their ability to predict the course of antibody affinity maturation along phylogenetic trees of BCR sequences. This included models of SHM, models of SHM combined with an estimate of selection, and protein language models. We evaluated these models for large human BCR repertoire data sets, as well as an antigen-specific mouse experiment with a pre-rearranged cognate naive antibody. We demonstrated that precise modeling of SHM, which requires the nucleotide context, provides a substantial amount of predictive power for predicting the course of affinity maturation. Notably, a simple nucleotide-based convolutional neural network modeling SHM outperformed state-of-the-art protein language models, including one trained exclusively on antibody sequences. Furthermore, incorporating estimates of selection based on a custom deep mutational scanning experiment brought only modest improvement in predictive power. To support further research, we introduce EPAM (Evaluating Predictions of Affinity Maturation), a benchmarking framework to integrate evolutionary principles with advances in language modeling, offering a road map for understanding antibody evolution and improving predictive models.}, }
@article {pmid40667113, year = {2025}, author = {MacLean, F and Zemek, RM and Tsegaye, AT and Graham, JB and Swarts, JL and Vick, SC and Potchen, NB and Talavera, IC and Warrier, L and Dubrulle, J and Schroeder, LK and Elz, A and Sowerby, D and Saito, A and Thomas, KK and Mack, M and Schiffer, JT and McClelland, RS and Jerome, KR and Chohan, BH and Ngure, K and Mugo, NR and Newell, EW and Lingappa, JR and Lund, JM}, title = {Genital herpes shedding episodes associate with alterations in the spatial organization and activation of mucosal immune cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667113}, issn = {2692-8205}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; R01 AI131914/AI/NIAID NIH HHS/United States ; K99 AI180649/AI/NIAID NIH HHS/United States ; R01 AI141435/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 AI007140/AI/NIAID NIH HHS/United States ; R01 HD114505/HD/NICHD NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; R01 AI129715/AI/NIAID NIH HHS/United States ; }, abstract = {Herpes Simplex Virus 2 (HSV-2) infection results in variable rates of local viral shedding in anogenital skin. The impact of episodic viral exposures on immune cells in adjacent mucosal tissues, including the genital tract, is unknown. However, any immune responses at this site could impact protective mucosal immunity, tissue homeostasis, and adverse health outcomes. To investigate the impact of HSV-2 on cervicovaginal tract immunity, we applied flow cytometry, immunofluorescent imaging, analysis of soluble immune factors, and spatial transcriptomics to cervicovaginal tissue and blood samples provided by a total of 232 HSV-2 seropositive and seronegative participants, with genital HSV-2 shedding evaluated at the time of biopsy. This unique dataset was used to define and spatially map immune cell subsets and localized gene expression via spatial transcriptomics. HSV-2 seropositivity alone was associated with minimal differences in cervicovaginal and circulating T cell phenotypes. However, the vaginal mucosa during active HSV-2 shedding was associated with alterations in T cell, macrophage, and dendritic cell localization and gene expression consistent with increased immune surveillance, with immune activating and suppressing signals potentially reinforcing mucosal tissue homeostasis.}, }
@article {pmid40667132, year = {2025}, author = {Walter, M and Haick, AK and Massa, PA and Klouser, LM and Stensland, L and Santo, TK and Xie, H and Jerome, KR}, title = {Herpes simplex virus 1 strain 17+ with R2 mutation in UL37 has residual retrograde transport.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667132}, issn = {2692-8205}, support = {R21 AI178255/AI/NIAID NIH HHS/United States ; }, abstract = {Herpes simplex virus 1 (HSV-1) causes lifelong recurrent infections. Following primary infection of the oral or genital mucosa, HSV-1 travels retrogradely through axons and establishes latency in the cell body of ganglionic neurons of the peripheral nervous system. Periodic reactivation in neurons and anterograde transport of virions back to peripheral regions causes oral or genital ulcerations. Many host and viral factors implicated in retrograde and anterograde transport of HSV-1 have been identified. In particular, studies reported that introducing five amino acid substitutions in the R2 region of the viral tegument protein UL37 was sufficient to completely eliminate retrograde transport of HSV-1 strain F. Here, we introduced the same R2 mutations in the highly neurovirulent HSV-1 strain 17+. We report that this R2[17] virus has residual retrograde travel. We show that R2[17] can establish latency in mouse models of ocular and vaginal infection and reactivate. These results contradict published evidence and show that the R2 mutation is not sufficient to fully prevent retrograde transport of HSV-1.}, }
@article {pmid40667331, year = {2025}, author = {Hu, C and Popchock, AR and Latino, AA and Asbury, CL and Biggins, S}, title = {Direct observation of interdependent and hierarchical kinetochore assembly on individual centromeres.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40667331}, issn = {2692-8205}, support = {F32 GM136010/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM134842/GM/NIGMS NIH HHS/United States ; R35 GM149357/GM/NIGMS NIH HHS/United States ; }, abstract = {Kinetochores are megadalton protein machines that harness microtubules to segregate chromosomes during cell division. The kinetochores must assemble after DNA replication during every cell cycle onto specialized regions of chromosomes called centromeres, but the order and regulation of their assembly remains unclear due to the complexity of kinetochore composition and the difficulty resolving individual kinetochores in vivo. Here, by adapting a prior single-molecule method for monitoring kinetochore assembly in budding yeast lysates, we identify a sequential order of assembly and uncover previously unknown interdependencies between subcomplexes. We show that inner kinetochore assembly depends partly on outer kinetochore components, and that outer kinetochore branches do not assemble independently of one another. Notably, Mif2 assembly is a rate-limiting step that can be accelerated by binding to the Mtw1 subcomplex, thereby promoting rapid assembly of many inner and outer kinetochore components. The importance of controlling kinetochore assembly kinetics is supported by a Mif2 mutant lacking both autoinhibition and Mtw1 subcomplex binding activity, which leads to defective kinetochore-microtubule attachments when the centromeric histone variant Cse4 is overexpressed. Altogether, our work provides a direct view of kinetochore assembly and reveals highly interdependent regulatory events that control its order and timing.}, }
@article {pmid40668104, year = {2025}, author = {Elias-Warren, A and Bennett, JC and Iwu, CD and Starita, LM and Stone, J and Capodanno, B and Prentice, R and Han, PD and Acker, Z and Grindstaff, SB and Reinhart, D and Logue, JK and Wolf, CR and Boeckh, M and Kong, K and Xie, H and Kim, G and Greninger, AL and Perofsky, AC and Viboud, C and Uyeki, TM and Englund, JA and Roychoudhury, P and Chu, HY}, title = {Epidemiology of Human Metapneumovirus Infection in a Community Setting, Seattle, Washington, USA.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {Supplement_1}, pages = {S78-S92}, pmid = {40668104}, issn = {1537-6613}, mesh = {Humans ; *Paramyxoviridae Infections/epidemiology/virology ; *Metapneumovirus/genetics/isolation &amp; purification ; Washington/epidemiology ; Child, Preschool ; Female ; Infant ; Male ; Child ; Adolescent ; Adult ; Middle Aged ; Young Adult ; Infant, Newborn ; Aged ; Risk Factors ; Whole Genome Sequencing ; }, abstract = {BACKGROUND: The clinical and genomic epidemiology of human metapneumovirus (hMPV) infections in community settings is not well understood.<br><br>METHODS: From 2018 to 2022, individuals with respiratory symptoms were recruited and enrolled from the greater Seattle, Washington community in the United States. Residual clinical specimens from individuals presenting with respiratory symptoms were additionally collected. Specimens were tested for hMPV by reverse-transcription polymerase chain reaction, with whole genome sequencing performed on a subset (209/1002).<br><br>RESULTS: hMPV positivity was higher among clinical specimens (835/21 539 [3.9%]) compared to community specimens (167/28 348 [0.6%]). Children aged 0-4 years had the highest percent positivity across both clinical and community settings (497/10 213 [4.9%] and 28/1640 [1.7%], respectively). In multivariate analysis, a household income of &#x2264;US$100 000 (adjusted odds ratio [aOR], 1.72 [95% confidence interval {CI}, 1.07-2.85]), and recent international travel (aOR, 6.51 [95% CI, 3.11-12.22]) were associated with hMPV positivity. A subset of 209 of 1002 samples (21%) was sequenced; the distribution of subtypes A2b, A2c, B1, and B2 were similar across both community and clinical settings, with an increase in the proportion of subtype B1 after the start of the pandemic.<br><br>CONCLUSIONS: Risk factors of testing positive for hMPV in a community setting included lower household income and recent international travel. Co-circulation of hMPV subtypes was observed across community and clinical settings.}, }
@article {pmid40670422, year = {2025}, author = {Blemker, SS and Riem, L and DuCharme, O and Pinette, M and Costanzo, KE and Weatherley, E and Statland, J and Tapscott, SJ and Wang, LH and Shaw, DWW and Song, X and Leung, D and Friedman, SD}, title = {Multi-scale machine learning model predicts muscle and functional disease progression.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {25339}, pmid = {40670422}, issn = {2045-2322}, support = {K23 NS091379/NS/NINDS NIH HHS/United States ; P50 AR065139/AR/NIAMS NIH HHS/United States ; }, mesh = {*Machine Learning ; *Muscular Dystrophy, Facioscapulohumeral/diagnosis/diagnostic imaging ; Humans ; Disease Progression ; Magnetic Resonance Imaging ; Whole Body Imaging ; Random Forest ; Muscles/diagnostic imaging/physiopathology ; Physical Functional Performance ; Models, Biological ; Datasets as Topic ; Male ; Female ; Adipose Tissue/diagnostic imaging ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is a genetic neuromuscular disorder characterized by progressive muscle degeneration with substantial variability in severity and progression patterns. FSHD is a highly heterogeneous disease; however, current clinical metrics used for tracking disease progression lack sensitivity for personalized assessment, which greatly limits the design and execution of clinical trials. This study introduces a multi-scale machine learning framework leveraging whole-body magnetic resonance imaging (MRI) and clinical data to predict regional, muscle, joint, and functional progression in FSHD. The goal this work is to create a 'digital twin' of individual FSHD patients that can be leveraged in clinical trials. Using a combined dataset of over 100 patients from seven studies, MRI-derived metrics-including fat fraction, lean muscle volume, and fat spatial heterogeneity at baseline-were integrated with clinical and functional measures. A three-stage random forest model was developed to predict annualized changes in muscle composition and a functional outcome (timed up-and-go (TUG)). All model stages revealed strong predictive performance in separate holdout datasets. After training, the models predicted fat fraction change with a root mean square error (RMSE) of 2.16% and lean volume change with a RMSE of 8.1 ml in a holdout testing dataset. Feature analysis revealed that metrics of fat heterogeneity within muscle predicts muscle-level progression. The stage 3 model, which combined functional muscle groups, predicted change in TUG with a RMSE of 0.6 s in the holdout testing dataset. This study demonstrates the machine learning models incorporating individual muscle and performance data can effectively predict MRI disease progression and functional performance of complex tasks, addressing the heterogeneity and nonlinearity inherent in FSHD. Further studies incorporating larger longitudinal cohorts, as well as comprehensive clinical and functional measures, will allow for expanding and refining this model. As many neuromuscular diseases are characterized by variability and heterogeneity similar to FSHD, such approaches have broad applicability.}, }
@article {pmid40670774, year = {2025}, author = {Rejeski, K and Hill, JA and Dahiya, S and Jain, MD}, title = {Noncanonical and mortality-defining toxicities of CAR T cell therapy.}, journal = {Nature medicine}, volume = {31}, number = {7}, pages = {2132-2146}, pmid = {40670774}, issn = {1546-170X}, mesh = {Humans ; *Immunotherapy, Adoptive/methods/mortality ; *Cytokine Release Syndrome/immunology/mortality ; *Neurotoxicity Syndromes/immunology/mortality ; *Cytotoxicity, Immunologic ; *Receptors, Chimeric Antigen/immunology ; T-Lymphocytes/immunology ; }, abstract = {Chimeric antigen receptor (CAR) T cell therapy is associated with a unique spectrum of toxicities that drive morbidity, mortality and patient quality of life. Previous efforts yielded consensus grading systems for the prototypical immunotoxicities-namely, cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These grading systems set the stage for severity-based and standardized treatment protocols that have contributed to a reduction in the acute toxicity burden of CAR T cell therapy and have enabled outpatient administration. However, understanding of CAR T cell therapy has since grown to encompass new targets, new diseases and broader patient populations-including long-term survivors. As side effects are better defined and novel toxicities emerge, there is a need to understand their mechanisms and standardize reporting to improve clinical management. Here we review the current state of knowledge for mortality-defining and rare toxicities of CAR T cell therapies, beyond CRS and ICANS. We discuss mechanisms, including on-target injury, cytokine-associated inflammation and dysregulated recovery, and how these mechanisms affect the timing and management of toxicities. Finally, we define key unmet needs and delineate future priorities and research directions.}, }
@article {pmid40671098, year = {2025}, author = {Zhou, HJ and Ge, X and Li, JJ}, title = {ClipperQTL: ultrafast and powerful eGene identification method.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {207}, pmid = {40671098}, issn = {1474-760X}, support = {R35 GM140888/GM/NIGMS NIH HHS/United States ; Sloan Research Fellowship//Alfred P. Sloan Foundation/ ; DGE-1829071//National Science Foundation/ ; WiSTEM2D Award//Johnson and Johnson/ ; R01GM120507/GM/NIGMS NIH HHS/United States ; T32 HL139450/HL/NHLBI NIH HHS/United States ; T32HL139450/HL/NHLBI NIH HHS/United States ; DBI-1846216//National Science Foundation/ ; R01 GM120507/GM/NIGMS NIH HHS/United States ; R35GM140888/GM/NIGMS NIH HHS/United States ; UCLA David Geffen School of Medicine W.M. Keck Foundation Junior Faculty Award//W. M. Keck Foundation/ ; }, mesh = {*Quantitative Trait Loci ; *Software ; Humans ; }, abstract = {A central task in expression quantitative trait locus analysis is to identify cis-eGenes, i.e., genes whose expression levels are regulated by at least one local genetic variant. Existing cis-eGene identification methods are either computationally expensive, requiring thousands of permutations per gene (FastQTL), or statistically underpowered (eigenMT and TreeQTL). We propose ClipperQTL, which requires only one permutation for data sets with large sample sizes (>450; ClipperQTL works on smaller data sets too). We show that ClipperQTL performs as well as FastQTL and runs up to 500 times faster. The R package ClipperQTL is available at https://github.com/heatherjzhou/ClipperQTL .}, }
@article {pmid40671547, year = {2025}, author = {Heffner, JL and Giustini, N and Anderson, N and Go, T and Scout, NFN and Hippe, DS and Triplette, M}, title = {Implementation of sexual orientation and gender identity data collection in a cancer care setting.}, journal = {Journal of the National Cancer Institute. Monographs}, volume = {2025}, number = {69}, pages = {139-146}, pmid = {40671547}, issn = {1745-6614}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; #P30CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Gender Identity ; Female ; Male ; *Sexual Behavior/statistics &amp; numerical data ; *Neoplasms/therapy/epidemiology/psychology ; *Sexual and Gender Minorities/statistics &amp; numerical data ; *Data Collection/methods ; Cancer Care Facilities ; United States ; Pilot Projects ; Adult ; Middle Aged ; }, abstract = {Cancer research focusing on sexual and gender minority populations is limited by lack of sexual orientation and gender identity data in medical records and cancer registries. We implemented multimethod sexual orientation and gender identity data collection in 2 pilot clinics at a National Cancer Institute-Designated Comprehensive Cancer Center, with first-line collection by telephone intake schedulers and second-line via physical form in clinics. Changes in data completion were compared with 2 control clinics, and staff shared intervention experiences. In pilot clinics, completion rates statistically significantly increased for gender identity (from 55.6% to 65.1%), sex assigned at birth (from 58.4% to 63.2%), sexual orientation (from 45.1% to 53.7%), and all 3 (from 37.8% to 44.7%) when compared with control clinics (P < .05). Staff reported a mix of patient reactions to sexual orientation and gender identity data collection. Sexual orientation and gender identity data collection can be enhanced in the cancer care setting with multimethod approaches.}, }
@article {pmid40672105, year = {2025}, author = {Nakasone, ES and Coveler, AL}, title = {Targeting metabolism in pancreatic ductal adenocarcinoma: challenges and insights from the AVENGER 500 trial.}, journal = {Journal of gastrointestinal oncology}, volume = {16}, number = {3}, pages = {1351-1355}, pmid = {40672105}, issn = {2078-6891}, }
@article {pmid40672332, year = {2025}, author = {Williamson, C and Moodley, C and Magaret, CA and Giorgi, EE and Rolland, M and Westfall, DH and Yssel, A and Deng, W and Rossenkhan, R and Mkhize, NN and Chen, L and Zhao, H and Bhattacharya, T and Pankow, A and Murrell, B and York, T and Gwashu-Nyangiwe, A and Ndabambi, N and Thebus, R and Cohen, P and Lambson, B and Kaldine, H and Bhebhe, S and Juraska, M and Bai, H and deCamp, AC and Ludwig, J and Molitor, C and Beaume, N and Matten, D and Huang, Y and Zhang, L and Reeves, DB and Mayer, B and Karuna, ST and Hural, JA and Morris, L and Montefiori, D and Bumgarner, RE and Moore, PL and Edlefsen, PT and Edupuganti, S and Mgodi, N and McElrath, MJ and Cohen, MS and Corey, L and Gilbert, PB and Mullins, JI}, title = {Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40672332}, issn = {2692-8205}, support = {K25 AI155224/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; R01 AI152115/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; INV-016189/GATES/Gates Foundation/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; R01 AI186721/AI/NIAID NIH HHS/United States ; R01 AI157854/AI/NIAID NIH HHS/United States ; UM1 AI069436/AI/NIAID NIH HHS/United States ; }, abstract = {In the HIV antibody mediated prevention (AMP) trials, the broadly neutralizing antibody VRC01 demonstrated protective efficacy against new diagnoses with susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, we performed deep sequencing on 172 participants in the placebo and treatment arms, generating 63,444 gag-Δpol (2.5 kb) and 53,088 rev-env-Δnef (3 kb) sequences. Sequences were classified into transmitted founder lineages (TFLs), and infections with multiple distinct lineages were determined. Multilineage infections were detected in ~38% of participants in both the African (HVTN 703/HPTN 081) and Americas/Europe (HVTN 704/HPTN 085) cohorts, regardless of placebo or treatment group, or cohort. The high levels of multilineage infections could be attributed to minor lineages (<5% abundance) identified in 20% of participants. Infection with VRC01 discordant viruses (IC80s >3-fold different) was observed in 40% of multilineage infections, with a trend toward greater intra-host neutralization differences with increasing VRC01 dose (Jonckheere-Terpstra test, p=0.072). In six VRC01 treated participants who acquired both sensitive (IC80<1μg/ml) and resistant viruses (IC80>3μg/ml), the sensitive lineages declined over time. Recombination was pervasive, observed in 63% of multilineage infections at the time of HIV diagnosis. In one treated participant infected with VRC01 discordant lineages, recombinant viruses preferentially inherited the resistance mutation (binomial p=0.004). In conclusion, our in-depth analysis of breakthrough viruses in the AMP trials revealed a high frequency of multilineage infections, including infections with viruses with different VRC01 sensitivities. This analysis also highlights the role of recombination in shaping intra-host viral evolution and facilitating escape from VRC01.}, }
@article {pmid40674082, year = {2025}, author = {Rini, BI and Best, AF and Bowman, MD and Mishkin, GE and Denicoff, AM and Rubinstein, LV and Harris, L and Geiger, AM and Mark, NM and Pergam, SA and Warner, JL and Khorana, AA and Gnjatic, S and Yen, TWF and Liles, DK and Bestvina, CM and Shah, NJ and Norrell, JT and Hershman, DL and Holter-Chakrabarty, JL and Poklepovic, AS and Chanock, SJ and Sankaran, H and Korde, LA}, title = {Risk Factors for COVID-19-Related Hospitalization and Death in Patients With Cancer: The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS).}, journal = {JAMA oncology}, volume = {11}, number = {9}, pages = {990-998}, pmid = {40674082}, issn = {2374-2445}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 CA287008/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *COVID-19/mortality/complications/therapy/epidemiology ; Female ; Male ; *Neoplasms/therapy/mortality/complications/epidemiology ; *Hospitalization/statistics &amp; numerical data ; Middle Aged ; Risk Factors ; Aged ; United States/epidemiology ; Adult ; SARS-CoV-2 ; Prospective Studies ; National Cancer Institute (U.S.) ; Aged, 80 and over ; Longitudinal Studies ; }, abstract = {IMPORTANCE: Retrospective case series have identified having cancer and receiving treatment for cancer as risk factors for inferior COVID-19 outcomes.<br><br>OBJECTIVE: To determine risk factors for hospitalization and death in patients with cancer with COVID-19 infection.<br><br>The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) is a prospective longitudinal natural history cohort study examining the impact of COVID-19 on patients with cancer. Adults were eligible within 14 days of an initial positive SARS-CoV-2 test result if they were receiving active treatment for cancer or had prior stem cell/bone marrow transplant or CAR T-cell treatment. The statistical analysis took place between September 2024 and April 2025.<br><br>MAIN OUTCOMES AND MEASURES: The primary objective of the study was to determine patient factors, therapy types, and cancer types associated with COVID-19 severity, defined as hospitalization for or death from COVID-19 within 30 and 90 days after the first positive SARS-CoV-2 test result. Multivariable regressions were performed for COVID-19-specific hospitalization and mortality (proportional hazard and cause-specific hazard models).<br><br>RESULTS: Of 1572 eligible adult patients (median [range] age, 60 [18-93] years; 840 female [53.4%]), 1066 (67.8%) had a solid tumor, with 683 (64.0%) having metastatic disease; breast (252 [23.6%]) and lung cancer (148 [13.9%]) were most common. At enrollment, 1013 patients (64.4%) were unvaccinated for SARS-CoV-2. COVID-19-related mortality at 90 days was 3.0% and did not increase at subsequent time points. The cumulative incidence of COVID-19-specific death in the first 90 days was highest in patients with lymphoma, intermediate in patients with acute leukemia and lung cancer, and lowest in patients with other solid tumors and other hematologic cancers. In multivariable analysis, receipt of chemotherapy (hazard ratio [HR], 1.97; 95% CI, 1.52-2.54) and baseline history of stroke, atrial fibrillation, or pulmonary embolism (HR, 1.78; 95% CI, 1.33-2.38) were associated with a higher risk of hospitalization. Vaccination prior to SARS-CoV-2 infection was associated with a lower risk of hospitalization (HR, 0.52; 95% CI, 0.38-0.70). Over 2 years of follow-up, there were 1739 cancer treatment disruptions, of which 881 (50.7%) were attributed to COVID-19, with most disruptions occurring within the first 30 days.<br><br>CONCLUSIONS AND RELEVANCE: The results of this prospective cohort study showed that COVID-19 had a significant impact on patients with cancer, including hospitalization, treatment disruptions, and death.}, }
@article {pmid40674120, year = {2025}, author = {Hadland, B}, title = {Unusual suspects: a surprise cast in making blood stem cells.}, journal = {Blood}, volume = {146}, number = {3}, pages = {265-266}, doi = {10.1182/blood.2025029369}, pmid = {40674120}, issn = {1528-0020}, }
@article {pmid40675159, year = {2025}, author = {Yang, X and Zhao, F and Ren, T and Chen, C and Byrne, KT and Danilov, AV and Sears, RC and Nelson, PS and Coussens, LM and Mills, GB and Xia, Z}, title = {OmicsTweezer: A distribution-independent cell deconvolution model for multi-omics Data.}, journal = {Cell genomics}, volume = {5}, number = {9}, pages = {100950}, pmid = {40675159}, issn = {2666-979X}, support = {R01 CA234715/CA/NCI NIH HHS/United States ; R01 CA283171/CA/NCI NIH HHS/United States ; R01 GM147365/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Proteomics/methods ; Prostatic Neoplasms/genetics/pathology ; Single-Cell Analysis/methods ; Male ; Transcriptome/genetics ; Tumor Microenvironment ; Deep Learning ; Colonic Neoplasms/genetics/pathology ; *Genomics/methods ; *Software ; *Computational Biology/methods ; Algorithms ; Gene Expression Profiling/methods ; Multiomics ; }, abstract = {Cell deconvolution estimates cell type proportions from bulk omics data, enabling insights into tissue microenvironments and disease. However, practical applications are often hindered by batch effects between bulk data and referenced single-cell data, a challenge that is frequently overlooked. To address this discrepancy, we developed OmicsTweezer, a distribution-independent cell deconvolution model. By integrating optimal transport with deep learning, OmicsTweezer aligns simulated and real data in a shared latent space, effectively mitigating data shifts and inter-omics distribution differences. OmicsTweezer is versatile, capable of deconvolving bulk RNA-seq, bulk proteomics, and spatial transcriptomics. Extensive evaluations on simulated and real-world datasets demonstrate its robustness and accuracy. Furthermore, applications in prostate and colon cancer showcase OmicsTweezer's ability to identify biologically meaningful cell types. As a unified deconvolution framework for multi-omics data, OmicsTweezer offers an efficient and powerful tool for studying disease microenvironments.}, }
@article {pmid40675169, year = {2025}, author = {Weinstein, E and Paredes, R and Gardner, A and Almas, M and Baniecki, ML and Guan, S and Tudone, E and Antonucci, S and Gregg, K and Garcia-Vidal, C and Camacho-Ortiz, A and Wisemandle, W and Terra, SG and Liu, S and Aberg, JA and Rana, MM and Corey, L and Ford, ES and Hammond, J and Rusnak, J}, title = {Extended nirmatrelvir-ritonavir treatment durations for immunocompromised patients with COVID-19 (EPIC-IC): a placebo-controlled, randomised, double-blind, phase 2 trial.}, journal = {The Lancet. Infectious diseases}, volume = {25}, number = {11}, pages = {1243-1253}, doi = {10.1016/S1473-3099(25)00221-X}, pmid = {40675169}, issn = {1474-4457}, mesh = {Humans ; *Ritonavir/administration &amp; dosage/therapeutic use ; Male ; Female ; Double-Blind Method ; Middle Aged ; *COVID-19 Drug Treatment ; SARS-CoV-2/drug effects ; Adult ; Aged ; *Immunocompromised Host ; *Antiviral Agents/administration &amp; dosage/therapeutic use ; *COVID-19/virology ; Treatment Outcome ; Young Adult ; Drug Administration Schedule ; Adolescent ; }, abstract = {BACKGROUND: Nirmatrelvir-ritonavir is approved for adults with mild-to-moderate COVID-19 who are at risk of severe disease. There are little clinical data to guide the duration of therapy in patients who are immunocompromised. We aimed to compare the approved 5-day regimen of nirmatrelvir-ritonavir with 10-day and 15-day regimens.<br><br>METHODS: This placebo-controlled, randomised, double-blind, phase 2 trial enrolled non-hospitalised, immunocompromised individuals aged 12 years or older with symptomatic COVID-19 from 73 sites across nine countries. Participants were randomly assigned (1:1:1) to receive 300 mg nirmatrelvir and 100 mg ritonavir orally twice per day for 5, 10, or 15 days. Randomisation was stratified according to whether participants were considered immunocompromised due to use of corticosteroids or tumour necrosis factor blockers. Investigators, participants, and caregivers were masked to the assigned study group. The primary endpoint was proportion of randomly assigned and dosed participants with sustained nasopharyngeal SARS-CoV-2 RNA concentrations below the lower limit of quantification (2&#xb7;0 log10 copies per mL) from days 15 to 44. Secondary endpoints included the incidence of viral rebound after the end of treatment up to day 44. Safety, a secondary endpoint, was assessed in all randomly assigned participants who received at least one dose of nirmatrelvir-ritonavir. This trial was registered with ClinicalTrials.gov (NCT05438602) and is completed.<br><br>FINDINGS: Among 156 participants (84 female, 72 male) randomly assigned from Aug 3, 2022 to July 17, 2023, 150 comprised the analysis population. The primary endpoint was reached in 32 (61&#xb7;5%, 95% CI 48&#xb7;3-74&#xb7;8) of 52 participants in the 5-day treatment group, 34 (70&#xb7;8%, 58&#xb7;0-83&#xb7;7) of 48 participants in the 10-day treatment group, and 33 (66&#xb7;0%, 52&#xb7;9-79&#xb7;1) of 50 participants in the 15-day treatment group. Viral rebound occurred in 17&#xb7;3% (95% CI 8&#xb7;2-30&#xb7;3) of participants in the 5-day group, 2&#xb7;1% (0&#xb7;1-11&#xb7;1) in the 10-day group, and 2&#xb7;0% (0&#xb7;1-10&#xb7;6) in the 15-day group. Adverse events occurred in 28 (52&#xb7;8%) of 53, 34 (66&#xb7;7%) of 51, and 31 (60&#xb7;8%) of 51 participants across the 5-day, 10-day, and 15-day groups, respectively. Two COVID-19-related hospitalisations were reported, both in the 5-day treatment group.<br><br>INTERPRETATION: No difference was observed between the three treatment durations in the primary endpoint. Extending nirmatrelvir-ritonavir treatment beyond 5 days resulted in a nominal improvement in the frequency of viral rebound and was generally well tolerated.<br><br>FUNDING: Pfizer.}, }
@article {pmid40675830, year = {2025}, author = {Moon, HH and Aragon-Ching, JB and Thompson, A and Abraham, A and Vlahiotis, A and Ike, C and Benjumea, D and Shao, A and Sun, H and Kearney, M and Gharibian, N and Hanson, S and Li, B and Kirker, M and Grivas, P}, title = {Early real-world utilization of avelumab switch maintenance among patients with advanced urothelial carcinoma without progression following treatment with first-line platinum-based chemotherapy.}, journal = {Urologic oncology}, volume = {43}, number = {10}, pages = {594.e19-594.e29}, doi = {10.1016/j.urolonc.2025.05.014}, pmid = {40675830}, issn = {1873-2496}, mesh = {Humans ; Male ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Female ; Retrospective Studies ; Aged ; Middle Aged ; *Carcinoma, Transitional Cell/drug therapy/pathology ; Disease Progression ; *Urinary Bladder Neoplasms/drug therapy/pathology ; *Urologic Neoplasms/drug therapy/pathology ; *Antineoplastic Agents, Immunological/therapeutic use ; Aged, 80 and over ; }, abstract = {BACKGROUND: A standard treatment option for patients with locally advanced/metastatic urothelial carcinoma (la/mUC) is first-line platinum-based chemotherapy (1L PBC) followed by avelumab 1L switch maintenance (1LM) in patients without progression. This study aimed to evaluate the real-world treatment patterns and outcomes in patients with la/mUC in the US treated with 1L PBC and characterize the early adoption of avelumab 1LM following FDA approval in June 2020.<br><br>METHODS: This retrospective cohort study identified adults diagnosed with la/mUC between January 2017 and September 2021 using electronic health records from the Flatiron Health database. Patients were grouped based on real-world response to 1L PBC: complete or partial response (rwCR/PR) or stable disease (rwSD). Baseline characteristics and treatment patterns were described. Clinical outcomes, including real-world overall survival (rwOS) and progression-free survival (rwPFS), were analyzed using the Kaplan-Meier method.<br><br>RESULTS: Of 1,703 identified patients with la/mUC treated with 1L PBC, 1,245 (73%) had response data available during the study period, with 998 (80%) having a best response of rwCR/PR (60%) or rwSD (20%). Demographic and clinical characteristics were similar between patients with rwCR/PR and rwSD. Patients with rwCR/PR had longer median rwOS and rwPFS from 1L PBC initiation vs patients with rwSD. Of patients evaluated after FDA approval of avelumab 1LM on June 30, 2020, 435 discontinued 1L PBC. Of these patients, 339 had response data, and 138 of those without progression were considered avelumab 1LM eligible. Of these, 97 (70%) initiated avelumab 1LM within 180 days following last administration of 1L PBC, with 40 patients receiving second-line (2L) treatment, most commonly enfortumab vedotin (60%).<br><br>CONCLUSION: In the post-FDA approval period, uptake of avelumab 1LM was high (70%) in patients with rwSD or rwCR/PR following 1L PBC, and 41% of these patients received 2L treatment, most commonly with enfortumab vedotin.}, }
@article {pmid40676597, year = {2025}, author = {Rajabli, F and Benchek, P and Tosto, G and Kushch, N and Sha, J and Bazemore, K and Zhu, C and Lee, WP and Haut, J and Hamilton-Nelson, KL and Wheeler, NR and Zhao, Y and Farrell, JJ and Grunin, MA and Leung, YY and Kuksa, PP and Li, D and da Fonseca, EL and Mez, JB and Palmer, EL and Pillai, J and Sherva, RM and Song, YE and Zhang, X and Ikeuchi, T and Iqbal, T and Pathak, O and Valladares, O and Reyes-Dumeyer, D and Kuzma, AB and Abner, E and Adams, LD and Adams, PM and Aguirre, A and Albert, MS and Albin, RL and Allen, M and Alvarez, L and Apostolova, LG and Arnold, SE and Asthana, S and Atwood, CS and Auerbach, S and Ayres, G and Baldwin, CT and Barber, RC and Barnes, LL and Barral, S and Beach, TG and Becker, JT and Beecham, GW and Beekly, D and Benitez, BA and Bennett, D and Bertelson, J and Bird, TD and Blacker, D and Boeve, BF and Bowen, JD and Boxer, A and Brewer, J and Burke, JR and Burns, JM and Buxbaum, JD and Cairns, NJ and Cantwell, LB and Cao, C and Carlson, CS and Carlsson, CM and Carney, RM and Carrasquillo, MM and Chasse, S and Chesselet, MF and Chin, NA and Chui, HC and Chung, J and Craft, S and Crane, PK and Cribbs, DH and Crocco, EA and Cruchaga, C and Cuccaro, ML and Cullum, M and Darby, E and Davis, B and De Jager, PL and DeCarli, C and DeToledo, J and Dick, M and Dickson, DW and Dombroski, BA and Doody, RS and Duara, R and Ertekin-Taner, N and Evans, DA and Faber, KM and Fairchild, TJ and Fallon, KB and Fardo, DW and Farlow, MR and Fernandez-Hernandez, V and Ferris, S and Friedland, RP and Foroud, TM and Frosch, MP and Fulton-Howard, B and Galasko, DR and Gamboa, A and Gearing, M and Geschwind, DH and Ghetti, B and Gilbert, JR and Go, RCP and Goate, AM and Grabowski, TJ and Graff-Radford, NR and Green, RC and Growdon, JH and Hakonarson, H and Hall, J and Hamilton, RL and Harari, O and Hardy, J and Harrell, LE and Head, E and Henderson, VW and Hernandez, M and Hohman, T and Honig, LS and Huebinger, RM and Huentelman, MJ and Hulette, CM and Hyman, BT and Hynan, LS and Ibanez, L and Jarvik, GP and Jayadev, S and Jin, LW and Johnson, K and Johnson, L and Kamboh, MI and Karydas, AM and Katz, MJ and Kauwe, JS and Kaye, JA and Keene, CD and Khaleeq, A and Kikuchi, M and Kim, R and Knebl, J and Kowall, NW and Kramer, JH and Kukull, WA and LaFerla, FM and Lah, JJ and Larson, EB and Lerner, A and Leverenz, JB and Levey, AI and Lieberman, AP and Lipton, RB and Logue, M and Lopez, OL and Lunetta, KL and Lyketsos, CG and Mains, D and Margaret, FE and Marson, DC and Martin, ER and Martiniuk, F and Mash, DC and Masliah, E and Massman, P and Masurkar, A and McCormick, WC and McCurry, SM and McDavid, AN and McDonough, S and McKee, AC and Mesulam, M and Miller, BL and Miller, CA and Miller, JW and Montine, TJ and Monuki, ES and Morris, JC and Mukherjee, S and Myers, AJ and Nguyen, T and Obisesan, T and O'Bryant, S and Olichney, JM and Ory, M and Palmer, R and Parisi, JE and Paulson, HL and Pavlik, V and Paydarfar, D and Perez, V and Peskind, E and Petersen, RC and Petrovitch, H and Pierce, A and Polk, M and Poon, WW and Potter, H and Qu, L and Quiceno, M and Quinn, JF and Raj, A and Raskind, M and Reiman, EM and Reisberg, B and Reisch, JS and Ringman, JM and Roberson, ED and Rodriguear, M and Rogaeva, E and Rosen, HJ and Rosenberg, RN and Royall, DR and Sabbagh, M and Sadovnick, AD and Sager, MA and Sano, M and Saykin, AJ and Schneider, JA and Schneider, LS and Seeley, WW and Slifer, SH and Small, S and Smith, AG and Smith, JP and Sonnen, JA and Spina, S and George-Hyslop, PS and Starks, TD and Stern, RA and Stevens, AB and Strittmatter, SM and Sultzer, D and Swerdlow, RH and Tanzi, RE and Tilson, JL and Trojanowski, JQ and Troncoso, JC and Tsolaki, M and Tsuang, DW and Van Deerlin, VM and van Eldik, LJ and Vance, JM and Vardarajan, BN and Vassar, R and Vinters, HV and Vonsattel, JP and Weintraub, S and Welsh-Bohmer, KA and Whitehead, PL and Wijsman, EM and Wilhelmsen, KC and Williams, B and Williamson, J and Wilms, H and Wingo, TS and Wisniewski, T and Woltjer, RL and Woon, M and Wright, CB and Wu, CK and Younkin, SG and Yu, CE and Yu, L and Zhu, X and Kunkle, BW and Bush, WS and Miyashita, A and Byrd, GS and Wang, LS and Farrer, LA and Haines, JL and Mayeux, R and Pericak-Vance, MA and Schellenberg, GD and Jun, GR and Reitz, C and Naj, AC and , }, title = {Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {210}, pmid = {40676597}, issn = {1474-760X}, support = {P50 AG008671/AG/NIA NIH HHS/United States ; UL1 RR029893/RR/NCRR NIH HHS/United States ; R56 AG074527/AG/NIA NIH HHS/United States ; R56 AG064877/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG053760/AG/NIA NIH HHS/United States ; P50 MH060451/MH/NIMH NIH HHS/United States ; R01 AG054060/AG/NIA NIH HHS/United States ; R01 AG064877/AG/NIA NIH HHS/United States ; R01 AG022374/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; U19 AG074865/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; U01 HG006375/HG/NHGRI NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; U01 AG058654/AG/NIA NIH HHS/United States ; U54 AG052427/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; RC2 AG036528/AG/NIA NIH HHS/United States ; P30 AG028377/AG/NIA NIH HHS/United States ; P50 AG005142/AG/NIA NIH HHS/United States ; R01 AG035137/AG/NIA NIH HHS/United States ; R01 AG009029/AG/NIA NIH HHS/United States ; P50 AG005131/AG/NIA NIH HHS/United States ; P50 AG005128/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; U24 AG021886/AG/NIA NIH HHS/United States ; R01 AG031581/AG/NIA NIH HHS/United States ; R01 AG009956/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; R01 AG067501/AG/NIA NIH HHS/United States ; RC2 AG036650/AG/NIA NIH HHS/United States ; R01 AG019085/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; U01 HG008657/HG/NHGRI NIH HHS/United States ; R01 AG013616/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P50 NS039764/NS/NINDS NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P30 AG008051/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; U24 AG056270/AG/NIA NIH HHS/United States ; RC2 AG036502/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; U01 AG057659/AG/NIA NIH HHS/United States ; R01 MH080295/MH/NIMH NIH HHS/United States ; R01 AG028786/AG/NIA NIH HHS/United States ; KL2 RR024151/RR/NCRR NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG012300/AG/NIA NIH HHS/United States ; P30 AG062422/AG/NIA NIH HHS/United States ; U01 AG062943/AG/NIA NIH HHS/United States ; R01 AG012101/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P50 AG016570/AG/NIA NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; R01 AG042437/AG/NIA NIH HHS/United States ; U24 AG041689/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; R01 AG033193/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; P01 AG060882/AG/NIA NIH HHS/United States ; U01 AG052410/AG/NIA NIH HHS/United States ; R01 CA129769/CA/NCI NIH HHS/United States ; U01 AG010483/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P01 AG002219/AG/NIA NIH HHS/United States ; U01 AG006781/AG/NIA NIH HHS/United States ; P50 AG005144/AG/NIA NIH HHS/United States ; R01 AG041232/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; R01 AG048927/AG/NIA NIH HHS/United States ; R01 AG020688/AG/NIA NIH HHS/United States ; R01 AG022018/AG/NIA NIH HHS/United States ; R01 AG030653/AG/NIA NIH HHS/United States ; P20 MD000546/MD/NIMHD NIH HHS/United States ; R01 AG017173/AG/NIA NIH HHS/United States ; R01 AG025259/AG/NIA NIH HHS/United States ; RF1 AG057519/AG/NIA NIH HHS/United States ; U01 HG004610/HG/NHGRI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; P50 AG016582/AG/NIA NIH HHS/United States ; R01 AG041718/AG/NIA NIH HHS/United States ; U01 AG066767/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; RF1 AG061351/AG/NIA NIH HHS/United States ; R01 AG072474/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; U19 AG066567/AG/NIA NIH HHS/United States ; R01 AG082730/AG/NIA NIH HHS/United States ; R01 AG026916/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; R01 NS059873/NS/NINDS NIH HHS/United States ; R01 AG070864/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; Male ; *Alzheimer Disease/genetics/ethnology ; Black or African American/genetics ; *Genetic Loci ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Hispanic or Latino/genetics ; Polymorphism, Single Nucleotide ; White/genetics ; }, abstract = {BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.<br><br>RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14).<br><br>CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n&#x2009;= 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.}, }
@article {pmid40679371, year = {2025}, author = {Gilad, M and Partridge, SC and Iima, M and Md, RR and Freiman, M}, title = {Radiomics-based Machine Learning Prediction of Neoadjuvant Chemotherapy Response in Breast Cancer Using Physiologically Decomposed Diffusion-weighted MRI.}, journal = {Radiology. Imaging cancer}, volume = {7}, number = {4}, pages = {e240312}, pmid = {40679371}, issn = {2638-616X}, support = {R01 CA190299/CA/NCI NIH HHS/United States ; R01 CA207290/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Middle Aged ; Breast/diagnostic imaging ; *Breast Neoplasms/diagnostic imaging/drug therapy/pathology ; Chemotherapy, Adjuvant ; *Diffusion Magnetic Resonance Imaging/methods ; *Machine Learning ; *Neoadjuvant Therapy ; Predictive Value of Tests ; Radiomics ; Retrospective Studies ; Treatment Outcome ; Multicenter Studies as Topic ; }, abstract = {Purpose To evaluate the performance of a machine learning model developed using radiomics data derived from physiologically decomposed diffusion-weighted MRI data for predicting pathologic complete response (pCR) following neoadjuvant chemotherapy for breast cancer compared with baseline and benchmark models. Materials and Methods This retrospective study included data from the Breast Multiparametric MRI for prediction of neoadjuvant chemotherapy Response (BMMR2) challenge dataset, comprising longitudinal multiparametric breast MRI studies (diffusion-weighted imaging [DWI] and dynamic contrast-enhanced MRI) from participants enrolled in the I-SPY 2/ACRIN 6698 trial (ClinicalTrials.gov: NCT01042379). Piecewise linear physiologic decomposition was applied to DWI data (PD DWI) to isolate pseudo-diffusion, pure-diffusion, and pseudo-diffusion fraction components for radiomics feature extraction. These features were used to develop a boosted decision tree model to predict pCR following neoadjuvant chemotherapy. Model performance was compared with performance of baseline models, including data on tumor size and mean apparent diffusion coefficient, and the BMMR2 challenge benchmark model using area under the receiver operating characteristic curve, F1 score, and positive and negative predictive values. Model calibration was assessed via the Brier score, and a decision curve analysis was performed to estimate the potential reduction in unnecessary interventions when using the proposed model. Results The study included multiparametric MRI scans from 190 female participants (mean age ± SD, 48.4 years ± 10.5). PD DWI achieved the highest area under the receiver operating characteristic curve (0.89, 95% CI: 0.81, 0.96) among all evaluated models, demonstrating statistically significant improvements over baseline approaches (all P < .04). Decision curve analysis showed that the PD DWI model provided a greater net benefit compared with the BMMR2 challenge benchmark model (0.17, 95% CI: 0.13, 0.21 vs 0.09, 95% CI: 0.05, 0.13; P < .001). Conclusion A machine learning model using radiomics data derived from PD DWI achieved higher performance than baseline and benchmark models in predicting pCR following neoadjuvant chemotherapy for breast cancer. Keywords: Image Postprocessing, MR-Diffusion Weighted Imaging, Breast, Tumor Response, Experimental Investigations ClinicalTrials.gov: NCT01042379 © RSNA, 2025.}, }
@article {pmid40679980, year = {2025}, author = {McCrady, A and Friedman, S and Wang, L and Shaw, D and Tawil, R and Statland, J and Tapscott, S and Blemker, S}, title = {3D finite element models reveal regional fatty infiltration modulates tibialis anterior force generating capacity in FSHD.}, journal = {PloS one}, volume = {20}, number = {7}, pages = {e0319881}, pmid = {40679980}, issn = {1932-6203}, mesh = {Humans ; *Muscular Dystrophy, Facioscapulohumeral/physiopathology/pathology/diagnostic imaging ; *Muscle, Skeletal/physiopathology/pathology/diagnostic imaging ; Finite Element Analysis ; Muscle Strength/physiology ; Male ; Magnetic Resonance Imaging ; *Adipose Tissue/pathology/physiopathology/diagnostic imaging ; Middle Aged ; Adult ; Female ; Imaging, Three-Dimensional ; }, abstract = {Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder characterized by muscle damage, fibro-fatty infiltration, and ultimately weakness. The tibialis anterior (TA), very often involved relatively early in FSHD, is a primary dorsiflexor and important for ambulation. Recent work using magnetic resonance imaging to quantify fat infiltration in the TA volume observed a steep decline in force generation after fat reached ~20% in volume. Additional imaging studies have identified regional fat infiltration patterns that may contribute to the non-linear relationship between fat volume and muscle strength due to the distribution of fat within the muscle structure. The goals of this study were to 1) develop a pipeline for creating subject-specific models of the TA that include fat infiltration patterns measured from MRI and predict force generation, 2) compare models created using this pipeline with clinical measures of muscle strength, and 3) use the models to investigate the impact of regional fat distribution on muscle force generation. Twelve subject-specific models were created, and the model-predicted forces strongly correlate to clinical measures of strength in the same subjects (manual muscle testing (MMT): r = 0.75, and quantitative muscle testing (QMT): r = 0.54). The models showed fat amount accounts for 48% and muscle volume accounts for 74% of the variation in force. To investigate the impact of fat distribution, we developed eight pseudo maps to systematically vary fat location and amount in all subject-specific geometries. The models revealed that fat location modulates force generation, with the middle region involvement having the greatest impact in reducing force. This work highlights the need to characterize and understand the impact of intra-muscular fat distributions in neuromuscular diseases.}, }
@article {pmid40680268, year = {2025}, author = {DeFilipp, Z and Choe, H and Efebera, YA and Saad, A and Farhan, S and Lekakis, L and Yared, JA and Schiller, G and Mapara, MY and Assal, A and Gooley, T and Bui, JD and Lee, D and Lane, H and Chen, YB}, title = {RGI-2001 for the prophylaxis of acute graft-versus-host disease after allogeneic HCT.}, journal = {Blood}, volume = {146}, number = {17}, pages = {2037-2046}, doi = {10.1182/blood.2025029584}, pmid = {40680268}, issn = {1528-0020}, mesh = {Humans ; *Graft vs Host Disease/prevention &amp; control/etiology ; Male ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Middle Aged ; Adult ; Transplantation, Homologous ; Aged ; Young Adult ; Adolescent ; Acute Disease ; *Galactosylceramides/therapeutic use/adverse effects/administration &amp; dosage ; Methotrexate/administration &amp; dosage/therapeutic use ; T-Lymphocytes, Regulatory/immunology ; *Ceramides/therapeutic use/adverse effects/administration &amp; dosage ; Tacrolimus/administration &amp; dosage/therapeutic use ; }, abstract = {RGI-2001, a glycolipid that binds CD1d receptor of antigen-presenting cells, can activate invariant natural killer T (NKT) cells and stimulate cytokine-dependent proliferation of regulatory T cells (Tregs). This open-label, multicenter phase 2b trial evaluated the safety and efficacy of RGI-2001 in combination with standard graft-versus-host disease (GVHD) prophylaxis in participants receiving myeloablative allogeneic hematopoietic cell transplantation (HCT). RGI-2001 was infused at a dose of 100 μg/kg for 6 weekly doses. The primary end point was grade 2 to 4 acute GVHD by day 100. A total of 49 participants received RGI-2001 in combination with tacrolimus and methotrexate. RGI-2001 was well tolerated, with no serious infusion reactions. Sixteen participants experienced grade ≥3 treatment-related adverse events, including decreased appetite, leukopenia, thrombocytopenia, and stomatitis. The cumulative incidence of grade 2 to 4 and 3 to 4 acute GVHD were 24.9% and 4.1%, respectively. Compared with the controls from the Center for International Blood and Marrow Research Transplant registry, participants receiving RGI-2001 experienced superior clinical outcomes, including day-180 grade 2 to 4 acute GVHD-free survival (70.8% vs 50.7%; adjusted hazard ratio, 0.45; 95% confidence interval, 0.30-0.68). Increasing NKT and Treg populations were observed after HCT, consistent with the proposed action of RGI-2001. In conclusion, RGI-2001 was well tolerated and was associated with low rates of acute GVHD and encouraging survival after myeloablative HCT. These results support strategies that target NKT and Treg cell populations to augment immunologic changes in allogeneic HCT recipients. This trial was registered at www.clinicaltrials.gov as #NCT04014790.}, }
@article {pmid40680922, year = {2025}, author = {Di Lauro, F and Probert, WJM and Pickles, M and Cori, A and Hinch, R and Ferretti, L and Panovska-Griffiths, J and Abeler-Dörner, L and Dunbar, R and Bock, P and Donnell, DJ and Ayles, H and Fidler, S and Hayes, R and Fraser, C and , }, title = {Large connected components in sexual networks and their role in HIV transmission in Sub-Saharan Africa: A model-based analysis of HPTN 071(PopART) data.}, journal = {Journal of theoretical biology}, volume = {613}, number = {}, pages = {112218}, doi = {10.1016/j.jtbi.2025.112218}, pmid = {40680922}, issn = {1095-8541}, mesh = {Humans ; *HIV Infections/transmission/epidemiology ; Male ; Female ; Africa South of the Sahara/epidemiology ; Adult ; Adolescent ; Young Adult ; *Sexual Behavior ; Incidence ; Middle Aged ; }, abstract = {The HIV epidemic in sub-Saharan Africa is historically characterised by high levels of prevalence and incidence. With the global effort to reach UNAIDS 95-95-95 targets, the scaling-up of HIV treatment, and focused preventive interventions, incidence has been declining over the past decade, albeit non-consistently across different sex and age groups. Two questions remain to be addressed to help tailor setting-specific interventions and allocate resources optimally. Firstly, are there unidentified demographic groups that are sources of transmission? Secondly, what are the patterns of decline in incidence across different groups? Model-based assessment is a valuable tool for the design of focused interventions and to answer these questions. PopART-IBM, an individual-based model calibrated to (anonymised) age-and-sex stratified data, was developed in the context of the HPTN-071 (PopART) trial, and it offers a unique opportunity to explore such questions in the context of high-burden HIV communities in Zambia and South Africa. The outputs of the model include the full HIV transmission and partnership networks. In this work, we explore these and show that the sexual partnership network exhibits a large connected component, usually comprising over 40 % of the population, in each of the studied communities. An analysis of the large connected component reveals that it is formed by young people (20-40 years old) and is centered around the most sexually active individuals of the community. At the same time, many individuals in the large connected component only have one partner, highlighting the complex dynamics of risk correlations in a population. Inspecting the transmission network reveals that, on average, more than 80% of transmissions occur among individuals belonging to the large connected component. These findings indicate that populations consisting of young and highly sexually active individuals should be given high priority when designing or deploying interventions.}, }
@article {pmid40685016, year = {2025}, author = {Leu, J and Narra, LR and Gooley, T and Cross, N and Vuong, W and Khan, H and Kang, J and Yang, JT and Grassberger, C and Gillespie, EF}, title = {Evaluating risk factors for skeletal-related events among bone metastases from solid tumors.}, journal = {Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology}, volume = {211}, number = {}, pages = {111048}, doi = {10.1016/j.radonc.2025.111048}, pmid = {40685016}, issn = {1879-0887}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; K08 CA252640/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Bone Neoplasms/secondary/radiotherapy/mortality ; Female ; Aged ; Retrospective Studies ; Risk Factors ; Middle Aged ; Aged, 80 and over ; Cancer Pain/radiotherapy ; }, abstract = {BACKGROUND AND PURPOSE: Skeletal-related events (SRE) are a major source of morbidity and mortality across cancer types. Identification of risk factors for SRE and association with survival would facilitate more targeted preventive treatment.<br><br>MATERIALS AND METHODS: This retrospective cohort study included patients with bone metastases from solid tumors undergoing systemic imaging from February-March 2022 who had not received radiation within one year. Survival was analyzed using Cox models, and multi-state models assessed factors linked to SRE with death as a competing risk. Outcomes were SRE (including radiation for pain) and all-cause death. Variables included tumor type, metastasis site, and trial eligibility.<br><br>RESULTS: Among 410 patients (median age 67&#xa0;years; 48% male), 162 (40%) experienced SRE over a median follow-up of 26.8&#xa0;months. Seventy-five (18%) received radiation for pain alone. Experiencing any type of SRE (HR 1.98, 95% CI 1.47 - 2.67, p<0.001) or radiation for pain alone (HR 2.14, 95% CI 1.57 - 2.92, p<0.001) were both associated with increased mortality. Patients eligible for a trial of early radiation were more likely to develop SRE (HR 1.67, 95% CI 1.18 - 2.37, p=0.004). Prostate cancer histology (HR 1.70, p=0.02) and metastases to the hip/acetabulum (HR 2.55, p=0.02) were associated with SRE.<br><br>CONCLUSION: Patients treated with radiation for pain alone demonstrated similar risk of death as those experiencing any type of SRE, supporting the inclusion of radiation in endpoint definitions. Prostate cancer type and hip/acetabulum metastasis location may help identify patients and lesions at elevated SRE risk, informing future preventive strategies.}, }
@article {pmid40685311, year = {2025}, author = {Mehra, N and Antonarakis, ES and Park, SH and Goh, JC and McDermott, R and Sala Gonzalez, N and Fong, PC and Greil, R and De Santis, M and Yanez, PE and Huang, YH and Begbie, SD and Rey, F and Kramer, G and Suzuki, H and Saretsky, TL and Ghate, SR and Cui, Y and Hosius, C and Yu, EY}, title = {Patient-reported Outcomes in KEYLYNK-010: Pembrolizumab Plus Olaparib Versus Abiraterone or Enzalutamide for Participants with Biomarker-unselected, Previously Treated Metastatic Castration-resistant Prostate Cancer.}, journal = {European urology oncology}, volume = {8}, number = {4}, pages = {1030-1040}, doi = {10.1016/j.euo.2025.04.018}, pmid = {40685311}, issn = {2588-9311}, mesh = {Humans ; Male ; *Prostatic Neoplasms, Castration-Resistant/drug therapy/pathology ; *Patient Reported Outcome Measures ; *Piperazines/therapeutic use/pharmacology ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; *Phthalazines/therapeutic use/pharmacology ; Aged ; *Phenylthiohydantoin/analogs &amp; derivatives/therapeutic use ; Benzamides/therapeutic use ; Nitriles ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Androstenes/therapeutic use ; Neoplasm Metastasis ; }, abstract = {BACKGROUND AND OBJECTIVE: Pembrolizumab plus olaparib did not significantly improve radiographic progression-free survival or overall survival versus a next-generation hormonal agent (NHA) in participants with biomarker-unselected, pretreated metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 KEYLYNK-010 trial. We present prespecified patient-reported outcomes (PROs) from KEYLYNK-010.<br><br>METHODS: Participants were randomly assigned 2:1 to receive pembrolizumab plus olaparib or an NHA (abiraterone acetate or enzalutamide). PROs were evaluated using the Brief Pain Inventory-Short Form (BPI-SF), Functional Assessment of Cancer Therapy-Prostate Cancer (FACT-P), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaires. The PRO endpoints included time to pain progression (TTPP) as per BPI-SF and the least squares mean (LSM) change from baseline to week 15 in FACT-P total, BPI-SF, and EQ-5D visual analog scale (VAS) scores.<br><br>KEY FINDINGS AND LIMITATIONS: The PRO analysis population included 774 participants (pembrolizumab plus olaparib, n&#xa0;=&#xa0;520; NHA, n&#xa0;=&#xa0;254). The median follow-up was 18.7 (range, 6.1-31.7) mo. No meaningful differences were observed in TTPP for pembrolizumab plus olaparib versus NHA (median: 13.5 vs 12.0 mo; hazard ratio 0.95; 95% confidence interval 0.72-1.26). From baseline to week 15, no meaningful LSM differences were observed between the treatment groups in FACT-P total, BPI-SF, and EQ-5D VAS scores. Limitations include no formal hypothesis testing.<br><br>No meaningful differences were observed in health-related quality of life (HRQoL) or disease-related symptom scores for pembrolizumab plus olaparib versus NHA in participants with biomarker-unselected, pretreated mCRPC. These findings suggest that pembrolizumab plus olaparib did not negatively impact HRQoL in participants with pretreated mCRPC.<br><br>CLINICAL TRIAL REGISTRY: NCT03834519.}, }
@article {pmid40689664, year = {2025}, author = {Ding, S and Tauzin, A and Pinto-Santini, D and Dasgupta, S and Yang, D and Tolbert, WD and Chandravanshi, M and Benlarbi, M and Verly, M and Lama, JR and Huryn, DM and Smith, AB and Pazgier, M and Finzi, A and Duerr, A}, title = {CD4-mimetics sensitize HIV-infected cells to ADCC mediated by plasma from persons with early-stage HIV-1 infection.}, journal = {Journal of virology}, volume = {99}, number = {8}, pages = {e0085825}, pmid = {40689664}, issn = {1098-5514}, support = {R01 AI176531/AI/NIAID NIH HHS/United States ; Operating Grant//CIHR/Canada ; R01 AI150322/AI/NIAID NIH HHS/United States ; P01 AI120756/AI/NIAID NIH HHS/United States ; R01 AI174908/AI/NIAID NIH HHS/United States ; UM1 AI164562/AI/NIAID NIH HHS/United States ; R01/NH/NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/immunology/virology/drug therapy/blood ; *HIV-1/immunology/drug effects ; *Antibody-Dependent Cell Cytotoxicity/immunology ; *HIV Antibodies/immunology/blood ; *CD4-Positive T-Lymphocytes/immunology/virology ; *CD4 Antigens/immunology ; HIV Envelope Protein gp120/immunology ; Male ; Female ; Adult ; Epitopes/immunology ; Antibodies, Neutralizing/immunology ; Middle Aged ; }, abstract = {UNLABELLED: The viral reservoir in long-lived memory CD4+ cells, established in the early stages of HIV infection, represents the main obstacle to an HIV cure. Some strategies being developed to target the reservoir rely on rendering HIV-1 envelope glycoproteins (Env) visible to the immune system. Small molecule CD4-mimetics (CD4mcs) expose vulnerable Env epitopes, which can be targeted by non-neutralizing antibodies (nnAbs) that are abundant in the plasma of people living with HIV (PLWH) and can mediate antibody-dependent cellular cytotoxicity (ADCC). Administration of CD4mcs in combination with plasma from PLWH or nnAbs efficiently reduces the size of the HIV-1 reservoir and postpones viral rebound upon antiretroviral therapy (ART) interruption in humanized mice. However, it remains unclear when these nnAbs are elicited after HIV infection. In this study, we collected longitudinal plasma samples before acquisition, at diagnosis, and at multiple time points up to 33 weeks after the estimated date of detectable infection (EDDI) and before ART treatment initiation. We found that plasma samples collected as early as 3 to 10 weeks after EDDI neutralized viral particles and mediated ADCC in the presence of the CJF-III-288 CD4mc. Recognition of HIV-1-infected cells and ADCC progressively increased over time, reaching a plateau by 19-25 weeks after EDDI. ADCC activity increased concomitantly with the elicitation of anti-gp120 and anti-gp41 CD4-induced (CD4i) Abs and improved over time with the appearance of anti-coreceptor binding site antibodies. Our results show that CD4i nnAbs, able to eliminate HIV-1-infected cells in the presence of CD4mc, are elicited within a few weeks after HIV acquisition.<br><br>IMPORTANCE: A viral reservoir is established at the early stages of HIV-1 infection. This reservoir persists during antiretroviral therapy (ART) treatment, and viral rebound is observed after ART interruption. New strategies are needed to reduce the size of the viral reservoir and prevent virus rebound. Several families of non-neutralizing antibodies, which are abundant in plasma from people living with HIV-1, neutralize viral particles and mediate the elimination of HIV-1-infected cells through antibody-dependent cellular cytotoxicity (ADCC) when combined with CD4-mimetic compounds. The presence of non-neutralizing antibodies in plasma during early-stage HIV-1 infection would support the use of CD4-mimetic compounds as an early intervention to decrease the size of the latent HIV-1 reservoir by eliminating infected cells.}, }
@article {pmid40690761, year = {2025}, author = {Banerjee, R and Mohan, M and Rejeski, K and Puliafito, BR and Cirstea, DD and Kaur, G and Midha, S and McCaughan, GJ and Kumar, NM and Mehra, N and Bagal, B and Raje, NS}, title = {Immunoglobulin prophylaxis should be initiated after bispecific antibody therapy in multiple myeloma, regardless of IgG levels.}, journal = {Blood advances}, volume = {9}, number = {18}, pages = {4720-4726}, pmid = {40690761}, issn = {2473-9537}, mesh = {Humans ; *Multiple Myeloma/drug therapy/therapy/immunology ; *Antibodies, Bispecific/therapeutic use ; *Immunoglobulin G/blood ; }, abstract = {Bispecific antibodies (bsAbs), such as teclistamab, elranatamab, linvoseltamab, and talquetamab, have impressive efficacy in multiple myeloma (MM) but come with substantial infectious risks that do not dissipate over time. Immunoglobulin replacement therapy (IgRT), which includes IV and subcutaneous (SC) immunoglobulins, may lower these risks. In this viewpoint, we contrast primary IgRT prophylaxis (initiation regardless of IgG levels) with preemptive IgRT treatment (initiation only once IgG levels fall below a certain threshold) in this setting. We make evidence-based arguments for primary prophylaxis as a safer and simpler approach than preemptive IgG-guided IgRT. We also discuss strategies to improve the cost-effectiveness of IV and SC immunoglobulins across the world. Given the overwhelmingly favorable benefit-risk profile of IgRT, coupled with the limitations inherent to IgG measurements in MM, withholding IgRT access based on arbitrary IgG thresholds is neither scientifically sound nor clinically appropriate for patients with MM who are receiving bsAb therapy.}, }
@article {pmid40691366, year = {2025}, author = {Smit, RAJ and Wade, KH and Hui, Q and Arias, JD and Yin, X and Christiansen, MR and Yengo, L and Preuss, MH and Nakabuye, M and Rocheleau, G and Graham, SE and Buchanan, VL and Chittoor, G and Graff, M and Guindo-Martínez, M and Lu, Y and Marouli, E and Sakaue, S and Spracklen, CN and Vedantam, S and Wilson, EP and Chen, SH and Ferreira, T and Ji, Y and Karaderi, T and Lüll, K and Machado, M and Malden, DE and Medina-Gomez, C and Moore, A and Rüeger, S and Akiyama, M and Allison, MA and Alvarez, M and Andersen, MK and Appadurai, V and Arbeeva, L and Bartell, E and Bhaskar, S and Bielak, LF and Bis, JC and Bollepalli, S and Bork-Jensen, J and Bradfield, JP and Bradford, Y and Brandl, C and Braund, PS and Brody, JA and Broeckel, U and Burgdorf, KS and Cade, BE and Cai, Q and Camarda, S and Campbell, A and Cañadas-Garre, M and Chai, JF and Chesi, A and Choi, SH and Christofidou, P and Couture, C and Cuellar-Partida, G and Danning, R and Degenhardt, F and Delgado, GE and Delitala, A and Demirkan, A and Deng, X and Dietl, A and Dimitriou, M and Dimitrov, L and Dorajoo, R and Eichelmann, F and Eliasen, AU and Engmann, JE and Erdos, MR and Fairhurst-Hunter, Z and Farmaki, AE and Faul, JD and Fernandez-Lopez, JC and Forer, L and Frank, M and Freitag-Wolf, S and Fritsche, LG and Fuchsberger, C and Galesloot, TE and Gao, Y and Geller, F and Giannakopoulou, O and Giulianini, F and Gjesing, AP and Goel, A and Gordon, SD and Gorski, M and Grove, J and Guo, X and Gustafsson, S and Haessler, J and Hansen, TF and Havulinna, AS and Haworth, SJ and Heard-Costa, N and Hemerich, D and Highland, HM and Hindy, G and Ho, YL and Hofer, E and Holliday, E and Horn, K and Hornsby, WE and Hottenga, JJ and Huang, H and Huang, J and Huerta-Chagoya, A and Huo, S and Hwang, MY and Hwu, CM and Iha, H and Ikeda, DD and Isono, M and Jackson, AU and Jansen, IE and Jiang, Y and Johansson, I and Jonsson, A and Jørgensen, T and Kalafati, IP and Kanai, M and Kanoni, S and Kårhus, LL and Kasturiratne, A and Katsuya, T and Kawaguchi, T and Kember, RL and Kentistou, KA and Kim, D and Kim, HN and Kim, YJ and Kleber, ME and Knol, MJ and Kurbasic, A and Lauzon, M and Le, P and Lea, R and Lee, JY and Lee, WJ and Leonard, HL and Li, H and Li, SA and Li, X and Li, X and Liang, J and Lin, H and Lin, K and Liu, J and Liu, X and Lo, KS and Long, J and Lores-Motta, L and Luan, J and Lyssenko, V and Lyytikäinen, LP and Mahajan, A and Malik, MZ and Mamakou, V and Mangino, M and Manichaikul, A and Marten, J and Mattheisen, M and McDaid, AF and Mei, Q and Meiselbach, H and Melendez, TL and Milaneschi, Y and Miller, JE and Millwood, IY and Mishra, PP and Mitchell, RE and Møllehave, LT and Mononen, N and Mucha, S and Munz, M and Mykkänen, J and Nakatochi, M and Nardone, GG and Nelson, CP and Nethander, M and Nho, CW and Nielsen, AA and Nolte, IM and Nongmaithem, SS and Noordam, R and Ntalla, I and Nutile, T and Pandit, A and Pauper, M and Petersen, ERB and Petersen, LV and Piluso, F and Polašek, O and Poveda, A and Pyarajan, S and Raffield, LM and Rakugi, H and Ramirez, J and Rasheed, A and Raven, D and Rayner, NW and Riveros, C and Rohde, R and Ruggiero, D and Ruotsalainen, SE and Ryan, KA and Sabater-Lleal, M and Santin, A and Saxena, R and Scholz, M and Shen, B and Shi, J and Shin, JH and Sidore, C and Sidorenko, J and Sim, X and Slieker, RC and Smith, AV and Smith, JA and Smyth, LJ and Southam, L and Steinthorsdottir, V and Sun, L and Takeuchi, F and Taylor, KD and Tayo, BO and Tcheandjieu, C and Terzikhan, N and Tesolin, P and Teumer, A and Theusch, E and Thompson, DJ and Thorleifsson, G and Timmers, PRHJ and Trompet, S and Turman, C and Vaccargiu, S and van der Laan, SW and van der Most, PJ and van Klinken, JB and van Setten, J and Verma, SS and Verweij, N and Veturi, Y and Wang, CA and Wang, C and Wang, JS and Wang, L and Wang, YX and Wang, Z and Warren, HR and Bin Wei, W and Wen, W and Wheeler, WA and Wickremasinghe, AR and Wielscher, M and Winsvold, BS and Wong, A and Wuttke, M and Xia, R and Yamamoto, K and Yang, J and Yao, J and Young, H and Yousri, NA and Yu, L and Zeng, L and Zhang, W and Zhang, X and Zhao, JH and Zhao, W and Zhou, W and Zimmermann, ME and Zoledziewska, M and 't Hart, LM and Adair, LS and Adams, HHH and Aguilar-Salinas, CA and Al-Mulla, F and Arnett, DK and Asselbergs, FW and Åsvold, BO and Attia, J and Banas, B and Bandinelli, S and Beilin, LJ and Bennett, DA and Bergler, T and Bharadwaj, D and Biino, G and Boerwinkle, E and Böger, CA and Borja, JB and Bouchard, C and Bowden, DW and Brandslund, I and Brumpton, B and Buring, JE and Caulfield, MJ and Chambers, JC and Chandak, GR and Chanock, SJ and Chaturvedi, N and Ida Chen, YD and Chen, Z and Cheng, CY and Cho, YS and Christensen, K and Christophersen, IE and Ciullo, M and Cole, JW and Collins, FS and Concas, MP and Cooper, RS and Cruz, M and Cucca, F and Cutler, MJ and Damrauer, SM and Dantoft, TM and de Borst, GJ and de Geus, EJC and de Groot, LCPGM and De Jager, PL and de Kleijn, DPV and de Silva, HJ and Dedoussis, GV and den Hollander, AI and Du, S and Easton, DF and Eckardt, KU and Elders, PJM and Eliassen, AH and Ellinor, PT and Elmståhl, S and Erdmann, J and Evans, MK and Fatkin, D and Feenstra, B and Feitosa, MF and Ferrucci, L and Florez, JC and Ford, I and Fornage, M and Franke, A and Franks, PW and Freedman, BI and Gieger, C and Girotto, G and Golightly, YM and Gonzalez-Villalpando, C and Gordon-Larsen, P and Grallert, H and Grant, SFA and Grarup, N and Griffiths, L and Gudnason, V and Haiman, C and Hakonarson, H and Hansen, T and Hartman, CA and Hattersley, AT and Hayward, C and Heid, IM and Heng, CK and Hengstenberg, C and Herzig, KH and Hewitt, AW and Hishigaki, H and Hougaard, DM and Hoyng, CB and Huang, PL and Huang, W and Huang, WY and Huffman, JE and Hunt, SC and Hutri, N and Hveem, K and Hyppönen, E and Iacono, WG and Ichihara, S and Ikram, MA and Isasi, CR and Jarvelin, MR and Jin, ZB and Jöckel, KH and Jonas, JB and Joshi, PK and Jousilahti, P and Jukema, JW and Kähönen, M and Kamatani, Y and Kang, KD and Kaprio, J and Kardia, SLR and Karpe, F and Kato, N and Kavousi, M and Kee, F and Kessler, T and Khera, AV and Khor, CC and Kiemeney, LALM and Kim, BJ and Kim, EK and Kim, HL and Kirchhof, P and Kivimaki, M and Koh, WP and Koistinen, HA and Kokkinos, A and Kooner, JS and Kooperberg, C and Kovacs, P and Kraaijeveld, A and Kraft, P and Krauss, RM and Kumari, M and Kutalik, Z and Laakso, M and Lange, LA and Langenberg, C and Launer, LJ and Lee, H and Lee, NR and Lehtimäki, T and Lemaitre, RN and Li, H and Li, L and Lieb, W and Lin, X and Lind, L and Linneberg, A and Liu, CT and Liu, J and Loeffler, M and London, B and Lu, F and Lubitz, SA and Mackey, DA and Magnusson, PKE and Manson, JE and Marcus, GM and Marques Vidal, P and Martin, NG and März, W and Matsuda, F and McCarthy, MI and McGarrah, RW and McGue, M and McKnight, AJ and Medland, SE and Mellström, D and Metspalu, A and Mitchell, BD and Mitchell, P and Mook-Kanamori, DO and Mori, TA and Morris, AD and Mucci, LA and Munroe, PB and Nalls, MA and Nazarian, S and Nelson, AE and Neville, MJ and Newton-Cheh, C and Nielsen, CS and Niinikoski, H and Nikus, K and Nöthen, MM and Ogunniyi, A and Ohlsson, C and Oldehinkel, AJ and Orozco, L and Pahkala, K and Pajukanta, P and Palmer, CNA and Parra, EJ and Pattaro, C and Pedersen, O and Pennell, CE and Penninx, BWJH and Perusse, L and Peters, A and Peyser, PA and Porteous, DJ and Posthuma, D and Power, C and Pramstaller, PP and Province, MA and Psaty, BM and Qi, Q and Qu, J and Rader, DJ and Raitakari, OT and Rallidis, LS and Rao, DC and Redline, S and Reilly, DF and Reiner, AP and Rhee, SY and Ridker, PM and Rienstra, M and Ripatti, S and Ritchie, MD and Rivadeneira, F and Roden, DM and Rosendaal, FR and Rotter, JI and Rudan, I and Rutters, F and Ryu, S and Sabanayagam, C and Salako, B and Saleheen, D and Salomaa, V and Samani, NJ and Sanghera, DK and Sattar, N and Schmidt, B and Schmidt, H and Schmidt, R and Schulze, MB and Schunkert, H and Scott, LJ and Scott, RJ and Sever, P and Sheu, WHH and Shoemaker, MB and Shu, XO and Simonsick, EM and Sims, M and Singleton, AB and Sinner, MF and Smith, JG and Snieder, H and Spector, TD and Spedicati, B and Stampfer, MJ and Stark, KJ and Strachan, DP and Tabara, Y and Tai, ES and Tang, H and Tardif, JC and Thanaraj, TA and Tönjes, A and Tuomi, T and Tuomilehto, J and Tusié-Luna, MT and van Dam, RM and van der Harst, P and Van der Velde, N and van Duijn, CM and van Schoor, NM and Vitart, V and Vohl, MC and Völker, U and Vollenweider, P and Völzke, H and Vrieze, S and Wacher-Rodarte, NH and Walker, M and Wander, GS and Wareham, NJ and Watanabe, RM and Watkins, H and Weir, DR and Werge, TM and Widen, E and Willemsen, G and Willett, WC and Wilson, JF and Wilson, PWF and Wong, TY and Woo, JT and Wright, AF and Xu, H and Yajnik, CS and Yang, J and Yokota, M and Yuan, JM and Zeggini, E and Zemel, BS and Zheng, W and Zhu, X and Zillikens, MC and Zonderman, AB and Zwart, JA and ,  and ,  and ,  and ,  and ,  and ,  and ,  and Abecasis, GR and Assimes, TL and Auton, A and Boehnke, M and Chasman, DI and Esko, T and Stefansson, K and Lettre, G and Lindgren, CM and Ng, MCY and O'Donnell, CJ and Thorsteinsdottir, U and Visscher, PM and Walters, RG and Winkler, TW and Wood, AR and Deloukas, P and Frayling, TM and Justice, AE and Kilpeläinen, TO and Locke, AE and Mohlke, KL and North, KE and Okada, Y and Willer, CJ and Young, KL and Fatumo, S and McCaffery, JM and Timpson, NJ and Hirschhorn, JN and Sun, YV and Berndt, SI and Loos, RJF}, title = {Polygenic prediction of body mass index and obesity through the life course and across ancestries.}, journal = {Nature medicine}, volume = {31}, number = {9}, pages = {3151-3168}, pmid = {40691366}, issn = {1546-170X}, support = {R01 DK093757/DK/NIDDK NIH HHS/United States ; RC2 MH089951/MH/NIMH NIH HHS/United States ; U10 HL054472/HL/NHLBI NIH 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States ; ZIA CP010152/ImNIH/Intramural NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; R01 CA055069/CA/NCI NIH HHS/United States ; U01 DK057078/DK/NIDDK NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; I01 BX003340/BX/BLRD VA/United States ; U01 HG008666/HG/NHGRI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; HHSN268201500001I/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; R01 DK118011/DK/NIDDK NIH HHS/United States ; R01 HD074711/HD/NICHD NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; N01 HC085079/HL/NHLBI NIH HHS/United States ; U01 HG011723/HG/NHGRI NIH HHS/United States ; K02 AA018755/AA/NIAAA NIH HHS/United States ; R01 NS114045/NS/NINDS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; UL1 TR004419/TR/NCATS NIH HHS/United States ; D43 TW009077/TW/FIC NIH HHS/United States ; K05 CA175147/CA/NCI NIH HHS/United States ; RC2 GM092618/GM/NIGMS NIH HHS/United States ; R01 CA082664/CA/NCI NIH HHS/United States ; R01 HL156991/HL/NHLBI NIH HHS/United States ; R01 HD100406/HD/NICHD NIH HHS/United States ; HHSN271201100005C/DA/NIDA NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; U01 HL054498/HL/NHLBI NIH HHS/United States ; R01 DK139598/DK/NIDDK NIH HHS/United States ; R01 HL172803/HL/NHLBI NIH HHS/United States ; U24 MH068457/MH/NIMH NIH HHS/United States ; UM1 CA182913/CA/NCI NIH HHS/United States ; U01 DK057131/DK/NIDDK NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; R01 DA012854/DA/NIDA NIH HHS/United States ; R01 CA054281/CA/NCI NIH HHS/United States ; K05 AA000145/AA/NIAAA NIH HHS/United States ; R01 AG028050/AG/NIA NIH HHS/United States ; KL2 RR024990/RR/NCRR NIH HHS/United States ; U01 CA063464/CA/NCI NIH HHS/United States ; P50 GM115305/GM/NIGMS NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; U01 DP003206/DP/NCCDPHP CDC HHS/United States ; R01 HG011432/HG/NHGRI NIH HHS/United States ; R01 CA128813/CA/NCI NIH HHS/United States ; U19 AG063893/AG/NIA NIH HHS/United States ; U54 MD007593/MD/NIMHD NIH HHS/United States ; M01 RR007122/RR/NCRR NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; R01 HD058886/HD/NICHD NIH HHS/United States ; KL2 TR002490/TR/NCATS NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; S10 OD030463/OD/NIH HHS/United States ; R01 CA080205/CA/NCI NIH HHS/United States ; HHSN268201700001C/HL/NHLBI NIH HHS/United States ; U01 HG008680/HG/NHGRI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; UM1 TR004528/TR/NCATS NIH HHS/United States ; R01 HL085144/HL/NHLBI NIH HHS/United States ; R01 DK089256/DK/NIDDK NIH HHS/United States ; U19 CA148112/CA/NCI NIH HHS/United States ; U01 HG006378/HG/NHGRI NIH HHS/United States ; HHSN268201700003C/HL/NHLBI NIH HHS/United States ; R01 DK124097/DK/NIDDK NIH HHS/United States ; R01 AA012502/AA/NIAAA NIH HHS/United States ; Z01 CP010119/ImNIH/Intramural NIH HHS/United States ; R01 DA037904/DA/NIDA NIH HHS/United States ; HHSN268201700005C/HL/NHLBI NIH HHS/United States ; I01 BX003362/BX/BLRD VA/United States ; R56 HL150186/HL/NHLBI NIH HHS/United States ; HHSN268201700002C/HB/NHLBI NIH HHS/United States ; U01 HG004436/HG/NHGRI NIH HHS/United States ; R01 NS105150/NS/NINDS NIH HHS/United States ; R01 HL086718/HL/NHLBI NIH HHS/United States ; U01 AG023746/AG/NIA NIH HHS/United States ; U01 CA098758/CA/NCI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; U01 HL054481/HL/NHLBI NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; U19 CA148065/CA/NCI NIH HHS/United States ; R01 DK092127/DK/NIDDK NIH HHS/United States ; U01 DK056990/DK/NIDDK NIH HHS/United States ; R01 DK125187/DK/NIDDK NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; R21 DK105913/DK/NIDDK NIH HHS/United States ; U01 DK057178/DK/NIDDK NIH HHS/United States ; U10 HL054473/HL/NHLBI NIH HHS/United States ; U01 HG008673/HG/NHGRI NIH HHS/United States ; R01 AA015416/AA/NIAAA NIH HHS/United States ; UL1 TR000077/TR/NCATS NIH HHS/United States ; R01 NS032830/NS/NINDS NIH HHS/United States ; R03 HL154284/HL/NHLBI NIH HHS/United States ; R01 DK053591/DK/NIDDK NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; RC2 AG036495/AG/NIA NIH HHS/United States ; UL1 RR024975/RR/NCRR NIH HHS/United States ; R01 HL157635/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; R01 HL160689/HL/NHLBI NIH HHS/United States ; U10 HL054495/HL/NHLBI NIH HHS/United States ; U01 DK057008/DK/NIDDK NIH HHS/United States ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; UL1 TR002243/TR/NCATS NIH HHS/United States ; U01 HG008685/HG/NHGRI NIH HHS/United States ; R01 HL077398/HL/NHLBI NIH HHS/United States ; U01 HG004423/HG/NHGRI NIH HHS/United States ; I01 BX005831/BX/BLRD VA/United States ; U10 HL054496/HL/NHLBI NIH HHS/United States ; U10 HL054471/HL/NHLBI NIH HHS/United States ; U01 HG004798/HG/NHGRI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; HHSN268201700005I/HL/NHLBI NIH HHS/United States ; R01 CA080122/CA/NCI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; U01 HG006379/HG/NHGRI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 HL117078/HL/NHLBI NIH HHS/United States ; U01 DK057149/DK/NIDDK NIH HHS/United States ; R01 HL095056/HL/NHLBI NIH HHS/United States ; R01 HL087641/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; U01 HL054512/HL/NHLBI NIH HHS/United States ; U01 HG008664/HG/NHGRI NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; R01 HG011035/HG/NHGRI NIH HHS/United States ; R01 CA092579/CA/NCI NIH HHS/United States ; HHSN268201800005I/HL/NHLBI NIH HHS/United States ; UM1 CA182910/CA/NCI NIH HHS/United States ; T32 HL007055/HL/NHLBI NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; R37 DA005147/DA/NIDA NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; HHSN268201800006I/HL/NHLBI NIH HHS/United States ; U01 HL054495/HL/NHLBI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; HHSN271201200022C/DA/NIDA NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; N01 HC085081/HL/NHLBI NIH HHS/United States ; R01 DK078150/DK/NIDDK NIH HHS/United States ; K07 AG061256/AG/NIA NIH HHS/United States ; R01 CA141298/CA/NCI NIH HHS/United States ; U01 HL054473/HL/NHLBI NIH HHS/United States ; R01 DA044283/DA/NIDA NIH HHS/United States ; U01 HG008701/HG/NHGRI NIH HHS/United States ; UM1 CA182876/CA/NCI NIH HHS/United States ; R37 AA012502/AA/NIAAA NIH HHS/United States ; R01 DK122503/DK/NIDDK NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; R01 AA013320/AA/NIAAA NIH HHS/United States ; K08 HG010155/HG/NHGRI NIH HHS/United States ; K01 HL135405/HL/NHLBI NIH HHS/United States ; P30 AR072580/AR/NIAMS NIH HHS/United States ; R01 AG056477/AG/NIA NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; Adiposity/genetics ; *Body Mass Index ; Genetic Predisposition to Disease ; *Multifactorial Inheritance/genetics ; *Obesity/genetics ; White People/genetics/statistics &amp; numerical data ; *Racial Groups/genetics/statistics &amp; numerical data ; }, abstract = {Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.}, }
@article {pmid40692216, year = {2025}, author = {Koo, J and Cooper, R and Edwards, SL and Lane, A and Loveless, SK and Strecker, L and Lake, KE and Myers, KC and Towe, C and Patti, J and Walkup, LL and Wikenheiser-Brokamp, KA and MacMillan, ML and Lacher, P and Griffin, T and Tekman, M and Cisneros, GS and Wu, K and Zinter, MS and Urrego, FA and Baker, KS and Abts, MF and Ballard, S and Freedman, JL and Caraballo, A and Young, LR and Josephson, MB and Allen, JL and Camburn, DM and Doherty, EE and Azamian, MS and Arredondo, M and Silva-Carmona, M and Lehmann, LE and Wong, W and Gaffin, JM and McAlpine, W and Li, M and Goldfarb, SB and Woods, JC and Davies, SM}, title = {High Prevalence of Abnormal Baseline Lung Function in Pediatric and Young Adult Hematopoietic Stem Cell Transplant Recipients: A Report from the TRANSPIRE Study.}, journal = {Pediatric blood &amp; cancer}, volume = {72}, number = {10}, pages = {e31916}, pmid = {40692216}, issn = {1545-5017}, support = {R01 HL157392/HL/NHLBI NIH HHS/United States ; R01HL157392/HB/NHLBI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Young Adult ; Follow-Up Studies ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Lung Diseases/etiology/epidemiology/physiopathology ; Prevalence ; Prognosis ; Prospective Studies ; Respiratory Function Tests ; Survival Rate ; }, abstract = {BACKGROUND: Pulmonary complications are a major cause of morbidity and mortality in pediatric and young adult hematopoietic stem cell transplant (HSCT) recipients. The impact of preexisting lung dysfunction on posttransplant outcomes remains understudied.<br><br>METHODS: In a multi-institutional prospective cohort of 444 patients (&#x2264;24 years) undergoing allogeneic HSCT at eight centers, baseline lung function was categorized as normal or abnormal using clinical history, imaging, pulmonary function tests (PFTs), and pulmonologist review. Spirometry and diffusion capacity were assessed at baseline, Day 100, 1 year, and 2 years post-HSCT.<br><br>RESULTS: Baseline pulmonary dysfunction was present in 224 patients (50.4%), including impaired spirometry (46.4%), low diffusion capacity (33.8%), and imaging abnormalities (e.g., nodules 19%, interstitial changes 7.9%). These patients had significantly lower median z-scores for forced expiratory volume in 1&#xa0;s (FEV1) (-2.3&#xa0;vs. -0.5), forced vital capacity (FVC) (-2.0&#xa0;vs. -0.3), and diffusion capacity of the lung for carbon monoxide (-2.4&#xa0;vs. -0.7; all p&#xa0;<&#xa0;0.001). Lung function impairments persisted through 2 years post-HSCT. FEV1 and FVC remained significantly lower at all time points; FEV1/FVC ratios were similar. Overall survival was lower in the abnormal group (88.4&#xa0;vs. 95.9%). Seven respiratory-related deaths occurred, including acute respiratory distress syndrome (n&#xa0;=&#xa0;3), respiratory failure (n&#xa0;=&#xa0;2), diffuse alveolar hemorrhage (n&#xa0;=&#xa0;1), and fibrotic lung disease (n&#xa0;=&#xa0;1).<br><br>CONCLUSIONS: Pretransplant pulmonary dysfunction is common and predicts sustained posttransplant impairment and lower survival. Comprehensive baseline assessment may aid in risk stratification and guide early interventions to improve long-term respiratory outcomes in pediatric and young adult HSCT patients.<br><br>GOV IDENTIFIER: NCT04098445.}, }
@article {pmid40694037, year = {2025}, author = {Rebolj, M and Brentnall, AR and Geppert, J and Kouppa, N and Shinkins, B and Freeman, K and Stinton, C and Randell, MJ and Johnson, S and Smith, RA and Sasieni, P and Janes, SM and Etzioni, R and Duffy, SW and Taylor-Phillips, S}, title = {Late-Stage Outcomes as Surrogates for Mortality in Cancer Screening Trials: A Systematic Review and Meta-analysis.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {10}, pages = {1694-1709}, pmid = {40694037}, issn = {1538-7755}, support = {R35 CA274442/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/mortality/diagnosis/pathology ; *Early Detection of Cancer/methods ; Incidence ; Neoplasm Staging ; }, abstract = {Late-stage cancer incidence has been proposed as a surrogate outcome for cancer-specific mortality in future screening trials. Two previous meta-analyses with 33 and 39 trials assessed trial-level surrogacy but provided inconsistent conclusions about the suitability of late-stage cancer endpoints replacing mortality. Our systematic review and meta-analysis (PROSPERO ID, CRD42023369320) investigated the association between the effect of cancer screening on the incidence of late-stage cancer and cancer-specific mortality. From 57 trials with 61 trial arm comparisons, correlation between late-stage incidence and mortality outcomes was 0.69 [95% confidence interval (CI), 0.47-0.84] for all cancers combined. Specifically, correlations were 0.58 (95% CI, 0.27-0.93) for bowel (N = 11 trials), 0.79 (95% CI, 0.49-0.94) for breast (N = 13), and 0.91 (95% CI, 0.84-0.96) for lung cancer (N = 14). Trial point estimates of the screening effect on mortality were within each trial's 95% CI late-stage incidence estimates in 56 of 61 (92%) trial arm comparisons and in 16 of 19 (84%) trial arm comparisons in which the entire 95% CI for screening effect on late-stage incidence was below one. Evidence suggests potential for late-stage cancer incidence as a key outcome in screening trials, but further research is needed to clarify when to measure late-stage outcomes, extrapolation for cancer types without trials, and the conditions when late-stage cancer does not accurately predict mortality.}, }
@article {pmid40694438, year = {2025}, author = {Pete, D and Lampe, JW and Liu, H and Salama, NR and Wu, MC and Phipps, AI}, title = {A Cross-Sectional Study of Dietary Patterns and Helicobacter pylori Infection Among American Indian Adults in the Southwest.}, journal = {Nutrition and cancer}, volume = {77}, number = {9}, pages = {1043-1051}, doi = {10.1080/01635581.2025.2535055}, pmid = {40694438}, issn = {1532-7914}, support = {F99 CA253685/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Young Adult ; Cross-Sectional Studies ; *Diet/adverse effects/ethnology ; Feces/microbiology ; *Feeding Behavior/ethnology ; Fruit ; *Helicobacter Infections/epidemiology/microbiology/ethnology ; *Helicobacter pylori/isolation &amp; purification ; *Indians, North American/statistics &amp; numerical data ; Pilot Projects ; Prevalence ; Risk Factors ; Surveys and Questionnaires ; Vegetables ; Southwestern United States/epidemiology/ethnology ; }, abstract = {High sodium diets have been shown to promote stomach colonization and the induction of tissue damage by Helicobacter pylori (H. pylori), a risk factor for gastric cancer. Among American Indians in the Southwest, where the H. pylori prevalence is 60%, the association between diet and H. pylori infection has not been studied. We conducted a cross-sectional pilot study with 93 adults (51%, 18-44 years, 73% female) in the Navajo Nation to assess their diet with self-administered food questionnaires and to detect H. pylori from stool samples using droplet digital PCR. Three diet patterns were identified using Principal Component Analysis: 1) Western, 2) Soups and Mixed Dishes, and 3) Fruits and Vegetables. Participants in the highest and middle tertiles of the Soups and Mixed Dishes pattern scores had higher odds of having H. pylori (ORHighest=5.59, 95% CI, 1.50-23.70; ORMiddle=3.48, 95% CI, 1.08-12.32) than those in the lowest tertile. This positive association may be linked to the sodium content of foods in this diet pattern. Soups and Mixed Dishes may contribute to H. pylori infection and may be incorporated in nutrition education for individuals positive for H. pylori infection in the Navajo Nation.}, }
@article {pmid40694868, year = {2025}, author = {Farland, LV and Degnan, WJ and Harris, HR and Sasamoto, N and Rexrode, KM and Missmer, SA}, title = {Laparoscopically confirmed endometriosis and midlife plasma markers of inflammation, cholesterol, and adipokines among participants in the Nurses' Health Study II.}, journal = {Maturitas}, volume = {200}, number = {}, pages = {108663}, doi = {10.1016/j.maturitas.2025.108663}, pmid = {40694868}, issn = {1873-4111}, support = {R21 HD099623/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Female ; Adult ; *Endometriosis/blood/complications ; Biomarkers/blood ; *Inflammation/blood ; C-Reactive Protein/metabolism ; Middle Aged ; *Cholesterol/blood ; Adiponectin/blood ; Body Mass Index ; Leptin/blood ; Laparoscopy ; Receptors, Tumor Necrosis Factor, Type II/blood ; Interleukin-6/blood ; *Adipokines/blood ; Cholesterol, HDL/blood ; Cholesterol, LDL/blood ; }, abstract = {OBJECTIVE: Endometriosis may increase the risk of cardiovascular disease, possibly through a detrimental impact on circulating biomarkers. However, there is a paucity of research on endometriosis and inflammation, lipids, and adipokines at midlife.<br><br>METHODS: We used generalized linear models to determine the association between laparoscopically confirmed endometriosis and log-transformed levels of plasma C-reactive protein (n&#xa0;=&#xa0;3936), interleukin-6 (n&#xa0;=&#xa0;3495), tumor necrosis factor-alpha receptor 2 (n&#xa0;=&#xa0;2967), high-density lipoprotein cholesterol (n&#xa0;=&#xa0;1533), low-density lipoprotein cholesterol (n&#xa0;=&#xa0;1324), total cholesterol (n&#xa0;=&#xa0;4898), leptin (n&#xa0;=&#xa0;2480), and adiponectin (n&#xa0;=&#xa0;4262) among participants with existing biomarker measurements in the Nurses' Health Study II (average age 44&#xa0;years). We investigated heterogeneity by body mass index (<25&#xa0;kg/m[2] vs. &#x2265; 25&#xa0;kg/m[2]).<br><br>RESULTS: We did not observe associations between endometriosis and midlife inflammatory biomarkers (C-reactive protein % difference: -4.6, 95&#xa0;% CI [-15.7,7.9]; interleukin-6: -0.4&#xa0;% [-7.2,7.1]; tumor necrosis factor-alpha receptor 2: -1.3&#xa0;% [-4.1,1.6]) or levels of high-density lipoprotein cholesterol (0.8&#xa0;% [-3.7,5.6]), low-density lipoprotein cholesterol (-0.2&#xa0;% [-5.2,5.1]), total cholesterol (1.0&#xa0;% [-0.7,2.7]), or adiponectin (-4.0 [-8.8,1.0]). Women with endometriosis had higher leptin levels (9.0&#xa0;% [0.5, 18.1]). Associations varied by body mass index for total cholesterol (p-value 0.05) and leptin (p-value 0.02). Among women with a body mass index &#x2265;25&#xa0;kg/m[2], those with endometriosis had a mean total cholesterol level that was 2.7&#xa0;% higher (0.2,5.2) than among those without; among those with a body mass index <25&#xa0;kg/m[2], those with endometriosis had a mean leptin level that was 15.7&#xa0;% higher (4.6, 28.1) than among those without endometriosis.<br><br>CONCLUSIONS: Endometriosis was not associated with midlife systemic inflammation, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or adiponectin. Endometriosis was associated with higher leptin among those with a body mass index <25&#xa0;kg/m[2] and higher total cholesterol among those with a body mass index &#x2265;25&#xa0;kg/m[2]. These findings suggest that endometriosis may influence cardiovascular disease risk via midlife cholesterol and leptin.}, }
@article {pmid40695269, year = {2025}, author = {Takle, M and Andrews, A and Riggle, BA and Zelleke, T and Harrar, D and Zhang, J and Zhang, B and Wilson, KJ and Beare, NAV and Taylor, TE and Seydel, KB and Ray, S and Postels, DG}, title = {Using Electroencephalography to Assess Coma Etiology in Children with Retinopathy-Negative Cerebral Malaria.}, journal = {The American journal of tropical medicine and hygiene}, volume = {113}, number = {4}, pages = {809-816}, pmid = {40695269}, issn = {1476-1645}, mesh = {Humans ; *Malaria, Cerebral/complications/physiopathology/diagnosis ; *Coma/etiology/diagnosis/parasitology/physiopathology ; Child ; *Electroencephalography/methods ; Child, Preschool ; Adolescent ; Male ; Female ; Infant ; Malawi/epidemiology ; *Retinal Diseases ; }, abstract = {Autopsy studies of children dying of cerebral malaria (CM) have revealed that those with malarial retinopathy exhibited high levels of sequestration in the cerebral vasculature, whereas children with retinopathy-negative CM exhibited lower sequestration levels and possible nonmalarial causes of death. This suggests that children dying of retinopathy-negative CM have nonmalarial coma etiologies with concomitant incidental parasitemia, which is common in high malaria transmission areas. Subsequent studies have challenged this assertion, positing that retinopathy-negative CM and retinopathy-positive CM are variants of the same disease pathophysiology or host biology, both caused by acute malaria infection. We recently determined that electroencephalography (EEG) can be used to discriminate between a malarial coma (CM) and a nonmalarial coma. To better understand the contribution of acute malaria infection in the pathophysiology of retinopathy-negative CM, we compared qualitative and quantitative EEG findings from 30-minute EEG recordings of Malawian children aged 3 months to 14 years hospitalized at Queen Elizabeth Central Hospital with retinopathy-negative CM, retinopathy-positive CM, and nonmalarial coma. Neither qualitative nor quantitative EEG interpretation methods allow for the discrimination between children with retinopathy-positive CM and those with retinopathy-negative CM. Conversely, quantitative EEG readily differentiated children with retinopathy-negative CM from those with nonmalarial coma (area under the receiving operating characteristic [AUROC] curve of 0.83). When combining qualitative and quantitative EEG interpretation methods, the ability of EEG to distinguish retinopathy-negative CM from nonmalarial EEG increases (AUROC of 0.87). The EEGs of children with retinopathy-negative CM are similar to those of children with retinopathy-positive CM and significantly different from those of children with nonmalarial coma, supporting the hypothesis that acute malarial infection is pathophysiologically important in retinopathy-negative CM.}, }
@article {pmid40698029, year = {2025}, author = {Stankiewicz Karita, HC and Magaret, AS and Selke, S and Pascual, R and Irimia, B and Barbee, LA and Wald, A and Soge, OO}, title = {Stability of Spiked Chlamydia Trachomatis and Neisseria Gonorrhea in Urine and Swab Specimens After Prolonged Storage at Room and Freezer Temperatures Using Aptima Combo-2 Test.}, journal = {Open forum infectious diseases}, volume = {12}, number = {7}, pages = {ofaf388}, pmid = {40698029}, issn = {2328-8957}, abstract = {We evaluated whether prolonged storage at room and freezer temperatures affects detection of Chlamydia trachomatis and Neisseria gonorrhoeae (CT/GC) using Aptima Combo-2 assay for research studies. Three hundred specimens were spiked with CT/GC; half were stored at room temperature and half at -80°C. All specimens remained CT/GC positive for 36 months.}, }
@article {pmid40699439, year = {2025}, author = {Alberts, NM and Stratton, KL and Leisenring, WM and Pizzo, A and Lamoureux, &#xc9; and Alschuler, K and Flynn, J and Krull, KR and Jibb, LA and Nathan, PC and Olgin, JE and Stinson, JN and Armstrong, GT}, title = {Intolerance of uncertainty, psychological symptoms, and pain in long-term childhood cancer survivors: a report from the Childhood Cancer Survivor Study.}, journal = {Journal of cancer survivorship : research and practice}, volume = {}, number = {}, pages = {}, pmid = {40699439}, issn = {1932-2267}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U2CEB021881/NH/NIH HHS/United States ; U2C EB021881/EB/NIBIB NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: Intolerance of uncertainty is central to many psychological disorders and may contribute to pain. Despite the uncertainty inherent in childhood cancer survivorship, little is known about intolerance of uncertainty in this population. This study aimed to characterize intolerance of uncertainty, its risk factors, and its associations with psychological symptoms and pain in childhood cancer survivors.<br><br>METHODS: Survivors from the Childhood Cancer Survivor Study completed psychosocial measures via online survey, including the Intolerance of Uncertainty Scale-12 (score range = 12-60). Cancer and treatment variables were abstracted from medical records. Multivariable regression models with 95% confidence intervals (CI) adjusted for age and sex examined the effects of demographic, disease, treatment, pain, and psychological variables on intolerance of uncertainty.<br><br>RESULTS: Participants included 228 adult survivors of childhood cancer (mean age = 39.6 years, 50.4% female, n = 93 chronic pain). Mean level of intolerance of uncertainty among survivors was 26.2 (SD = 10.0, 95% CI 24.9 to 27.5). Intolerance of uncertainty was associated with female sex (&#x3b2; [95% CI]; 2.7 [0.2-5.3]), unemployment (5.2 [1.9-8.5]), neurologic (4.1 [0.5-7.7]) and cardiovascular (5.0 [2.2-7.8]) chronic health conditions, elevated anxiety (10.9 [8.1-13.7]), and perceived poor health status (4.5 [1.4-7.6]). Higher levels of intolerance of uncertainty were observed in survivors with chronic pain (LS mean = 29.2) compared to survivors without (LS mean = 23.5; p < 0.01).<br><br>CONCLUSIONS: Mean levels of intolerance of uncertainty in childhood cancer survivors are comparable to the general population and associated with psychological symptoms and chronic pain.<br><br>Intolerance of uncertainty may be a modifiable target for transdiagnostic interventions in survivorship care.}, }
@article {pmid40701614, year = {2025}, author = {Nemutlu, GS and Mercaldo, ND and Thayumanavan, E and Zhan, T and Duggan, C and Blauvelt, BM and Chhatwal, J}, title = {Forecasting global progress in breast cancer control in the context of the sustainable development goals.}, journal = {BMJ global health}, volume = {10}, number = {7}, pages = {}, pmid = {40701614}, issn = {2059-7908}, mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology/mortality/prevention &amp; control ; *Global Health ; *Sustainable Development ; *Forecasting ; Incidence ; Developing Countries/statistics &amp; numerical data ; Early Detection of Cancer/trends ; Mortality/trends ; *Global Burden of Disease/trends ; }, abstract = {INTRODUCTION: The United Nations Sustainable Development Goal (UN-SDG) 3.4 aims to reduce premature mortality from non-communicable diseases, including breast cancer, by one-third by 2030 relative to 2015. However, many countries, particularly those with lower income, appear off track. Although mortality rates are commonly used to gauge progress, mortality-to-incidence ratios (MIRs) may provide additional insight by accounting for varying incidence and the effectiveness of cancer control measures.<br><br>METHODS: We obtained age-standardised breast cancer incidence and mortality rates for women aged 30-69 years from 2000 to 2019, covering 199 countries stratified by World Bank income groups (low, lower middle, upper middle and high) from the Institute for Health Metrics and Evaluation Global Burden of Disease (GBD) 2019 study. Using vector autoregressive time-series analyses, we modelled and forecasted income-level and county-level mortality rates and MIRs for female breast cancer from 2020 to 2030.<br><br>RESULTS: From 2015 to 2030, breast cancer mortality is projected to increase by 22.8% and 7.8% in low-income and lower middle-income countries, while decreasing by 10% and 5.4% in upper middle-income and high-income countries. MIR is projected to decrease across all income groups, with the most significant reductions seen in lower income countries, highlighting incremental improvements in breast cancer control initiatives. Only nine countries, predominantly higher income, are expected to achieve the one-third mortality reduction target. Despite MIR improvements in lower income countries, substantial mortality reductions remain elusive.<br><br>CONCLUSION: Relying solely on mortality underestimates progress in breast cancer control. Although most countries are unlikely to meet the SDG 3.4 target, concurrent use of mortality and MIR provides a more nuanced understanding of screening, diagnosis and treatment advances. Integrating MIR trends into global health evaluations may better inform breast cancer prevention strategies.}, }
@article {pmid40702172, year = {2025}, author = {Dai, Y and Aizenbud, L and Qin, K and Austin, M and Jaycox, JR and Cunningham, J and Wang, EY and Zhang, L and Fischer, S and Carroll, SM and van Aggelen, H and Kluger, Y and Herold, KC and Furchtgott, L and Kluger, HM and Ring, AM}, title = {Humoral determinants of checkpoint immunotherapy.}, journal = {Nature}, volume = {644}, number = {8076}, pages = {527-536}, pmid = {40702172}, issn = {1476-4687}, support = {//Yale Medical Scientist Training Program/ ; //Mark Foundation for Cancer Research and the Pew Charitable Trusts/ ; }, mesh = {Humans ; Animals ; Mice ; *Immunotherapy/adverse effects ; *Immunity, Humoral/immunology ; *Autoantibodies/immunology ; *Neoplasms/immunology/therapy ; Female ; Male ; Cohort Studies ; Interferon Type I/immunology ; Middle Aged ; *Immune Checkpoint Inhibitors/therapeutic use/adverse effects ; }, abstract = {Although the role of cellular immunity in checkpoint immunotherapy (CPI) for cancer is well established[1,2], the effect of antibody-mediated humoral immunity is comparably underexplored. Here we used rapid extracellular antigen profiling[3] to map the autoantibody reactome within a cohort of 374 patients with cancer treated with CPIs and 131 healthy control participants for autoantibodies to 6,172 extracellular and secreted proteins (the 'exoproteome'). Globally, patients with cancer treated with CPIs had diverse autoreactivities that were elevated relative to control individuals but changed minimally with treatment. Autoantibody signatures in patients treated with CPI strikingly distinguished them from healthy individuals. Although associations of specific autoantibodies with immune-related adverse events were sparse, we detected numerous individual autoantibodies that were associated with greatly altered odds ratios for response to therapy. These included autoantibodies to immunomodulatory proteins, such as cytokines, growth factors and immunoreceptors, as well as tumour surface proteins. Functional evaluation of several autoantibody responses indicated that they neutralized the activity of their target proteins, which included type I interferons (IFN-I), IL-6, OSM, TL1A, and BMPR1A and BMPR2. Modelling the effects of autoantibodies to IFN-I and TL1A in preclinical mouse tumour models resulted in enhanced CPI efficacy, consistent with their effects in patients. In conclusion, these findings indicate that autoantibodies to the exoproteome modify CPI responses and highlight therapeutically actionable pathways that can be exploited to augment immunotherapy.}, }
@article {pmid40703805, year = {2025}, author = {Campian, JL and Grossman, SA and Kask, AS and Kosydar, S and Strowd, R and Piotrowski, A and Tang, J and Chheda, MG and DiPersio, JF and Schullery, D and D'Amico, L and Desideri, S and Danda, N and Ferrando-Martinez, S and Lee, BH and Fling, SP and Ye, X}, title = {Phase I study of NT-I7, a long-acting interleukin-7, in severe treatment-related lymphopenia following standard radiation and temozolomide for high-grade glioma.}, journal = {Neuro-oncology advances}, volume = {7}, number = {1}, pages = {vdaf117}, pmid = {40703805}, issn = {2632-2498}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA288862/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: High-grade gliomas (HGG) have a poor prognosis despite aggressive treatment. Severe, persistent lymphopenia occurring in HGG patients after concurrent chemoradiation is associated with worse survival. NT-I7, a long-acting interleukin-7 analog, has been shown to increase CD4 and CD8 counts in healthy, septic, and HIV-positive adults. This multi-institutional, NCI-funded dose-escalation trial is the first to evaluate NT-I7 safety and activity in HGG patients with severe treatment-related lymphopenia (TRL) and the effect of co-administered glucocorticoids.<br><br>METHODS: Eligible HGG patients had CD4 counts <300 cells/mm[3] after 5 weeks of standard chemoradiation and were receiving either &#x2264;0.75 or &#x2265;4&#xa0;mg/day of dexamethasone. Patients received a single intramuscular dose of NT-I7 (60 or 360 &#xb5;g/kg) post-chemoradiation, followed by safety evaluation and multi-parameter, longitudinal monitoring of lymphocyte populations and immunologic function.<br><br>RESULTS: NT-I7 was well tolerated in all 12 patients (median age 64; median CD4 count 161 cells/mm&#xb3;) before the study closed prematurely. Absolute lymphocyte counts doubled in 83% (10/12; 95% CI: 51.6%-97.9%) of patients, and CD4 counts doubled in 42% (5/12; 95% CI: 15.2%-72.3%) of patients. Glucocorticoid use did not significantly affect CD4 or lymphocyte increases. Correlative immune profiling revealed increased Ki67 expression in CD4 (P&#x2005;<&#x2005;.005) and CD8 (P&#x2005;<&#x2005;.05) after one week, along with the expansion of CD4 and CD8 T-cell subsets and CD56&#x2005;+&#x2005;natural killer cells.<br><br>CONCLUSIONS: NT-I7 is well tolerated and effectively increases lymphocyte and CD4 counts in severe TRL patients, regardless of glucocorticoid use, suggesting its potential to mitigate TRL and improve outcomes in HGG.}, }
@article {pmid40704585, year = {2025}, author = {Conley, HE and Oh, SY and Garrett, N and Kublin, J and Monaco, CL and Watts, S and Jha, S and Ferrari, G and Tomaras, GD and Geraghty, DE and Chan, C and Pollara, J}, title = {IgG and Fc Receptor Genetic Variation Associates With Functional Antibody Responses in a DNA and Protein Candidate HIV Vaccine Trial.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {100}, number = {4}, pages = {371-375}, pmid = {40704585}, issn = {1944-7884}, support = {T32 AI007392/AI/NIAID NIH HHS/United States ; R25 AI140495/AI/NIAID NIH HHS/United States ; AI007392/GF/NIH HHS/United States ; R25-AI140495/GF/NIH HHS/United States ; P01 AI120756/AI/NIAID NIH HHS/United States ; P01-AI162242/GF/NIH HHS/United States ; P30-AI064518/GF/NIH HHS/United States ; P30 AI064518/AI/NIAID NIH HHS/United States ; P01 AI162242/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *AIDS Vaccines/immunology/administration &amp; dosage ; *Immunoglobulin G/genetics/immunology ; *Receptors, Fc/genetics ; *HIV Antibodies/immunology/blood ; *HIV Infections/prevention &amp; control/immunology ; South Africa ; *Genetic Variation ; Female ; Male ; United States ; Vaccines, DNA/immunology/administration &amp; dosage ; Genotype ; Adult ; Antibody-Dependent Cell Cytotoxicity ; *Antibody Formation ; }, abstract = {BACKGROUND: The HVTN108 trial evaluated the safety and immunogenicity of a DNA prime, adjuvanted protein boost HIV vaccine in the United States and South Africa. The underlying factors influencing individual variation in vaccine responsiveness are unknown. In this study, we defined the IgG Fc and Fc receptor (FcR) genotypes in the HVTN108 cohort to test our hypothesis that IgG and FcR genetic variation can affect vaccine-elicited functional antibody responses.<br><br>METHODS: IgG Fc and FcR alleles were determined by targeted PCR amplification and next-generation sequencing. Vaccine-elicited functional antibody responses, including binding antibody multiplex assay (BAMA), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) activity, were measured using standardized and qualified methods. Relationships between alleles and antibody responses were identified by linear regression controlling for treatment group and region.<br><br>RESULTS: The distribution of many polymorphisms significantly differed between the United States and South Africa. Within the subset of the cohort tested for functional antibody responses (IgG, n = 41; FcR, n = 55), IgG genotypes such as IGHG1*12 (P = 0.012), IGHG3*11 (P = 0.033), IGHG2*02 (P = 0.038), IGHG4*07 (P = 0.076), and others were associated with ADCC antibody responses when corrected for vaccine group and regional effects. In the same way, we identified that the FCER1A rs2427827 mutation had a significant association with lower peak ADCC activity and the FCER2 rs2228137 mutation was associated with lower antibody binding to Con6 gp120 protein.<br><br>CONCLUSIONS: Genetic variation in both antibodies and FcRs associated with levels of HIV-vaccine-elicited functional antibodies. Significant regional differences in distribution of this variation support the need for vaccine testing in diverse populations.}, }
@article {pmid40704716, year = {2025}, author = {Boloori, A and Nategh, E and Su, CT}, title = {Association of social vulnerability index and chimeric antigen receptor T-cell therapy administration, 2018-2023.}, journal = {The oncologist}, volume = {30}, number = {9}, pages = {}, pmid = {40704716}, issn = {1549-490X}, support = {//American Society of Hematology/ ; //American Society of Clinical Oncology/ ; }, mesh = {Humans ; Male ; Female ; *Immunotherapy, Adoptive/methods ; Aged ; *Receptors, Chimeric Antigen ; Middle Aged ; United States ; *Hematologic Neoplasms/therapy ; Social Class ; *Vulnerable Populations ; }, abstract = {Chimeric antigen receptor T-cell (CAR T) therapy for patients with relapsed/refractory hematologic malignancies demands numerous visits, which may pose challenges for patients with lower socioeconomic status (SES). The Centers for Disease Control and Prevention publishes the Social Vulnerability Index (SVI), which summarizes area-level SES factors that predict how residents respond to stressors, including a new cancer -diagnosis. We used the nationwide MarketScan commercial and Medicare insurance claims database to analyze the association between SVI and CAR T therapy completion. We performed multivariable logistic regressions (adjusting for patient-level covariates) and found that patients with hematologic malignancies residing in areas of higher SVI (lower SES) have decreased odds of CAR T therapy completion (odds ratio [OR] 0.84 for leukemia, P = .02; OR 0.72 for lymphoma, P < .001; OR 0.70 for myeloma, P < .001). Therefore, strategies to mitigate CAR T disparities may be focused on patients living in areas with higher SVI.}, }
@article {pmid40705892, year = {2025}, author = {Liu, B and Greenwood, NF and Bonzanini, JE and Motmaen, A and Meyerberg, J and Dao, T and Xiang, X and Ault, R and Sharp, J and Wang, C and Visani, GM and Vafeados, DK and Roullier, N and Nourmohammad, A and Scheinberg, DA and Garcia, KC and Baker, D}, title = {Design of high-specificity binders for peptide-MHC-I complexes.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6758}, pages = {386-391}, pmid = {40705892}, issn = {1095-9203}, support = {R35 CA241894/CA/NCI NIH HHS/United States ; P01 CA023766/CA/NCI NIH HHS/United States ; OT2 CA297288/CA/NCI NIH HHS/United States ; R01 AI103867/AI/NIAID NIH HHS/United States ; R50 CA265328/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; OT2 CA297242/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; }, mesh = {*Histocompatibility Antigens Class I/chemistry/immunology/metabolism ; *Peptides/chemistry/immunology/metabolism ; Humans ; T-Lymphocytes/immunology ; Lymphocyte Activation ; Receptors, Chimeric Antigen/chemistry/immunology/genetics ; Protein Engineering ; Protein Binding ; }, abstract = {Class I major histocompatibility complex (MHC-I) molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance. Proteins that recognize peptide-MHC-I (pMHCI) complexes with specificity for diseased cells could have considerable therapeutic utility. Specificity requires recognition of outward-facing amino acid residues within the disease-associated peptide as well as avoidance of extensive contacts with ubiquitously expressed MHC. We used RFdiffusion to design pMHCI-binding proteins that make extensive contacts with the peptide and identified specific binders for 11 target pMHCs starting from either experimental or predicted pMHCI structures. Upon incorporation into chimeric antigen receptors, designs for eight targets conferred peptide-specific T cell activation. Our approach should have broad utility for both protein- and cell-based pMHCI targeting.}, }
@article {pmid40706035, year = {2025}, author = {Ahmed, N and Thiruvengadam, SK and Hamadani, M and Hu, ZH and Grover, N and Shadman, M and Locke, FL and Gerson, J and Frank, MJ and Budde, LE and Wang, M and Kim, S and Bye, M and Kharfan-Dabaja, MA and Sauter, C and Hematti, P and Turtle, CJ and Ahmed, S and Moskop, A and Logan, B and Nunes, A and Dalton, D and Kloos, I and Lee, D and Xu, H and Pasquini, MC and Herrera, AF}, title = {Real-world outcomes of brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma: a CIBMTR analysis.}, journal = {Blood advances}, volume = {9}, number = {20}, pages = {5382-5396}, pmid = {40706035}, issn = {2473-9537}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24 CA233032/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, Mantle-Cell/therapy/mortality ; Male ; Female ; Middle Aged ; Aged ; *Immunotherapy, Adoptive/methods/adverse effects ; Treatment Outcome ; Recurrence ; Adult ; Prospective Studies ; Aged, 80 and over ; Receptors, Chimeric Antigen ; }, abstract = {Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T-cell therapy approved for relapsed/refractory mantle cell lymphoma (R/R MCL). Here, we report real-world effectiveness and safety outcomes of brexu-cel in a prospective study of patients with R/R MCL, including subgroups based on prior treatment with Bruton's tyrosine kinase inhibitor, bendamustine, or autologous hematopoietic cell transplant (auto-HCT) and number of prior therapy lines, using Center for International Blood and Marrow Transplant Research registry data. A total of 476 patients with R/R MCL who received brexu-cel between July 2020 and December 2022 were included in the analysis. With a median follow-up of 13.5 months, the overall response rate was 91% and complete response rate was 82%. One-year overall survival and progression-free survival rates were 76% and 63%, respectively. One-year cumulative incidence of nonrelapse mortality was 8%. Prior auto-HCT was associated with better duration of response within 6 months after infusion (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.28-0.85) but greater risk of immune effector cell-associated neurotoxicity syndrome (odds ratio [OR], 1.66; 95% CI, 1.06-2.60). Prior bendamustine was associated with increased risk of prolonged thrombocytopenia (OR, 1.90; 95% CI, 1.13-3.21). In patients with 1 to 2 prior therapy lines, relapse or progression was less frequent compared with those with ≥3 prior lines (HR, 0.64; 95% CI, 0.42-1.00). Collectively, our results suggest that real-world outcomes with brexu-cel were consistent with those of the ZUMA-2 trial, regardless of prior therapy type or number of prior therapy lines.}, }
@article {pmid40709277, year = {2025}, author = {Cao, J and Ferguson, M and Sun, J and Shen, M and Small, R and Hippe, DS and Zhao, X and Zhang, D and Watase, H and Yuan, C and Gao, P and DeMarco, JK and Nicosia, RF and Wang, Y and Li, H and Li, Z and Wang, Y and Kohler, T and Hatsukami, T and Sui, B}, title = {Composition of Carotid Plaques Differs Between Chinese and United States Patients: A Histology Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40709277}, issn = {2693-5015}, support = {R01 HL073401/HL/NHLBI NIH HHS/United States ; R01 HL103609/HL/NHLBI NIH HHS/United States ; R01 NS083503/NS/NINDS NIH HHS/United States ; }, abstract = {BACKGROUND: The clinical manifestations of cerebrovascular disease are known to differ between the Chinese and United States (U.S.) populations as do the plaque features on imaging.<br><br>OBJECTIVES: The aim of this study was to investigate and compare the histological features of excised carotid plaques from Chinese and U.S. patients.<br><br>METHODS: Carotid endarterectomy specimens collected from two prospective studies were included. The entire plaque was serially sectioned (10 &#x3bc;m thickness) at 0.5-1 mm intervals. Hematoxylin and eosin staining and Mallory's trichrome staining were performed. The morphology and components of the plaques were measured and compared between the two groups.<br><br>RESULTS: A total of 1,152 histological sections from 75 Chinese patients and 1,843 sections from 111 U.S. patients were analyzed. The Chinese group had significantly smaller minimum lumen diameters (median: 1.1 vs. 1.3 mm, p=0.046) and a larger percent wall volume (median: 74% vs. 70%, p=0.018) than the U.S. group. After adjusting for confounding factors, carotid plaques in the Chinese population were more likely to have more lipid pools (&#x3b2;=10.0%, 95%CI: 4.9 to 15.9%), more recent intraplaque hemorrhage (IPH; &#x3b2;=8.4%, 95%CI: 4.5 to 12.7%), and less late IPH (&#x3b2;=-8.2%, 95%CI: -11.3 to -5.4), and fewer fibrous cap disruptions (45% vs. 67%, p=0.061). Chinese plaques were more homogeneous and had a higher percentage of plaques with features of xanthomas than did U.S. plaques (20% vs 2.7%, p<0.001).<br><br>CONCLUSIONS: The histology of Chinese plaques differs significantly from that of U.S. plaques, suggesting substantial differences in the pathophysiology of atherosclerotic cerebrovascular disease between Chinese and North American populations, which could enhance the gap in racial pathology comparison, indicating a need for a different management approach.}, }
@article {pmid40711480, year = {2025}, author = {Wesolowski, R and Rugo, HS and Specht, JM and Han, HS and Kabos, P and Vaishampayan, U and Wander, SA and Gogineni, K and Spira, A and Schott, AF and Abu-Khalaf, M and Mutka, SC and Suzuki, S and Sullivan, B and Gorbatchevsky, I and Layman, RM}, title = {Gedatolisib Combined with Palbociclib and Letrozole in Patients with No Prior Systemic Therapy for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {19}, pages = {4040-4048}, pmid = {40711480}, issn = {1557-3265}, mesh = {Humans ; Female ; *Breast Neoplasms/drug therapy/pathology/genetics/metabolism/mortality ; Letrozole/administration &amp; dosage ; Pyridines/administration &amp; dosage/adverse effects ; Piperazines/administration &amp; dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects/administration &amp; dosage ; Erb-b2 Receptor Tyrosine Kinases/metabolism/genetics ; Middle Aged ; Receptors, Estrogen/metabolism ; Aged ; Receptors, Progesterone/metabolism ; Adult ; Aged, 80 and over ; Class I Phosphatidylinositol 3-Kinases/genetics ; }, abstract = {PURPOSE: Nonclinical evidence demonstrating that estrogen receptor, cyclin-dependent kinases 4 and 6 (CDK4/6), and PI3K/AKT/mTOR (PAM) pathways cross-promote tumor proliferation in hormone receptor-positive (HR+)/HER2- breast cancer cell lines led to the development of CDK4/6 inhibitors and agents inhibiting single PAM pathway nodes to treat HR+/HER2- advanced breast cancer. Simultaneous blockade of the estrogen receptor, CDK4/6, and PAM pathways may optimize antitumor control in the treatment-naïve advanced breast cancer setting. Gedatolisib, a pan-PI3K/mTOR inhibitor, was evaluated as first-line therapy, combined with standard-of-care palbociclib and letrozole, for patients with HR+/HER2- advanced breast cancer.<br><br>PATIENTS AND METHODS: Treatment-na&#xef;ve patients from a phase Ib study with HR+/HER2- advanced breast cancer treated with gedatolisib plus palbociclib and letrozole were analyzed. The primary endpoint of the overall study was investigator-assessed objective response. Secondary endpoints included safety, duration of response, progression-free survival (PFS), and overall survival.<br><br>RESULTS: Of 41 patients, all had stage IV disease, 93% had measurable disease, 78% had visceral metastases, and 22% had detectable PIK3CA mutations. The objective response rate was 79% in patients with evaluable disease (N = 33). The median duration of response was 48 months for confirmed responders. The median PFS was 48.4 months, and the median overall survival was 77.3 months. The overall response rate and PFS were comparable in patients with and without PIK3CA mutations. Fewer than 10% discontinued treatment due to treatment-related adverse events. The most frequent grade 3/4 adverse events were neutropenia (61%), rash (39%), and oral stomatitis (29%).<br><br>CONCLUSIONS: Gedatolisib plus palbociclib and letrozole demonstrated preliminary efficacy in patients with no prior systemic therapy for advanced breast cancer. These results warrant further evaluation of gedatolisib added to standard-of-care, first-line therapy for HR+/HER2- advanced breast cancer.}, }
@article {pmid40712781, year = {2025}, author = {Espinoza-Gutarra, MR and Collins, J and Kennedy, V and Randall, J and Su, CT and Banerjee, R and Wuliji, N and Odstricil-Bobillo, S and Amonoo, HL and Wood, WA and Hamilton, B and Sung, A and Lee, CJ}, title = {Assessing Social Determinants of Health in Transplantation and CAR-T Recipients: Expert Panel Recommendations from the Survivorship Special Interest Group of ASTCT.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {12}, pages = {959-972}, pmid = {40712781}, issn = {2666-6367}, support = {K12 TR004930/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *Social Determinants of Health ; *Hematopoietic Stem Cell Transplantation ; *Immunotherapy, Adoptive/methods ; Survivorship ; *Receptors, Chimeric Antigen ; }, abstract = {Social determinants of health (SDOH) are an increasingly recognized prognostic factor in patients undergoing hematopoietic cell transplantation (HCT) and chimeric antigen receptor-T cell (CAR-T) therapy. However, awareness among providers of their importance and appropriate evaluation of SDOH factors in transplant candidates is insufficient in standard clinical practice and in research. As part of a coordinated effort by 3 American Society for Transplantation and Cellular Therapy (ASTCT) Special Interest Groups, we have developed a general overview of SDOH in transplantation and cellular therapy (TCT) along with suggested best practices. We strongly encourage the assessment of SDOH pre-TCT by a trained member of the team as well as the development of a communication plan tailored to an individual patient's background. Other recommendations include the development and validation of longitudinal instruments for SDOH evaluation in patients undergoing TCT, with emphasis on those that use primary sources of information, the inclusion of SDOH in outcome and mortality benchmarks established by regulatory bodies, and the development of intervention strategies in the context of clinical trials.}, }
@article {pmid40713377, year = {2025}, author = {Safyan, RA and Chiorean, EG}, title = {Updates on molecular targets and clinical trials with targeted therapies for pancreatic cancer.}, journal = {Surgical oncology}, volume = {63}, number = {}, pages = {102268}, doi = {10.1016/j.suronc.2025.102268}, pmid = {40713377}, issn = {1879-3320}, mesh = {Humans ; *Pancreatic Neoplasms/drug therapy/genetics/pathology ; *Molecular Targeted Therapy/methods ; Clinical Trials as Topic ; Precision Medicine ; *Biomarkers, Tumor/antagonists &amp; inhibitors/genetics ; *Carcinoma, Pancreatic Ductal/drug therapy/genetics/pathology ; }, abstract = {Pancreatic ductal adenocarcinoma (PDA) is highly aggressive and has few treatment options. To personalize therapy, it is critical to delineate molecular subtypes and understand inter- and intra-tumoral heterogeneity. KRAS mutations are present in 90 % of PDA, while 10 % are KRAS wild type and are potentially targetable with epidermal growth factor receptor (EGFR) blockade. KRAS[G12C] inhibitors have shown activity in G12C mutated cancers, and novel G12D and pan-RAS inhibitors are in clinical trials. Fewer than 1 % of PDA harbor microsatellite instability high (MSI-High) status and are susceptible to immune checkpoint blockade. Albeit rare, and occurring in KRAS wild type PDAs, BRAF V600E mutations, HER2 amplification, and RET, NTRK, and NRG1 fusions are targetable with cancer agnostic FDA approved therapies. In this review, we highlight clinically relevant molecular alterations and clinical trials with focus on targeted therapies that can improve pancreatic cancer patients' outcomes through precision medicine.}, }
@article {pmid40713931, year = {2025}, author = {Akaike, T and Ch'en, PY and Hippe, DS and Gilmour, MW and Gong, E and Fu, A and Singh, N and Cahill, K and Gunnell, L and Vohra, N and Hall, E and Bhatia, S and Lipson, EJ and Blosser, CD and Nghiem, P}, title = {Merkel cell carcinoma in solid organ transplant recipients: prognosis and response to immunotherapy.}, journal = {The British journal of dermatology}, volume = {193}, number = {6}, pages = {1221-1231}, pmid = {40713931}, issn = {1365-2133}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; //Bloomberg&#x223c;Kimmel Institute for Cancer Immunotherapy/ ; //Marilyn and Michael Glosserman Fund for Basal Cell Carcinoma and Melanoma Research/ ; //Barney Family Foundation/ ; //Laverna Hahn Charitable Trust/ ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/immunology/mortality/therapy/drug therapy/pathology ; Male ; *Skin Neoplasms/immunology/mortality/therapy/drug therapy/pathology ; Female ; Middle Aged ; Aged ; *Organ Transplantation/adverse effects ; Prognosis ; Treatment Outcome ; Immunocompromised Host ; *Immune Checkpoint Inhibitors/adverse effects/therapeutic use/administration &amp; dosage ; *Transplant Recipients/statistics &amp; numerical data ; Adult ; Retrospective Studies ; Graft Rejection/epidemiology/immunology/prevention &amp; control ; B7-H1 Antigen/antagonists &amp; inhibitors/immunology ; Immunosuppressive Agents/adverse effects ; Aged, 80 and over ; *Immunotherapy/methods/adverse effects ; }, abstract = {BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with an increased risk of occurrence in immunocompromised patients, including solid organ transplant recipients (SOTRs). As the number of SOTRs rises worldwide, MCC cases in this population are also expected to increase. While anti-programmed cell death 1 ligand 1 (anti-PD-L1; also known as anti-programmed death ligand 1) immunotherapy generates durable tumour responses in ∼50% of immunocompetent (IC) patients with advanced MCC, its efficacy and safety in SOTRs remain uncertain as these patients have been excluded from most clinical trials.<br><br>OBJECTIVES: To compare baseline characteristics and outcomes among SOTRs and IC patients with MCC, and to evaluate the efficacy and toxicity of anti-PD-L1 in SOTRs.<br><br>METHODS: We queried an MCC registry from our institution (April 1988-May 2024), extracting data on demographics, anti-PD-L1 response and immunosuppression regimens, along with incidence of allograft rejection and failure, for analysis.<br><br>RESULTS: We identified 1214 patients with MCC (37 SOTRs and 1177 IC patients); 8 of 37 SOTRs received anti-PD-L1. Median time from SOT to MCC diagnosis was 10&#x2005;years (range 0.4-43). The proportion of patients with advanced MCC (&#x2265; stage III) was 76% in SOTRs compared with 51% in IC patients (P = 0.004). SOTR status was associated with worse outcomes, including higher rates of disease progression [adjusted hazard ratio (aHR) 2.3], MCC-specific mortality (aHR 3.0) and overall mortality (aHR 3.9) (all P < 0.001 for the respective comparisons). Median time to death due to MCC for SOTRs was 2.7&#x2005;years; 24% of SOTRs died within one year of diagnosis, in contrast with just 4% of IC patients. Median time to MCC progression for SOTRs was 8.6&#x2005;months vs. 12&#x2005;years for IC patients. Among SOTRs, 70% developed distant metastases within 2&#x2005;years vs. 25% of IC patients. All eight MCC SOTRs treated with anti-PD-L1 were kidney transplant recipients, with five (63%) experiencing an objective response (two complete response, three partial response). However, two patients (29%) experienced irreversible graft failure within 9 weeks.<br><br>CONCLUSIONS: SOTR status is a significant independent risk factor of a worse prognosis for MCC. This study represents the largest cohort evaluating the efficacy and safety of anti-PD-L1 in SOTRs with advanced MCC, highlighting the potential benefits in this population.}, }
@article {pmid40716572, year = {2025}, author = {Hong, L and Di Federico, A and Liu, B and Cooper, AJ and Alessi, JV and Clark, P and Rinsurongkawong, W and Young, C and Li, H and Qin, K and Aminu, M and Santo, V and Elamin, Y and Sepesi, B and Lewis, J and Gibbons, DL and Vaporciyan, AA and Lee, JJ and Le, X and Wu, J and Roy-Chowdhuri, S and Routbort, MJ and Futreal, PA and Heymach, JV and Awad, MM and Schoenfeld, AJ and Zhang, J and Ricciuti, B and Deng, L and Vokes, NI}, title = {Distinct Clinicogenomic Features and Immunotherapy Associations in Pulmonary Sarcomatoid Carcinoma: A Multicenter Retrospective Study.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {20}, number = {12}, pages = {1763-1777}, pmid = {40716572}, issn = {1556-1380}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; R01 CA262425/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; P50 CA070907/CA/NCI NIH HHS/United States ; R01 CA276178/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/genetics/pathology/drug therapy/immunology ; Retrospective Studies ; Female ; Male ; Middle Aged ; Aged ; *Immunotherapy/methods ; *Immune Checkpoint Inhibitors/therapeutic use ; *Carcinoma, Non-Small-Cell Lung/genetics/drug therapy/pathology ; Prognosis ; Adult ; Aged, 80 and over ; Survival Rate ; }, abstract = {INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare NSCLC subtype with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) and genomic features in PSC remain underexplored compared with other NSCLC subtypes.<br><br>METHODS: Patients from three institutions and the National Cancer Database (NCDB) with metastatic NSCLC treated with ICI alone or with chemotherapy were identified. Clinicogenomics and treatment outcomes were compared across PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC).<br><br>RESULTS: We analyzed 4841 patients including 165 PSC cases treated with ICI-based therapy from three institutions and 201 PSC from NCDB. In MDACC, 65 (4.3%) were PSC, 1138 (75.1%) LUAD, and 312 (20.6%) LUSC. Patients with PSC were older and more likely to present with metastatic disease. In both the MDACC and NCDB cohorts, ICIs resulted in better outcomes for patients with PSC compared with chemotherapy. In these patients, there was no difference in outcome between ICI-monotherapy and ICI-chemotherapy. Across the three institutional cohorts, 37% to 43% of patients with PSC who received ICIs were responders, compared with 26% to 29% in LUAD and 22% to 46% in LUSC (p < 0.05). Improved ICI outcomes in PSC appeared driven by high PD-L1 (&#x2265;50% in 73%-77% cases). Among patients with high PD-L1, response rates were similar across histologic subtypes. Conversely, TMB was similar in PSC compared with LUAD or LUSC and was not associated with ICI outcomes. Across cohorts, PSC tumors were enriched for TP53, NF1, NF2, and NRAS, with relative depletion of STK11 and KEAP1 compared with LUAD. Case observation revealed relatively better outcomes to ICI than targeted therapies in patients with PSC with MET exon 14 skipping or KRAS G12C.<br><br>CONCLUSION: PSC exhibits improved outcomes to ICI relative to other therapies, potentially driven by high PD-L1 expression. Genomic analysis highlights a distinct genomic landscape of PSC when compared with LUAD.}, }
@article {pmid40719521, year = {2025}, author = {Rillamas-Sun, E and Woods, NF and Pike, KC and LaCroix, AZ and Zaslavsky, O and Dobra, A and Stefanick, ML and Cochrane, BB}, title = {Latent Class Analysis of Well-Being in Older Women.}, journal = {Journal of women's health (2002)}, volume = {34}, number = {10}, pages = {1273-1281}, doi = {10.1177/15409996251363398}, pmid = {40719521}, issn = {1931-843X}, mesh = {Humans ; Female ; Aged ; *Quality of Life/psychology ; Latent Class Analysis ; *Personal Satisfaction ; *Women's Health ; Happiness ; Surveys and Questionnaires ; Aged, 80 and over ; *Health Status ; }, abstract = {Background: Previous efforts to assess well-being and health focused on individual indicators of hedonic, evaluative, or eudaemonic measures or summated scores reflecting all dimensions. The objectives of this study were to develop profiles that preserve distinct dimensions of hedonic, evaluative, and eudemonic well-being while permitting its exploration as a predictor of health endpoints. Methods: A total of 81,148 Women's Health Initiative (WHI) participants with well-being measures collected in 2011-2012 (mean age = 76.4 years) were included. Women were recruited to the WHI Clinical Trial and Observational Cohort, continued participation in WHI Extensions (2005-2010 and 2010-2015), and completed the 2011-2012 questionnaire. Classes were identified from hedonic (life enjoyment, happiness, life satisfaction, quality of life) and eudaemonic (personal growth, purpose in life, environmental mastery, self-mastery, self-control) measures using latent class analysis. Characteristics were described by classes, and associations with all-cause mortality were examined using logistic regression. Results: Four well-being classes were identified. Class 2 (17.8%) had the lowest (worst) well-being scores, and class 4 (53.9%) had the highest (best) well-being scores in all dimensions. Class 1 (6.4%) had high hedonic and moderate eudaemonic with low life enjoyment. Class 3 (21.9%) had high hedonic and moderate eudaemonic scores with low self-mastery. Women in class 4 were younger, more educated, reported higher annual incomes, least likely to smoke, and most likely to drink alcohol daily. Relative to class 4, odds ratios (95% confidence interval) of all-cause mortality were 1.33 (1.24-1.43), 1.75 (1.67-1.84), and 1.26 (1.20-1.31) for classes 1, 2, and 3, respectively, even after adjustment for demographic and behavioral confounders. Conclusion: Latent class analysis identified groups by levels of hedonic and eudaemonic indicators, preserving information about well-being dimensions while supporting interpretation of relationships with well-being important to older women and health research.}, }
@article {pmid40720905, year = {2025}, author = {Bricker, JB and Santiago-Torres, M and Mull, KE and Sullivan, BM and Mehrotra, R}, title = {Population-Level Dissemination of a Smoking Cessation Smartphone App: Quasi-Experimental Comparison of Values-Based Messages in Social Media Advertisements.}, journal = {JMIR mHealth and uHealth}, volume = {13}, number = {}, pages = {e71619}, pmid = {40720905}, issn = {2291-5222}, mesh = {Humans ; *Smoking Cessation/methods/psychology/statistics &amp; numerical data ; India ; *Social Media/statistics &amp; numerical data/instrumentation/standards ; *Advertising/methods/standards/statistics &amp; numerical data ; *Mobile Applications/standards/statistics &amp; numerical data ; Adult ; Male ; Female ; Smartphone/statistics &amp; numerical data/instrumentation ; Middle Aged ; Cost-Benefit Analysis ; }, abstract = {BACKGROUND: Cigarette smoking is prevalent in many countries worldwide, especially in low- and middle-income countries (LMICs), presenting an urgent public health challenge. Disseminating freely available smoking cessation treatments that effectively decrease cigarette smoking globally is urgently needed.<br><br>OBJECTIVE: Identify the highest impact and most cost-effective values-based social media advertisements to disseminate our smoking cessation smartphone app, "iCanQuit", among adults living in 7 major cities of India. Values represented in the advertisements included family, relationships, self-care, health, and self-control. Using a quasi-experimental design, we aimed to determine (1) which values-based advertisements had the highest smoking cessation app dissemination reach, as measured by click-through rate (CTR), app installs, and app usage metrics; and (2) which values-based message advertisements were more cost-effective as measured by cost-per-impression, cost-per-click, and cost-per-install. The study population included a selected media market of individuals living in 7 metro cities of India - Delhi, Mumbai, Kolkata, Chennai, Bengaluru, Hyderabad, and Pune - who were exposed to one of 6 social media advertisements from January 16 to May 5, 2024.<br><br>METHODS: The advertisement campaign design for each of the identified values, based on previous smoking cessation trial data, followed a collaborative iterative process. Advertisements ran sequentially for 16 weeks. Advertisement exposure and app usage data were objectively collected via Google's Display &amp; Video 360 advertisements campaign management and Firebase app development platforms. Advertisement exposure impact on app engagement was measured via several metrics, including click-through rate (CTR, ie, the likelihood of user clicks on an advertisement after seeing it), the number of app installs (ie, a user opening the app for the first time after downloading it), and the number of app sessions (ie, app usage). Cost efficiency was measured via cost per click and cost per install for each ad.<br><br>RESULTS: Overall, the CTR was 5%. The app was installed 5111 times. The average cost per click and cost per app install across all advertisements were US $ 0.006 and US $ 6.43, respectively. The advertisements with the lowest cost per install (range: US $4.83-US $5.16) and highest CTR (between 6% and 9%) focused on the values of family, health, and self-control. Advertisements focused on the values of relationships and self-care had modestly higher levels of engagement.<br><br>CONCLUSIONS: Advertisements focusing on the values of family, health, and self-control had the highest potential reach at the lowest cost. Overall, these findings provide insights into the reach and cost-effectiveness of values-based messages in social media advertisements, guiding future outreach efforts for population-level dissemination of smoking cessation apps.}, }
@article {pmid40721386, year = {2025}, author = {Ferguson-Steele, ZO and Kilgore, MR and Lam, DL}, title = {Ovarian Cancer Metastasis to the Breast: Radiologic-Pathologic Correlation.}, journal = {Journal of breast imaging}, volume = {7}, number = {4}, pages = {463-473}, doi = {10.1093/jbi/wbaf029}, pmid = {40721386}, issn = {2631-6129}, mesh = {Humans ; Female ; *Ovarian Neoplasms/pathology/diagnostic imaging ; *Breast Neoplasms/secondary/diagnostic imaging/pathology/diagnosis ; Mammography ; Diagnosis, Differential ; Ultrasonography, Mammary ; Biomarkers, Tumor/analysis ; }, abstract = {Ovarian metastasis to the breast is extremely rare. The clinical and radiologic presentation of metastasis to the breast is nonspecific and can mimic primary breast cancers. The most common mammographic findings of ovarian metastasis are superficial, circumscribed, high-density masses without architectural distortion. Compared with other malignancies that metastasize to the breast, ovarian cancer can more frequently show microcalcifications. On US, these masses can be hypoechoic or have heterogeneous echogenicity with posterior acoustic enhancement. Less commonly, ovarian metastasis can present similarly to inflammatory breast cancer, demonstrating diffuse skin thickening on mammography and US. Immunohistochemistry is useful in differentiating ovarian metastasis from primary breast lesions. Ovarian and breast markers, including Wilm's tumor, paired box 8, cancer antigen 125, GATA binding protein 3, and gross cystic disease fluid protein 15, are particularly helpful. Overall, metastatic ovarian cancer to the breast provides a diagnostic challenge requiring close radiologic and pathologic correlation to reach the correct diagnosis.}, }
@article {pmid40721534, year = {2025}, author = {Grosely, R and Alvarado, C and Ivanov, IP and Nicholson, OB and Puglisi, JD and Dever, TE and Lapointe, CP}, title = {eIF1 and eIF5 dynamically control translation start site fidelity.}, journal = {Nature structural &amp; molecular biology}, volume = {32}, number = {11}, pages = {2308-2318}, pmid = {40721534}, issn = {1545-9985}, support = {R35 GM160398/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM145306/GM/NIGMS NIH HHS/United States ; R00 GM144678/GM/NIGMS NIH HHS/United States ; K99 GM144678/GM/NIGMS NIH HHS/United States ; RF1 AG064690/AG/NIA NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Eukaryotic Initiation Factor-1/metabolism/chemistry/genetics ; *Peptide Chain Initiation, Translational ; Protein Binding ; Codon, Initiator/metabolism/genetics ; Ribosomes/metabolism ; Eukaryotic Translation Initiation Factor 5A ; *Peptide Initiation Factors/metabolism ; Protein Biosynthesis ; Neoplasm Proteins ; Nerve Tissue Proteins ; Eukaryotic Initiation Factors ; }, abstract = {Human translation initiation requires accurate recognition of translation start sites. While AUG codons are canonical start sites, non-AUG codons are also used, typically with lower efficiency. The initiator tRNA and initiation factors eIF1 and eIF5 control recognition. How they distinguish different start sites yet allow flexible recognition remains unclear. Here we used real-time single-molecule assays and an in vitro reconstituted human system to reveal how eIF1 and eIF5 direct start site selection. eIF1 binds initiation complexes in two modes: stable binding during scanning, followed by transient, concentration-dependent rebinding after start site recognition. Termination of eIF1 rebinding requires transient and concentration-dependent binding by eIF5, which allows the formation of translation competent ribosomes. Non-AUG start sites differentially stabilize eIF1 and destabilize eIF5 binding, blocking initiation at multiple points. We confirmed these opposing effects in human cells. Collectively, our findings uncover that eIF1 and eIF5 directly compete to bind initiation complexes and illuminate how their dynamic interplay tunes the fidelity of start site recognition, which has broad connections to health and disease.}, }
@article {pmid40723206, year = {2025}, author = {Gang, M and Othus, M and Olix, AC and Markey, KA and Stirewalt, DL and Connelly-Smith, LS and Lee, SJ and Milano, F and Walter, RB}, title = {CD34+ Cell Dose, Measurable Residual Disease, and Outcome After Myeloablative HLA-Matched Peripheral Blood Hematopoietic Cell Transplantation for Adults with Acute Myeloid Leukemia.}, journal = {Cancers}, volume = {17}, number = {14}, pages = {}, pmid = {40723206}, issn = {2072-6694}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; P01-CA018029//National Cancer Institute/National Institutes of Health/ ; P01-CA078902//National Cancer Institute/National Institutes of Health/ ; T32-HL007093//NIH/National Heart, Lung, and Blood Institute/ ; P30-CA015704//National Cancer Institute/National Institutes of Health/ ; }, abstract = {Background: The impact of donor graft cell composition on post-HCT outcomes in AML remains controversial. Furthermore, it is unknown whether this interacts with pre-HCT MRD status. We evaluated the impact of CD34+ and CD3+ cell doses on outcomes of myeloablative conditioning (MAC) HCT in patients with myelodysplastic neoplasm (MDS)/AML or AML with and without detectable MRD in pre-HCT bone marrow specimens. Methods: We utilized an electronic database to identify all adults ≥18 years with MDS/AML or AML who underwent MAC and received 10/10 HLA-matched sibling or unrelated donor mobilized PBSC allografts in first morphologic remission between 2006 and 2023 at the University of Washington/Fred Hutchinson Cancer Center. Results: Among 385 adults, we found a progressive decrease in relapse incidence and improved survival with increasing CD34+ doses up to a threshold of 5.61 × 10[6]/kg, above which the relapse risk no longer decreased. After multivariable adjustment, a low CD34+ dose was associated with increased risk of relapse as well as lower overall and relapse-free survival. Similar results were obtained for patients with and without pre-HCT MRD. Higher CD3+ doses were linearly associated with an increased incidence of moderate-severe chronic GVHD. Conclusions: Our data identify a non-linear relationship between CD34+ cell dose and relapse risk in AML patients undergoing myeloablative allogeneic HCT, with no apparent added benefit beyond a CD34+ dose threshold. Our findings suggest that donor graft composition impacts outcomes in adults with AML undergoing allogeneic HCT after MAC, independent of pre-HCT MRD status; however, additional studies are needed for other donor cell scenarios.}, }
@article {pmid40723216, year = {2025}, author = {Powles, T and Sridhar, SS and Bellmunt, J and Sternberg, CN and Grivas, P and Hunter, E and Salter, M and Powell, R and Dring, A and Green, J and Akoulitchev, A and Ronen, R and Dutkowski, J and Amezquita, R and Huang, CH and Fernandez, D and Nameki, R and Ching, KA and Pu, J and Saul, M and Deng, S and di Pietro, A and Davis, CB}, title = {Blood-Epigenetic Biomarker Associations with Tumor Immunophenotype in Patients with Urothelial Carcinoma from JAVELIN Bladder 100.}, journal = {Cancers}, volume = {17}, number = {14}, pages = {}, pmid = {40723216}, issn = {2072-6694}, support = {N/A//Merck (CrossRef Funder ID: 10.13039/100009945) and was previously conducted under an alliance between Merck and Pfizer./ ; }, abstract = {BACKGROUND/OBJECTIVES: Response to immune checkpoint inhibitors (ICIs) is associated with several biological pathways, including tumor immunogenicity and antitumor immunity. Identifying host factors involved in these pathways may guide personalized ICI treatment.<br><br>METHODS: We describe the application of chromatin conformation assays to blood from patients with advanced urothelial carcinoma from the phase 3 JAVELIN Bladder 100 trial (NCT02603432). This trial demonstrated a significant survival benefit with avelumab maintenance plus best supportive care (BSC) vs. BSC alone following non-progression with platinum-based chemotherapy as first-line therapy. Blood-based chromatin conformation markers (CCMs) were screened for associations with high/low immune effector gene expression in tumors and for interactions with outcomes and tumor mutation burden.<br><br>RESULTS: Candidate CCMs included genes involved in several immune response pathways, such as POU2F2, which encodes a transcription factor that regulates B-cell maturation.<br><br>CONCLUSIONS: Our findings suggest that polygenic host factors may affect response to ICIs and support further investigation of chromatin conformation assays.}, }
@article {pmid40727571, year = {2025}, author = {Vega, P and Newby, R and Bender Ignacio, RA and Fisher, CE and Oken, E and Harbell, JW and Mour, GK and Shubeilat, J and Ng, YH and Li, M and Bhattacharya, R and Bakthavatsalam, R and Sibulesky, L and Vikram, HR and Rakita, RM and Tayyar, R}, title = {Donor-Derived Tuberculosis in 3 Solid Organ Transplant Recipients From the Same Donor.}, journal = {Open forum infectious diseases}, volume = {12}, number = {7}, pages = {ofaf372}, pmid = {40727571}, issn = {2328-8957}, support = {T32 AI118690/AI/NIAID NIH HHS/United States ; }, abstract = {Donor-derived tuberculosis is a rare complication following solid organ transplantation, and tuberculosis screening is not a current transplant prerequisite for most donors. Donor-derived tuberculosis usually presents sooner than reactivation tuberculosis, and the most common finding is fever. We present 3 cases of donor-derived tuberculosis in the recipients of 2 kidneys and 1 liver from the same donor, who presented with unexplained fevers occurring 4-5 weeks after transplantation. Initial antibacterial therapy failed in all 3 patients, leading to further testing, which identified Mycobacterium tuberculosis by culture and molecular studies. All recipients successfully received tuberculosis therapy but had significant morbidity and prolonged hospital stays. Donor-derived tuberculosis should be among the differential diagnoses of unexplained fever in solid organ transplant recipients in the first few months after transplantation. Screening protocols should be implemented for donors with an epidemiologic risk of tuberculosis, with special emphasis on deceased donors.}, }
@article {pmid40728034, year = {2025}, author = {Horne, DJ and Zifodya, JS and Shapiro, AE and Church, EC and Kreniske, JS and Kay, AW and Scandrett, K and Steingart, KR and Takwoingi, Y}, title = {Xpert MTB/RIF Ultra assay for pulmonary tuberculosis and rifampicin resistance in adults and adolescents.}, journal = {The Cochrane database of systematic reviews}, volume = {7}, number = {7}, pages = {CD009593}, pmid = {40728034}, issn = {1469-493X}, support = {K01 TW011482/TW/FIC NIH HHS/United States ; T32 AI007613/AI/NIAID NIH HHS/United States ; K23 AI140918/AI/NIAID NIH HHS/United States ; TL1 TR002318/TR/NCATS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Child ; Humans ; *Antibiotics, Antitubercular/therapeutic use/pharmacology ; Bias ; *Drug Resistance, Bacterial/genetics ; *Mycobacterium tuberculosis/drug effects/genetics/isolation &amp; purification ; Randomized Controlled Trials as Topic ; *Rifampin/therapeutic use/pharmacology ; Sensitivity and Specificity ; *Tuberculosis, Pulmonary/diagnosis/drug therapy/microbiology ; }, abstract = {BACKGROUND: Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF.<br><br>OBJECTIVES: To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x-ray suggestive of tuberculosis.<br><br>SEARCH METHODS: We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov and the WHO ICTRP) to 16 October 2023 without language restrictions. A WHO Public Call for ongoing and unpublished studies was made between 30 November 2023 and 15 February 2024.<br><br>SELECTION CRITERIA: We included cross-sectional studies, cohort studies, and randomised controlled trials that provided data on the diagnostic accuracy of Xpert Ultra using respiratory specimens in adolescents (aged 10 to 14 years) and adults (aged 15 years and older) with presumptive pulmonary tuberculosis. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based phenotypic drug susceptibility testing with or without whole genome sequencing.<br><br>DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardised form. We assessed risk of bias using QUADAS-2. We performed meta-analyses using a bivariate model to produce summary sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarised Xpert Ultra trace-positive results.<br><br>MAIN RESULTS: Pulmonary tuberculosis detection For detection of pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity against culture were 90.7% (95% confidence interval (CI) 88.2 to 92.7) and 94.8% (95% CI 92.8 to 96.3) (32 studies, 12,529 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss nine cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 47. In people living with HIV, Xpert Ultra summary sensitivity and specificity were 87.7% (82.0 to 91.7) and 95.3% (92.2 to 97.2) (11 studies, 1164 participants). Amongst people with smear-negative, culture-positive pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity were 80.7% (75.4 to 85.0) and 94.0% (91.3 to 95.9) (16 studies, 6460 participants). In people with a history of tuberculosis, Xpert Ultra summary sensitivity and specificity were 84.8% (78.2 to 89.7) and 86.2% (78.9 to 91.3) (9 studies, 809 participants). The proportion of Ultra trace-positive results that were true positives compared to the microbiological reference standard was 38.8%. Reclassifying trace-positive results as Xpert Ultra-negative led to a reduction in sensitivity and modest increase in specificity. Rifampicin resistance detection For detection of rifampicin resistance, Xpert Ultra summary sensitivity and specificity were 95.8% (93.2 to 97.4) and 98.3% (97.0 to 99.0) (10 studies, 1644 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss four cases. The number of people wrongly diagnosed with rifampicin resistance would be 16 out of the 900 who do not have rifampicin resistance. Xpert Ultra performed similarly, for rifampicin resistance, in people with smear-positive and smear-negative tuberculosis.<br><br>AUTHORS' CONCLUSIONS: Xpert Ultra has high sensitivity and specificity for detection of pulmonary tuberculosis rifampicin resistance. Xpert Ultra for the detection of pulmonary tuberculosis has lower sensitivity in people with smear-negative/culture-positive tuberculosis and lower sensitivity and specificity in people with a history of tuberculosis. Xpert Ultra trace-positive results were common. Strengths of this review include the approach to identifying relevant studies, the number of studies and participants included in this systematic review, and that most studies were at low risk of bias. The small number of studies (six) and participants who were adolescents is a limitation to our accuracy estimates in this age group. Xpert Ultra testing provides accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multiple-drug-resistant tuberculosis.<br><br>FUNDING: The WHO supported this systematic review. Liverpool School of Tropical Medicine hosted the Cochrane Infectious Diseases Group (CIDG) editorial base, which supported the authors in the development of this review update. The Foreign, Commonwealth and Development Office funded the CIDG.<br><br>REGISTRATION: Generic protocol available on Open Science Framework via https://osf.io/26wg7/wiki/home/. Previous protocol and review versions available via DOI 10.1002/14651858.CD009593 and DOI 10.1002/14651858.CD009593.pub5.}, }
@article {pmid40728846, year = {2025}, author = {Kamp, KJ and Hendrickson, K and Iqbal, A and Saad, K and Clark-Snustad, K and Dey, N and Gui, X and Lee, S}, title = {Correlation of Fecal, Plasma, Serum, and Salivary Calprotectin to Endoscopic and Histologic Outcomes in Patients With Crohn's Disease: A Pilot Study.}, journal = {Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates}, volume = {48}, number = {4}, pages = {265-270}, pmid = {40728846}, issn = {1538-9766}, support = {K23 NR020044/NR/NINR NIH HHS/United States ; P30 NR016585/NR/NINR NIH HHS/United States ; }, mesh = {Humans ; *Leukocyte L1 Antigen Complex/analysis/blood/metabolism ; *Crohn Disease/pathology/metabolism/diagnosis/blood ; Pilot Projects ; *Feces/chemistry ; Female ; Male ; Adult ; *Saliva/chemistry ; Biomarkers/analysis/blood ; Colonoscopy ; Middle Aged ; Severity of Illness Index ; Young Adult ; }, abstract = {Easily obtained, noninvasive biomarkers are needed for Crohn's disease monitoring. This pilot study compared associations between calprotectin levels in stool, saliva, and blood to assess their correlation with endoscopic and histologic outcomes among patients with Crohn's disease. Participants recruited from an Inflammatory Bowel Disease center provided stool, blood, and saliva samples prior to undergoing scheduled colonoscopy (n = 17). We collected participant demographics and clinical disease activity. Endoscopic disease was assessed with the Simple Endoscopic Score. Histologic disease was assessed with the Robarts Histological Index. The mean age of the sample was 32.3 (SD 7.5) years. Correlations with endoscopic disease activity were 0.83 for fecal calprotectin, 0.26 for plasma calprotectin, 0.24 for serum calprotectin, and 0.02 for salivary calprotectin. Correlations with histologic disease activity were 0.80 for fecal calprotectin, 0.55 for plasma calprotectin, 0.15 for serum calprotectin, and -0.03 for salivary calprotectin. Fecal calprotectin had the strongest correlations with endoscopic and histologic disease outcomes, but fecal calprotectin levels were lower among those with ileal disease. For blood-based calprotectin, plasma calprotectin had a higher correlation with histology than serum, and plasma calprotectin levels were higher among those with ileal disease.}, }
@article {pmid40729699, year = {2025}, author = {Shadman, M and Davids, MS}, title = {How I treat patients with CLL after prior treatment with a covalent BTK inhibitor and a BCL-2 inhibitor.}, journal = {Blood}, volume = {146}, number = {17}, pages = {2029-2036}, doi = {10.1182/blood.2024025482}, pmid = {40729699}, issn = {1528-0020}, mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/therapy ; *Agammaglobulinaemia Tyrosine Kinase/antagonists &amp; inhibitors ; *Proto-Oncogene Proteins c-bcl-2/antagonists &amp; inhibitors ; *Protein Kinase Inhibitors/therapeutic use ; Male ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use ; Female ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Sulfonamides ; }, abstract = {The treatment landscape for chronic lymphocytic leukemia (CLL) has been transformed by the advent of covalent Bruton tyrosine kinase (BTK) inhibitors (cBTKis) and B-cell lymphoma 2 (BCL-2) inhibitors, leading to markedly improved outcomes and, for many, near-normal life expectancy. However, patients progressing after both classes of therapy (double-refractory) have limited options and poor prognoses. This review outlines a practical approach to managing double-exposed or double-refractory CLL, incorporating clinical cases, trial data, and expert perspectives. For cBTKi intolerance, second-generation agents may remain effective. Venetoclax retreatment is reasonable after prior fixed-duration use. In true double-refractory disease, noncovalent BTK inhibitors (eg, pirtobrutinib) and CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy (lisocabtagene maraleucel) are standard-of-care options. Pirtobrutinib induces rapid responses, though often of limited duration, underscoring the need for early consolidation planning with CAR-T or allogeneic stem cell transplant. Persistent disease after CAR-T therapy warrants close monitoring and timely transplant referral in eligible patients. Phosphoinositide 3-kinase inhibitors remain available but are limited by toxicity and modest benefit. Emerging agents, including BTK degraders, bispecific antibodies, and novel cellular therapies, offer promising future directions. Optimizing outcomes in double-refractory CLL requires an individualized, nuanced strategy integrating available treatments with innovative approaches under investigation.}, }
@article {pmid40729824, year = {2025}, author = {Yoshida, Y and Nguyen, NQ and Moon, EH and Rebholz, C and Skali, H and Arthur, V and Echouffo-Tcheugui, JB and Ballantyne, C and Selvin, E and Shah, A and Kaplan, R and Rodriguez, CJ and Qi, Q and Cheng, S and Yu, B}, title = {A Metabolomics Study of Cardiac Dysfunction in Hyperglycemia: Findings From the Atherosclerosis Risk in Communities (ARIC) Study and the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Diabetes care}, volume = {48}, number = {9}, pages = {1589-1597}, pmid = {40729824}, issn = {1935-5548}, support = {N01 HC065236/HL/NHLBI NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; U54 GM104940/GM/NIGMS NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; R01 HL168683/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; R01 HL141824/HL/NHLBI NIH HHS/United States ; R01HL141824/HL/NHLBI NIH HHS/United States ; R01HL168683/HL/NHLBI NIH HHS/United States ; 7-23-JDFWH-10//American Diabetes Association/ ; 1P20GM152305/GM/NIGMS NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; P20 GM152305/GM/NIGMS NIH HHS/United States ; R01 HL104199/HL/NHLBI NIH HHS/United States ; N01 HC065233/HL/NHLBI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Atherosclerosis/metabolism ; Cross-Sectional Studies ; Heart Failure/metabolism ; Hispanic or Latino ; *Hyperglycemia/metabolism/physiopathology ; *Metabolomics ; Prospective Studies ; }, abstract = {OBJECTIVE: Hyperglycemic states (prediabetes and diabetes) are associated with heart failure (HF) risk. We aimed to identify distinct metabolites for subclinical cardiac dysfunction, a precursor of HF, in hyperglycemic or euglycemic individuals.<br><br>RESEARCH DESIGN AND METHODS: We conducted cross-sectional and prospective analyses of 2,492 HF-free participants from the Atherosclerosis Risk in Communities (ARIC) study visit 5, 2011-2013. A total of 1,297 participants were hyperglycemic (assessed on the basis of hemoglobin A1c >5.7%, fasting glucose >100 mg/dL, use of diabetes medication, or diagnosis), and 1,195 were euglycemic. We used logistic regression for analysis of association between 790 metabolites and cardiac dysfunction, defined according to echocardiographic abnormalities (left ventricular hypertrophy, systolic or diastolic dysfunction) or elevated NT-proBNP or troponin T, in two glycemic groups separately. We used Cox regression for prospective association between cardiac dysfunction-related metabolites identified in the prior step and HF risk, adjusting for clinical risk factors. Analyses were replicated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n = 5,167).<br><br>RESULTS: Microvascular disease-related metabolites (e.g., pseudouridine, N6-carbamoylthreonyladenosine, N6-acetyllysine, N2,N5-diacetylornithine) were associated with cardiac dysfunction in hyperglycemic individuals. Carbohydrate and cofactor-derived metabolites (e.g., gulonate, erythrocyte) were associated with cardiac dysfunction in euglycemic individuals. These cardiac dysfunction-related metabolites were prospectively associated with HF risk in the two glycemic groups (follow-up 7.5 years, 137 and 94 HF cases, per-SD increase hazard ratios range 1-1.9 and 1.1-2.9), respectively. HCHS/SOL results were consistent with those from ARIC.<br><br>CONCLUSIONS: Metabolites known for microvascular complications were associated with cardiac dysfunction in hyperglycemic individuals but not among their euglycemic counterparts, supporting the premise that microvascular dysfunction contributes to HF pathogenesis in diabetes.}, }
@article {pmid40730678, year = {2025}, author = {Hagan, CE and Sheehan, VM and Rezanka, CM and Li, MA and Martínez-Escardó, L and Campbell, KJ and Snyder, AG and Headley, M and Oberst, A}, title = {Apoptotic cells promote circulating tumor cell survival and metastasis.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1121}, pmid = {40730678}, issn = {2399-3642}, support = {S10 OD024979/OD/NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; U01 CA289564/CA/NCI NIH HHS/United States ; U01CA289564//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; T32GM007270//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; }, mesh = {*Neoplastic Cells, Circulating/pathology/metabolism ; *Apoptosis ; Humans ; Animals ; Cell Survival ; Mice ; Cell Line, Tumor ; *Lung Neoplasms/secondary ; Neoplasm Metastasis ; Female ; Thromboplastin/metabolism ; Phosphatidylserines/metabolism ; Blood Coagulation ; }, abstract = {During tumor progression and especially following cytotoxic therapy, cell death of both tumor and stromal cells is widespread. Despite clinical observations that high levels of apoptotic cells correlate with poorer patient outcomes, the physiological effects of dying cells on tumor progression remain incompletely understood. Here, we report that circulating apoptotic cells robustly enhance tumor cell metastasis to the lungs. Using intravenous metastasis models, we observed that the presence of apoptotic cells, but not cells dying by other mechanisms, supports circulating tumor cell (CTC) survival following arrest in the lung vasculature. Apoptotic cells promote CTC survival by recruiting platelets to the forming metastatic niche. Apoptotic cells externalize the phospholipid phosphatidylserine to the outer leaflet of the plasma membrane, which we found increased the activity of the coagulation initiator Tissue Factor, thereby triggering the formation of platelet clots that protect proximal CTCs. Inhibiting the ability of apoptotic cells to induce coagulation by knocking out Tissue Factor, blocking phosphatidylserine, or administering the anticoagulant heparin abrogated the pro-metastatic effect of apoptotic cells. This work demonstrates a previously unappreciated role for apoptotic cells in facilitating metastasis by establishing CTC-supportive emboli, and suggests points of intervention that may reduce the pro-metastatic effect of apoptotic cells.}, }
@article {pmid40730747, year = {2025}, author = {Marchi, F and Shastri, VM and Marrero, RJ and Nguyen, NHK and Öttl, A and Schade, AK and Landwehr, M and Krali, O and Nordlund, J and Ghavami, M and Sckaff, F and Mansinghka, VK and Cao, X and Slayton, W and Starostik, P and Cogle, CR and Ribeiro, RC and Rubnitz, JE and Klco, J and Elsayed, A and Gamis, AS and Triche, TJ and Ries, R and Kolb, EA and Aplenc, R and Alonzo, T and Pounds, S and Meshinchi, S and Lamba, JK}, title = {Epigenomic diagnosis and prognosis of Acute Myeloid Leukemia.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {6961}, pmid = {40730747}, issn = {2041-1723}, support = {R01 CA270120/CA/NCI NIH HHS/United States ; R01 CA132946/CA/NCI NIH HHS/United States ; R01CA270120//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; U10 CA098413/CA/NCI NIH HHS/United States ; SAP 21-061-01//American Cancer Society (American Cancer Society, Inc.)/ ; U10 CA098543/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; P30 CA247796/CA/NCI NIH HHS/United States ; R01CA132946//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; *Leukemia, Myeloid, Acute/genetics/diagnosis/mortality ; Prognosis ; DNA Methylation/genetics ; *Epigenomics/methods ; Adult ; Child ; Female ; Male ; Adolescent ; Machine Learning ; CpG Islands/genetics ; Middle Aged ; Child, Preschool ; Young Adult ; Epigenesis, Genetic ; Cohort Studies ; }, abstract = {Despite the critical role of DNA methylation, clinical implementations harnessing its promise have not been described in acute myeloid leukemia. Utilizing DNA methylation from 3314 leukemia patient samples across 11 harmonized cohorts, we describe the Acute Leukemia Methylome Atlas, which includes robust models capable of accurately predicting AML subtypes. A genome-wide prognostic model as well as a targeted panel of 38 CpGs significantly predict five-year survival in our pediatric and adult test cohorts. To accelerate rapid clinical utility, we develop a specimen-to-result protocol that uses long-read nanopore sequencing and machine learning to characterize patients' whole genomes and epigenomes. Clinical validation on patient samples confirms high concordance between epigenomic signatures and genomic lesions, though uniquely rare karyotypes remained challenging due to limited available training data. These results unveil the potential for increased affordability, speed, and accuracy for patients in need of complex molecular diagnosis and prognosis.}, }
@article {pmid40730902, year = {2025}, author = {Devi, KSP and Wang, E and Jaiswal, A and Konieczny, P and Kim, TG and Nirschl, CJ and Verma, A and Liu, Y and Milczanowski, J and Christo, SN and Gandolfo, LC and Haitz, K and Vardam, TD and Wu, P and King, SL and Tse, SW and Pradhan, K and Jiang, X and Tian, T and Fuhlbrigge, RC and Schmults, CD and Clark, RA and Kupper, TS and Freeman, GJ and Mackay, LK and Naik, S and Newell, EW and Elemento, O and Suarez-Farinas, M and Anandasabapathy, N}, title = {PD-1 is requisite for skin TRM cell formation and specification by TGFβ.}, journal = {Nature immunology}, volume = {26}, number = {8}, pages = {1339-1351}, pmid = {40730902}, issn = {1529-2916}, support = {R01 AI097128/AI/NIAID NIH HHS/United States ; R01 AI168462/AI/NIAID NIH HHS/United States ; DP2 AR079173/AR/NIAMS NIH HHS/United States ; K99 AR083536/AR/NIAMS NIH HHS/United States ; R01 CA203721/CA/NCI NIH HHS/United States ; R01 AR063962/AR/NIAMS NIH HHS/United States ; R01 AI041707/AI/NIAID NIH HHS/United States ; K22 AI135099/AI/NIAID NIH HHS/United States ; P01 AI056299/AI/NIAID NIH HHS/United States ; T32 AR007098/AR/NIAMS NIH HHS/United States ; R01 AR080436/AR/NIAMS NIH HHS/United States ; R01 AR083208/AR/NIAMS NIH HHS/United States ; }, mesh = {*Programmed Cell Death 1 Receptor/metabolism/immunology/genetics ; Animals ; *Transforming Growth Factor beta/metabolism/immunology ; *Skin/immunology/cytology ; Mice ; Humans ; *Immunologic Memory ; *CD8-Positive T-Lymphocytes/immunology ; Mice, Inbred C57BL ; Signal Transduction/immunology ; *Memory T Cells/immunology ; Mice, Knockout ; Cell Differentiation/immunology ; Female ; }, abstract = {Tissue-resident memory T (TRM) cells provide infectious, cancer and vaccine-trained immunity across barrier sites. TRM cells are implicated in autoimmunity, successful response to immune checkpoint blockade in the tumor microenvironment and toxicities that occur after immune checkpoint blockade in peripheral tissues. Here, we identified that signaling through the immune checkpoint programmed death receptor 1 (PD-1) strongly impacts the early specification of CD8[+] TRM cells in the skin. PD-1 is expressed broadly across mouse and human skin TRM cells, in the absence of persistent infection, and is retained on skin TRM cells in aged mice. PD-1 supports early TRM cell colonization, skin-specific programming and silencing of other differentiation programs and promotes TGFβ responsivity and skin engraftment. Thus, PD-1 signaling mediates skin TRM cell specification during immune initiation. These findings may inform therapeutic PD-1 agonist and antagonist use to modulate successful peripheral memory.}, }
@article {pmid40730903, year = {2025}, author = {Peters, Q and Prlic, M}, title = {Six degrees of TGFβ.}, journal = {Nature immunology}, volume = {26}, number = {8}, pages = {1221-1222}, pmid = {40730903}, issn = {1529-2916}, }
@article {pmid40735070, year = {2025}, author = {Sarfraz, Z and Maharaj, A and Venur, VA and Lathia, JD and Odia, Y and Ahluwalia, MS}, title = {Immunotherapy in Glioblastoma: An Overview of Current Status.}, journal = {Clinical pharmacology : advances and applications}, volume = {17}, number = {}, pages = {185-209}, pmid = {40735070}, issn = {1179-1438}, abstract = {Glioblastoma (GB) is an aggressive brain tumor with standard therapies offering limited but measurable survival benefit. Immunotherapy is expanding the treatment landscape for GB. Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have shown benefit in several cancers and are being studied in GB, with ongoing efforts to address the tumor's immunosuppressive environment. Chimeric Antigen Receptor (CAR) T-cell therapies are also being explored, with new approaches designed to overcome antigen variability and improve access across the blood-brain barrier. Cancer vaccines, especially dendritic cell-based platforms like DCVax-L, have shown promising survival outcomes in clinical trials. Advances in biomarker analysis and genomics are supporting more personalized immunotherapy approaches. In addition, combination strategies involving ICIs, CAR T-cells, vaccines, and oncolytic viruses are being developed to enhance immune response. This review outlines current immunotherapy approaches in GB, focusing on their mechanisms, clinical development, and future directions.}, }
@article {pmid40736255, year = {2025}, author = {Andrews, A and Harrar, DB and Zelleke, T and Zhang, J and Zhang, B and Barber, J and Dasan, R and Amoah, N and Findorff, O and Krieger, S and Barrett, E and O'Brien, N and Fuller, CE and Moxon, CA and Taylor, TE and Griffiths, MJ and Ray, STJ and Postels, DG}, title = {Electroencephalogram Features Distinguish Cases of Cerebral Malaria Among Malawian Children With Fever and Coma.}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, volume = {81}, number = {4}, pages = {766-775}, pmid = {40736255}, issn = {1537-6591}, support = {R03 NS124536/NS/NINDS NIH HHS/United States ; R03NS124536//US National Institutes of Health/ ; }, mesh = {Humans ; *Malaria, Cerebral/diagnosis/complications ; *Electroencephalography/methods ; Malawi ; *Coma/etiology/diagnosis ; Male ; Female ; Retrospective Studies ; Case-Control Studies ; Child, Preschool ; *Fever/etiology/diagnosis ; Infant ; Child ; ROC Curve ; Diagnosis, Differential ; Machine Learning ; }, abstract = {BACKGROUND: In febrile comatose patients living in malaria-endemic areas, overlapping symptoms and limited laboratory capacity make it difficult to distinguish parasitic, bacterial, and viral central nervous system infections. We evaluated electroencephalography (EEG) as a biomarker to differentiate the microbiologic etiology of pediatric febrile coma at a major referral center in Malawi.<br><br>METHODS: This was a retrospective case-control study comparing EEG recordings of Malawian children with cerebral malaria to those with febrile coma of nonmalarial cause (bacterial meningitis, viral encephalitis, or unknown cause). Participants were admitted to Queen Elizabeth Central Hospital (Blantyre, Malawi) between 2013 and 2021. Inclusion criteria were fever, coma (Blantyre Coma Score &#x2264;2), and coma etiology (malarial or nonmalarial) defined by laboratory testing. Four supervised machine learning algorithms were used to train a balanced ensemble classifier, SuperLearner, generating test characteristics of the diagnostic ability of EEG features.<br><br>RESULTS: Two hundred three children with cerebral malaria and 87 children with nonmalarial coma were included. Univariate analysis of qualitative (visual) EEG interpretations revealed higher voltage, slower background frequency, more sleep elements, less variability, more abnormal organization, and less continuity in cerebral malaria. Quantitative waveform analysis showed greater power in cerebral malaria. Both quantitative and qualitative EEG interpretation distinguished coma etiology (area under the receiver operating characteristic curve [AUROC] = 0.85 and 0.86, respectively). Combining qualitative and quantitative interpretation methods, the test characteristic improved (AUROC = 0.90).<br><br>CONCLUSIONS: EEG features distinguish malarial from nonmalarial coma in febrile Malawian children. This technology may aid in distinguishing the microbiologic etiology of febrile coma in malaria-endemic areas.}, }
@article {pmid40736449, year = {2025}, author = {Brenner, AT and Odebunmi, OO and Waters, AR and Wangen, M and Marciniak, MW and Ferrari, RM and Wheeler, SB and Shah, PD}, title = {It Is a Good Idea, but Are They Willing? Assessing Pharmacist Willingness to Deliver Colorectal Cancer Screening.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {10}, pages = {1820-1827}, pmid = {40736449}, issn = {1538-7755}, support = {T32 CA116339/CA/NCI NIH HHS/United States ; U48 DP006400/DP/NCCDPHP CDC HHS/United States ; U48DP006400//Centers for Disease Control and Prevention (CDC)/ ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis ; *Pharmacists/psychology/statistics &amp; numerical data ; Male ; Female ; *Early Detection of Cancer/methods ; Middle Aged ; Surveys and Questionnaires ; Aged ; Adult ; *Community Pharmacy Services ; *Attitude of Health Personnel ; }, abstract = {BACKGROUND: Accessibility, expanding scope of practice, and a rapidly changing policy landscape make US community pharmacies a promising delivery setting for colorectal cancer screening. It is not clear, however, whether community pharmacists are willing to incorporate colorectal cancer screening into their pharmacy practice, what potential drivers of willingness are, and, if unwilling, under what conditions pharmacists would be willing to provide PharmFIT.<br><br>METHODS: From September 2022 to January 2023, we surveyed 578 currently practicing community pharmacists. We assessed willingness to provide a pharmacy-based colorectal cancer screening program (PharmFIT). We used multiple linear regression to identify correlates of perceived implementation complexity and multiple logistic regression to explore overall willingness to implement PharmFIT.<br><br>RESULTS: Most pharmacists (80%) were willing to implement PharmFIT. The most common reasons for unwillingness were that results needed to be reported to the patients' primary care providers (52%), that appropriate training in delivering colorectal cancer screening be provided (48%), and that care coordination with primary care providers be clear (46%). Perceived complexity of the intervention decreased as years in practice increased [&#x3b2; = 0.013; 95% confidence interval (CI), 0.01-0.02] and as the level of knowledge about colorectal cancer screening increased (&#x3b2; = 0.085; 95% CI, 0.01-0.16). Respondents' willingness to implement PharmFIT increased as perceived complexity decreased (OR = 5.68; 95% CI, 3.96-8.15).<br><br>CONCLUSIONS: Most community pharmacists in the United States would be willing to integrate PharmFIT into their current workflows. Training in how to deliver fecal immunochemical testing and preparation for the coordination of test results and follow-up care should be completed prior to implementing PharmFIT.<br><br>IMPACT: Community pharmacies are a viable venue for delivering colorectal cancer screening.}, }
@article {pmid40737329, year = {2025}, author = {Yeh, KB and Bahnfleth, WP and Bradford, E and Cardona, C and Coleman, KK and Hudson, PJ and Dadonaite, B and Hutchins, RJ and Maresso, A and MacIntyre, CR and Scotch, M}, title = {Three things we can do now to reduce the risk of avian influenza spillovers.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {31}, pages = {e2503565122}, pmid = {40737329}, issn = {1091-6490}, support = {89233218CNA000001//DOE | NNSA | Los Alamos National Laboratory (LANL)/ ; }, }
@article {pmid40737434, year = {2025}, author = {Parks, KR and Moodie, Z and Allen, MA and Yen, C and Furch, BD and MacPhee, KJ and Ozorowski, G and Heptinstall, J and Hahn, WO and Zheng, Z and Lu, H and Grant, S and Domin, E and Duff, MO and Seese, A and Marini-Macouzet, C and Ballweber-Fleming, L and Lee, WH and Cottrell, CA and Liguori, A and Georgeson, E and Alavi, N and Kubitz, M and Phelps, N and Seaton, KE and Cohen, KW and Anderson, MA and Mondal, K and Laufer, DS and Kublin, JG and Ward, AB and Hyrien, O and De Rosa, SC and Himansu, S and Leav, B and Reuter, C and Tomaras, GD and Montefiori, D and Walsh, SR and Frank, I and Sobieszczyk, ME and Goepfert, PA and Stephenson, KE and Baden, LR and Van Tieu, H and Keefer, MC and Clark, J and Riddler, SA and Schief, WR and McElrath, MJ}, title = {Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers elicited tier 2 neutralizing antibodies in a phase 1 clinical trial.}, journal = {Science translational medicine}, volume = {17}, number = {809}, pages = {eady6831}, pmid = {40737434}, issn = {1946-6242}, support = {UM1 AI069494/AI/NIAID NIH HHS/United States ; UL1 TR001857/TR/NCATS NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI144462/AI/NIAID NIH HHS/United States ; INV-007522/GATES/Gates Foundation/United States ; P30 AI045008/AI/NIAID NIH HHS/United States ; INV-008813/GATES/Gates Foundation/United States ; P30 AI036214/AI/NIAID NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Neutralizing/immunology/blood ; *AIDS Vaccines/immunology/adverse effects ; *RNA, Messenger/genetics ; *Vaccination ; *env Gene Products, Human Immunodeficiency Virus/immunology ; Female ; Male ; Adult ; *HIV Antibodies/immunology ; HIV Infections/immunology/prevention &amp; control ; HIV-1/immunology ; *Protein Multimerization ; Middle Aged ; }, abstract = {mRNA technology might accelerate development of an urgently needed preventive human immunodeficiency virus (HIV) vaccine. We evaluated the safety and immunogenicity of three mRNA-encoded envelope trimers, including two doses of soluble and membrane-anchored forms, in a randomized, open-label, phase 1 clinical trial. Vaccines were generally well tolerated, although 6.5% (7 of 108) of participants developed urticaria, a higher proportion than seen with other mRNA vaccines. mRNA-encoded trimers induced strong envelope-specific B and T cell responses. Immunization with membrane-anchored trimers, intended to obscure epitopes at the trimer base targeted by nonneutralizing antibodies, reduced the frequency of base-binding serum antibodies in comparison with soluble trimers. Three immunizations elicited autologous tier 2 serum neutralizing antibodies in 80% of vaccinees receiving the membrane-anchored trimers, in contrast to only 4% receiving the soluble trimer. Thus, with demonstration of more favorable safety, mRNA-encoded membrane-anchored HIV envelope trimers represent a promising platform for HIV vaccine clinical development.}, }
@article {pmid40737504, year = {2026}, author = {Nascimento de Lima, P and Bartholomew, L and May, FP and Coronado, GD and Rutter, CM}, title = {The triple effect of colorectal cancer screening: reducing deaths, government spending, and mortality disparities.}, journal = {Journal of the National Cancer Institute}, volume = {118}, number = {2}, pages = {360-363}, pmid = {40737504}, issn = {1460-2105}, support = {R01 MD017599/MD/NIMHD NIH HHS/United States ; /CA/NCI NIH HHS/United States ; U01-CA253913/MD/NIMHD NIH HHS/United States ; //Cancer Intervention and Surveillance Modeling Network/ ; R01-MD017599/MD/NIMHD NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/mortality/diagnosis/economics/prevention &amp; control/ethnology/epidemiology ; *Early Detection of Cancer/economics/methods ; United States/epidemiology ; *Colonoscopy/economics ; *Black or African American/statistics &amp; numerical data ; Occult Blood ; Cost-Benefit Analysis ; *Healthcare Disparities/economics ; Female ; Male ; *Mass Screening/economics/methods ; Aged ; Middle Aged ; Medicare/economics ; Incidence ; White People/statistics &amp; numerical data ; White ; }, abstract = {Colorectal cancer (CRC) screening accounts for over 60% of cancer screening costs in the United States, prompting recurrent debates about its value. Yet CRC screening remains the main tool to curb overall CRC incidence, mortality, and disparities that affect Black Americans. Using the race-specific CRC-SPIN microsimulation model, we show that CRC screening in the United States simultaneously achieves three goals: it saves lives by preventing 24 deaths per 1000 Black Americans screened with the fecal immunochemical test (FIT) and 26 screened with colonoscopy; saves tax dollars by shifting costs from Medicare to private payers; and reduces racial incidence and mortality disparities, helping offset disparities in CRC survival. Both FIT and colonoscopy screening are cost-effective relative to no screening, with annual FIT remaining the most cost-effective option. Changes to policy requiring coverage of preventive care services must avoid compromising the effectiveness of CRC screening-arguably the greatest equalizer of cancer disparities.}, }
@article {pmid40737539, year = {2025}, author = {Rangarajan, HG and Satwani, P and Herr, MM and Chen, M and Martens, MJ and Wudhikarn, K and John, S and Fabrizio, VA and Hsieh, EM and Kelkar, AH and Doherty, E and Marks, DI and Ringden, O and Friend, B and Kelly, MS and Farhadfar, N and Prestidge, T and Hossain, NM and Liu, H and Hashmi, S and Modi, D and Winestone, LE and El Boghdadly, Z and Murthy, HS and Perales, MA and Chemaly, RF and Dandoy, CE and Hill, JA and Huppler, A and Riches, M and Auletta, JJ}, title = {Real-world outcomes of infections following tisagenlecleucel in patients with B-cell ALL: a CIBMTR analysis.}, journal = {Blood advances}, volume = {9}, number = {21}, pages = {5489-5500}, pmid = {40737539}, issn = {2473-9537}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; R01 CA231838/CA/NCI NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; R21 AG077024/AG/NIA NIH HHS/United States ; U24 HL157560/HL/NHLBI NIH HHS/United States ; U01 AI069197/AI/NIAID NIH HHS/United States ; R01 HL155741/HL/NHLBI NIH HHS/United States ; C0000008/CL/CLC NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA100019/CA/NCI NIH HHS/United States ; R01 AI150999/AI/NIAID NIH HHS/United States ; R01 CA218285/CA/NCI NIH HHS/United States ; R01 HL171117/HL/NHLBI NIH HHS/United States ; R01 CA262899/CA/NCI NIH HHS/United States ; R01 AI158861/AI/NIAID NIH HHS/United States ; U01 AI184132/AI/NIAID NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; OT3 HL147741/HL/NHLBI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; P01 CA111412/CA/NCI NIH HHS/United States ; R01 AI128775/AI/NIAID NIH HHS/United States ; 27307C0009/ES/NIEHS NIH HHS/United States ; }, mesh = {Humans ; Adolescent ; Male ; Female ; Child ; Young Adult ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/complications ; Child, Preschool ; Adult ; *Infections/etiology ; Treatment Outcome ; *Receptors, Antigen, T-Cell ; *Immunotherapy, Adoptive/adverse effects ; }, abstract = {Tisagenlecleucel (tisa-cel) is a CD19-directed chimeric antigen receptor T-cell therapy for relapsed/refractory precursor B-cell acute lymphoblastic leukemia (R/R B-ALL). We report infectious complications for 100 days (D100) following tisa-cel therapy in 471 pediatric and young adults (median age 13.8 years) with R/R B-ALL reported from September 2017 to June 2022. By D100, 137 (29%) patients had an infectious event, with an infection density of 0.542 per 100 person-days at risk. D100 cumulative incidences of bacterial, viral, and fungal infections were 14.1%, 11.6%, and 1.3%, corresponding to infection density scores of 0.296, 0.213, and 0.033 per 100 person-days at risk, respectively. In a multivariable analysis, receipt of ≥3 lines of therapy before tisa-cel (hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.13-3.08; P = .015), any-grade cytokine release syndrome (HR, 1.78; 95% CI, 1.17-2.71; P = .007), and lack of neutrophil recovery (HR, 2.63; 95% CI, 1.47-4.69; P = .001) were associated with an increased risk for any infection. Similar associations were observed for bacterial infections, with the addition of younger age as an adverse risk (<6 vs 6-15 years; HR, 2.38; 95% CI, 1.23-4.61; P = .01). Risk factors for viral infections included increasing age (1-year increase; HR, 1.05; 95% CI, 1.01-1.09; P = .016), prior history of any infection (HR, 2.76, 95% CI, 1.40-5.46; P = .004), and prior hematopoietic cell transplant (HR, 2.10; 95% CI, 1.18-3.71; P = .011). D100 infection-related mortality (IRM) rate was low at 0.2% (95% CI, 0.0-0.8). In this multicenter real-world study, we observed a high incidence of infectious complications but a low IRM following tisa-cel for R/R B-ALL.}, }
@article {pmid40737820, year = {2025}, author = {VoPham, T and Liu, T and Cortez, M and Karasaki, S and Falkenberg, NF and Zewdie, HY and Lin, J and Nondin, C and Chao, SLS and Knowlton, T and Quennehen, B and Mendoza, JA and Ioannou, GN and Berry, K and Adamkiewicz, G and Li, CI and Hart, JE}, title = {Exposure to outdoor air pollution, wildfires, and cancer survival in the United States.}, journal = {Cancer epidemiology}, volume = {98}, number = {}, pages = {102899}, pmid = {40737820}, issn = {1877-783X}, support = {K01 DK125612/DK/NIDDK NIH HHS/United States ; P30 ES000002/ES/NIEHS NIH HHS/United States ; T32 CA094880/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; United States/epidemiology ; *Air Pollution/adverse effects/statistics &amp; numerical data ; *Neoplasms/mortality/etiology/epidemiology ; Female ; Male ; *Environmental Exposure/adverse effects/statistics &amp; numerical data ; Middle Aged ; *Wildfires/statistics &amp; numerical data ; Particulate Matter/adverse effects/analysis ; SEER Program/statistics &amp; numerical data ; Aged ; Adult ; *Cancer Survivors/statistics &amp; numerical data ; Ozone/analysis/adverse effects ; Air Pollutants/adverse effects ; Nitrogen Dioxide/analysis/adverse effects ; }, abstract = {BACKGROUND: Climate change has led to an increase in wildfires, a major source of air pollution, which may be particularly harmful to individuals diagnosed with cancer. The objective of this study was to examine the relationships of air pollution and wildfires with mortality risk among cancer survivors.<br><br>METHODS: Surveillance, Epidemiology, and End Results (SEER) cancer registries provided information on 7,051,014 patients diagnosed with cancer from 2000 to 2021 in the United States. Cox regression was used to calculate adjusted hazard ratios (HRs) and 95&#x202f;% confidence intervals (CIs) for the associations between exposures to particulate matter <&#x202f;2.5&#x202f;&#xb5;m (PM2.5), nitrogen dioxide (NO2), ozone (O3), and wildfires (estimated using high-resolution geospatial datasets) with all-cause and cause-specific mortality risk.<br><br>RESULTS: There were 3,452,593 deaths, including 2,369,364 from cancer, 525,409 from cardiopulmonary, and 557,820 from other causes. Among cancer survivors, higher exposure to PM2.5 and wildfires (but not NO2 or O3) were associated with increased risk for all-cause, cancer, and other mortality. The association between PM2.5 and cancer mortality was stronger in counties more heavily impacted by wildfires (HR per 10 &#x3bc;g/m[3] in counties with &#x2265; median 0.39 wildfires per year: 1.17, 95&#x202f;% CI 1.04-1.33) vs. no wildfires (HR 1.06, 95&#x202f;% CI 0.97-1.15) (p interaction = 0.0064).<br><br>CONCLUSIONS: Among patients diagnosed with cancer, PM2.5 air pollution, particularly in areas heavily impacted by wildfires, is associated with increased risk for mortality.}, }
@article {pmid40738478, year = {2025}, author = {Murakami, N and Blosser, CD and Webber, AB and Gupta, G and Singh, N and Boppana, S and Master, S and Parasuraman, R and Campagnaro, EL and Java, A and Sprangers, B and Bhasin-Chhabra, B and Lum, E and Khirfan, D and Alexander, MP and Molnar, MZ and Benes, B and Thakur, AK and Bumma, N and Karam, S and Hultcrantz, M and Bridoux, F and Sanchorawala, V and Leung, N and Landau, H}, title = {Management recommendations for kidney transplantation in patients with plasma cell dyscrasia.}, journal = {Kidney international}, volume = {108}, number = {5}, pages = {780-790}, doi = {10.1016/j.kint.2025.07.011}, pmid = {40738478}, issn = {1523-1755}, mesh = {Humans ; *Kidney Transplantation/adverse effects/standards ; *Kidney Failure, Chronic/surgery/mortality/etiology ; *Paraproteinemias/complications/therapy ; Immunosuppressive Agents/therapeutic use/adverse effects ; Patient Selection ; Treatment Outcome ; Risk Assessment ; Recurrence ; Risk Factors ; }, abstract = {Patients with plasma cell dyscrasia, including multiple myeloma, AL amyloidosis, and monoclonal gammopathy of renal significance, face a high burden of end-stage kidney disease, which limits survival and quality of life. Although kidney transplant offers potential benefits, it remains underused because of the high risk of recurrence and historically poor outcomes. A multidisciplinary panel of transplant nephrologists, hematologists/oncologists, and pathologists convened to evaluate contemporary evidence and evolving strategies in kidney transplant for plasma cell dyscrasias and end-stage kidney disease. Advances in plasma cell dyscrasia therapies are improving survival and expanding kidney transplant eligibility. However, key challenges remain, including optimizing hematologic response pre-kidney transplant and managing immunosuppression to mitigate recurrence and avoid infection complications. Ongoing research and multidisciplinary collaboration are essential to refine transplant selection, integrate biomarkers for risk stratification, and develop tailored post-kidney transplant surveillance. These efforts may increase access to kidney transplant and improve outcomes for patients with plasma cell dyscrasia and end-stage kidney disease.}, }
@article {pmid40739193, year = {2025}, author = {Trejo, MJ and Floyd, JS and Massera, D and Daviglus, M and Garcia-Bedoya, O and Cai, J and Talavera, GA and Tamayo-Murillo, DE and Labovitz, D and Kaplan, R}, title = {Association of liver related biomarkers with incident cardiovascular disease and all-cause mortality in the Hispanic community health study/study of Latinos (HCHS/SOL), a population-based cohort study.}, journal = {BMC gastroenterology}, volume = {25}, number = {1}, pages = {543}, pmid = {40739193}, issn = {1471-230X}, support = {N01-HC65233/HL/NHLBI NIH HHS/United States ; N01-HC65237/HL/NHLBI NIH HHS/United States ; 1R01AG085320//National Institute of Aging/ ; N01HC65235/HL/NHLBI NIH HHS/United States ; N01-HC65236/HL/NHLBI NIH HHS/United States ; R01 AG085320/AG/NIA NIH HHS/United States ; P30 ES027792/ES/NIEHS NIH HHS/United States ; 1R01DK134672/DK/NIDDK NIH HHS/United States ; L60 DK137294/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Adult ; *Cardiovascular Diseases/mortality/blood/ethnology/epidemiology ; Biomarkers/blood ; *Hispanic or Latino/statistics &amp; numerical data ; *Alanine Transaminase/blood ; Aged ; *Aspartate Aminotransferases/blood ; Young Adult ; Adolescent ; Incidence ; Cohort Studies ; *Fatty Liver/blood/ethnology/complications ; United States/epidemiology ; Cause of Death ; White ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) increases risk of cardiovascular disease (CVD). Despite the high prevalence of MASLD among Hispanic populations, there is a scarcity of research on the associations between non-invasive markers of liver disease and incident CVD and all-cause mortality. In this study we investigated the association of liver related biomarkers with CVD events and all-cause mortality in a population based Hispanic/Latino cohort.<br><br>METHODS: We included 15,216 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 years with no pre-existing CVD. The composite outcome combined incident CVD and all-cause mortality. Having "elevated ALT/AST" was defined as ALT&#x2009;>&#x2009;40 IU/mL or AST&#x2009;>&#x2009;37 IU/mL for males, and ALT or AST&#x2009;>&#x2009;31 IU/mL for females. We estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) relating our composite outcome to elevated ALT/AST, FIB-4 and MASLD. Using interaction terms, we assessed whether the relationship between elevated ALT/AST and the composite outcome differed by MASLD status.<br><br>RESULTS: The study population was 40 years old on average, 52.7% female and had 740 CVD or all-cause mortality events. Elevated FIB-4 had the strongest association with incident CVD or all-cause mortality (comparing FIB-4&#x2009;>&#x2009;2.67 versus &#x2264;&#x2009;2.67, HR:3.47; CI:2.34-5.14). Elevated AST was found to be associated with incident CVD or all-cause mortality (HR:1.53; CI:1.14-2.05). MASLD was not associated with incident CVD or all-cause mortality (HR:1.14; CI: 0.94-1.40), but it was associated with incident CVD alone (HR:1.69; CI:1.19-2.39). The relationship between elevated ALT/AST and incident or all-cause mortality was modified by MASLD, such that the strongest association between elevated ALT/AST and incident CVD or all-cause mortality was in the absence of MASLD (HR:1.95; CI:1.20-3.18).<br><br>CONCLUSIONS: Among Hispanic adults FIB-4 was strongly associated with CVD or all-cause mortality and among persons without MASLD, elevated ALT/AST were associated with CVD or all-cause mortality.}, }
@article {pmid40739416, year = {2025}, author = {Shin, MB and Vu, T and Masud, M and Duran, MC and Escoffery, NC and Bishop, S and Winer, RL and Ko, LK}, title = {Evaluation of an implementation support program for rural communities using a two-tiered, embedded framework.}, journal = {Cancer causes &amp; control : CCC}, volume = {36}, number = {11}, pages = {1539-1548}, pmid = {40739416}, issn = {1573-7225}, support = {U48 DP006398 and U48 DP006377//Division of Cancer Prevention and Control, the National Center for Chronic Disease Prevention and Health Promotion of the Centers for Disease Control and Prevention, U.S. Department of Health and Human Services/ ; UL1 TR002319/TR/NCATS NIH HHS/United States ; UL1 TR002319/TR/NCATS NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Breast Neoplasms/diagnosis/prevention &amp; control ; Colorectal Neoplasms/diagnosis/prevention &amp; control ; *Early Detection of Cancer/statistics &amp; numerical data/methods ; Hispanic or Latino/statistics &amp; numerical data ; Program Evaluation ; *Rural Population/statistics &amp; numerical data ; Surveys and Questionnaires ; *Health Plan Implementation/statistics &amp; numerical data ; }, abstract = {PURPOSE: Evaluate the impact of Implementation Studio (the "Studio") on community-based organizations' (CBOs) EBI implementation, including changes in breast and colorectal (CRC) cancer screening status among Hispanic/Latino/a EBI recipients.<br><br>METHODS: A two-tiered, embedded framework consisted of 1) surveys (n&#x2009;=&#x2009;38) comparing up-to-date breast and CRC screening status among EBI recipients pre/post-EBI delivery (Tier 1); and semi-structured interviews (n&#x2009;=&#x2009;13 total; n&#x2009;=&#x2009;7 leaders, n&#x2009;=&#x2009;6 community health workers) with CBO staff assessing EBI implementation outcomes using rapid qualitative analysis methods (Tier 2) guided by Proctor's Implementation Research Outcomes Framework. Surveys and interviews were conducted in Spanish/English by phone/virtually September 2022-September 2023.<br><br>RESULTS: Up-to-date screening status increased by 16.6% for breast and 19.3% for CRC screening pre/post-EBI implementation, albeit not statistically significant overall (p&#x2009;=&#x2009;0.168). CBOs reported that implementing EBIs cultivated their confidence and enhanced CBOs' workforce capacity (acceptability). CHWs (the primary EBI implementers) proficiently used the Studio tools to adapt the EBIs to improve fit and implement them in the rural Hispanic/Latino/a communities (appropriateness). Remote delivery increased the EBI accessibility for the community (feasibility). Key drivers of costs were CHWs' time to adapt and implement EBIs (costs). CBOs expressed the need to address clients' social needs to maintain EBI's impact (sustainability).<br><br>CONCLUSION: CBOs successfully implemented CHW-led EBIs, and their efforts increased up-to-date cancer screening among rural Hispanic/Latino/a community members. These findings demonstrate that Studio is a promising strategy for building CBOs' capacity to implement EBIs and increase cancer screening.}, }
@article {pmid40740502, year = {2025}, author = {Nolan, CT and Campbell, I and Farrell-Sherman, A and Briones Ortiz, BA and Yang, C and Naish, KA and Di Stilio, VS and Kaldy, JE and Donoghue, C and Ruesink, JL and Imaizumi, T}, title = {Florigen and antiflorigen gene expression correlates with reproductive state in a marine angiosperm, Zostera marina.}, journal = {iScience}, volume = {28}, number = {8}, pages = {113082}, pmid = {40740502}, issn = {2589-0042}, support = {R01 GM079712/GM/NIGMS NIH HHS/United States ; }, abstract = {Florigen and antiflorigen genes within the phosphatidylethanolamine-binding protein (PEBP) family regulate flowering in angiosperms. In eelgrass (Zostera marina), an estuarine foundation species, flowering, and seed production are crucial for population resilience. Yet, the molecular mechanism underpinning flowering remains unknown. Among 13 PEBP genes in Z. marina (ZmaPEBP), we showed that four genes (ZmaFT2, ZmaFT4, ZmaFT9, and ZmaTFL1a) altered flowering time when overexpressed in Arabidopsis. We analyzed gene expression in different tissues and throughout the growth season from perennial and annual populations in Willapa Bay and Yaquina Bay, USA. Across six sites exhibiting different degrees of population genetic structure, ZmaFT2 and ZmaFT4 were expressed in leaves of vegetative and reproductive shoots and in rhizomes of reproductive shoots. ZmaFT9 was solely expressed in leaves of vegetative shoots, while ZmaTFL1a levels increased after flowering shoots developed. Our results suggest that ZmaFT2 and ZmaFT4 may promote flowering, while ZmaFT9 may inhibit flowering in eelgrass.}, }
@article {pmid40740737, year = {2025}, author = {Bulosan, H and Nunez, YC and Wu, B and George, E and Cogen, AL}, title = {A patient with a purple, edematous great toe.}, journal = {JAAD case reports}, volume = {62}, number = {}, pages = {113-115}, pmid = {40740737}, issn = {2352-5126}, }
@article {pmid40742180, year = {2025}, author = {Tang, G and Carr, AV and Perez, C and Ramos Sarmiento, K and Levy, L and Lampe, JW and Diener, C and Gibbons, SM}, title = {Metagenomic estimation of absolute bacterial biomass in the mammalian gut through host-derived read normalization.}, journal = {mSystems}, volume = {10}, number = {8}, pages = {e0098425}, pmid = {40742180}, issn = {2379-5077}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 DK133468/DK/NIDDK NIH HHS/United States ; T32 GM007266/GM/NIGMS NIH HHS/United States ; R01DK133468//HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)/ ; }, mesh = {Humans ; *Gastrointestinal Microbiome/genetics ; *Metagenomics/methods ; Feces/microbiology ; Biomass ; *Bacteria/genetics/isolation &amp; purification ; *Metagenome ; Animals ; Host Microbial Interactions/genetics ; }, abstract = {Absolute bacterial biomass estimation in the human gut is crucial for understanding microbiome dynamics and host-microbe interactions. Current methods for quantifying bacterial biomass in stool, such as flow cytometry, quantitative polymerase chain reaction (qPCR), or spike-ins, can be labor-intensive, costly, and confounded by factors like water content, DNA extraction efficiency, PCR inhibitors, and other technical challenges that add bias and noise. We propose a simple, cost-effective approach that circumvents some of these technical challenges: directly estimating bacterial biomass from metagenomes using bacterial-to-host (B:H) read count ratios. We compared B:H ratios to the standard methods outlined above, demonstrating that B:H ratios are useful proxies for bacterial biomass in stool and possibly in other host-associated substrates. B:H ratios in stool were correlated with bacterial-to-diet (B:D) read count ratios, but B:D ratios exhibited a substantial number of outlier points. Host read depletion methods reduced the total number of human reads in a given sample, but B:H ratios were strongly correlated before and after host read depletion, indicating that host read depletion did not reduce the utility of B:H ratios. B:H ratios showed expected variation between health and disease states and were generally stable in healthy individuals over time. Finally, we showed how B:H and B:D ratios can be used to track antibiotic treatment response and recovery. B:H ratios offer a convenient alternative to other absolute biomass quantification methods, without the need for additional measurements, experimental design considerations, or machine learning, enabling robust absolute biomass estimates directly from stool metagenomic data.IMPORTANCEIn this study, we asked whether normalization by host reads alone was sufficient to estimate absolute bacterial biomass directly from stool metagenomic data, without the need for synthetic spike-ins, additional experimental biomass measurements, or training data. The approach assumes that the contribution of host DNA to stool is more constant or stable than biologically relevant fluctuations in bacterial biomass. We find that host read normalization is an effective method for detecting variation in gut bacterial biomass. Absolute bacterial biomass is a key metric that often gets left out of gut microbiome studies, and empowering researchers to include this measure more broadly in their metagenomic analyses should serve to improve our understanding of host-microbiota interactions.}, }
@article {pmid40742241, year = {2025}, author = {Graham, LS and Yu, EY}, title = {Early and Precise: Treating HRR Alterations in Hormone-Sensitive Prostate Cancer.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {19}, pages = {4001-4003}, doi = {10.1158/1078-0432.CCR-25-2359}, pmid = {40742241}, issn = {1557-3265}, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/drug therapy/pathology ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Mutation ; *Recombinational DNA Repair/drug effects/genetics ; BRCA2 Protein/genetics ; BRCA1 Protein/genetics ; }, abstract = {Patients with prostate cancer and homologous recombination repair alterations face worse outcomes. Early use of PARP inhibitors, especially in BRCA-mutated cancers, is promising. However, optimal timing, sequencing, and benefits for non-BRCA alterations remain unclear, underscoring the need for well-designed clinical trials and personalized treatment discussions. See related article by Hage Chehade et al., p. 4101.}, }
@article {pmid40746155, year = {2025}, author = {Dong, M and Thakral, A and Byrne, KS and Bosse, Y and Zhou, H and Zhang, Y and Atkins, J and Haycock, P and Brown, MC and Murison, K and Timens, W and Sin, DD and Kothari, J and Gabriel, AAG and Zaridze, D and Savic, M and Lissowska, J and Świątkowska, B and Janout, V and Holcatova, I and Mukeria, A and Fernandez-Tardon, G and Davies, MPA and Triplette, M and Schabath, MB and Andrew, AS and Chen, C and Taylor, F and Field, JK and Tardon, A and Shete, SS and Brennan, P and Landi, MT and McKay, J and Amos, CI and Lin, X and Christiani, DC and Hung, RJ and Liu, G and Xu, W}, title = {Genome-wide association study of early-stage non-small cell lung cancer prognosis: a pooled analysis in the International Lung Cancer Consortium.}, journal = {Carcinogenesis}, volume = {46}, number = {2}, pages = {}, pmid = {40746155}, issn = {1460-2180}, support = {001/WHO_/World Health Organization/International ; P30 CA076292/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Non-Small-Cell Lung/genetics/pathology/mortality ; *Genome-Wide Association Study ; Prognosis ; *Lung Neoplasms/genetics/pathology/mortality ; Female ; Male ; Polymorphism, Single Nucleotide ; Middle Aged ; Aged ; Neoplasm Staging ; }, abstract = {Lung cancer is the leading cause of cancer mortality. To investigate genetic determinants for prognosis among patients diagnosed with early-stage non-small cell lung cancer (NSCLC), we conducted the first large-scale genome-wide association prognostic study using data from the International Lung Cancer Consortium (ILCCO) through a two-phase analysis. Phase 1 includes the discovery of genome-wide association studies analysis using a multivariable Cox PH model on 3428 NSCLC patients of European ancestry from 10 ILCCO participating studies to identify genetic variants associated with overall survival and validation analysis for genome-wide significant variants (P-value ≤5 × 10-8) using the Cancer Genome Atlas (TCGA). Phase 2 aims to identify causal variants using functional analyses of genome-wide significant and suggestive variants (P-value ≤1 × 10-5), including variant-epigenetic functional annotation (FAVOR), CHIP-seq data, variant-gene expression association, and colocalization analysis. We identified two significant variants; of those, a locus at 9q21.31 (rs117979484) was significant at the genome-wide level (P = 3.67 × 10-8) and validated in TCGA (P = 0.03). Three suggestive variants were found to have a putative epigenetic function: intronic variants rs149281784 (BCL7B gene) and rs148031766 (POM121 gene) both located at 7q11.23 and in moderate linkage disequilibrium with each other; and variant rs2471630 (SRCIN1 gene; 17q12). Specifically, variants rs149281784 and rs148031766 have potential regulatory roles in the transcriptional activation of the BCL7B gene and POM121 gene. Exploratory survival analyses in the squamous cell carcinomas subgroup also identified a significant variant, rs138467404 (GRHL-2 gene; 8q22.3) at a genome-wide level (P = 4.75 × 10-8) and validated by TCGA (P = 0.02). These new findings indicate potential novel pathways associated with early-stage NSCLC prognosis. Future research may validate additional genome-wide suggestive variants as being relevant for lung cancer outcomes.}, }
@article {pmid40748049, year = {2025}, author = {Xia, B and Kim, AR and Liu, F and Han, M and Stoneburner, E and Makdissi, S and Di Cara, F and Mohr, SE and Ring, A and Perrimon, N}, title = {Phage-displayed synthetic library and screening platform for nanobody discovery.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {40748049}, issn = {2050-084X}, support = {NIH 5R24OD035556/NH/NIH HHS/United States ; R24 OD035556/OD/NIH HHS/United States ; NIH NIGMS P41 GM132087/NH/NIH HHS/United States ; P41 GM132087/GM/NIGMS NIH HHS/United States ; 2021R1A6A3A14039622//National Research Foundation/ ; }, mesh = {*Single-Domain Antibodies/isolation &amp; purification/immunology/genetics ; Animals ; *Peptide Library ; Cell Surface Display Techniques ; Drosophila Proteins/immunology ; Drosophila ; }, abstract = {Nanobodies, single-domain antibodies derived from camelid heavy-chain antibodies, are known for their high affinity, stability, and small size, which make them useful in biological research and therapeutic applications. However, traditional nanobody generation methods rely on camelid immunization, which can be costly and time-consuming, restricting their practical feasibility. In this study, we present a phage-displayed synthetic library for nanobody discovery. To validate this approach, we screened nanobodies targeting various Drosophila secreted proteins. The nanobodies identified were suitable for applications such as immunostaining and immunoblotting, supporting the phage-displayed synthetic library as a versatile platform for nanobody development. To address the challenge of limited accessibility to high-quality synthetic libraries, this library is openly available for non-profit use.}, }
@article {pmid40748144, year = {2025}, author = {Flamand, L and Arbuckle, J and Bonnafous, P and Descamps, V and Hill, JA and Jarrett, R and Jerome, K and Kaufer, BB and Koide, R and Komaroff, AL and Medveczky, P and Miura, H and Mori, Y and Parrish, N and Pellett, PE and Wood, M and Yoshikawa, T and Zerr, DM}, title = {Endogenous human herpesviruses 6A/B.}, journal = {Journal of virology}, volume = {99}, number = {9}, pages = {e0105425}, pmid = {40748144}, issn = {1098-5514}, mesh = {Humans ; DNA, Viral/genetics ; *Herpesvirus 6, Human/genetics/physiology ; *Roseolovirus Infections/virology ; *Virus Integration ; }, abstract = {Human herpesviruses 6A and 6B (HHV-6A/B) can integrate into the germline, resulting in inherited viral DNA-now proposed to be called "endogenous HHV-6A/B (eHHV-6A/B)." Present in 0.2-3% of humans, this integrated DNA is passed to offspring and may reactivate, posing health risks such as angina or lupus. To reduce confusion caused by varied terminology, researchers advocate using "eHHV-6A/B" for inherited forms and reserving "chromosomally integrated" for somatic integrations only.}, }
@article {pmid40748320, year = {2025}, author = {Ziller, SG and Blew, RM and Roe, DJ and Odegaard, A and Chen, Z and Caan, BJ and Luo, J and Manson, JE and Neuhouser, ML and Rohan, TE and Bea, JW}, title = {Dual-energy X-ray Absorptiometry-Derived Adiposity and Colorectal Cancer Incidence and Mortality in Postmenopausal Women.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {10}, pages = {1801-1809}, pmid = {40748320}, issn = {1538-7755}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; P30 CA023074/CA/NCI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R25 CA217725/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; R01 CA253302/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01CA253302//National Cancer Institute (NCI)/ ; R01CA253302-02S1//National Cancer Institute (NCI)/ ; R25CA217725//National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Female ; *Colorectal Neoplasms/mortality/epidemiology ; *Postmenopause ; *Absorptiometry, Photon/methods ; Incidence ; Middle Aged ; *Adiposity ; Aged ; Risk Factors ; Prospective Studies ; }, abstract = {BACKGROUND: Determine if dual-energy X-ray absorptiometry (DXA)-derived adiposity was associated with colorectal cancer incidence and mortality in postmenopausal women from the Women's Health Initiative DXA cohort.<br><br>METHODS: Whole-body DXA scans estimated adiposity. Women with a history of cancer (except nonmelanoma skin cancer) or missing baseline DXA were excluded. For 27 years of follow-up, outcomes and deaths were adjudicated. Descriptive statistics by colorectal cancer status were calculated. Fine and Gray's competing risks regression was used to estimate sub-HRs and 95% confidence intervals. Observation time was from enrollment to the first colorectal cancer event or competing risk (other cancer, other cause of death); women without cancer at the last follow-up were censored. Covariates included sociodemographic, clinical, and study characteristics.<br><br>RESULTS: After exclusions, 9,950 women were included, with 191 first-incident colorectal cancer cases and 88 colorectal cancer-related deaths identified. At baseline, the mean (&#xb1;SD) age was 63.3 (&#xb1;7.4) years, and the body mass index (BMI) was 28.2 (&#xb1;5.7) kg/m2. In adjusted models, baseline continuous abdominal visceral adipose tissue (VAT; per 100 cm2) and android fat (per kg) were significantly associated with a higher risk of first-incident colorectal cancer: sub-HRs (95% confidence interval) were 1.23 (1.04-1.45) and 1.15 (1.01-1.31), respectively. There were no significant associations between adiposity and colorectal cancer mortality.<br><br>CONCLUSIONS: Higher amounts of abdominal VAT and android fat were associated with a higher risk of colorectal cancer incidence in postmenopausal women.<br><br>IMPACT: Associations between VAT and colorectal cancer, independent of BMI, support the clinical assessment of body composition across weight categories. A head-to-head comparison of VAT and BMI for colorectal cancer prediction is recommended in future research.}, }
@article {pmid40749165, year = {2025}, author = {McManus, D and Copsel, SN and Pfeiffer, BJ and Wolf, D and Barreras, H and Ma, S and Khodor, A and Komai, S and Burgos da Silva, M and Hazime, H and Gallardo, M and Lime, SG and van den Brink, MRM and Park, JH and Abreu, MT and Hill, GR and Perez, VL and Levy, RB}, title = {Pretransplant targeting of TNFRSF25 and CD25 stimulates recipient Tregs in target tissues, ameliorating GVHD post-HSCT.}, journal = {Blood}, volume = {146}, number = {22}, pages = {2710-2727}, pmid = {40749165}, issn = {1528-0020}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; R01 DK099076/DK/NIDDK NIH HHS/United States ; R01 EY024484/EY/NEI NIH HHS/United States ; R01 EY030283/EY/NEI NIH HHS/United States ; }, mesh = {Animals ; *T-Lymphocytes, Regulatory/immunology/drug effects ; *Graft vs Host Disease/prevention &amp; control/immunology/etiology ; Mice ; *Interleukin-2 Receptor alpha Subunit/immunology/antagonists &amp; inhibitors ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Receptors, Tumor Necrosis Factor, Member 25/immunology/antagonists &amp; inhibitors ; Tumor Necrosis Factor Ligand Superfamily Member 15/immunology ; Mice, Inbred C57BL ; Mice, Inbred BALB C ; Interleukin-2/pharmacology ; Female ; Recombinant Fusion Proteins/pharmacology ; Transplantation, Homologous ; }, abstract = {The current approach to minimize transplant-associated complications, including graft-versus-host disease (GVHD) includes long-term pharmacological immune suppression frequently accompanied by unwanted side effects. Advances in targeted immunotherapies regulating alloantigen responses in the recipient continue to reduce the need for pan-immunosuppression. Here, in vivo targeting of the tumor necrosis factor superfamily receptor TNFRSF25 (also known as DR3) and the high-affinity interleukin-2 (IL-2) receptor with a TL1A-immunoglobulin (TL1A-Ig) fusion protein and low-dose IL-2, respectively, was used to pretreat recipient mice before allogeneic hematopoietic stem cell transplantation (aHSCT). Pretreatment induced regulatory T cell (Treg) expansion persisting 1 to 2 weeks after HSCT, leading to diminished GVHD and improved transplant outcomes. Expansion was accompanied by an increase in the frequency of stable and active Tregs, creating a suppressive tissue environment in the colon, liver, and eye. Importantly, pretreatment supported epithelial cell function/integrity, a diverse microbiome including reduction of pathologic bacteria outgrowth, and promotion of butyrate producing bacteria, while maintaining physiologic levels of obligate/facultative anaerobes. Notably, using a sphingosine 1-phosphate receptor agonist to sequester T cells in lymphoid tissues, it was found that the increased tissue Treg frequency included resident CD69+CD103+FoxP3+ hepatic Tregs. In contrast to infusion of donor Tregs, the strategy developed here resulted in the presence of immunosuppressive target tissue environments in the recipient before the receipt of donor allogeneic-reactive T cells and successful perseveration of graft-versus-leukemia responses. We posit strategies that circumvent the need of producing large numbers of ex vivo manipulated Tregs may be accomplished through in vivo recipient Treg expansion, providing translational approaches to improve aHSCT outcomes.}, }
@article {pmid40750760, year = {2025}, author = {Golmohammadi, M and Raza, S and Albayyadhi, M and Sholehrasa, H and Khouri, J and Williams, L and Hansen, DK and Moradi, A and Xu, X and Albliwi, M and Ali, AH and Dima, D and Anwer, F and Paul, B and Jaberi-Douraki, M}, title = {Comprehensive assessment of adverse event profiles associated with bispecific antibodies in multiple myeloma.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {130}, pmid = {40750760}, issn = {2044-5385}, mesh = {Humans ; *Multiple Myeloma/drug therapy ; *Antibodies, Bispecific/adverse effects/therapeutic use ; B-Cell Maturation Antigen/immunology ; Male ; *Antineoplastic Agents, Immunological/adverse effects/therapeutic use ; Female ; Aged ; }, abstract = {Bispecific antibodies (BsAbs) have shown promise in the management of relapsed/refractory multiple myeloma (MM). Despite its efficacy, this class of drugs is associated with significant toxicities. In this study, we conducted a pooled analysis of the available clinical trials on BsAbs for the treatment of MM, including full publications and abstracts until April 2025. BsAbs were classified into two groups: B-cell maturation antigen (BCMA), and GPRC5D/FcRH5 BsAbs. Welch's t-test was performed to compare the safety profiles of each agent. For clustering, we used principal component analysis (PCA). Our study analyzed 22 trials involving 2374 patients with MM from early 2023 to April 2025. Among these, 1276 patients received BCMA BsAbs, 841 treated with GPRC5D/FcRH5 BsAbs, 157 received teclistamab + talquetamab, and 65 patients received a talquetamab + daratumumab, and 35 patients received talquetamab + pomalidomide. The median follow-up for all groups was 11.83 months. Among all-grade hematologic adverse events (AEs), neutropenia occurred in 40.4%, anemia in 39.2%, thrombocytopenia in 21.4%, lymphopenia in 19.2%, infections in 45.8%, and cytokine release syndrome (CRS) in 65%. For grade 3/4 AEs, infections occurred in 20.3%, CRS in 1.5%, neutropenia in 35.2%, anemia in 24.5%%, thrombocytopenia in 13.5%, and lymphopenia in 17.7%. CRS and the need for tocilizumab were significantly less frequent with BCMA BsAbs vs GPRC5D/FcRH5 BsAbs, (P < 0.002). Skillings Mack (Generalized Friedman's) findings emphasized substantial distinctions between BCMA and GPRC5D/FcRH5×CD3 in both overall and severe grade 3/4 AEs (p ≤ 0.0002). PCA revealed agents with all grades and grade 3/4 showed similar clustering patterns except for three agents. Overall, our findings demonstrated the excellent efficacy on the use of BsAbs in MM; however, these agents have been linked to a unique AE profile. GPRC5D/FcRH5 are associated with less grade 3/4 hematologic toxicity whereas BCMA BsAbs were associated with lower grade 3/4 CRS rates, compared to GPRC5D/FcRH5. These insights are crucial for guiding treatment decisions and developing strategies to improve patient outcomes.}, }
@article {pmid40750774, year = {2025}, author = {Domingo-Domènech, E and Pro, B and Illidge, T and Horwitz, S and Trumper, L and Iyer, S and Advani, R and Bartlett, NL and Christensen, JH and Kim, WS and Feldman, T and Choi, I and Gritti, G and Belada, D and Shustov, A and Illes, A and Zinzani, PL and Hüttmann, A and Trneny, M and Le Gouill, S and Jagadeesh, D and Friedberg, JW and Little, M and Dong, C and Fanale, M and Fenton, K and Savage, KJ}, title = {Brentuximab vedotin plus chemotherapy for the treatment of front-line systemic anaplastic large cell lymphoma: subgroup analysis of the ECHELON-2 study at 5 years' follow-up.}, journal = {Blood cancer journal}, volume = {15}, number = {1}, pages = {129}, pmid = {40750774}, issn = {2044-5385}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Brentuximab Vedotin/administration &amp; dosage/therapeutic use/adverse effects ; Follow-Up Studies ; *Lymphoma, Large-Cell, Anaplastic/drug therapy/mortality/pathology ; Treatment Outcome ; }, abstract = {ClinicalTrials.gov number: NCT01777152.}, }
@article {pmid40751436, year = {2025}, author = {Samandari, T and Achola, M and Hutter, JN and Mboya, G and Otieno, W and Kee, JJ and Huang, Y and Aponte, JJ and Ockenhouse, CF and Lee, CK and Polakowski, L and Yacovone, M and Tapley, A and Dadabhai, S and Mkhize, NN and Kaldine, H and Bhebhe, S and Moore, PL and Hural, J and Garrett, N and Kublin, JG}, title = {Plasmodium falciparum Parasitemia Does Not Diminish Neutralizing Antibody Responses After mRNA COVID-19 Booster Vaccination in HIV-infected Adults.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {4}, pages = {e565-e570}, pmid = {40751436}, issn = {1537-6613}, support = {INV007217/GATES/Gates Foundation/United States ; T32 AI007044/AI/NIAID NIH HHS/United States ; UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; U01 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068614-14/NH/NIH HHS/United States ; INV-007217/GATES/Gates Foundation/United States ; U01 AI068614/AI/NIAID NIH HHS/United States ; T32AI007044-45/NH/NIH HHS/United States ; //National Institute of Allergy and Infectious Diseases/ ; 3UM1AI068618-15S1/NH/NIH HHS/United States ; UM1 AI068635/NH/NIH HHS/United States ; }, mesh = {Humans ; *Malaria, Falciparum/immunology/parasitology/complications ; *Antibodies, Neutralizing/blood/immunology ; Adult ; *COVID-19/prevention &amp; control/immunology ; Male ; Female ; *HIV Infections/immunology/complications ; *Parasitemia/immunology/parasitology ; Immunization, Secondary ; Plasmodium falciparum/immunology ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Middle Aged ; SARS-CoV-2/immunology ; Antibodies, Viral/blood/immunology ; 2019-nCoV Vaccine mRNA-1273/immunology ; }, abstract = {mRNA vaccines have emerged as powerful tools for the prevention of infectious diseases, but subclinical malaria may reduce vaccine immunogenicity. We evaluated neutralizing antibody responses in asymptomatic HIV-infected adults with and without polymerase chain reaction-confirmed Plasmodium falciparum who received either monovalent mRNA-1273 or bivalent mRNA-1273.222 (WA-1 and BA.4/5) booster vaccines. In previous studies, a 50% pseudovirus inhibitory dose neutralizing antibody (ID50) titer of 1000 correlated with 96% efficacy in preventing COVID-19. We observed ID50 geometric mean titers >22 000 in both parasitemic and nonparasitemic participants 1 month after boosting. We conclude that COVID-19 mRNA vaccine antibody responses are unimpaired by concurrent asymptomatic parasitemia.}, }
@article {pmid40752589, year = {2025}, author = {Ng, SK and Flaherty, PW and Ancheta, M and Tindbaek, KA and Sekhon, MK and Huang, JJ and Portuguese, AJ and Albittar, A and Kopmar, NE and Cowan, AJ and Shadman, M and Hirayama, AV and Till, BG and Cassaday, RD and Turtle, CJ and Liu, C and Xie, H and Leisenring, WM and Gauthier, J and Liang, EC and Hill, JA}, title = {Opportunities to Improve Antibiotic Stewardship, and Identification of Blood Biomarkers Associated with Bacteremia Following CAR-T Cell Therapy.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {10}, pages = {838.e1-838.e16}, doi = {10.1016/j.jtct.2025.07.022}, pmid = {40752589}, issn = {2666-6367}, mesh = {Humans ; *Biomarkers/blood ; *Bacteremia/blood/drug therapy/etiology ; Male ; Female ; Middle Aged ; *Antimicrobial Stewardship/methods ; *Immunotherapy, Adoptive/adverse effects/methods ; *Anti-Bacterial Agents/therapeutic use ; Aged ; Case-Control Studies ; *Cytokine Release Syndrome/etiology/blood/drug therapy ; Adult ; }, abstract = {Cytokine release syndrome (CRS) is frequent after chimeric antigen receptor T-cell therapy (CAR-T). CRS and bacteremia share clinical features, making it difficult to distinguish between the two and deliver targeted treatment. As a result, most patients with CRS receive empiric broad-spectrum antibiotics that may adversely impact long-term outcomes. The objectives of this study were to identify blood biomarkers that distinguish between CRS and bacteremia in the first month after CAR-T. We also describe the utilization of empiric antibiotics to identify opportunities for improved antimicrobial stewardship. We identified patients who received CAR-T for hematologic malignancies between July 2013 and April 2024. We calculated the cumulative incidences of CRS and bacteremia within 30 days post-CAR-T. In a matched case control analysis, where three patients with CRS and no bacteremia (controls) were matched to each patient with bacteremia (cases), we described the clinical characteristics of CRS, bacteremia, and antibiotic exposure. We then assessed the levels and kinetics of six biomarkers (C-reactive protein [CRP], interleukin-6, ferritin, fibrinogen, lactate dehydrogenase, and D-dimer) for their ability to discriminate between bacteremia and CRS using Mann-Whitney U tests and generalized estimating equation (GEE) models. Among 694 CAR-T recipients, 517 (75%; 95% confidence interval [CI], 71%-78%) developed CRS. Bacteremia occurred in 19 patients with a cumulative incidence of 2.7% (95% CI, 1.7%-4.2%) within 30 days and 1.4% (95% CI, 0.7%-2.6%) within 14 days of CAR-T. The median time from blood culture to a positive result was one day (interquartile range [IQR], 1-1). Among the 57 matched controls, CRS occurred a median of four days (IQR, 1-5) post-CAR-T, all were hospitalized for fevers, and 92% of CRS events were treated with empiric antibiotics for a median of seven days (IQR, 5-8). As a result, for every patient with bacteremia treated with antibiotics within the first 14 days, an estimated 52 patients with CRS and no serious bacterial infection received empiric antibiotics. The levels and kinetics of biomarkers were similar among cases and controls within 14 days after CAR-T. Beyond day +14, CRP, D-dimer, and ferritin levels were significantly higher among patients with bacteremia and distinguished cases from controls with moderate discrimination (area under the curve of 0.77, 0.77, and 0.81, respectively). In addition, increasing CRP and fibrinogen ≥14 days post-CAR-T were significantly associated with bacteremia (odds ratio [OR], 1.46; 95% CI, 1.07-2.01 and OR, 4.32; 95% CI, 1.28-14.61 per 0.25 log10 increase in biomarker level per day, respectively). We demonstrate that most CAR-T recipients who developed CRS received empiric broad-spectrum antibiotics, but bacteremia was rare. Although blood biomarkers were unable to distinguish between CRS and bacteremia early after CAR-T, higher CRP, D-dimer, and ferritin and rising levels of CRP and fibrinogen ≥14 days post-CAR-T were associated with bacteremia and can facilitate earlier targeted interventions. These data highlight opportunities for improved antibiotic stewardship in the context of CRS, which is critical given the association between broad-spectrum antibiotic exposure, gut microbiome dysbiosis, and worse outcomes after CAR-T.}, }
@article {pmid40753019, year = {2025}, author = {Selukar, S and Yin, V and Othus, M}, title = {Synthetic control arms and other uses of external data in clinical trials for hematological malignancies.}, journal = {Blood reviews}, volume = {74}, number = {}, pages = {101324}, doi = {10.1016/j.blre.2025.101324}, pmid = {40753019}, issn = {1532-1681}, support = {U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Hematologic Neoplasms/therapy/diagnosis ; *Clinical Trials as Topic/methods ; }, abstract = {Clinical trialists have been debating the use of data external to the study for decades. In this review, we develop concepts for interested readers to consider the use of external data in clinical trials, and we provide perspectives on the real-world usage of external data in phase 2 and 3 clinical trials for hematological malignancies across US academic cancer clinical trial networks. Only a minority of these studies have included external data (beyond use in establishing outcome benchmarks) in recent years, but improvements in data sharing and advances in methodologies may lead to more sources of potentially high-quality data for the broader clinical trials community. Identifying appropriate external data specific to the clinical trial and developing plans to adequately address differences between study and external data will remain key considerations for including external data in clinical trials.}, }
@article {pmid40754035, year = {2025}, author = {Jafari, O and Ma, S and Lam, BD and Jiang, JY and Zhou, E and Ranjan, M and Ryu, J and Bandyo, R and Maghsoudi, A and Peng, B and Amos, CI and Oluyomi, A and Fillmore, NR and La, J and Li, A}, title = {Development and validation of venous thromboembolism-bidirectional encoder representations from transformers (VTE-BERT) natural language processing model.}, journal = {Journal of thrombosis and haemostasis : JTH}, volume = {}, number = {}, pages = {}, pmid = {40754035}, issn = {1538-7836}, support = {K23 HL159271/HL/NHLBI NIH HHS/United States ; OT2 OD032581/OD/NIH HHS/United States ; }, abstract = {BACKGROUND: Accurate and rapid phenotyping of venous thromboembolism (VTE) in longitudinal studies is important. A natural language processing (NLP) tool externally validated in representative patients is lacking.<br><br>OBJECTIVES: To train and validate an efficient NLP model to detect incident VTE event.<br><br>METHODS: We designed a novel NLP platform, NLPMed, to assist thrombosis researchers with data preprocessing, phenotype annotation, language model finetuning, and NLP application. Using clinical notes, discharge summaries, and radiology reports from patients with cancer at 2 healthcare institutions, we finetuned Bio_Clinical Bidirectional Encoder Representations from Transformers (BERT) to develop VTE-BERT. The new model was trained to detect acute VTE events and their anatomical locations longitudinally. We internally and externally validated the model's performance in 2 randomly sampled cohorts of patients with advanced cancer.<br><br>RESULTS: The training cohort consisted of 715 patients and 14 013 annotated notes with &#x2265;1 VTE keyword from the Harris Health System. The internal validation cohort included 400 additional patients with 7190 VTE keyword-containing notes from Harris Health System. The external validation cohort included 400 patients with 7371 VTE keyword-containing notes from the national Veterans Affairs healthcare system. VTE-BERT was trained until it reached a precision of 95% and recall of 98% on the patient level. Using independent datasets, the model achieved precision and recall of 95% and 91% in internal validation and of 85% and 92% in external validation.<br><br>CONCLUSION: We trained and externally validated an efficient NLP model to detect incident VTE events longitudinally. We believe its adoption will accelerate thrombosis research by improving VTE detection at scale and decreasing the time and expense involved with manual chart review in big data epidemiological studies.}, }
@article {pmid40754223, year = {2025}, author = {Nadiminti, KV and Ahn, KW and Patel, J and Lian, Q and Bezerra, E and Chen, A and Ganguly, S and Gergis, U and Hashmi, H and Kharfan-Dabaja, MA and Kuruvilla, J and Lekakis, L and Locke, FL and Murthy, H and Mousthafa, MA and Perales, MA and Pophali, P and Riedell, PA and Shah, NN and Wang, T and Pasquini, M and Hamadani, M and Turtle, CJ and Herrera, AF and Shadman, M}, title = {Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: A CIBMTR Analysis.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {12}, pages = {1000.e1-1000.e11}, pmid = {40754223}, issn = {2666-6367}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; U01 AI184132/AI/NIAID NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; K08 CA282987/CA/NCI NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Female ; Middle Aged ; Male ; Aged ; *Immunotherapy, Adoptive/methods ; Adult ; *Receptors, Chimeric Antigen/immunology ; *Lymphoma, Large B-Cell, Diffuse/therapy/mortality/pathology/immunology ; Registries ; Receptors, Antigen, T-Cell ; Young Adult ; Aged, 80 and over ; Antigens, CD19/immunology ; }, abstract = {Relapsed and/or refractory Richter transformation (RT) is generally associated with poor response to available therapies and a short survival time. As RT patients were excluded from participating in the pivotal studies of chimeric antigen receptor T cell therapy (CAR-T) for large B-cell lymphoma, there is a paucity of information about the efficacy of CAR-T in RT. Therefore, through the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed data from 140 RT patients who received anti-CD19 CAR-T between 2018 and 2023. Patients had received a median of 3 lines of therapy for RT (range: 1 to 8), with nearly 43% being exposed to a Bruton's tyrosine kinase inhibitor and/or venetoclax. Axicabtagene ciloleucel (axi-cel) (65%) and tisagenlecleucel (tisa-cel) (28%) were the most commonly prescribed products. Grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 9.4% and 20%, respectively. After a median follow-up of 25 months (range: 1.8 to 61.5) from CAR-T infusion, 2-year progression-free and overall survival were 32.5% (95% CI, 24 to 41) and 46.6% (95% CI, 38 to 58), respectively. The 2-year cumulative incidence of relapse and non-relapse mortality were 58.8% (95% CI, 50 to 67), and 8.7% (95% CI, 4% to 14%), respectively. Poor performance status and refractory disease before CAR-T infusion were predictive of inferior survival and disease progression. Our results show that anti-CD19 CAR-T can function as an effective treatment modality for a proportion of RT patients.}, }
@article {pmid40754387, year = {2025}, author = {Moosavi, D and Mullens, DA and Davidson, LA and Fan, YY and Goldsby, JS and Ivanov, IV and Levy, L and Kahsai, OJ and Curtis, KR and Raftery, D and Purcell, HJ and Mather, E and Ammar, H and Randolph, T and Issaka, RB and Navarro, SL and Lampe, JW and Hullar, MA and Chapkin, RS}, title = {Gut microbial community and host intestinal gene expression with combined fish oil and soluble corn fiber compared with corn oil and maltodextrin: A randomized crossover trial in healthy older individuals.}, journal = {The American journal of clinical nutrition}, volume = {122}, number = {2}, pages = {396-412}, pmid = {40754387}, issn = {1938-3207}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Fish Oils/pharmacology/administration &amp; dosage ; *Gastrointestinal Microbiome/drug effects ; Middle Aged ; Cross-Over Studies ; Aged ; Male ; *Polysaccharides/pharmacology/administration &amp; dosage ; Female ; *Dietary Fiber/administration &amp; dosage/pharmacology ; *Corn Oil/administration &amp; dosage/pharmacology ; Feces/microbiology ; *Intestines/microbiology/drug effects ; }, abstract = {BACKGROUND: Concurrent consumption of dietary fiber and n-3 polyunsaturated fatty acids reduces colon tumor formation. However, their combined effects on colorectal cancer risk remain unexplored in human trials.<br><br>OBJECTIVES: This study investigated the synergistic effects of fish oil (FO) and fermentable fiber on the gut transcriptional profiles and microbiome composition in older adults.<br><br>METHODS: In a randomized controlled crossover pilot study, 30 adults (ages 50-75 y), received fermentable fiber (33 g/d soluble corn fiber; SCF) plus eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA as FO, 7.7 g/d) or a comparator (similar doses of maltodextrin plus corn oil; MD + CO) for 30 d, followed by a 60-d washout period before crossing over to the alternate intervention. Serum phospholipid fatty acids, stool exfoliome [ribonucleic acid sequencing (RNAseq)], microbiome (16S ribosomal ribonucleic acid gene sequencing), butyrate kinase (but) gene abundance (digital droplet polymerase chain reaction), and fecal short-chain fatty acids were analyzed. Linear mixed models were used for the majority of outcome analyses. Differential expression and pathway enrichment analyses were applied to RNAseq data, whereas microbiome diversity was assessed using &#x3b1; and &#x3b2; diversity.<br><br>RESULTS: Serum EPA and DHA concentrations were higher after SCF + FO than MD + CO supplementation [EPA: &#x3b2; = 0.51; 95% confidence interval: 0.31, 0.72; DHA: &#x3b2; = 0.18; 95% confidence interval: 0.10, 0.27; P < 0.0001]. Analysis of host gut transcriptional networks revealed that SCF + FO supplementation inhibited the glucose-insulin receptor-phosphatidylinositol-3 kinase-signaling axis. Microbiome analysis revealed significant intervention differences in &#x3b2;-diversity (F = 4.4, R[2] = 0.08, P = 0.001), and 27 of 73 genera analyzed, several known short-chain fatty acid producers, differed between the 2 interventions (false discovery rate <0.05). Abundance of the but gene from Roseburia sp (P < 0.001) and the genera Roseburia (P = 0.006) were lower in the SCF + FO compared to MD + CO intervention, although fecal butyrate concentrations did not differ.<br><br>CONCLUSIONS: Thirty-day supplementation of SCF + FO compared with MD + CO showed significant shifts in intestinal cell pathways relevant to colorectal cancer with concomitant differences in gut microbial community structure and butyrate-producing taxa.}, }
@article {pmid40757627, year = {2025}, author = {Truong, L and Adams, AK and Bishop, S and Dupuis, V and Garza, L and Quigley, T and Hassell, L and Drain, PK and Ibarra, G and Sorrell, AW and Warne, T and Gregor, C and Webber, E and Ko, LK}, title = {"It's not about me. It's about what's best for my community": Factors impacting COVID-19 vaccine uptake among Native Americans and Latinos from two agricultural communities.}, journal = {The Journal of rural health : official journal of the American Rural Health Association and the National Rural Health Care Association}, volume = {41}, number = {3}, pages = {e70057}, pmid = {40757627}, issn = {1748-0361}, support = {P20 GM104417/GM/NIGMS NIH HHS/United States ; /TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *COVID-19 Vaccines/administration &amp; dosage/therapeutic use ; *COVID-19/prevention &amp; control/ethnology ; Male ; Female ; Adult ; Focus Groups ; Middle Aged ; *Rural Population/statistics &amp; numerical data ; *Hispanic or Latino/psychology/statistics &amp; numerical data ; Montana/epidemiology ; Washington/epidemiology ; SARS-CoV-2 ; Aged ; *Patient Acceptance of Health Care/ethnology ; *Indians, North American/psychology/statistics &amp; numerical data ; Qualitative Research ; White ; }, abstract = {PURPOSE: While SARS-CoV-2 significantly impacts rural Native American and Latino communities, COVID-19 vaccines offer an effective and safe mitigation strategy. Vaccine uptake is disproportionately lower in rural communities than in urban communities across the nation. This study examined barriers and motivators of COVID-19 vaccine uptake in two Native American and Latino rural agricultural communities in eastern Washington and Montana.<br><br>METHODS: We conducted 28 key informant interviews with trusted community members and six community focus groups with 39 participants from May 2021 to June 2021. Participants were from the Yakima Valley (WA) and Flathead Reservation (MT). The Social Cognitive Theory and Social Context Framework informed development of the interview and focus group moderator guides. We used deductive and inductive approach to code transcripts and thematic analysis to generate themes.<br><br>FINDINGS: Barriers to COVID-19 vaccine uptake were misconceptions about COVID-19 vaccines shaped by misinformation, politicization of vaccines, historical trauma and mistrust in government, and structural barriers in rural agricultural communities. Having access to accurate and understandable COVID-19 vaccine information and receiving information from trusted sources were motivators of COVID-19 vaccine uptake. Protecting families, children, elders, and the community, and striving to return to normal life were also noted as motivators.<br><br>CONCLUSIONS: Understanding the community's perceptions and experiences around the COVID-19 vaccine is critical for successful implementation of strategies to increase vaccine uptake during future public health emergencies. Strategies for vaccine uptake among communities in the Flathead Reservation and Yakima Valley need to address barriers and highlight motivators of COVID-19 vaccine uptake.}, }
@article {pmid40757857, year = {2025}, author = {Shi, Z and Tsuge, M and Collier, N and Takeuchi, Y and Uchida, T and Rutter, CM and Teraoka, Y and Uprichard, SL and Ishida, Y and Tateno, C and Ozik, J and Dahari, H and Chayama, K}, title = {Modeling of hepatitis B virus infection spread in primary human hepatocytes.}, journal = {Journal of virology}, volume = {99}, number = {9}, pages = {e0092725}, pmid = {40757857}, issn = {1098-5514}, support = {R01 AI144112/AI/NIAID NIH HHS/United States ; R01 AI146917/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Hepatocytes/virology ; *Hepatitis B virus/physiology/genetics/drug effects ; DNA, Viral/metabolism/genetics ; Virus Replication ; *Hepatitis B, Chronic/virology ; Cells, Cultured ; Virus Internalization/drug effects ; Kinetics ; Animals ; Models, Biological ; *Hepatitis B/virology ; }, abstract = {Chronic hepatitis B virus (HBV) infection poses a significant global health threat, causing severe liver diseases including cirrhosis and hepatocellular carcinoma. We characterized HBV DNA kinetics in primary human hepatocytes (PHHs) over 32 days post-inoculation (p.i.) and modified our in-vivo agent-based modeling (ABM) to gain insights into the HBV lifecycle and spread in vitro. Parallel PHH cultures were mock-treated or treated with HBV entry inhibitor Myr-preS1 (6.25 µg/mL) was initiated 24 h p.i. In untreated PHH, three viral DNA kinetic patterns were identified: (i) an initial decline, followed by (ii) rapid amplification and (iii) slower amplification/accumulation. In the presence of Myr-preS1, viral DNA and infected cell numbers in phase 3 were effectively blocked, with minimal to no increase. This suggests that phase 2 represents viral amplification in initially infected cells, while phase 3 corresponds to viral spread to naïve cells. The ABM reproduced well the HBV kinetic patterns observed and predicted that the viral eclipse phase lasts between 18 and 38 h. After the eclipse phase, the viral production rate increased over time, starting with a slow production cycle of 1 virion per day, which gradually accelerated to 1 virion per hour after 3 days. Approximately 4 days later, virion production reached a steady state production rate of 4 virions/h. The estimated median efficacy of Myr-preS1 in blocking HBV spread was 91% (range: 90-92%). The HBV kinetics and the predicted estimates of the HBV eclipse phase duration and HBV production cycles in PHH are similar to those predicted in uPA/SCID mice with human livers.IMPORTANCEWhile primary human hepatocytes (PHHs) are the most physiologically relevant culture system for studying HBV infection in vitro, a comprehensive understanding of HBV infection kinetics and spread in PHH is lacking. In this study, we characterize HBV viral kinetics and modify our in vivo agent-based modeling (ABM) to provide quantitative insights into the HBV production cycle and viral spread in PHH. The ABM provides an estimate of the HBV eclipse phase duration, HBV production cycles, and Myr-preS1 efficacy in blocking HBV spread in PHH. The results resemble those predicted in uPA/SCID mice with human livers, demonstrating that estimated HBV infection kinetic parameters in PHH in vitro mirror those observed in the in vivo HBV infection chimeric mouse model.}, }
@article {pmid40758381, year = {2026}, author = {Kumar, R and Hwang, S and Antony, M and Valenzuela, RFP and Kumar, M}, title = {Musculoskeletal Myeloid Sarcoma: Clinical, Imaging, Management, and Outcomes in 41 Adult Patients.}, journal = {Journal of computer assisted tomography}, volume = {50}, number = {1}, pages = {133-143}, doi = {10.1097/RCT.0000000000001788}, pmid = {40758381}, issn = {1532-3145}, mesh = {Humans ; Male ; Female ; *Sarcoma, Myeloid/diagnostic imaging/therapy/pathology ; Adult ; Middle Aged ; Retrospective Studies ; Aged ; *Bone Neoplasms/diagnostic imaging/therapy ; *Muscle Neoplasms/diagnostic imaging/therapy ; Magnetic Resonance Imaging/methods ; Young Adult ; Treatment Outcome ; Adolescent ; }, abstract = {OBJECTIVE: To analyze symptoms, imaging features, management, and outcomes of musculoskeletal myeloid sarcoma in adult leukemic patients.<br><br>MATERIALS AND METHODS: This is a retrospective analysis of clinical symptoms, imaging features, management, and outcomes in 41 adult leukemic patients with biopsy-proven myeloid sarcomas of bones and muscles.<br><br>RESULTS: Nineteen patients had acute, and 15 had chronic myeloid leukemia. Additional 5 previously treated leukemia patients included 1 with chronic myeloid leukemia, 3 with myelofibrosis, and 1 with myelodysplastic syndrome. The remaining 2 patients had isolated myeloid sarcoma with normal marrow without a history of hematologic disorder. Twenty-nine patients had bone tumors only, 3 muscle tumors only, 8 both bone and soft tissue tumors, and 1 intraarticular synovial tumor of an ankle. Of the 71 focal bone tumors, 68 were lytic and 3 were sclerotic. In addition, diffuse sclerotic bone lesions were present in 1 patient, and diffuse mixed lytic/sclerotic bone lesions in 2 patients. Most tumors were asymptomatic and were discovered incidentally on imaging. Local pain, mass, and pathologic fractures were the most common complaints when present. Vertebral bone and paravertebral soft tissue tumors caused neurological symptoms. Muscle tumors became symptomatic when they involved adjoining bone, nerve, or spinal cord. Only 3 among 13 muscle tumors presented as palpable masses. The imaging features of these musculoskeletal tumors were nonspecific. On MRI, both muscle and lytic bone MSs were hypo-to-iso-intense on T1WI, hyperintense on fat-suppressed T2WI, and enhanced on post-contrast fat-suppressed T1WI. A synovial myeloid sarcoma of the ankle showed diffusely thickened synovium on MRI. F-18 FDG PET-CT was helpful in the detection, monitoring of treatment response, and post-treatment surveillance in 5 patients. All patients were treated with cytarabine-based systemic anti-leukemic treatment and optional radiation, surgical resection, bone marrow transplant, and/or a combination of these. The known mean survival time of 35 dead patients after the appearance of musculoskeletal MS was 12.1 months.<br><br>CONCLUSIONS: Musculoskeletal myeloid sarcoma, which can occasionally precede it, is a rare complication of AML. Most tumors are asymptomatic. Imaging, particularly MRI and 18-F FDG PET-CT, plays a crucial role in detecting and monitoring treatment response, as well as post-treatment surveillance. The disease has poor clinical outcomes and short-term survival.}, }
@article {pmid40758858, year = {2025}, author = {Vasconcelos, AG and Johnson, M and Cai, Y and Hsu, L and Franceschini, N and Auer, PL and Kooperberg, C and Raffield, LM and Reiner, AP}, title = {Methylation profile of individuals with sickle cell trait.}, journal = {Epigenetics}, volume = {20}, number = {1}, pages = {2539234}, pmid = {40758858}, issn = {1559-2308}, support = {HHSN268201100037C/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL116446/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; HHSN268201800012I/HB/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; }, mesh = {Humans ; *DNA Methylation ; *Sickle Cell Trait/genetics ; Female ; Male ; Adult ; Black or African American/genetics ; Middle Aged ; CpG Islands ; Epigenesis, Genetic ; Genome-Wide Association Study ; beta-Globins/genetics ; Epigenome ; White ; }, abstract = {Sickle cell trait (SCT) is due to heterozygosity for the β-globin sickle cell mutation. SCT recently has been associated with increased risk of various adverse health outcomes. DNA methylation (DNAm) is one potential mechanism by which SCT may impact disease risk. To identify DNAm sites associated with SCT, we conducted an epigenome-wide association (EWAS) meta-analysis using whole blood Illumina EPIC array data available in a total of 3,677 African American participants (including 1,071 with SCT) from the Women's Health Initiative and Jackson Heart Study. We identified 103 differentially methylated CpGs and 119 differentially methylated regions associated with SCT. The strongest signals were hypermethylated cis loci within predicted regulatory elements within or near the β-globin gene cluster on chromosome 11. Beyond the globin locus, SCT-associated DMPs were enriched in genes involved in redox regulation and oxidative stress. We also demonstrate an association of SCT with differences in biological age and epigenetic age acceleration, though the pattern and strength of association differ according to the epigenetic clock used. Specifically, more recent epigenetic clocks that incorporate clinical phenotypes or laboratory biomarkers related to adverse health outcomes are associated with accelerated aging among individuals with SCT compared to African American controls. Our results lay the groundwork for future study of the role of DNAm in biologic aging and related health outcomes among individuals with SCT.}, }
@article {pmid40758946, year = {2025}, author = {Nilius, H and Sinitsa, E and Studt, JD and Tsakiris, DA and Greinacher, A and Mendez, A and Schmidt, A and Wuillemin, WA and Gerber, B and Vishnu, P and Graf, L and Kremer Hovinga, JA and Bakchoul, T and Nagler, M}, title = {Outcomes of patients with suspected heparin-induced thrombocytopenia in a contemporary multicenter cohort.}, journal = {Blood advances}, volume = {9}, number = {21}, pages = {5546-5555}, pmid = {40758946}, issn = {2473-9537}, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; *Anticoagulants/adverse effects/therapeutic use ; Arginine/analogs &amp; derivatives ; *Heparin/adverse effects ; Hirudins ; Pipecolic Acids/therapeutic use ; Platelet Factor 4/immunology ; Prospective Studies ; *Thrombocytopenia/chemically induced/diagnosis/drug therapy/mortality ; Treatment Outcome ; Peptide Fragments ; Recombinant Proteins ; Sulfonamides ; }, abstract = {Managing patients with suspected heparin-induced thrombocytopenia (HIT) poses significant clinical challenges. Limited evidence exists on how management decisions impact clinical outcomes, leading to treatment recommendations based on low-certainty evidence. This study aimed to evaluate the treatment strategies and clinical outcomes of patients with suspected HIT in a contemporary multicenter cohort. We conducted a prospective, multicenter cohort study including consecutive patients with suspected HIT from 11 centers. Patients were stratified into 3 groups: (1) HIT confirmed, (2) HIT-negative but heparin/platelet factor 4 (PF4) antibody-positive, and (3) HIT-negative without antibodies. Clinical and laboratory data were systematically collected. HIT was diagnosed using the washed-platelet heparin-induced platelet activation test as the reference standard. Among 1393 patients (46% female, median age 67 years), HIT was confirmed in 119 (8.5%). Most patients were in intensive care (37%), or had undergone cardiac surgery (32%). Argatroban was the predominant treatment (70%), and platelet recovery occurred in 77% of patients with HIT. Among patients with HIT, subsequent venous thromboembolism occurred in 23%, arterial thromboembolism in 9%, major bleeding in 12.6%, and mortality in 18%, with no significant differences between anticoagulants. Treatment with argatroban, bivalirudin, or direct oral anticoagulants (DOACs) significantly reduced arterial thromboembolism risk. Outcomes did not differ between patients who were HIT-negative with or without heparin/PF4 antibodies. HIT, as well as the mere suspicion of HIT, remains a serious condition with a high risk of adverse outcomes, including death. Our findings provide further evidence supporting the effectiveness of DOACs, argatroban, and bivalirudin in reducing arterial thromboembolism risk.}, }
@article {pmid40759764, year = {2025}, author = {Talbert, PB and Henikoff, S}, title = {Centromeres drive and take a break.}, journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology}, volume = {33}, number = {1}, pages = {17}, pmid = {40759764}, issn = {1573-6849}, mesh = {*Centromere/genetics/metabolism ; Animals ; Humans ; DNA Replication ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; DNA, Satellite/genetics ; Meiosis ; Kinetochores/metabolism ; Evolution, Molecular ; }, abstract = {The identification of CENPA, CENPB, and CENPC by Earnshaw and Rothfield 40 years ago has revealed the remarkable diversity and complexity of centromeres and confirmed most seed plants and animals have centromeres comprised of complex satellite arrays. The rapid evolution of centromeres and positive selection on CENPA and CENPC led to the centromere drive model, in which competition between tandem satellite arrays of differing size and centromere strength for inclusion in the egg of animals or megaspore of seed plants during female meiosis drives rapid evolution of centromeres and kinetochore proteins. Here we review recent work showing that non-B-form DNA structures in satellite centromeres make them sites of frequent replication fork stalling, and that repair of collapsed forks by break-induced replication rather than unequal sister chromatid exchange is likely the primary mode of satellite expansion and contraction, providing the variation in satellite copy number that is the raw material of centromere drive. Centromere breaks at replication, rather than errors at mitosis, can account for most centromere misdivisions that underlie aneuploidies in cancer.}, }
@article {pmid40762207, year = {2025}, author = {Thiruvengadam, SK and Ahn, KW and Patel, J and Lian, Q and Hertzberg, M and Epperla, N and Metheny, L and Hong, S and Jain, T and Aljurf, M and Beitinjaneh, A and Vaughn, J and Gopal, A and Iqbal, M and Wirk, B and Manjappa, S and Oliver, C and Mohty, R and Shadman, M and Turtle, C and Hamadani, M and Herrera, AF}, title = {CD19 Directed CAR T Therapy for Transformed Follicular Lymphoma: A CIBMTR Analysis.}, journal = {American journal of hematology}, volume = {100}, number = {10}, pages = {1803-1812}, pmid = {40762207}, issn = {1096-8652}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; U01 AI184132/AI/NIAID NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, Follicular/therapy/mortality/immunology ; Middle Aged ; Aged ; Male ; Adult ; Female ; *Antigens, CD19/immunology ; *Immunotherapy, Adoptive/methods/adverse effects ; Aged, 80 and over ; *Receptors, Chimeric Antigen ; Registries ; Biological Products ; }, abstract = {Transformed follicular lymphoma (tFL) is typically associated with chemotherapy resistance and a poor prognosis. There are limited data regarding outcomes after CD19-directed chimeric antigen receptor T-cell (CAR T) therapy in relapsed/refractory (R/R) tFL. A total of 923 adult patients with R/R tFL who received commercial CD19 CAR T therapy between 2017 and 2023 were identified in the Center for International Blood and Marrow Transplant Research registry. Median age was 64 years (range: 30-86) and median prior lines of therapy was 4 (range: 1-18). Most patients (78%) received axicabtagene ciloleucel, with 67% of patients having resistant disease at the time of CAR T infusion. At a median follow-up of 25 months (range: 1-72) from CAR T infusion, the 2-year overall survival (OS) was 57% (95% CI: 53-60) and progression-free survival (PFS) was 43% (95% CI: 40-47). The 2-year cumulative incidences of relapse or progression (rel/prog) and non-relapse mortality (NRM) were 47% (95% CI: 44-51) and 9% (95% CI: 7-11), respectively. The overall response rate to CAR T was 76%, with a complete response rate of 63%. Grade ≥ 3 cytokine release syndrome (CRS) was observed in 7.1% and grade ≥ 3 immune effector cell-associated neurologic syndrome (ICANS) in 21.6% of patients. Multivariable analysis suggested that resistant disease status at the time of CAR T, use of bridging therapy, and high comorbidity index ≥ 3 were associated with inferior PFS and OS. Older age ≥ 60 significantly increased the risk of NRM. Our study suggests that CD19 CAR T is effective and safe for tFL.}, }
@article {pmid40762835, year = {2025}, author = {Duffy, AM and Goenka, A and Azeem, MI and Taz, A and Potdar, SV and Scott, SA and Marin, E and Kaufman, JL and Hofmeister, CC and Joseph, NS and Gupta, VA and Lonial, S and Nooka, AK and Dhodapkar, MV and Dhodapkar, KM}, title = {Early CD4+ T cell proliferation and chronic T cell engagement impact myeloma outcomes following T cell engager therapy.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {19}, pages = {}, pmid = {40762835}, issn = {1558-8238}, support = {R01 CA289978/CA/NCI NIH HHS/United States ; }, }
@article {pmid40763029, year = {2025}, author = {McGuire, DJ and Akondy, RS and Yang, S and Edupuganti, S and Nagar, S and Michael, G and De Rosa, SC and Newell, EW and Farber, DL and Kissick, HT and McElrath, MJ and Ahmed, R}, title = {Regulation of CD45 isoforms during human effector and memory CD8 T cell differentiation: Implications for T cell nomenclature.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {32}, pages = {e2322982122}, pmid = {40763029}, issn = {1091-6490}, support = {U19 AI057266/AI/NIAID NIH HHS/United States ; UL1 TR002378/TR/NCATS NIH HHS/United States ; U19 AI057266-S1//HHS | NIH | NIAID | Division of Intramural Research (DIR, NIAID)/ ; }, mesh = {Humans ; *Leukocyte Common Antigens/immunology/metabolism/genetics ; *CD8-Positive T-Lymphocytes/immunology/cytology/metabolism ; *Immunologic Memory/immunology ; *Cell Differentiation/immunology ; Protein Isoforms/immunology ; *Memory T Cells/immunology ; Receptors, CCR7 ; SARS-CoV-2/immunology ; Yellow Fever Vaccine/immunology ; COVID-19/immunology ; Yellow fever virus/immunology ; }, abstract = {This study examines the expression of CD45 isoforms on human yellow fever virus vaccine (YFV-17D) specific CD8 T cells longitudinally after vaccination. As expected, effector CD8 T cells at day 14 express CD45RO but within 4 to 6 wk these virus-specific CD8 T cells become CD45RA positive and remain CD45RA for >10 y. The journey for these YFV-specific CD8 T cells goes from naive (CD45RA+ CCR7+) to effector/effector memory (CD45RO+ CCR7-) to Temra (CD45RA+ CCR7-) to stem-cell memory (CD45RA+ CCR7+). These YFV-specific CD8 T cells rarely acquire the canonical Tcm phenotype (CD45RO+ CCR7+). This CD45RO to RA switch coincides with clearance of YFV, so we hypothesized that antigen may be playing a role in regulating CD45 expression. We addressed this issue by ex vivo analysis and provide evidence that this switch is indeed regulated by antigen. Sorted YFV-specific CD45RO effector CD8 T cells reexpress CD45RA when cultured ex vivo in the absence of antigen and retain CD45RO in the presence of cognate peptide. We also extended these ex vivo analysis to human cytomegalovirus (CMV)-specific CD8 T cells and show that CD45RO cells transition to CD45RA in the absence of antigen and CD45RA cells become CD45RO when stimulated with CMV peptide. We then show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-specific CD8 T cells can repeatedly undergo the same CD45RA to RO to RA transition in vivo after the SARS-CoV-2 mRNA vaccination. Again, the canonical Tcm phenotype spike-specific memory CD8 T cells were not readily detectable. These studies warrant a reevaluation of how human memory CD8 T cells are defined.}, }
@article {pmid40763278, year = {2025}, author = {Simonin, M and Boissel, N and Petit, A and Mullighan, CG and Hunger, SP and Loh, ML and Winter, SS and Macintyre, E and Teachey, DT and Baruchel, A and Asnafi, V}, title = {Prognostic impact of the PredicT-ALL classifier in the AALL0434 trial: a model combining NGS, MRD, and WBC at diagnosis.}, journal = {Blood advances}, volume = {9}, number = {20}, pages = {5323-5326}, pmid = {40763278}, issn = {2473-9537}, }
@article {pmid40763299, year = {2025}, author = {Gauderman, WJ and Fu, Y and Queme, B and Kawaguchi, E and Wang, Y and Morrison, J and Brenner, H and Chan, A and Gruber, SB and Keku, T and Li, L and Moreno, V and Pellatt, AJ and Peters, U and Samadder, NJ and Schmit, SL and Ulrich, CM and Um, C and Wu, A and Lewinger, JP and Drew, DA and Mi, H}, title = {Pathway polygenic risk scores (pPRS) for the analysis of gene-environment interaction.}, journal = {PLoS genetics}, volume = {21}, number = {8}, pages = {e1011543}, pmid = {40763299}, issn = {1553-7404}, support = {U01 HG004446/HG/NHGRI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA042182/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; R01 CA097325/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; P30 ES007048/ES/NIEHS NIH HHS/United States ; U01 HG004438/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U10 CA037429/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA006973/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA152753/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA242218/CA/NCI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; R01 CA143237/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; U01 CA093326/CA/NCI NIH HHS/United States ; U01 CA086308/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R03 CA153323/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; R01 CA136726/CA/NCI NIH HHS/United States ; K05 CA152715/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; R35 CA253185/CA/NCI NIH HHS/United States ; UM1 CA182883/CA/NCI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; }, mesh = {Humans ; *Gene-Environment Interaction ; *Multifactorial Inheritance/genetics ; *Colorectal Neoplasms/genetics/pathology ; Genetic Predisposition to Disease ; Risk Factors ; Polymorphism, Single Nucleotide ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Genome-Wide Association Study ; Genetic Risk Score ; }, abstract = {A polygenic risk score (PRS) is used to quantify the combined disease risk of many genetic variants. For complex human traits there is interest in determining whether the PRS modifies, i.e. interacts with, important environmental (E) risk factors. Detection of a PRS by environment (PRS x E) interaction may provide clues to underlying biology and can be useful in developing targeted prevention strategies for modifiable risk factors. The standard PRS may include a subset of variants that interact with E but a much larger subset of variants that affect disease without regard to E. This latter subset will dilute the underlying signal in former subset, leading to reduced power to detect PRS x E interaction. We explore the use of pathway-defined PRS (pPRS) scores, using state of the art tools to annotate subsets of variants to genomic pathways. We demonstrate via simulation that testing targeted pPRS x E interaction can yield substantially greater power than testing overall PRS x E interaction. We also analyze a large study (N = 78,253) of colorectal cancer (CRC) where E = non-steroidal anti-inflammatory drugs (NSAIDs), a well-established protective exposure. While no evidence of overall PRS x NSAIDs interaction (p = 0.41) is observed, a significant pPRS x NSAIDs interaction (p = 0.0003) is identified based on SNPs within the TGF-β/ gonadotropin releasing hormone receptor (GRHR) pathway. NSAIDS is protective (OR=0.84) for those at the 5th percentile of the TGF-β/GRHR pPRS (low genetic risk, OR), but significantly more protective (OR=0.70) for those at the 95th percentile (high genetic risk). From a biological perspective, this suggests that NSAIDs may act to reduce CRC risk specifically through genes in these pathways. From a population health perspective, our result suggests that focusing on genes within these pathways may be effective at identifying those for whom NSAIDs-based CRC-prevention efforts may be most effective.}, }
@article {pmid40764177, year = {2025}, author = {Raychaudhuri, R and Khaki, AR and Redman, MW and Baker, KK and Ng, K and Chen, X and Mao, J and Woo, B and Lin, A and Hannochka, A and Conrad, N and Kahugu, M and Panlasigui, P and Haffner, MC and Hsieh, AC and Lam, HM and Vakar-Lopez, F and Yezefski, T and Schweizer, MT and Montgomery, RB and Yu, EY and Dash, A and Psutka, SP and Lin, DW and Schade, GR and Gore, JL and Wright, JL and Grivas, P}, title = {Neoadjuvant Pembrolizumab and Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Nonurothelial Histologic Subtypes of Muscle-invasive Bladder Cancer: A Phase 2 Trial.}, journal = {European urology}, volume = {88}, number = {6}, pages = {559-563}, doi = {10.1016/j.eururo.2025.07.002}, pmid = {40764177}, issn = {1873-7560}, mesh = {Humans ; *Urinary Bladder Neoplasms/pathology/drug therapy/mortality ; Cisplatin/administration &amp; dosage/adverse effects ; Methotrexate/administration &amp; dosage/adverse effects ; Doxorubicin/administration &amp; dosage/adverse effects ; Male ; Neoadjuvant Therapy ; Female ; Vinblastine/administration &amp; dosage/adverse effects ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects ; Middle Aged ; Aged ; Neoplasm Invasiveness ; Treatment Outcome ; }, abstract = {Muscle-invasive bladder cancer (MIBC) with histologic subtypes represents a clinical challenge because of poor responses to conventional therapies and under-representation in clinical trials. This single-center phase 2 trial evaluated the combination of neoadjuvant pembrolizumab and accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (aMVAC) chemotherapy in patients with pure or predominant nonurothelial histologies. Seventeen patients were enrolled, with squamous differentiation being the most common variant. The primary endpoint, a pathologic complete response (pCR), was achieved in nine of 17 patients (53%), with an additional patient achieving ypTisN0 (downstaging rate 59%) and another achieving a clinical complete response. Grade ≥3 toxicities were observed in 47% of patients, primarily attributable to aMVAC. At median follow-up of 35 mo (range 11-48) the estimated 2-yr event-free survival (EFS) and overall survival rates were 64% (95% confidence interval 32-84%) and 79% (95% confidence interval 47-93%), respectively. Preliminary biomarker analysis did not reveal significant correlations between immune-cell subsets at baseline and pCR or EFS. These findings suggest that chemoimmunotherapy is a very promising approach for MIBC with histology subtypes. Larger studies are warranted to further refine therapeutic strategies.}, }
@article {pmid40764319, year = {2025}, author = {Wilcox-King, A and Wan, YH and Scharffenberger, SC and Chhan, CB and Davis, AR and Homad, LJ and Seydoux, E and MacPhee, KJ and Siddaramaiah, LK and Melo, M and Dosenovic, P and Irvine, DJ and Hyrien, O and Stamatatos, L and McGuire, AT}, title = {Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope.}, journal = {NPJ vaccines}, volume = {10}, number = {1}, pages = {185}, pmid = {40764319}, issn = {2059-0105}, support = {UM1 AI144462/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; INV-032929/GATES/Gates Foundation/United States ; UM1AI144462//National Institute of Allergy and Infectious Diseases/ ; INV-032929/GATES/Gates Foundation/United States ; P01 AI138212/AI/NIAID NIH HHS/United States ; P01AI138212//National Institute of Allergy and Infectious Diseases/ ; }, abstract = {VRC01-class antibodies are a genetically restricted class of antibodies capable of potently neutralizing diverse strains of HIV-1. Unmutated VRC01 precursors fail to recognize recombinant HIV-1 Envelope (Env) proteins, which necessitated the development of germline targeting vaccine immunogens capable of initiating VRC01-class B cell response. Among these, we developed an anti-idiotypic monoclonal antibody (ai-mAb)-derived VRC01 class targeting immunogen. Because it is distinct from Env, we speculated that the ai-mAb will selectively engage naive VRC01 class B cells while limiting B cell responses directed at off-target epitopes on Env during prime-boost regimens. Here, we evaluated the serum and B cell responses to ai-mAb prime/Env boost, and Env-prime/Env boost regimens in a murine adoptive transfer model where VRC01 precursor B cells are present at physiological levels. We found that the Env-Env regimen led to the greatest expansion of on-target VRC01 B cells, drove larger VRC01-class GC responses, and elicited higher titers of circulating antibodies despite also eliciting substantial off-target Env-specific responses. Single-cell sorting experiments revealed that the ai-mAb was driving off-track somatic mutations. IgG transfer experiments demonstrated that circulating off-target antibodies provide a positive feedback mechanism that potentiates on-target B cell responses. Collectively, the results suggest that non-Env immunogens are not ideal for priming VRC01-class B cells, where sequential boosting with Env will be required to drive maturation of neutralizing breadth.}, }
@article {pmid40765672, year = {2025}, author = {Heit, M and Cohen, SA}, title = {Contemporary Use of ctDNA for the Colorectal Surgeon.}, journal = {Clinics in colon and rectal surgery}, volume = {38}, number = {5}, pages = {334-338}, pmid = {40765672}, issn = {1531-0043}, abstract = {While advances in treatment and diagnostics have improved prognosis in colorectal cancer (CRC), room for advancement remains, highlighting the importance of improving tools for early detection and treatment guidance. Current national guidelines rely on stage-based treatment recommendations but fail to identify patients with lower stage disease who have a higher likelihood of recurrence or those for whom additional therapy may not be beneficial. Circulating tumor DNA (ctDNA) is an emerging noninvasive blood-based assay, which can inform cancer status as a single time point and/or longitudinal biomarker. ctDNA can be used for the diagnosis of cancer, detection of minimal/molecular residual disease, molecular profiling, and assessing treatment response. In patients for whom operative management is indicated, detectable ctDNA is associated with worse survival outcomes. This review highlights the expanding field of ctDNA in CRC, underlining pivotal data and areas with the need for more research that are key for colorectal surgeons to understand.}, }
@article {pmid40765894, year = {2025}, author = {Naifeh, JA and Edwards, ER and Bentley, KH and Gildea, SM and Kennedy, CJ and King, AJ and Kleiman, EM and Luedtke, A and Nassif, TH and Nock, MK and Sampson, NA and Zainal, NH and Stein, MB and Capaldi, VF and Ursano, RJ and Kessler, RC}, title = {Predicting suicide attempts among US Army soldiers using information available at the time of periodic health assessments.}, journal = {Nature. Mental health}, volume = {3}, number = {2}, pages = {242-252}, pmid = {40765894}, issn = {2731-6076}, support = {U01 MH087981/MH/NIMH NIH HHS/United States ; }, abstract = {The value of population screening for suicide risk remains unclear. The U.S. Army's annual medical examination, the Periodic Health Assessment (PHA), screens for suicidality and other mental and physical health problems. This 2014-2019 cohort study used PHA and Army administrative data (n=1,042,796 PHAs from 452,473 soldiers) to develop a model to predict 6-month nonfatal and fatal suicide attempts (SAs). The model was designed to establish eligibility for a planned high-risk SA prevention intervention. The PHA suicide risk screening questions had limited value, as 95% of SAs occurred among soldiers who denied suicidality. However, a simple lasso penalized regression model that included a wide range of administrative predictors had good test sample discrimination (0.794 [SE=0.009] area under the receiver operating characteristic curve) and calibration (0.0001 integrated calibration index). The 25% of soldiers at highest predicted risk accounted for 69.5% of 6-month SAs, supporting use of the model to target preventive interventions.}, }
@article {pmid40766138, year = {2025}, author = {Harmon, LM and Hattig, ZS and Huang, YP and Beckford, C and Farrar, J and Pollard, JA and Zarnegar-Lumley, S and Ma, X and Ries, RE and Meshinchi, S and Godley, LA and Triche, TJ}, title = {Germline Variant Burden Warrants Universal Genetic Testing in Pediatric Myeloid Leukemia.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40766138}, support = {F99 CA294248/CA/NCI NIH HHS/United States ; R03 CA290259/CA/NCI NIH HHS/United States ; }, abstract = {Causal germline genetic variants are frequently detected in young (under age 40) patients presenting with myelodysplastic syndromes (MDS) or bone marrow failure (BMF), where progression to acute myeloid leukemia (AML) contributes substantially to mortality in these patients. We reasoned that de novo pediatric AML, which shares clinical and biological characteristics, might also share germline genetic risk variants. We investigated germline variants in a large cohort (n=365) of pediatric AML patients with whole-genome sequencing (WGS), 29 with matched marrow-derived stromal cells, and 336 with matched remission marrow samples. Variants were deemed "likely germline" based on variant allele frequency (VAF) across available samples. Following American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guidelines, we annotated pathogenic/likely pathogenic (P/LP) variants in 555 genes linked to leukemia risk. P/LP variants were identified in 5.5% (95% CI: (3.3%,7.9%)) of patients in genes linked to familial myeloid malignancy and an additional 3.3% (95% CI: (1.6%,5.2%)) of patients in genes conferring risk to lymphoid malignancy or solid tumors. The large cohort enabled burden testing, which we employed by comparing loss-of-function variants between patients and 2504 control subjects from the 1000 Genomes Project. There was a 6.9-fold (95% CI: (3.1,14.9)) increase in loss-of-function variants in genes implicated in myeloid malignancy risk, a 2.4-fold (95% CI: (1.7,3.2)) increase in candidate risk genes, and a 1.6-fold (95% CI: (1.1,2.3)) increase in randomly-selected genes. We then assembled cohorts totaling 4,622 pediatric and adult patients with acute leukemia or MDS from 10 published studies, and compared P/LP variant burdens across age and diagnosis. The prevalence of germline variants in myeloid malignancies across age groups exceeds 5% consistently and with high confidence. Because the National Comprehensive Cancer Network recommends that all patients receive screening if their pre-test germline variant probability exceeds 5%, our results support germline genetic variant testing as an integral component of diagnostic work-up for myeloid malignancies, including donor selection for stem cell transplantation.}, }
@article {pmid40766360, year = {2025}, author = {Dosey, A and Dadonaite, B and Gillespie, RA and Leaf, EM and Vukovich, MJ and McGowan, J and Grey, E and Muramatsu, H and Jun, RHJ and Pardi, N and Kanekiyo, M and Bloom, JD and King, NP}, title = {Stabilization of H5 highly pathogenic avian influenza hemagglutinin improves vaccine-elicited neutralizing antibody responses.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766360}, issn = {2692-8205}, support = {75N93021C00015/AI/NIAID NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; U19 AI181881/AI/NIAID NIH HHS/United States ; }, abstract = {Transmission of highly pathogenic avian influenza from H5 clade 2.3.4.4b has expanded in recent years to infect large populations of birds and mammals, heightening the risk of a human pandemic. Influenza viruses adapted to transmission in birds and some other animals tend to have a less stable hemagglutinin (HA) than seasonal influenza viruses, enabling membrane fusion at comparatively high pH levels. Here, we combine five mutations within H5 HA that dramatically increase its melting temperature and promote stable closure of the HA trimer. Structural analysis by cryo-electron microscopy revealed that the stabilizing mutations create several new hydrophobic interactions, while maintaining local HA structure. We found that vaccinating mice with stabilized H5 HA immunogens resulted in higher hemagglutination inhibition and neutralization titers than non-stabilized comparators. Epitope mapping of vaccine-elicited polyclonal antibody responses using negative stain electron microscopy and deep mutational scanning showed that site E on the side of the HA receptor binding domain was immunodominant across all groups; however, the stabilized immunogens shifted responses toward the receptor binding site (RBS), eliciting a higher proportion of neutralizing antibodies. These findings highlight that H5 HA-stabilizing mutations enhance the quality of antibody responses across different vaccine formats, underscoring their potential to improve pandemic preparedness vaccines targeting viruses from this widely circulating clade.}, }
@article {pmid40766425, year = {2025}, author = {Chambwe, N and Kennedy, SR and Kohrn, BF and Lazarchuk, P and Leutert, M and Qin, G and Tercan, B and Sanchez-Contreras, M and Tang, W and Graber, JJ and Paddison, PJ and Villén, J and Shmulevich, I and Monnat, RJ}, title = {Cellular heterogeneity and therapeutic response profiling of human IDH+ glioma stem cell cultures.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766425}, issn = {2692-8205}, support = {R35 GM153370/GM/NIGMS NIH HHS/United States ; P01 CA077852/CA/NCI NIH HHS/United States ; R35 GM152061/GM/NIGMS NIH HHS/United States ; R21 CA259780/CA/NCI NIH HHS/United States ; R35 GM133428/GM/NIGMS NIH HHS/United States ; R21 HG011229/HG/NHGRI NIH HHS/United States ; }, abstract = {Glioblastoma stem cell (GSC) cultures are initiated from glioblastoma (GBM) surgical resection tissue. They can capture and propagate key GBM primary tumor molecular and cellular features. We have deeply characterized four isocitrate dehydrogenase (IDH)-expressing (or IDH+) GSC cultures from unrelated adults to serve as cellular models for the majority of adult primary GBM. We demonstrate that GSC cultures can be continuously propagated in defined, serum-free media and 5% oxygen without requiring specialized growth substrates; have well-defined genomic and mtDNA variants and gene/protein expression profiles; and highly reproducible dose-survival curves when treated with the GBM standard-of-care therapies of ionizing radiation (IR) and temozolomide (TMZ). We also illustrate how expressed lentiviral barcodes, mtDNA variants and single cell gene expression profiling can be used to define and track cellular heterogeneity over 40 days after IR treatment. These well-characterized IDH+ GSC cultures can support many high throughput in vitro assay formats, including xenograft, organoid and other GBM disease modeling protocols. They should prove a useful resource to better understand GBM biology, and to identify new and more effective GBM therapies and treatment regimens.}, }
@article {pmid40766464, year = {2025}, author = {Holland, M and Ahmed, M and Young, JM and McFadyen, S and Drurey, JR and Ostrowski, EA and Levin, TC}, title = {Hypermutable hotspot enables the rapid evolution of self/non-self recognition genes in Dictyostelium.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766464}, issn = {2692-8205}, support = {R01 GM074108/GM/NIGMS NIH HHS/United States ; R35 GM150681/GM/NIGMS NIH HHS/United States ; }, abstract = {Cells require highly polymorphic receptors to perform accurate self/non-self recognition. In the amoeba Dicytostelium discoideum, polymorphic TgrB1 &amp; TgrC1 proteins are used to bind sister cells and exclude cheaters, but it remains unknown how cells continually generate this extreme genetic diversity. Here, we created a collection of chromosome-length, whole genome sequences from 10 Dictyostelium discoideum isolates and sister species to understand the evolution of the large tgr gene family. Our dataset includes AX2-214, a widely used D. discoideum lab strain, as well as complete genomes for two Chlamydia-like endosymbionts harbored within amoebae. We find that tgrB1 and C1 lie in a hypermutational hotspot, with haplotypes that undergo repeated intralocus recombination, duplications, transpositions, and inversions. These structural dynamics are highly localized adjacent to tgrB and C, resulting in the gain and loss of dozens of genes. The tgrBC genes themselves frequently duplicate and recombine, leading to the rapid generation of unique tgrBC repertoires. In the broader tgr gene family, some genes (e.g. tgrN) are single copy and syntenic across all the genomes, whereas others (e.g. tgrA) prolifically duplicate at similar rates to Dictyostelium transposons. Thus, the tgr genes are among the most rapidly evolving families genome-wide. We propose that the intense diversification within the tgrBC locus can help explain how these genes acquire such extreme levels of polymorphism, with parallels to the MHC immune genes in mammals and other allorecognition systems. This collection of amoeba genomes is also an ideal dataset for comparative genomics and molecular evolution in Amoebozoa.}, }
@article {pmid40766494, year = {2025}, author = {Shih, RM and Arimura, Y and Konishi, HA and Funabiki, H}, title = {IMPACTS OF DNA METHYLATION ON H2A.Z DEPOSITION AND NUCLEOSOME STABILITY.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40766494}, issn = {2692-8205}, support = {R35 GM132111/GM/NIGMS NIH HHS/United States ; }, abstract = {In eukaryotes with DNA methylation, the histone variant H2A.Z and DNA methylation are maintained in mutually exclusive sections of the genome. How this antagonism is established, however, remains an open question. Here, we examined the impacts of DNA methylation on both the intrinsic stability of H2A.Z nucleosomes and chaperone-mediated H2A.Z deposition. Cryo-EM and endonuclease accessibility analyses show that H2A.Z nucleosomes with methylated DNA are more open and accessible compared to their unmethylated counterparts. In Xenopus laevis, H2A.Z preferentially associates with unmethylated DNA in both the fibroblast cell line XTC-2 and sperm pronuclei formed in the transcriptionally silent egg extract. The proportion of H2A.Z that colocalizes with methylated DNA, however, is higher in sperm pronuclei than in XTC-2. By monitoring nucleosome assembly on synthetic DNA constructs in Xenopus egg extracts, we find that the H2A.Z bias for unmethylated substrates is dependent on the SRCAP complex, the major H2A.Z deposition chaperone. Consistently, recruitment of the SRCAP complex to DNA is suppressed by DNA methylation. Altogether, we propose that the SRCAP complex is the major determinant for preferential H2A.Z enrichment on unmethylated DNA, whereas DNA methylation destabilizes DNA wrapping in H2A.Z-containing nucleosomes.}, }
@article {pmid40767528, year = {2025}, author = {Lee, HJ and Gulati, R and Sayar, E and Patel, RA and Itagi, P and Richards, HM and Persse, T and Arora, S and Coleman, I and Adil, M and Schuster, SL and Shokri, F and Wright, JL and Yu, EY and True, LD and Chambers, M and Hawley, JE and Cheng, HH and Schweizer, MT and Grivas, P and Nelson, PS and Montgomery, RB and Hsieh, AC and Vakar-Lopez, F and Morrissey, C and Lam, HM and Ha, G and Tretiakova, MS and Haffner, MC and Raychaudhuri, R}, title = {Patterns of HER2 Expression in Metastatic Prostate and Urothelial Cancers: Implications for HER2-Targeted Therapies.}, journal = {Cancer research communications}, volume = {5}, number = {8}, pages = {1419-1428}, pmid = {40767528}, issn = {2767-9764}, support = {//Institute for Prostate Cancer Research (IPCR)/ ; 2021184//Doris Duke Charitable Foundation (DDCF)/ ; R21 CA277368/CA/NCI NIH HHS/United States ; W81XWH-20-1-0111//U.S. Department of Defense (DOD)/ ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; //V Foundation for Cancer Research (VFCR)/ ; R37CA286450//National Cancer Institute (NCI)/ ; W81XWH-21-1-0264//U.S. Department of Defense (DOD)/ ; W81XWH-21-1-0229//U.S. Department of Defense (DOD)/ ; PC-SYNERGY//Prostate Cancer Foundation (PCF)/ ; R37 CA286450/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; P50CA097186//National Cancer Institute (NCI)/ ; R50 CA221836/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA280056/CA/NCI NIH HHS/United States ; R50CA274336//National Cancer Institute (NCI)/ ; R50 CA274336/CA/NCI NIH HHS/United States ; R50CA221836//National Cancer Institute (NCI)/ ; R21CA277368//National Cancer Institute (NCI)/ ; R01CA276308//National Cancer Institute (NCI)/ ; R35CA274442//National Cancer Institute (NCI)/ ; HT94252410755//U.S. Department of Defense (DOD)/ ; R01CA266452//National Cancer Institute (NCI)/ ; R50CA22183//National Cancer Institute (NCI)/ ; RS-2024-00334566//National Research Foundation of Korea (NRF)/ ; K08 CA282978/CA/NCI NIH HHS/United States ; R35 CA274442/CA/NCI NIH HHS/United States ; R37 CA230617/CA/NCI NIH HHS/United States ; W81XWH-22-1-0278//U.S. Department of Defense (DOD)/ ; W81XWH-17-2-0043//U.S. Department of Defense (DOD)/ ; R37CA230617//National Cancer Institute (NCI)/ ; P01 CA163227/CA/NCI NIH HHS/United States ; W81XWH-18-1-0689//U.S. Department of Defense (DOD)/ ; R01 CA276308/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Erb-b2 Receptor Tyrosine Kinases/genetics/metabolism/antagonists &amp; inhibitors ; *Prostatic Neoplasms/pathology/genetics/drug therapy/metabolism ; Aged ; Middle Aged ; *Biomarkers, Tumor/metabolism/genetics ; Molecular Targeted Therapy ; Neoplasm Metastasis ; Aged, 80 and over ; *Urinary Bladder Neoplasms/pathology/genetics/drug therapy/metabolism ; }, abstract = {UNLABELLED: HER2 is an oncogenic driver in multiple cancers and a predictive biomarker for HER2-targeted therapies. Although HER2-directed therapies like fam-trastuzumab deruxtecan are approved for HER2-positive breast and other solid tumors, the landscape of HER2 expression in advanced prostate cancer and urothelial carcinoma remains inadequately characterized. We evaluated HER2 protein expression in metastatic prostate cancer and urothelial carcinoma using a validated IHC assay on tissue microarrays constructed from the University of Washington Tissue Acquisition Necropsy Program. HER2 expression was scored using standardized gastric cancer criteria. Genomic analysis of ERBB2 alterations was conducted on a subset of samples. HER2 expression heterogeneity and its relationship with other surface markers were also evaluated. In the prostate cancer cohort (n = 52 patients, 1-19 tumors per patient), HER2 expression was low, with no 3+ expression observed and only five (10%) patients exhibiting 2+ expression. Low-level ERBB2 copy-number gains were observed in some tumors but did not correlate with HER2 protein expression (P = 0.2). In urothelial carcinoma (n = 20, 2-6 tumors per patient), HER2 expression was more frequent, with ≥2+ expression observed in six (30%) cases and 3+ expression observed in three (15%) cases in at least one tumor. Urothelial carcinoma samples showed less heterogeneity, with more consistent expression across metastases. HER2 overexpression is rare and heterogeneous in metastatic prostate cancer, limiting its utility as a therapeutic target. HER2 expression is more prevalent and uniform in urothelial carcinoma. These findings underscore the importance of comprehensive HER2 assessment in advanced urothelial carcinoma and suggest that success of HER2-directed therapies in prostate cancer will require careful case selection.<br><br>SIGNIFICANCE: This study demonstrates that HER2 is rarely overexpressed in metastatic prostate cancer but is more common and consistent in urothelial carcinoma. These findings highlight the need for HER2 testing in urothelial cancer and suggest that HER2-targeted therapies in prostate cancer will require careful patient selection.}, }
@article {pmid40767935, year = {2025}, author = {Brennan, MA and Plichta, JK and Rozenblit, M and Flanagan, MR}, title = {Surgeon Attitudes on the Management of de novo Oligometastatic Breast Cancer.}, journal = {Annals of surgical oncology}, volume = {32}, number = {13}, pages = {9478-9479}, pmid = {40767935}, issn = {1534-4681}, }
@article {pmid40769077, year = {2025}, author = {Goya, S and Nunley, EB and Longley, PC and Mathis, JR and Varela, CG and Kim, DY and Nurik, M and Naccache, SN and Greninger, AL}, title = {Phylodynamics of human metapneumovirus and evidence for a duplication-deletion model in G gene variant evolution.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {180}, number = {}, pages = {105848}, doi = {10.1016/j.jcv.2025.105848}, pmid = {40769077}, issn = {1873-5967}, mesh = {*Metapneumovirus/genetics/classification ; Humans ; Phylogeny ; *Paramyxoviridae Infections/epidemiology/virology ; *Evolution, Molecular ; Genome, Viral ; Washington/epidemiology ; Gene Duplication ; Genetic Variation ; COVID-19/epidemiology/virology ; Gene Deletion ; Seasons ; }, abstract = {BACKGROUND: In December 2024, human metapneumovirus (hMPV) gained global attention amid rising cases in Chinese hospitals, prompting a World Health, Organization (WHO) statement indicating case numbers remained within expected ranges. To assess whether a variant of public health concern was emerging and to examine global hMPV phylodynamics, we conducted a genomic surveillance study in western Washington State.<br><br>STUDY DESIGN: We sequenced hMPV genomes from inpatient and outpatient samples collected between 2021 and 2025 in western Washington State and constructed phylogenomic and phylodynamic trees.<br><br>RESULTS: We obtained 60 hMPV-A and 39 hMPV-B genomes, including 13 from November 2024 to January 2025. Following COVID-19 pandemic disruptions, hMPV seasonality returned to typical patterns after 2023. Genomic analysis showed hMPV-A predominance since 2022-23, with co-circulation of A2b1, A2b2, B1, and B2 sublineages. The A2b2 sublineage was most prevalent and all genomes carried a 111-nt G gene duplication. Phylogenetic evidence suggests the 111-nt variant evolved from a prior 180-nt duplication via a 69-nt deletion rather than through independent duplication events. Most sublineages showed multiple co-circulating clades, except A2b1. Phylodynamics showed recovery of global diversity after pandemic-related declines and a higher evolutionary rate in hMPV-A compared to hMPV-B. No distinct evolutionary features of heightened concern were detected.<br><br>CONCLUSIONS: Despite recent concerns, our findings indicate that hMPV circulation in, the USA follows expected seasonal patterns, with ongoing introductions of diverse viral variants from preexisting sublineages rather than emergence of a novel variant. Continued genomic surveillance is essential, particularly as vaccine development progresses.}, }
@article {pmid40769150, year = {2025}, author = {Durfey, SL and Kapnadak, SG and Pena, T and Willmering, MM and Godwin, JD and Teresi, ME and Heltshe, SL and Vo, AT and Villacreses, RA and Aliukonyte, I and Boyken, L and Stroik, MR and Morgan, SJ and Wang, GM and Betts, HL and Zhang, S and Goss, CH and Clancy, JP and Aitken, ML and Steele, C and Feder, AF and Esther, CR and Tiddens, HAWM and Woods, JC and Stoltz, DA and Singh, PK}, title = {Pseudomonas infections persisting after CFTR modulators are widespread throughout the lungs and drive lung inflammation.}, journal = {Cell host &amp; microbe}, volume = {33}, number = {8}, pages = {1428-1445.e4}, pmid = {40769150}, issn = {1934-6069}, support = {P30 DK089507/DK/NIDDK NIH HHS/United States ; R01 HL148274/HL/NHLBI NIH HHS/United States ; }, mesh = {*Pseudomonas Infections/pathology/drug therapy/microbiology ; Humans ; *Cystic Fibrosis Transmembrane Conductance Regulator ; *Lung/pathology/microbiology ; *Pseudomonas aeruginosa ; *Cystic Fibrosis/drug therapy/complications/microbiology ; *Pneumonia/pathology/microbiology ; Male ; Female ; *Persistent Infection/pathology/microbiology ; Adult ; Aminophenols/therapeutic use ; Middle Aged ; }, abstract = {Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve the physiological defect causing cystic fibrosis, but the lungs of most people remain infected and inflamed. A leading hypothesis implicates damaged segments as the cause of persistent infection and predicts that mildly diseased segments within an individual's lungs will clear after treatment, whereas severely diseased segments will not. Our findings contradict this hypothesis. We used bronchoscopy to sample the least- and most-damaged lung segments in Pseudomonas aeruginosa (Pa)-infected individuals before modulators and returned to these same segments after 1.5 years. Surprisingly, we find an "all-or-none" infection clearance response: the most-diseased segments clear if any other lung segment in that person clears, and the least-diseased segments remain infected if others in that person do. Furthermore, neutrophilic inflammation completely resolves where Pa clears but remains elevated where Pa persists. These data indicate that post-modulator infections are not limited to severely diseased segments and that Pa infections drive persistent lung inflammation after modulators.}, }
@article {pmid40769632, year = {2025}, author = {Arter, ZL and Park, C and Deng, L}, title = {MET Tyrosine Kinase Domain Mutations in NSCLC: Expanding the Landscape of Acquired Resistance in Oncogene-Driven Tumors.}, journal = {Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer}, volume = {20}, number = {8}, pages = {998-1000}, doi = {10.1016/j.jtho.2025.05.001}, pmid = {40769632}, issn = {1556-1380}, }
@article {pmid40769720, year = {2025}, author = {Nicoletti, C and Massenet, J and Pintado-Urbanc, AP and Connor, LJ and Nicolau, M and Sundar, S and Xu, M and Schmitt, A and Zhang, W and Fang, Z and Chan, TCI and Wang, YX and Tapscott, SJ and Cheung, TH and Simon, MD and Caputo, L and Puri, PL}, title = {MYOD represses gene expression from non-E-box motifs.}, journal = {Genes &amp; development}, volume = {39}, number = {21-22}, pages = {1299-1317}, pmid = {40769720}, issn = {1549-5477}, support = {R01 AR056712/AR/NIAMS NIH HHS/United States ; }, mesh = {*MyoD Protein/metabolism/genetics ; Humans ; Chromatin/metabolism ; *Gene Expression Regulation ; Cell Differentiation/genetics ; Promoter Regions, Genetic ; Protein Binding ; *E-Box Elements/genetics ; Fibroblasts/metabolism/cytology ; Animals ; Cell Line ; Cells, Cultured ; Chromatin Assembly and Disassembly ; }, abstract = {We report here on the identification of a previously unrecognized property of MYOD as a repressor of gene expression via E-box-independent chromatin binding during the process of somatic cell trans-differentiation into skeletal muscle. When ectopically expressed in proliferating human fibroblasts or endogenously induced in activated muscle stem cells (MuSCs), MYOD was detected at accessible regulatory elements of expressed genes, invariably leading to reduced chromatin accessibility and gene repression. At variance with conventional E-box-driven increased chromatin accessibility and H3K27 acetylation at previously silent loci of MYOD-activated genes, MYOD-mediated chromatin compaction and repression of transcription was associated with high occurrence of non-E-box motifs and did not lead to reduced levels of H3K27ac but coincided with reduced levels of H4 acetyl-methyl lysine modification (Kacme). Using MYOD mutants, we dissected the molecular mechanism of MYOD-mediated repression, whereby repression of mitogen-responsive and growth factor-responsive genes occurred via promoter binding, which requires a conserved domain within the first helix; conversely, repression of cell of origin/alternative lineage genes occurred via binding and decommissioning of distal regulatory elements such as superenhancers (SEs), required either the N-terminal activation domain or the two chromatin remodeling domains, and coincided with reduced strength of CTCF-mediated chromatin interactions. These data extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator. They also reveal an unprecedented functional versatility arising from alternative chromatin recruitment through E-box or non-E-box sequences, whereby genetic determinants dictate differential usage of MYOD functional domains.}, }
@article {pmid40770768, year = {2025}, author = {Wu, L and Zhu, X and Liu, Y and Zhao, D and Yu, BC and Wei, Z and Lin, X and Qi, LS}, title = {Identification of replicative aging and inflammatory aging signatures via whole-genome CRISPRi screens.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {233}, pmid = {40770768}, issn = {1474-760X}, support = {R21 AG077193/AG/NIA NIH HHS/United States ; R21AG077193//NIH National Institute of Aging/ ; no. 2046650//the National Science Foundation CAREER award/ ; }, mesh = {Humans ; *Cellular Senescence/genetics ; *Inflammation/genetics ; *Aging/genetics ; Genome-Wide Association Study ; Mesenchymal Stem Cells/metabolism/cytology ; *CRISPR-Cas Systems ; Genomics ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genome, Human ; }, abstract = {BACKGROUND: Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.<br><br>RESULTS: We perform multiple genome-wide CRISPR interference (CRISPRi) screenings in human primary mesenchymal stem cells derived from adipose tissue during either replicative senescence or inflammation-induced senescence. These screens reveal distinct sets of potential novel regulators specific to each senescence pathway. Combining our perturbation-based functional genomic data with 405 genome-wide association study datasets, including 50 aging-related studies, we find that the inflammatory aging signatures identified from CRISPRi screenings are significantly associated with diverse aging processes, suggesting novel molecular signatures for analyzing and predicting aging status and aging-related disease.<br><br>CONCLUSIONS: The signatures verified through comprehensive functional genomics and genetic analyses may provide new targets for modulating the aging process and enhancing the quality of cell therapy products.}, }
@article {pmid40772450, year = {2025}, author = {Webster, RT and Mirzaei, S and Bhatia, S and Srivastava, DK and Mostoufi-Moab, S and Dixon, SB and Chow, EJ and Armstrong, GT and Krull, KR and van der Plas, E}, title = {Diabetes mellitus and neurocognition: A report from the Childhood Cancer Survivor Study.}, journal = {Cancer}, volume = {131}, number = {16}, pages = {e70011}, pmid = {40772450}, issn = {1097-0142}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; //American Lebanese Syrian Associated Charities/ ; }, mesh = {Humans ; Female ; Male ; *Cancer Survivors/psychology ; Adult ; *Neoplasms/complications/therapy ; Cardiovascular Diseases/epidemiology ; Child ; *Diabetes Mellitus/epidemiology ; Adolescent ; Young Adult ; Risk Factors ; *Cognitive Dysfunction/epidemiology/etiology ; }, abstract = {BACKGROUND: The objective of this research was to examine associations between diabetes mellitus (DM) and neurocognitive impairment in survivors of childhood cancer while exploring mechanistic associations with treatment exposures and moderating associations with cardiovascular disease (CVD) and risky lifestyle factors.<br><br>METHODS: Survivors of the Childhood Cancer Survivor Study (N&#xa0;=&#xa0;16,196; mean&#xa0;&#xb1;&#xa0;standard deviation age, 32.9&#xa0;&#xb1;&#xa0;7.9 years; 50.2% female; N&#xa0;=&#xa0;615 with DM) self-reported neurocognitive functioning, risky drinking, physical inactivity, and tobacco use. Medical data were collected from chart review. Multivariable regression determined the association of DM with neurocognitive impairment while adjusting for relevant treatment exposures. Interactions between DM and treatment, risky lifestyle, and cardiovascular predictors on impairment were explored. Path analysis was used to examine the effects of treatment exposures through DM and CVD on impairment. Among survivors with DM, multivariable regressions examined predictors of neurocognitive change over time (mean, 11.21 years).<br><br>RESULTS: Survivors with DM had an increased risk of impairment relative to survivors without DM (task completion: odds ratio [OR], 1.5; 95% confidence limits [CI], 1.2-1.9; emotion regulation: OR, 1.4; 95% CI, 1.1-2.0; and organization: OR, 1.5; 95% CI, 1.1-2.0). The effects of cranial radiation on neurocognition were mediated by DM, including task completion (&#x3b2;&#xa0;=&#xa0;0.02), emotion regulation (&#x3b2;&#xa0;=&#xa0;0.02), memory (&#x3b2;&#xa0;=&#xa0;0.01), and organization (&#x3b2;&#xa0;=&#xa0;0.02; all p&#xa0;<&#xa0;.01). Among survivors with DM, CVD was associated with declines in task completion (estimate&#xa0;=&#xa0;0.44; p&#xa0;<&#xa0;.01) and organization (estimate&#xa0;=&#xa0;0.27; p&#xa0;=&#xa0;.03).<br><br>CONCLUSIONS: Survivors with DM are at increased risk of neurocognitive impairment. Although CVD did not exacerbate concurrent risk for impairment, it was associated with a decline in neurocognitive functioning over time in survivors with DM. Preventing/managing CVD in survivors with DM could mitigate additional neurocognitive decline.}, }
@article {pmid40772634, year = {2025}, author = {Cohen, SA and Aushev, VN and Laliotis, G and Jabbal, IS and Nagarajan, A and Wang, C and Fakih, M and Sharif, S and Alyunis, F and Tejani, MA and Alqahtani, A and Marshall, J and Chang, J and Botta, G and Manage, K and George, GV and Sharma, S and Malhotra, M and Chandana, S and Mehler, S and Somer, BG and Babadi, E and Wu, C and Hanna, D and Chidharla, A and Kasi, A and Vosoughi, E and Dayyani, F and Pedersen, K and Briski, RE and Azzi, G and Katiyar, V and Chan, A and Sharma, V and Shreenivas, A and Chakrabarti, S and Fuqua, J and Malla, M and Polite, B and Bent, AH and Rabinowitz, M and Jurdi, A and Liu, MC and Aleshin, A and Kopetz, S}, title = {Real-world Monitoring of ctDNA Reliably Predicts Cancer Recurrence and Treatment Efficacy in Patients with Resected Stages I-III Colon Cancer.}, journal = {Annals of surgery}, volume = {}, number = {}, pages = {}, doi = {10.1097/SLA.0000000000006887}, pmid = {40772634}, issn = {1528-1140}, abstract = {OBJECTIVE: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application.<br><br>SUMMARY BACKGROUND DATA: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment.<br><br>METHODS: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes.<br><br>RESULTS: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients.<br><br>CONCLUSIONS: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.}, }
@article {pmid40772965, year = {2025}, author = {Venkatesh, H and Fong, L}, title = {CD4+ T cell dysfunction in cancer.}, journal = {The Journal of experimental medicine}, volume = {222}, number = {9}, pages = {}, doi = {10.1084/jem.20241417}, pmid = {40772965}, issn = {1540-9538}, support = {R35CA253175/NH/NIH HHS/United States ; }, mesh = {Humans ; *Neoplasms/immunology/therapy/pathology ; *CD4-Positive T-Lymphocytes/immunology ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Immunotherapy ; }, abstract = {While the importance of CD8+ T cells in successful cancer immunotherapy is well-established, CD4+ T cells are increasingly recognized as key mediators of effective anti-tumor immunity. However, the mechanisms underlying the functional impairment of CD4+ T cells in tumors are not as well characterized as in CD8+ T cells. In this review, we will explore how CD4+ T cells are altered in tumor-bearing hosts, compare these changes to those observed in CD8+ T cells, and discuss how these changes impact tumor control. Approaches that counteract functional impairment in tumor-reactive CD4+ T cells may further enhance the efficacy of cancer immunotherapy.}, }
@article {pmid40773210, year = {2025}, author = {Yeh, JM and Ward, ZJ and Leisenring, W}, title = {Childhood Cancer Survivor Risk Estimates and Age, Overdispersion, and Social Context-Reply.}, journal = {JAMA oncology}, volume = {11}, number = {10}, pages = {1244-1245}, doi = {10.1001/jamaoncol.2025.2424}, pmid = {40773210}, issn = {2374-2445}, }
@article {pmid40773709, year = {2025}, author = {Yuen, K and Meagher, M and Mercer, J and Yilma, B and Stoppler, M and Fragkogianni, S and Mar, N and Kalebasty, AR and Gupta, S and Grivas, P and Bagrodia, A and Mckay, R and Stewart, T and Salmasi, A}, title = {Comprehensive Comparison of Somatic, Germline, and Immune Cell Profiles in Upper Tract and Bladder Urothelial Carcinoma.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500289}, doi = {10.1200/PO-25-00289}, pmid = {40773709}, issn = {2473-4284}, mesh = {Humans ; *Urinary Bladder Neoplasms/genetics/immunology/pathology ; Retrospective Studies ; Female ; Male ; Aged ; Middle Aged ; Microsatellite Instability ; *Carcinoma, Transitional Cell/genetics/immunology ; Germ-Line Mutation ; Aged, 80 and over ; Mutation ; DNA Mismatch Repair ; *Ureteral Neoplasms/genetics/immunology ; }, abstract = {PURPOSE: Molecular characterization of anatomically distinct urothelial carcinoma in the upper tract (UTUC) and bladder (UCB) has been challenging because of the rarity of UTUC. However, recent advances in real-world data curation have facilitated the generation of larger UTUC cohorts. In this study, we investigated the somatic, germline, and immunologic landscapes of UTUC compared with UCB.<br><br>METHODS: From the Tempus Database, we retrospectively analyzed 505 UTUC and 2,416 UCB cases. Tumors were sequenced using Tempus xT DNA and xR RNA assays. Pathogenic somatic mutations, immune cell infiltration, tumor mutational burden (TMB), PD-L1, microsatellite instability (MSI), and mismatch repair (MMR) were evaluated. Potential germline alterations were assessed in 46 genes for patients with tumor/normal matched sequencing (UTUC, n = 285; UCB, n = 1,359).<br><br>RESULTS: Alterations in TERT, TP53, RB1, ERBB2, and CDKN1A were more frequent in UCB, whereas KMT2D, FGFR3, CDKN2B, KRAS, and MYC were more frequent in UTUC. Germline variants were found in 4.8% of UCB and 5.6% of UTUC, with trends toward higher Lynch syndrome-associated gene alterations (MLH1, MSH2, MSH6, PMS2) in UTUC (0.6% v 1.8%, P = .059). The prevalence of TMB &#x2265;10 mut/Mb was higher in UCB (17% v 11%, P < .001). UCB had higher PD-L1 positivity (P = .013), whereas UTUC had more MSI-high (UTUC = 3.2% v UCB = 1%, P = .001) and MMR-deficient (P = .020) cases. CD4[+] and regulatory T-cell infiltrates were similar in both.<br><br>CONCLUSION: By comprehensive molecular characterization of UC, we observed distinct genomic alterations and tumor microenvironment patterns in UTUC and UCB. Further research is warranted to elucidate the clinical implications of these findings. We compared the genetic and immune features of upper tract and bladder cancers. Our study found key differences that could affect treatment decisions, such as specific gene changes and immune markers. These insights may help doctors personalize therapies and improve patient care.}, }
@article {pmid40773733, year = {2025}, author = {Minalga, B and Feuer, C}, title = {Addressing Transgender Erasure in HIV Clinical Trials: The Scorecard for Transgender and Gender-Diverse Inclusion.}, journal = {American journal of public health}, volume = {115}, number = {10}, pages = {1621-1630}, pmid = {40773733}, issn = {1541-0048}, mesh = {Humans ; *Transgender Persons/statistics &amp; numerical data ; *HIV Infections/drug therapy/prevention &amp; control ; Male ; Female ; Cross-Sectional Studies ; *Patient Selection ; *Randomized Controlled Trials as Topic ; *Clinical Trials as Topic ; }, abstract = {We sought to offer a structured framework for evaluating transgender and gender-diverse (TGD) inclusion in HIV clinical trials, with actionable criteria for trial design and conduct, and to quantify and characterize TGD inclusion in pivotal HIV studies as supporting evidence of the need for this framework. We devised a tool (scorecard) consisting of 14 scoreable indicators for TGD-responsive HIV research with input from global TGD communities. We tested the scorecard in a cross-sectional review of 41 randomized controlled HIV biomedical efficacy trials to measure TGD responsiveness. Studies were selected to represent the spectrum of groundbreaking HIV therapeutic and prevention studies enrolling participants in countries around the world from 1991 to 2023. We found that TGD individuals represent a reported 2532 (1.4%) of 178 893 participants in the selected HIV clinical trials. Scorecard indicators reveal a dearth of HIV research responsive to the needs of TGD communities. The lack of TGD representation in HIV clinical trials indicates a historical erasure of TGD communities with potential public health consequences. The scorecard might guide future HIV research to be more responsive to the needs of TGD people. (Am J Public Health. 2025;115(10):1621-1630. https://doi.org/10.2105/AJPH.2025.308134).}, }
@article {pmid40774326, year = {2025}, author = {Triplette, M and Aldrich, MC}, title = {Lung Cancer in Special Populations.}, journal = {Seminars in respiratory and critical care medicine}, volume = {46}, number = {5}, pages = {479-489}, doi = {10.1055/a-2657-9494}, pmid = {40774326}, issn = {1098-9048}, mesh = {Humans ; *Lung Neoplasms/epidemiology/diagnosis/etiology/therapy ; Risk Factors ; *HIV Infections/epidemiology/complications ; Immunocompromised Host ; Female ; *Lung Diseases, Interstitial/complications/epidemiology ; Early Detection of Cancer ; Male ; }, abstract = {Lung cancer is the leading cause of cancer deaths worldwide, claiming more lives than other age-related and screen-detectable cancers. Cigarette smoking remains the most important risk factor. However, despite common perceptions, risk is not related solely to cigarette smoking. Several vulnerable and special populations experience a disproportionate burden of lung cancer, often complicated by overlapping medical issues, diagnostic challenges, and treatment limitations. This review highlights four populations (people with HIV, persons who are immunocompromised, lung cancer in nonsmoking women, and individuals with interstitial lung disease [ILD]) who experience unique risks that impact early detection, diagnosis, and management of lung cancer. Three of these populations are frequently underrepresented in clinical trials, yet they may be at elevated risk due to chronic inflammation, immune dysregulation, or previous medical therapies. Individuals with HIV have a significantly increased incidence of lung cancer, often presenting at younger ages and with more advanced disease. Similarly, patients who are immunocompromised following organ or stem cell transplantation are at heightened risk due to prolonged immune dysfunction and prior exposures to toxic therapies. Individuals with ILD, especially idiopathic pulmonary fibrosis (IPF), have an increased risk of developing lung cancer, which is challenging to detect with imaging given architectural distortion and even more challenging to treat given limited pulmonary reserve. We also highlight women, as there has been a striking trend of rising incidence of lung cancer among women worldwide, particularly among those who have never smoked. The intersection of these risks with traditional lung cancer risk factors like tobacco smoking highlights a critical need for increased awareness, improved risk stratification, and adapted screening strategies that take these complexities into account. In this review, we explore the epidemiology, clinical presentation, and early detection and management challenges unique to each population, underscoring the necessity of precision approaches to support individualized care.}, }
@article {pmid40774832, year = {2025}, author = {Sheppard, DP and Psutka, SP and Hunter, H}, title = {Prehabilitation: Cognitive considerations.}, journal = {Urologic oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.urolonc.2025.06.017}, pmid = {40774832}, issn = {1873-2496}, abstract = {Urologic cancers and their treatments confer risk for cognitive dysfunction, which can have significant impact on quality of life and overall well-being during survivorship. Current approaches to ameliorate cognitive dysfunction in urologic and other cancers emphasize post-treatment rehabilitation methods of cognitive compensatory strategies or training-based restorative practice. Prehabilitation involves supporting resilience prior to treatment initiation and has demonstrated promise for supporting various clinical outcomes in urologic cancers. However, there is a paucity of studies that have utilized prehabilitation approaches to support cognitive functioning, and few existing prehabilitation studies in urologic cancers have examined cognitive functioning endpoints. The objectives of this literature review are to describe: (1) common cognitive findings in urologic cancers, (2) contemporary evidence for cognitive rehabilitation in cancer populations, (3) existing cognitive prehabilitation approaches that have yet to be implemented in urologic cancers, and (4) prehabilitation efforts addressing physical activity, nutrition, and mood/mental health that could be used in the future to support and study cognitive endpoints. A model for cognitive prehabilitation is proposed to guide future research in urologic cancers.}, }
@article {pmid40775447, year = {2025}, author = {Chang, YH and Bresnahan, ST and Taylor Head, S and Harrison, TA and Yu, Y and Huff, CD and Pasaniuc, B and Lindström, S and Bhattacharya, A}, title = {Isoform-level analyses of 6 cancers uncover extensive genetic risk mechanisms undetected at the gene-level.}, journal = {British journal of cancer}, volume = {133}, number = {6}, pages = {874-885}, pmid = {40775447}, issn = {1532-1827}, support = {R01 CA194393/CA/NCI NIH HHS/United States ; R21 CA293419/CA/NCI NIH HHS/United States ; U01 CA194393/CA/NCI NIH HHS/United States ; CA293419//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Humans ; Genome-Wide Association Study ; *Genetic Predisposition to Disease ; Female ; Male ; Polymorphism, Single Nucleotide ; *Neoplasms/genetics ; Protein Isoforms/genetics ; Lung Neoplasms/genetics ; Transcriptome ; Breast Neoplasms/genetics ; Prostatic Neoplasms/genetics ; Gene Expression Profiling ; Alternative Splicing ; Ovarian Neoplasms/genetics ; Colorectal Neoplasms/genetics ; Endometrial Neoplasms/genetics ; }, abstract = {BACKGROUND: Integrating genome-wide association study (GWAS) and transcriptomic datasets can identify mediators for genetic risk of cancer. Traditional methods often are insufficient as they rely on total gene expression measures and overlook alternative splicing, which generates different transcript-isoforms with potentially distinct effects.<br><br>METHODS: We integrate multi-tissue isoform expression data from the Genotype Tissue-Expression Project with GWAS summary statistics (all N&#x2009;>&#x2009;~20,000 cases) to identify isoform- and gene-level associations with six cancers (breast, endometrial, colorectal, lung, ovarian, prostate) and six related cancer subtype classifications (N&#x2009;=&#x2009;12 total).<br><br>RESULTS: Directly modeling isoforms using transcriptome-wide association studies (isoTWAS) significantly improves discovery of genetic associations compared to gene-level approaches, identifying 164% more significant associations (6163 vs. 2336) with isoTWAS-prioritized genes enriched 4-fold for evolutionarily-constrained genes. isoTWAS tags transcriptomic associations at 52% more independent GWAS loci across the six cancers. Isoform expression mediates an estimated 63% greater proportion of cancer risk SNP heritability compared to gene expression. We highlight several isoTWAS associations that demonstrate GWAS colocalization at the isoform level but not at the gene level, including CLPTM1L (lung cancer), LAMC1 (colorectal), and BABAM1 (breast).<br><br>CONCLUSION: These results underscore the importance of modeling isoforms to maximize discovery of genetic risk mechanisms for cancers.}, }
@article {pmid40777412, year = {2025}, author = {Gao, G and Yan, R and Song, AH and Hsieh, HC and Barner, LAE and Wang, F and Brenes, D and Chow, SSL and Wang, R and Bishop, KW and Liu, Y and Farre, X and Divatia, M and Downes, MR and Vakar-Lopez, F and Lal, P and Burke, W and Madabhushi, A and True, LD and Reddi, DM and Grady, WM and Mahmood, F and Liu, JTC}, title = {Deep-learning triage of 3D pathology datasets for comprehensive and efficient pathologist assessments.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777412}, issn = {2692-8205}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; U01 CA182940/CA/NCI NIH HHS/United States ; U2C CA271902/CA/NCI NIH HHS/United States ; R01 CA220004/CA/NCI NIH HHS/United States ; R01 DK138948/DK/NIDDK NIH HHS/United States ; U01 CA269181/CA/NCI NIH HHS/United States ; U01 CA239055/CA/NCI NIH HHS/United States ; R01 EB031002/EB/NIBIB NIH HHS/United States ; R01 CA268287/CA/NCI NIH HHS/United States ; R01 CA249992/CA/NCI NIH HHS/United States ; R01 CA220581/CA/NCI NIH HHS/United States ; R01 CA216579/CA/NCI NIH HHS/United States ; R01 CA268207/CA/NCI NIH HHS/United States ; R01 CA202752/CA/NCI NIH HHS/United States ; R01 CA208236/CA/NCI NIH HHS/United States ; U01 CA248226/CA/NCI NIH HHS/United States ; I01 BX004121/BX/BLRD VA/United States ; R01 CA257612/CA/NCI NIH HHS/United States ; U54 CA254566/CA/NCI NIH HHS/United States ; U01 CA152756/CA/NCI NIH HHS/United States ; U54 CA163060/CA/NCI NIH HHS/United States ; }, abstract = {Standard-of-care slide-based 2D histopathology severely undersamples spatially heterogeneous tissue specimens, with each thin 2D section representing <1% of the entire tissue volume (in the case of a biopsy). Recent advances in non-destructive 3D pathology, such as open-top light-sheet microscopy (OTLS), enable comprehensive high-resolution imaging of large clinical specimens. While fully automated computational analyses of such 3D pathology datasets are being explored, a potential low-risk route for accelerated clinical adoption would be to continue to rely upon pathologists to provide final diagnoses. Since manual review of these massive and complex 3D datasets is infeasible for routine clinical practice, we present CARP3D, a deep learning triage framework that identifies high-risk 2D cross sections within large 3D pathology datasets to enable time-efficient pathologist evaluation. CARP3D assigns risk scores to all 2D levels within a tissue volume by leveraging context from a subset of neighboring depth levels, outperforming models in which predictions are based on isolated 2D levels. In two use cases - risk stratification based on prostate cancer biopsies and screening for dysplasia/cancer in endoscopic biopsies of Barrett's esophagus - AI-triaged 3D pathology, enabled by CARP3D, demonstrates the potential to improve the detection of high-risk diseases in comparison to slide-based 2D histopathology while optimizing pathologist workloads.}, }
@article {pmid40777454, year = {2025}, author = {Mayer-Blackwell, K and Minervina, A and Pogorelyy, M and Rawat, P and Shapiro, MR and Peters, LD and Ford, ES and Posgai, AL and Vengesana, K and Minot, S and Koelle, DM and Greiff, V and Bradley, P and Brusko, TM and Thomas, PG and Fiore-Gartland, A}, title = {TCR2HLA: calibrated inference of HLA genotypes from TCR repertoires enables identification of immunologically relevant metaclonotypes.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40777454}, issn = {2692-8205}, support = {P01 AI042288/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U01 AI144616/AI/NIAID NIH HHS/United States ; P01 AI165077/AI/NIAID NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; 75N93019C00063/AI/NIAID NIH HHS/United States ; K99 DK140511/DK/NIDDK NIH HHS/United States ; }, abstract = {T cell receptors (TCRs) recognize peptides presented by polymorphic human leukocyte antigen (HLA) molecules, but HLA genotype data are often missing from TCR repertoire sequencing studies. To address this, we developed TCR2HLA, an open-source tool that infers HLA genotypes from TCRβ repertoires. Expanding on work linking public TRBV-CDR3 sequences to HLA genotypes, we incorporated "quasi-public" metaclonotypes - composed of rarer TCRβ sequences with shared amino acid features - enriched by HLA genotypes. Using four TCRβseq datasets from 3,150 individuals, we applied TRBV gene partitioning and locality-sensitive hashing to identify ~96,000 TCRβ features strongly associated with specific HLA alleles from 71M input TCRs. Binary HLA classifiers built with these features achieved high balanced accuracy (>0.9) across common HLA-A (9/12), B (9/12), C (6/13), DRB1 (11/11) alleles and prevalent DPA1/DPB1 (6/10), DQA1/DQB1 (8/17) heterodimers. We also introduced a high-sensitivity calibration to support predictions in samples with as few as 5,000 unique clonotypes. Calibrated predictions with confidence filtering improved reliability. Beyond genotype imputation, TCR2HLA enables the discovery of novel HLA- and exposure-associated TCRs, as shown by the identification of SARS-CoV-2 related TCRs in a large COVID-19 dataset lacking HLA data. TCR2HLA provides a scalable framework for bridging the gap between TCRseq data and HLA genotype for biomarker discovery.}, }
@article {pmid40778089, year = {2025}, author = {Thonglert, K and Greer, MD and Schaub, SK and Bowen, SR and Menghini, AM and Nyflot, MJ and Grassberger, C and Tsai, J and Zaki, P and Kim, EY and Wong, T and Apisarnthanarax, S}, title = {Simultaneous integrated boost and protection proton beam therapy approach for hepatocellular carcinoma.}, journal = {Clinical and translational radiation oncology}, volume = {54}, number = {}, pages = {101008}, pmid = {40778089}, issn = {2405-6308}, abstract = {PURPOSE: Although simultaneous integrated boost and protection with proton beam therapy (SIB-PBT) facilitates tumor dose escalation while maintaining organ-at-risk (OAR) dose constraints, clinical outcomes are limited. This study assessed the safety and efficacy of using the SIB-PBT technique in hepatocellular carcinoma (HCC) patients.<br><br>METHODS: We reviewed 47 patients with HCC who underwent SIB-PBT between 2014-2021. The radiation dose ranged from 36-67.5&#xa0;Gy(RBE) in 15 fractions. SIB-PBT was used for the following reasons: minimize high-dose exposure to organs-at-risk (OARs) (n&#xa0;=&#xa0;22, 47&#xa0;%), treat targets with different dose levels (n&#xa0;=&#xa0;6, 13&#xa0;%), or both (n&#xa0;=&#xa0;19, 40&#xa0;%). Survival, local control, and toxicities were assessed using Kaplan-Meier, Fine-Gray cumulative incidence, and descriptive statistics, respectively.<br><br>RESULTS: Forty-one patients (87&#xa0;%) had tumors located&#xa0;&#x2264;2&#xa0;cm from luminal gastrointestinal (GI) OARs. The median tumor diameter was 9.2&#xa0;cm (range, 2.0-21.5&#xa0;cm). The median EQD2 D50%, D95% and D99% of gross tumor volume were 79.8 (range, 51.1-85.9), 66.7 (range, 36.9-84.6) and 50.2 (range, 34.1-83.6) Gy(RBE)10, respectively. Most patients (91&#xa0;%) received a D0.5&#xa0;cc of <45&#xa0;Gy(RBE) to luminal GI OARs. At a median follow-up of 22&#xa0;months (range, 0.8-77.0&#xa0;months), the 2-year cumulative incidence of local failure was 12&#xa0;%. The 2-year progression-free survival and overall survival rates were 12&#xa0;% (95&#xa0;% CI 4.7-23.4&#xa0;%), and 49&#xa0;% (95&#xa0;% CI, 33.2-63.2&#xa0;%), respectively. One patient experienced grade 3 acute nausea/vomiting. No GI bleeding/ulcers or grade 4&#xa0;+&#xa0;toxicity were observed. CP&#xa0;+&#xa0;2 occurred in 5 patients.<br><br>CONCLUSION: SIB-PBT enables OAR protection along with heterogeneous tumor dose escalation and is a safe and effective treatment for HCC tumors.}, }
@article {pmid40778152, year = {2025}, author = {Huerta-Chagoya, A and Kim, J and Mandla, R and Lu, Y and Suzuki, K and Petty, LE and Ng, HK and Choi, J and Lee, S and Rout, M and Lin, K and Adair, LS and Adeyemo, A and Ahsan, H and Akiyama, M and An, P and Anand, SS and Becker, DM and Bertoni, AG and Bian, Z and Bielak, LF and Blangero, J and Boehnke, M and Bottinger, EP and Bowden, DW and Bragg, F and Brody, JA and Buchanan, TA and Cade, BE and Chai, JF and Chambers, JC and Chandak, GR and Chang, LC and Chang, KM and Chee, ML and Chen, CH and Chen, YT and Chen, Z and Chen, YI and Chen, J and Chen, G and Chen, SH and Chen, WM and Cheng, CY and Cho, YS and Choi, HS and Chuang, LM and Cruz, M and Cushman, M and Das, SK and DeFronzo, RA and deSilva, HJ and Dimitrov, L and Doumatey, AP and Du, S and Duan, Q and Duggirala, R and Emery, LS and Engert, JC and Evans, DS and Evans, MK and Finer, S and Florez, JC and Floyd, JS and Fornage, M and Frankel, EG and Freedman, BI and García-García, L and Genter, P and Gerstein, HC and Goodarzi, MO and Gordon-Larsen, P and Graff, M and Gross, M and Guo, Y and Guo, X and Hai, Y and Hanis, CL and Hayes, M and Horikoshi, M and Howard, AG and Hsu, S and Hsueh, W and Huang, W and Huang, M and Hung, YJ and Hwang, MY and Hwu, CM and Ichihara, S and Igase, M and Ipp, E and Islam, MT and Isono, M and Jang, HM and Jasmine, F and Jonas, JB and Joo, YY and Kabagambe, E and Kadowaki, T and Kamatani, Y and Kandeel, FR and Kardia, SLR and Karlson, EW and Kasturiratne, A and Kato, N and Katsuya, T and Kaur, V and Kawaguchi, T and Keaton, JM and Kho, AN and Khor, CC and Kibriya, M and Kim, BJ and Koh, WP and Kohara, K and Kooner, JS and Kooperberg, C and Kreienkamp, RJ and Lamri, A and Lange, LA and Lee, NR and Lee, MS and Lee, JJ and Lehman, DM and Li, L and Li, Y and Lim, VJ and Liu, J and Liu, Y and Liu, S and Long, J and Louie, T and Luo, X and Lv, J and Lynch, JA and Maeda, S and Mahajan, A and Maruthur, NM and Matsuda, F and McCarthy, MI and McKean-Cowdin, R and Meigs, JB and Millwood, IY and Mohlke, KL and Motala, AA and Nadkarni, GN and Nadler, JL and Nakatochi, M and Nalls, MA and Nayak, U and Nicolas, A and North, KE and Nousome, D and Okada, Y and Pan, I and Pankow, JS and Paré, G and Park, J and Park, KS and Parra, EJ and Patel, SR and Pereira, MA and Peyser, PA and Pirie, FJ and Preuss, M and Province, MA and Psaty, BM and Raffel, LJ and Raffield, LM and Rasmussen-Torvik, LJ and Redline, S and Reiner, AP and Rich, SS and Rohde, R and Roll, K and Roshani, R and Rotimi, CN and Sabanayagam, C and Saleheen, D and Sandow, K and Schurmann, C and Shahriar, M and Shaw, DM and Sheu, WH and Shi, J and Shu, XO and Shuey, MM and Siddiqui, MK and Smith, JA and Sofer, T and Spracklen, CN and Stilp, AM and Sun, M and Tabara, Y and Tai, ES and Tajuddin, SM and Takahashi, A and Takeuchi, F and Tan, J and Taylor, KD and Taylor, K and Thameem, F and Tong, L and Tsai, FJ and Tsao, PS and Udler, MS and Valladares-Salgado, A and van Heel, DA and vanDam, RM and Varma, R and Vora, M and Wacher-Rodarte, N and Wang, YX and Wheeler, E and Whitsel, EA and Wickremasinghe, AR and Wojcik, GL and Wong, TY and Wu, JY and Xiang, YB and Xiang, AH and Yajnik, CS and Yamamoto, K and Yamauchi, T and Yanek, LR and Yao, J and Yokota, M and Yu, C and Yuan, JM and Yusuf, S and Zeggini, E and Zhang, L and Zhang, W and Zheng, W and Zonderman, AB and ,  and ,  and ,  and Aguilar-Salinas, CA and González-Villalpando, C and Haiman, CA and Kim, YJ and Kwak, SH and Leong, A and Loos, RJF and Moreno-Estrada, A and Morris, AP and Orozco, L and Rotter, JI and Sanghera, D and Tusie-Luna, T and Voight, BF and Vujkovic, M and Walters, RG and Ge, T and Manning, AK and Loh, M and Below, JE and Sim, X and Mercader, JM and Ng, MCY and , }, title = {Multi-ancestry polygenic risk scores for the prediction of type 2 diabetes and complications in diverse ancestries.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40778152}, support = {U01 DK140757/DK/NIDDK NIH HHS/United States ; UM1 DK126194/DK/NIDDK NIH HHS/United States ; R01 DK135938/DK/NIDDK NIH HHS/United States ; R01 DK118011/DK/NIDDK NIH HHS/United States ; R56 HL150186/HL/NHLBI NIH HHS/United States ; R01 EY036258/EY/NEI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; R01 HL158884/HL/NHLBI NIH HHS/United States ; U01 CA288325/CA/NCI NIH HHS/United States ; R01 EB015611/EB/NIBIB NIH HHS/United States ; U01 DK105556/DK/NIDDK NIH HHS/United States ; R01 DK136671/DK/NIDDK NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 DK137993/DK/NIDDK NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; R01 DK066358/DK/NIDDK NIH HHS/United States ; U01 HG011723/HG/NHGRI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; R01 DK139598/DK/NIDDK NIH HHS/United States ; R01 HL172803/HL/NHLBI NIH HHS/United States ; }, abstract = {BACKGROUND: Polygenic risk scores (PRSs) improve type 2 diabetes (T2D) prediction beyond clinical risk factors but perform poorly in non-European populations, where T2D burden is often higher, undermining their global clinical utility.<br><br>METHODS: We conducted the largest global effort to date to harmonize T2D genome-wide association study (GWAS) meta-analyses across five ancestries-European (EUR), African/African American (AFR), Admixed American (AMR), South Asian (SAS), and East Asian (EAS)-including 360,000 T2D cases and 1&#xb7;8 million controls (41% non-EUR). We constructed ancestry-specific and multi-ancestry PRSs in training datasets including 11,000 T2D cases and 32,000 controls, and validated their performance in independent datasets including 39,000 T2D cases and 126,000 controls of diverse ancestries. In the All of Us Research Program, we compared these PRSs to those from the Polygenic Score Catalog and assessed their ability to predict diabetes micro- and macrovascular complications.<br><br>FINDINGS: Ancestry-specific PRSs showed limited prediction power for T2D in AFR, AMR, and SAS compared to EUR and EAS. In contrast, multi-ancestry PRSs, built using GWAS data from five ancestries, substantially improved T2D prediction across all ancestries. Compared to those in the interquartile range, individuals at the 97&#xb7;5[th] percentile of their PRSs had a 6-fold increased T2D risk in AMR, EAS, and EUR, and &#x2265;3-fold in AFR and SAS. These PRSs were also associated with the development of microvascular complications and outperformed all previously reported PRSs for all ancestries.<br><br>INTERPRETATION: We developed and extensively validated the most up-to-date T2D PRSs across diverse ancestry groups. These PRSs are publicly available to support further evaluation of their clinical utility in diverse ancestries.}, }
@article {pmid40779102, year = {2025}, author = {Ramos, M and Shepherd, L and Sheffield, NC and Mahmoud, A and Pagès, H and Wokaty, A and Righelli, D and Risso, D and Davis, S and Oh, S and Waldron, L and Morgan, M and Carey, V}, title = {Bioconductor's Computational Ecosystem for Genomic Data Science in Cancer.}, journal = {Methods in molecular biology (Clifton, N.J.)}, volume = {2932}, number = {}, pages = {1-46}, pmid = {40779102}, issn = {1940-6029}, support = {U24 CA180996/CA/NCI NIH HHS/United States ; }, mesh = {*Neoplasms/genetics ; *Genomics/methods ; Humans ; *Software ; *Computational Biology/methods ; Databases, Genetic ; *Data Science/methods ; }, abstract = {The Bioconductor project enters its third decade with over two thousand packages for genomic data science, over 100,000 annotation and experiment resources, and a global system for convenient distribution to researchers. Over 60,000 PubMed Central citations and terabytes of content shipped per month attest to the impact of the project on cancer genomic data science. This report provides an overview of cancer genomics resources in Bioconductor. After an overview of Bioconductor project principles, we address exploration of institutionally curated cancer genomics data such as TCGA. We then review genomic annotation and ontology resources relevant to cancer and then briefly survey analytical workflows addressing specific topics in cancer genomics. Concluding sections cover how new software and data resources are brought into the ecosystem and how the project is tackling needs for training of the research workforce. Bioconductor's strategies for supporting methods developers and researchers in cancer genomics are evolving along with experimental and computational technologies. All the tools described in this report are backed by regularly maintained learning resources that can be used locally or in cloud computing environments.}, }
@article {pmid40779330, year = {2025}, author = {Wang, Q and Duerr, A and Gao, F}, title = {Addressing Population Heterogeneity for HIV Incidence Estimation Based on Recency Test.}, journal = {Statistics in medicine}, volume = {44}, number = {18-19}, pages = {e70216}, pmid = {40779330}, issn = {1097-0258}, support = {R37AI029168/NH/NIH HHS/United States ; R01AI177078/NH/NIH HHS/United States ; R37 AI029168/AI/NIAID NIH HHS/United States ; R01DA032106/NH/NIH HHS/United States ; R01 AI177078/AI/NIAID NIH HHS/United States ; R01 DA032106/DA/NIDA NIH HHS/United States ; ISR-US-20-10990//Gilead/ ; }, mesh = {Humans ; *HIV Infections/epidemiology ; Incidence ; Cross-Sectional Studies ; Computer Simulation ; Models, Statistical ; }, abstract = {Cross-sectional HIV incidence estimation leverages recency test results to determine the HIV incidence of a population of interest, where recency test uses biomarker profiles to infer whether an HIV-positive individual was "recently" infected. This approach possesses an obvious advantage over the conventional cohort follow-up method since it avoids longitudinal follow-up and repeated HIV testing. In this manuscript, we consider the extension of cross-sectional incidence estimation to estimate the incidence of a different target population, addressing potential population heterogeneity. We propose a general framework that incorporates two scenarios: one when the target population is a subset of the population with cross-sectional recency testing data and the other with an external target population. In addition, we propose estimators to incorporate HIV subtypes, a special type of covariate that modifies the properties of recency tests, into our framework. Through simulation studies and a data application, we demonstrate the performance of the proposed methods. We conclude with a discussion on sensitivity analysis and future work to improve our framework.}, }
@article {pmid40779552, year = {2025}, author = {Ahmed, S and DiPersio, J and Essell, J and Diefenbach, C and Perales, MA and Castilla-Llorente, C and Dahiya, S and Liu, Y and Xu, H and Fanton, C and Chaudhry, S and Lee, ZH and Marcondes, AMQ and Tagliaferri, MA and Zalevsky, J and Miklos, D and Turtle, CJ and McGuirk, J}, title = {NKTR-255 enhances complete response following CD19 CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma.}, journal = {Blood advances}, volume = {9}, number = {23}, pages = {6092-6095}, pmid = {40779552}, issn = {2473-9537}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, }
@article {pmid40779734, year = {2025}, author = {Wang, L and Xu, H and Simons, RL and Beach, SRH and Lei, MK and Ong, ML and Philibert, RA and Mielke, MM and Sun, Y and Lu, Y and Chiang, CWK and Darst, BF and Ye, K}, title = {Associations of Longitudinal Changes in Blood Biomarkers of Dementia With the Proportion of Genetically Inferred African Ancestry.}, journal = {Neurology}, volume = {105}, number = {5}, pages = {e213976}, pmid = {40779734}, issn = {1526-632X}, support = {R01 HL118045/HL/NHLBI NIH HHS/United States ; R35 GM143060/GM/NIGMS NIH HHS/United States ; T32 GM142623/GM/NIGMS NIH HHS/United States ; R01 AG077386/AG/NIA NIH HHS/United States ; R01 AG055393/AG/NIA NIH HHS/United States ; }, mesh = {Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Alzheimer Disease/blood/genetics ; Biomarkers/blood ; *Black or African American/genetics ; Cross-Sectional Studies ; *Dementia/blood/genetics/ethnology ; *Glial Fibrillary Acidic Protein/blood ; Longitudinal Studies ; *Neurofilament Proteins/blood ; *tau Proteins/blood ; }, abstract = {BACKGROUND AND OBJECTIVES: African American individuals have a higher risk of Alzheimer disease (AD) and related dementia (ADRD) than non-Hispanic White individuals. Some cross-sectional studies with self-reported race and ethnicity have reported racial differences in circulating ADRD biomarkers, including phosphorylated tau181 (p-Tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL). We aimed to examine the associations of genetically inferred African ancestry proportion with the longitudinal changes in these biomarkers and to evaluate the associations of previously identified ADRD-related genetic factors in European cohorts with these biomarkers in an African American cohort.<br><br>METHODS: This study used longitudinal data from the Family and Community Health Study, which was initiated in 1996, recruited and followed 889 African American families residing in Georgia and Iowa. Circulating p-Tau181, GFAP, and NfL were measured in serum samples collected in 2008 (wave 5) and 2019 (wave 8). Closely related individuals, genetically inferred to be third-degree relatives or closer, were excluded. Genetic ancestry proportions were inferred using the ADMIXTURE analysis. Multivariable regression analyses were performed to test the associations of African ancestry proportion with cross-sectional biomarker levels and their longitudinal changes over 11 years. We also tested the associations of selected genetic variants, polygenic scores, and APOE &#x3b5;4 status with these biomarkers.<br><br>RESULTS: Our cross-sectional sample included 573 participants (mean age = 55.1 years; 69% female), whereas our longitudinal sample included 225 (57.2 years; 80% female). African ancestry proportion was not associated with cross-sectional biomarker levels but was inversely associated with the longitudinal change in p-Tau181 (&#x3b2; = -14.50 pg/mL, p = 0.02). The significant inverse association was robust to adjustment for age, sex, APOE &#x3b5;4, socioeconomic status, physical activity, smoking, subjective cognitive decline, and various cardiovascular risk factors and comorbidities. Finally, genetic factors associated with AD and biomarkers in European cohorts were not associated with the 3 biomarkers in our African American cohort.<br><br>DISCUSSION: We found suggestive evidence that a higher African ancestry proportion is associated with an attenuated increase in the blood p-Tau181 level over time. More research is needed to characterize the longitudinal dynamics of ADRD biomarkers across ancestry and the driving biological or sociocultural factors.}, }
@article {pmid40781068, year = {2025}, author = {Kelnhofer-Millevolte, LE and Smith, JR and Nguyen, DH and Wilson, LS and Lewis, HC and Arnold, EA and Brinkley, MR and Shin, K and Ahn, JH and Kim, ET and Kulej, K and Geballe, AP and Ramachandran, S and Avgousti, DC}, title = {Human cytomegalovirus induces neuronal gene expression through IE1 for viral maturation.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7316}, pmid = {40781068}, issn = {2041-1723}, support = {T32 AI007509/AI/NIAID NIH HHS/United States ; R35 GM133434/GM/NIGMS NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; GM133441//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; GM133434//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; P30 CA008748/CA/NCI NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; AI145945//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; T32 GM153182/GM/NIGMS NIH HHS/United States ; R01 AI145945/AI/NIAID NIH HHS/United States ; R35 GM133441/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; *Cytomegalovirus/physiology/genetics/metabolism ; *Immediate-Early Proteins/metabolism/genetics ; Histones/metabolism/genetics ; *Neurons/metabolism/virology ; *Cytomegalovirus Infections/virology/genetics/metabolism ; *Virus Assembly/genetics ; Host-Pathogen Interactions/genetics ; Gene Expression Regulation ; }, abstract = {Viral invasion of the host cell causes some of the most dramatic changes in biology. Human cytomegalovirus (HCMV) extensively remodels host cells, altering nuclear shape and generating a cytoplasmic viral-induced assembly compartment (vIAC). How these striking morphology changes occur in the context of host gene regulation is still emerging. Histone variant macroH2A1 is both important for maintaining nuclear integrity and functions to promote herpes simplex virus infection. Therefore, we hypothesized it may also function in cytomegalovirus infection. Here, we discovered that macroH2A1 is necessary for HCMV-induced cellular reorganization and formation of infectious progeny. Using RNA-seq in infected cells, we find that while all viral genes are highly expressed in the absence of macroH2A1, many HCMV-induced host genes are not. Remarkably, hundreds of these HCMV-induced macroH2A1-dependent host genes are associated with a neuronal signature. Further, we find that HCMV immediate early protein, IE1, is both necessary and sufficient to induce these neuronal genes, providing a mechanism of activation. Together, our findings demonstrate that HCMV hijacks a dormant neuronal secretory pathway through chromatin manipulation for efficient virion maturation.}, }
@article {pmid40781345, year = {2025}, author = {Alson, JG and Doll, KM and Hempstead, BH and Barr, L and Lavallee, DC and Sage, L and Moore, A and Ramsey, SD and Wolff, EM and Comstock, BA and Monsell, SE and Katz, R and Gamble, CR and Beavis, AL and Watat, M and , }, title = {Advancing equity in cancer research through principled partnership: stakeholder engagement practices in The Social Interventions for Support during Treatment for Endometrial cancer and Recurrence (SISTER) Study.}, journal = {Research involvement and engagement}, volume = {11}, number = {1}, pages = {95}, pmid = {40781345}, issn = {2056-7529}, support = {AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; AD-2020C1-19210//Patient Centered Outcomes Research In/ ; }, abstract = {BACKGROUND: In cancer, lack of social support is associated with reduced survival. Peer support interventions have reduced social isolation among Black women with cancer but have yet to be adapted for Black people diagnosed with endometrial cancer - a growing, high-need demographic that has been historically excluded from community-engaged research. Our research team at the University of Washington addressed this gap by working within an established community partnership to develop a pragmatic randomized controlled trial to adapt and test social support interventions among Black women with EC - the Social Interventions for Support during Treatment of Endometrial Cancer and Recurrence (SISTER) Study. The goal of this commentary is to describe the stakeholder engagement practices used in the conceptualization and start-up of the SISTER Study.<br><br>MAIN TEXT: The research team, including Black endometrial cancer survivors, developed a grant proposal, grounded in engagement values derived from the Patient-Centered Outcomes Research Institute[&#xae;] and the Public Health Critical Race Praxis. The team implemented values-aligned stakeholder engagement activities, including the creation of an advisory board charter, structuring meetings and roles, incorporating stakeholder input into study material and protocols, establishing an external advisory board, and developing an engagement evaluation plan. Overall, we learned that it is possible to design and operationalize a community-engaged pragmatic randomized controlled trial in alignment with a racial equity social justice research methodology and patient-centered outcomes research engagement practices. We describe other lessons learned, including operational challenges to implementing our engagement practices and our approaches to addressing these challenges, and&#xa0;promising practices to replicate in future studies or partnerships.<br><br>CONCLUSION: The SISTER Study is an example of establishing principled methods of stakeholder engagement within an area of study and population that has been underrepresented in stakeholder-engaged research. The engagement practices within the SISTER Study can inform community-academic partnership practices in health equity research.}, }
@article {pmid40781843, year = {2025}, author = {Zhang, QS and Kang, J and Lybarger, K and Glenn, MC and Sponseller, P and Blau, KH and Ford, E}, title = {Semi-automated topic identification for radiation oncology safety event reports using natural language processing and statistical modeling.}, journal = {Medical physics}, volume = {52}, number = {8}, pages = {e17936}, doi = {10.1002/mp.17936}, pmid = {40781843}, issn = {2473-4209}, mesh = {*Natural Language Processing ; *Radiation Oncology ; *Models, Statistical ; Automation ; Humans ; *Safety ; Bayes Theorem ; }, abstract = {BACKGROUND: Incident learning provides valuable narrative text about safety and quality, but the large-volume unstructured data is difficult to analyze.<br><br>PURPOSE: We present a semi-automated method to categorize safety-related event reports and validate it using Radiation Oncology reports.<br><br>METHODS: We analyzed English text from 7174 safety-related event reports in a Radiation Oncology department, dated between 2012 and 2021. Units of text called "tokens" were preprocessed for meaningful content, resulting in 4216 tokens. 6760 reports had at least one filtered token. We fit a correlated topic model (CTM) with K&#xa0;=&#xa0;50 topics, estimating Bayesian posterior probability distributions over tokens and proportions of each report that were about each topic. To validate the model by assessing for expert agreement on meaningful topic labels for topics, five experts independently assigned topic labels to topics by reading the top-10 most probable tokens per topic and tokens' posterior probabilities ("top-10 tokens" approach), and by separately reading any reports that were estimated to be at least 90% about a topic ("case-reports" approach). Consensus topic labels (CTLs) such as "Brachytherapy" or "Orders" were assigned to topics.<br><br>RESULTS: Of 50 modeled topics, 37 (74%) had a majority agreement of experts on the CTL assignment, supporting the model's validity. 36 topics had a CTL assigned to them via the top-10 tokens approach. Of 50 topics, 20 had at least one report that was&#xa0;&#x2265;&#xa0;90% about the topic such that the case-reports approach applied. 18 of the 20 had a CTL assigned via that approach. Of 55 CTLs assigned, seven were not found by prior labeling of reports' topics during review of reports over the years.<br><br>CONCLUSIONS: We demonstrated a semi-automated method to categorize Radiation Oncology safety-related event reports by topic, offering an expedited alternative to a person reading many reports and enabling the identification of topics not discovered by reading individual reports.}, }
@article {pmid40784763, year = {2025}, author = {Puschel, K and Arancibia, V and Rioseco, A and Paz, S and Soto, MG and Martinez, J and Faundez, M and Acevedo, F and Di Biase, F and Emery, J and León, A and Are, C and Thompson, B}, title = {Challenges of cancer survivorship care in Chile: a longitudinal study comparing the quality of care and quality of life for cancer survivors in a primary care network and a cancer centre in Chile.}, journal = {BMJ open}, volume = {15}, number = {8}, pages = {e097015}, pmid = {40784763}, issn = {2044-6055}, mesh = {Humans ; *Quality of Life ; Chile/epidemiology ; Female ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Male ; *Primary Health Care/standards ; Middle Aged ; *Quality of Health Care ; Retrospective Studies ; Longitudinal Studies ; Aged ; Adult ; *Survivorship ; *Cancer Care Facilities ; *Colorectal Neoplasms/therapy/psychology ; *Breast Neoplasms/therapy/psychology ; }, abstract = {OBJECTIVE: The rapid growth in the cancer survivor population in Chile and Latin America raises new challenges in addressing their care needs. This study assesses the health status and compares the quality of care and quality of life in cancer survivors at a primary care network and a private cancer centre in Santiago, Chile.<br><br>DESIGN: Retrospective cohort study.<br><br>SETTING: Three primary care clinics and one cancer centre in Chile.<br><br>PARTICIPANTS: All breast and colorectal cancer patients identified from a primary care retrospective cohort of 61&#x2009;174 were followed from 2018 to 2023 and compared with an equivalent sample of patients from a university cancer centre identified during the same period.<br><br>OUTCOME MEASURES: Quality of care was assessed based on American Cancer Society standards, while quality of life was measured using the EuroQol 5 Dimensions-5 Levels survey instrument.<br><br>RESULTS: A total of 420 cancer survivors participated in the study; 208 from primary care and 212 from the cancer centre. All participants received substandard care. Patients in primary care had lower educational levels and higher rates of comorbidity. They reported a lower quality of life score (72.22 vs 78.43, p<0.001), a higher prevalence of chronic pain (37.02% vs 25.6%, p=0.016) and more severe mental health symptoms (19.89% vs 10.05%, p=0.03). Differences in educational level and cancer stage at diagnosis explained the observed disparities in chronic pain and mental health disorders between the two populations. Primary care patients received more psychosocial care (OR=2.29; 95%&#x2009;CI: 1.55 to 3.39), cardiovascular assessment (OR=2.66; 95% CI:2.17 to 3.26) and psychosocial evaluations (OR: 9.07; 95%&#x2009;CI:4.75 to 17.32).<br><br>CONCLUSION: Cancer survivors face a significant disease burden and receive substandard care in Chile. As the primary source of care for this population, primary care is challenged to better integrate with speciality care to develop an effective shared care model for cancer survivors.}, }
@article {pmid40785644, year = {2025}, author = {Gauthier, J and Ahn, KW and Patel, J and Lian, Q and Badawy, S and Cairo, MS and Delgado, J and Grover, N and Haverkos, B and de Lima, M and Malone, A and Mussetti, A and Nieto, Y and Pawarode, A and Pearson, L and Solh, M and Sureda, A and Tun, AM and Wudhikarn, K and Yamshon, S and Shadman, M and Turtle, CJ and Hamadani, M and Herrera, AF}, title = {CD19 CAR T-Cell Therapy for Primary Mediastinal Large B-Cell Lymphoma: A CIBMTR Analysis.}, journal = {American journal of hematology}, volume = {100}, number = {10}, pages = {1792-1802}, pmid = {40785644}, issn = {1096-8652}, support = {U24CA076518/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; N00014-20-1-2705//Office of Naval Research/ ; N00014-20-1-2832//Office of Naval Research/ ; HHSH250201700006C/HRSA/HRSA HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Antigens, CD19/immunology ; Immune Checkpoint Inhibitors/therapeutic use ; *Immunotherapy, Adoptive/methods/adverse effects ; *Lymphoma, Large B-Cell, Diffuse/therapy/mortality ; *Mediastinal Neoplasms/therapy/mortality ; *Receptors, Chimeric Antigen ; Registries ; Retrospective Studies ; }, abstract = {T cells engineered with CD19-directed chimeric antigen receptors (CD19 CAR) T cells have become standard treatment for patients with high risk, relapsed or refractory (R/R) large B-cell lymphomas (LBCL). However, outcomes in patients with rare subsets of LBCL, such as primary mediastinal large B-cell lymphoma (PBMCL), have not been well characterized. The impact of prior immune checkpoint inhibitor (ICI) treatment, commonly used to treat R/R PMBCL, is also unknown. To address these gaps, we retrospectively analyzed CIBMTR registry data including PMBCL patients undergoing CD19 CAR T-cell therapy per standard-of-care. A total of 135 PMBCL adults from 66 centers were included. Median age at the time of CAR T-cell therapy was 32. Thirty-nine patients (28.9%) had received an ICI prior to CAR T-cell therapy. The best overall and complete response (CR) rates after CD19 CAR T-cell therapy were 79% and 67.7%, respectively. The 2-year progression-free (PFS) and overall survival (OS) were 58.6% (95% CI, 49.7-67.3) and 80.8% (95% CI, 72.6-87.8), respectively. The 2-year cumulative incidence (CI) of relapse and non-relapse mortality (NRM) were 36% (95% CI, 27.8-44.7) and 5.4% (95% CI, 1.9-10.5), respectively. We observed grade ≥ 3 CRS and ICANS in 6.1% and 14.7%, respectively. Prior ICI exposure was associated with lower 2-year CI of relapse (ICI-exposed, 21.7%; ICI-naïve, 41.6%; p = 0.03) and higher 2-year NRM (ICI-exposed, 11.7%; ICI-naïve, 2.8%; p = 0.03). We could not confirm statistically different PFS (p = 0.19) or OS (p = 0.26) between ICI-exposed and ICI-naïve patients. CD19 CAR T-cell therapy led to high rates of durable responses in PMBCL patients with low rates of severe toxicities.}, }
@article {pmid40788762, year = {2025}, author = {Khyzha, N and Ahmad, K and Henikoff, S}, title = {Protocol for the spatiotemporal profiling of RNA within nuclear compartments in human cell lines using SLAM-RT&amp;Tag.}, journal = {STAR protocols}, volume = {6}, number = {3}, pages = {104017}, pmid = {40788762}, issn = {2666-1667}, mesh = {Humans ; *RNA/metabolism/genetics/analysis ; *Cell Nucleus/metabolism/genetics ; Cell Line ; }, abstract = {Measuring RNA residence time within nuclear compartments provides insight into their roles as either storage sites or transient processing hubs. This protocol describes SLAM-RT&amp;Tag, a genomic technique that integrates RNA metabolic labeling with RT&amp;Tag, an RNA proximity labeling method. We detail steps for RNA labeling, library preparation, and computational quantification of T-to-C conversion events to infer RNA dynamics within nuclear compartments in human cell lines. For complete details on the use and execution of this protocol, please refer to Khyzha et al.[1].}, }
@article {pmid40789020, year = {2025}, author = {Stolla, M and Cap, AP and Spinella, PC}, title = {Chilling controversy: cold-stored platelets for prophylactic transfusions.}, journal = {Blood}, volume = {146}, number = {17}, pages = {2023-2028}, doi = {10.1182/blood.2025029252}, pmid = {40789020}, issn = {1528-0020}, mesh = {Humans ; *Platelet Transfusion/methods ; *Blood Preservation/methods ; *Blood Platelets/cytology ; Cold Temperature ; *Hemorrhage/prevention &amp; control/therapy ; Thrombocytopenia/therapy ; *Cryopreservation/methods ; Platelet Count ; }, abstract = {The US Food and Drug Administration recently licensed 14-day cold-stored platelets for bleeding patients. This policy change represents a reversal from the 1970s when cold-stored platelets were discontinued because of their short circulation time in healthy humans. This change will increase their availability in US hospitals with large trauma populations and in remote and rural settings in the United States. In some of these hospitals, cold-stored platelets will be the only platelets available. It is currently unclear whether patients with hypoproliferative thrombocytopenia who need platelet transfusion for prophylaxis benefit from cold-stored platelets. However, it is noteworthy that in recent clinical trials using room temperature-stored platelets, the transfusion interval in patients with hematologic and oncologic conditions can be as short as 1 transfusion per day, very similar to what one would expect to achieve with cold-stored platelets. Furthermore, the emphasis on the posttransfusion count increment and the platelet count as a transfusion trigger per se is questionable. In the PLADO trial, there was only a poor correlation between the morning platelet count and bleeding events, implicating other factors, such as red blood cells, coagulation factors, and vascular health, as possible culprits. In this perspective article, we review the history of cold platelets and the reason for their discontinuation, focus on recent clinical trial data using room temperature-stored platelets, and review the platelet count as a transfusion trigger. Overall, using cold platelets for prophylaxis may seem counterintuitive, but a closer look at the available data suggests that the indication expansion may hold more promise.}, }
@article {pmid40789098, year = {2025}, author = {Johns, TS and Estrella, MM and Hébert, J and Franceschini, N and Larson, JC and Boulware, LE and Snetselaar, L and Golestaneh, L and Shadyab, AH and Shivappa, N and Mossavar-Rahmani, Y and Melamed, ML}, title = {Dietary Inflammatory Potential and the Risk of Incident Kidney Failure in the Women's Health Initiative.}, journal = {Kidney360}, volume = {6}, number = {8}, pages = {1338-1349}, pmid = {40789098}, issn = {2641-7650}, support = {HHSN268201600002C/HL/NHLBI NIH HHS/United States ; R01 AG055527/AG/NIA NIH HHS/United States ; K26 DK138488/DK/NIDDK NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; R01 AG055527/NH/NIH HHS/United States ; K23 DK124644/DK/NIDDK NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; U01 CA272977/CA/NCI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; }, abstract = {KEY POINTS: A pro-inflammatory diet was associated with a higher risk of incident kidney failure. Clinical trials should assess the impact of an anti-inflammatory dietary pattern on CKD risk and progression.<br><br>BACKGROUND: Diet affects inflammation and kidney health, but few studies have investigated dietary inflammatory potential in CKD progression, particularly in women. We aim to examine this association in the Women's Health Initiative.<br><br>METHODS: We conducted a nonconcurrent prospective cohort study among Women's Health Initiative participants enrolled in the clinical trials and observational study (1993&#x2013;1998) without baseline CKD and with available dietary intake assessments, Medicare data, and creatinine measurements at enrollment. The inflammatory potential of diets was assessed using the dietary inflammatory index, an acultural tool that quantifies diets from anti-inflammatory to proinflammatory. Scores were categorized into quartiles, with Q1 (reference group) and Q4 indicating the least and most inflammatory diets, respectively. Incident kidney failure (CKD stage G5, ESKD, or transplantation) was identified using diagnosis codes in Medicare claims from enrollment through December 31, 2019. We performed multivariable Cox proportional hazards regression and modeled death as a competing risk to determine the risk of incident kidney failure.<br><br>RESULTS: Among the 17,334 women included in our study, the baseline mean age was 64.9 years (standard deviation 7.1); 33.5% self-identified as Black, 8.8% as Hispanic, 38% had hypertension, and 6.8% had diabetes mellitus. The baseline mean eGFR was 87.2 ml/min per 1.73 m[2]. Over a mean follow-up of 11.2 years, 1852 women (10.7%) developed kidney failure. Compared with Q1, women with dietary patterns in Q4 had a 18% higher risk (95% confidence interval, 1.03 to 1.37; P trend = 0.01) of developing kidney failure after adjusting for age, race and ethnicity, education, region, comorbidities, medications, smoking, energy intake, physical activity, eGFR, and body mass index. Competing risk models yielded similar results.<br><br>CONCLUSIONS: A proinflammatory diet (e.g., enriched in processed foods, refined sugars, and red meat) was associated with incident kidney failure in postmenopausal women without baseline CKD. Clinical trials are needed to assess the effect of an anti-inflammatory dietary pattern on CKD risk and progression.}, }
@article {pmid40789102, year = {2025}, author = {Bhandari, R and Chen, Y and Chow, EJ and Howell, RM and Kenney, LB and Krull, KR and Leisenring, W and Nathan, PC and Neglia, JP and Ness, KK and Oeffinger, KC and Snyder, C and Turcotte, LM and Wong, FL and Yasui, Y and Armstrong, GT and Armenian, SH}, title = {Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {27}, pages = {2998-3010}, pmid = {40789102}, issn = {1527-7755}, support = {K12 CA001727/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer Survivors/statistics &amp; numerical data ; Male ; Female ; *Neoplasms/mortality/epidemiology/therapy ; Middle Aged ; Child ; Adolescent ; Adult ; United States/epidemiology ; Risk Factors ; Young Adult ; Health Status ; Child, Preschool ; Incidence ; Frailty/epidemiology ; Age Factors ; }, abstract = {PURPOSE: There are limited data on the risk for mortality and health outcomes among the increasing population of older (age >50 years) survivors of childhood cancer during this later stage in life when there is an expected increase in aging-related morbidities.<br><br>METHODS: We assessed cause-specific mortality, incident new cancers, chronic health conditions (CHCs), frailty, and health status among survivors from the Childhood Cancer Survivor Study, conditional on surviving to 50 years. We calculated conditional survival rates, standardized mortality ratios (SMRs), and, for incident new cancers, cumulative burden, standardized incidence ratios (SIRs), and relative rates (RRs), compared with the general US population. RRs for CHCs and prevalence ratios for frailty and health status outcomes were calculated for survivors compared with siblings. Piecewise exponential regression identified risk factors.<br><br>RESULTS: Among 7,490 childhood cancer survivors alive at age 50 years, subsequent 5-, 10-, and 15-year mortality risks were 8%, 18%, and 32%, respectively; overall SMR was 3.2 (95% CI, 3.0 to 3.4). SMRs were highest for death due to new cancer (SMR = 4.7; 95% CI, 4.2 to 5.2). In subset analysis, survivors without radiation therapy (RT) exposure had similar new cancer rates as the general population. The population attributable fraction of new cancers to RT was 40%. Survivors had >2-fold risk of severe, life-threatening, or fatal CHCs (any: RR, 2.6 [95% CI, 2.2 to 3.1]; multiple: RR, 3.3 [95% CI, 2.5 to 4.4]), specifically among survivors with history of RT exposure, compared with siblings. We identified no associations between chemotherapy and late health outcomes.<br><br>CONCLUSION: Older survivors of childhood cancer continue to have an elevated burden of premature mortality, new cancers, and adverse health outcomes as they age. The increased risk for cancer and CHCs among these older survivors is associated with RT, but not chemotherapy, exposure.}, }
@article {pmid40789739, year = {2025}, author = {Tachiki, L and Moshiri, Y and Hippe, DS and Gong, E and Zawacki, L and Pulliam, T and Lachance, K and Church, C and Fu, A and Huynh, E and Remington, AJ and Harikrishnan, N and Bierma, M and Doolittle-Amieva, C and Akaike, T and Park, SY and Alexander, NA and Zaba, L and Bhatia, S and Nghiem, PT}, title = {Risk of disease progression after discontinuing immunotherapy in 105 patients with Merkel cell carcinoma who responded to PD-1 pathway blockade.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {8}, pages = {}, pmid = {40789739}, issn = {2051-1426}, support = {F30 CA254168/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/drug therapy/pathology/mortality ; Male ; Female ; Disease Progression ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; Aged ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; *Skin Neoplasms/drug therapy/pathology ; *Immunotherapy/methods ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; }, abstract = {BACKGROUND: Immune checkpoint inhibitors (ICIs) are the preferred systemic therapy for most patients with advanced Merkel cell carcinoma (MCC). However, the optimal duration of treatment for patients responding to ICI is unclear. Emerging data from retrospective analyses indicate a higher risk of MCC progression after ICI discontinuation, as compared with continuing ICI.<br><br>METHODS: We performed a retrospective cohort study to evaluate the rate of progressive disease (PD) after treatment discontinuation in patients with advanced MCC who experienced objective responses to first-line ICI. We evaluated whether the risk of PD was associated with the reason for treatment discontinuation (elective vs due to toxicity) and depth of response (complete vs partial response (CR vs PR)).<br><br>RESULTS: Among 105 responders, 58 discontinued ICI (median treatment duration: 12 months), and 47 continued ICI (median treatment duration: 20 months) at data cut-off. With a median follow-up of 34 months from ICI initiation, 33% of the entire cohort experienced disease progression at 2 years. 2 years after ICI initiation, 39% of patients who discontinued ICI had disease progression, compared with 14% of patients who continued ICI (HR=2.34 (95% CI: 1.07 to 5.12), p=0.034). Among patients who discontinued ICI, those with PR had a numerically higher rate of progression compared with patients with CR at 2 years after ICI discontinuation (56% vs 29%, respectively; HR=1.74 (95% CI: 0.72 to 4.20), p=0.22). Patients who discontinued due to toxicity had numerically higher rates of progression at 2 years (N=28) compared with patients who discontinued electively (N=30) (45% vs 31%, respectively; HR=2.08 (95% CI: 0.79 to 5.46), p=0.14). Among responders who stayed on ICI and had not progressed by 1 year, those who electively discontinued ICI had a high chance of remaining progression-free at 2 years (89%), similar to those who continued ICI (96%, p=0.59).<br><br>CONCLUSIONS: This study highlights the high progression risk following ICI discontinuation in advanced MCC, especially among patients with non-CRs or those discontinuing early. While elective discontinuation may be appropriate after durable CRs (response&#x2265;1 year), greater caution is warranted in other settings.}, }
@article {pmid40791471, year = {2025}, author = {Skeate, JG and Slipek, NJ and Lahr, WS and Roy, S and Wick, BJ and Stelljes, EM and Gilkey, AK and Thenge, PP and Diers, MD and Kar, B and Krueger, JB and Niemeyer, EM and Lonetree, CL and Kluesner, MG and Bell, JB and Clement, K and Provenzano, P and Moriarity, BS and Webber, BR}, title = {A Singular Base Editing Platform for Polyfunctional Multiplex Engineering of Immune Cells.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40791471}, issn = {2692-8205}, support = {R01 AI161017/AI/NIAID NIH HHS/United States ; P30 CA077598/CA/NCI NIH HHS/United States ; R21 CA237789/CA/NCI NIH HHS/United States ; R01 CA245550/CA/NCI NIH HHS/United States ; U54 CA232561/CA/NCI NIH HHS/United States ; R21 AI163731/AI/NIAID NIH HHS/United States ; T32 HL007062/HL/NHLBI NIH HHS/United States ; U24 OD026641/OD/NIH HHS/United States ; P01 CA254849/CA/NCI NIH HHS/United States ; R01 AI146009/AI/NIAID NIH HHS/United States ; U54 CA268069/CA/NCI NIH HHS/United States ; P50 CA136393/CA/NCI NIH HHS/United States ; }, abstract = {Current methods to engineer antigen-specific receptors rely on randomly integrating vectors or double-strand break induced targeted integration, both of which pose safety risks. To implement an all-in-one tool for multiplex knockout (KO) and knock in (KI), we expand the use of cytosine and adenine base editor (ABE) nickase activity to stimulate homology-directed repair (HDR) and insert clinically relevant chimeric antigen receptors (CARs) into specific loci. Through a novel sgRNA design strategy and a recombinant adeno-associated virus (rAAV) delivered DNA template, we enhanced the efficiency of ABE8e-stimulated HDR in human T cells. By combining KI of CD19-, CD33-, or mesothelin-targeting CARs with >95% quadplex gene KO (B2M/CD3ε/PDCD1/CISH), we achieve single-step generation of highly functional off-the-shelf CAR T cell products with enhanced function. Importantly, we found no detectable translocations or significant off-target edits and demonstrated efficacy against multiple cancer lines, and a suppressive 3D spheroid culture model. This efficient engineering process of Iterative Nicking for Synchronous Engineered Reprogramming of T cells (INSERT) establishes a safe, simplified platform for advanced therapeutic CAR T engineering.}, }
@article {pmid40792014, year = {2025}, author = {DaSilva, B and Darwin, A and Zhang, A and Vyas, RD and Russell, K and Gilbert, JS and Tan, V and Feldt, S and Johnston, H and Liang, EC and DuVall, AS and Liedtke, M and Stock, W and Cassaday, RD and Schwartz, M and Leonard, JT and Muffly, LS and Luskin, MR}, title = {Real-world performance of the CALGB 10403 regimen in young adults in the United States.}, journal = {Blood neoplasia}, volume = {2}, number = {3}, pages = {100111}, pmid = {40792014}, issn = {2950-3280}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {The Cancer and Leukemia Group B 10403 (C10403) trial prospectively demonstrated the safety and efficacy of administering an asparaginase-containing pediatric regimen for the treatment of adolescents and young adults (AYAs) with acute lymphoblastic leukemia. Since its implementation as standard of care, it is unknown how the C10403 regimen performs beyond the clinical trial setting. To bridge this knowledge gap, we designed a multicenter retrospective cohort study to examine the safety, efficacy, and challenges of completing C10403 in the "real world." From October 2012 through June 2020, a total of 139 patients began induction as per the C10403 regimen across 6 US academic cancer centers. The median age was 26 years (range, 17-39), 69% were male, 55% were non-Hispanic White, and 27% were Hispanic. Among them, 122 patients (88%) achieved complete remission or complete remission with incomplete count recovery (CR/CRi) with C10403, 48 (35%) completed maintenance therapy, and 47 (34%) changed postremission regimens while in CR/CRi. The 3-year event-free survival (EFS) was 66% (95% confidence interval [CI], 55-74), and the 3-year overall survival (OS) was 81% (95% CI, 74-87). Four deaths occurred while on C10403 treatment: 1 during induction; and 3 later in the treatment course. The most common grade 3 or 4 adverse events during induction included alanine aminotransferase elevation (22%) and sepsis (14%). B-cell immunophenotype (hazard ratio [HR], 2.45; 95% CI, 1.09-5.48), Philadelphia chromosome-like genetics (HR, 3.05; 95% CI, 1.25-7.44), and Hispanic ethnicity (HR, 2.00; 95% CI, 1.06-3.78) were associated with worse EFS in univariate analyses. Overall, these real-world results are comparable to those of the C10403 trial. Further improvements are needed to enhance outcomes and regimen tolerability in the AYA population.}, }
@article {pmid40792015, year = {2025}, author = {Raychaudhuri, S and Othus, M and Percival, MM and Garcia-Manero, G and Appelbaum, FR and Erba, HP and Appelbaum, JS}, title = {Treatment discontinuation due to toxicity for patients with acute myeloid leukemia receiving intensive chemotherapy.}, journal = {Blood neoplasia}, volume = {2}, number = {3}, pages = {100129}, pmid = {40792015}, issn = {2950-3280}, support = {T32 HL007093/HL/NHLBI NIH HHS/United States ; }, }
@article {pmid40792429, year = {2025}, author = {Zhou, P and Mills, CB and Dong, ZM and Barber, BR and Beronja, S}, title = {Barcoded Orthotopic Patient-Derived Head &amp; Neck Squamous Cell Carcinoma Model Demonstrating Clonal Stability and Maintenance of Cancer Driver Mutational Landscape.}, journal = {Cancer medicine}, volume = {14}, number = {15}, pages = {e71137}, pmid = {40792429}, issn = {2045-7634}, support = {//Fred Hutchinson Cancer Research Center/ ; //Dick and Loraine Burger Pilot Funding/ ; //AAO-HNSF Resident Research Grant/ ; }, mesh = {Humans ; Animals ; Mice ; *Squamous Cell Carcinoma of Head and Neck/genetics/pathology ; *Head and Neck Neoplasms/genetics/pathology ; *Mutation ; Disease Models, Animal ; Female ; Xenograft Model Antitumor Assays ; Mice, SCID ; Exome Sequencing ; Male ; *DNA Barcoding, Taxonomic ; }, abstract = {OBJECTIVE: To illustrate a new barcoded orthotopic patient-derived xenograft (PDX) mouse model where one can investigate phenotypic effects of single-cell level gene manipulation in a pooled format. To address some concerns of current PDX mouse models of head and neck squamous cell carcinoma (HNSCC): (1) genomic evolution with passage by generating high-purity cancer cells, which can also be utilized for other downstream applications, including cell culture-based studies, and (2) cost-effectiveness of current PDX models.<br><br>METHODS: Two-millimeter tumor cubes from nine patients were implanted into immunodeficient mouse flanks subcutaneously. Purified tumor cells were obtained from subcutaneous xenografts. Various numbers of purified tumor cells were then injected into the lingual tissue of immunodeficient mice, and the lowest amount of cells needed to achieve a 100% orthotopic engraftment rate were identified. Clonal stability was tested using a lentiviral barcoding system. The orthotopic PDXs' genetic landscapes were characterized using whole exome sequencing.<br><br>RESULTS: This approach yielded an overall engraftment rate of 88.9%. The purification process increased cancer cell purity from 34% to 92%. Lingual injection of 100,000 purified tumor cells achieved a 100% orthotopic engraftment rate from purified subcutaneous PDX tumor cells while maintaining clonal and genetic stability.<br><br>CONCLUSION: Our study presents a barcoded orthotopic patient-derived xenograft model for head and neck squamous cell carcinoma with clonal stability. This model provides a way to study phenotypic effects of single cell level gene manipulation in a pooled format. The method can be adapted for in&#xa0;vitro work as well.}, }
@article {pmid40794593, year = {2025}, author = {Matsen, FA and Sung, K and Johnson, MM and Dumm, W and Rich, D and Starr, TN and Song, YS and Bradley, P and Fukuyama, J and Haddox, HK}, title = {A Sitewise Model of Natural Selection on Individual Antibodies via a Transformer-Encoder.}, journal = {Molecular biology and evolution}, volume = {42}, number = {8}, pages = {}, pmid = {40794593}, issn = {1537-1719}, support = {R01-HG013117/GF/NIH HHS/United States ; R56-HG013117/GF/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; DP2-AI177890/GF/NIH HHS/United States ; R35-GM141457/GF/NIH HHS/United States ; DP2 AI177890/AI/NIAID NIH HHS/United States ; R01-AI146028/GF/NIH HHS/United States ; R56 HG013117/HG/NHGRI NIH HHS/United States ; R01 HG013117/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; R01-AI136514/GF/NIH HHS/United States ; }, mesh = {*Selection, Genetic ; *Models, Genetic ; *Antibodies/genetics ; Evolution, Molecular ; Humans ; Complementarity Determining Regions/genetics ; Antibody Affinity ; }, abstract = {During affinity maturation, antibodies are selected for their ability to fold and to bind a target antigen between rounds of somatic hypermutation. Previous studies have identified patterns of selection in antibodies using B cell repertoire sequencing data. However, these studies are constrained by needing to group many sequences or sites to make aggregate predictions. In this paper, we develop a transformer-encoder selection model of maximum resolution: given a single antibody sequence, it predicts the strength of selection on each amino acid site. Specifically, the model predicts for each site whether evolution will be slower than expected relative to a model of the neutral mutation process (purifying selection) or faster than expected (diversifying selection). We show that the model does an excellent job of modeling the process of natural selection on held out data, and does not need to be enormous or trained on vast amounts of data to perform well. The patterns of purifying vs diversifying natural selection do not neatly partition into the complementarity-determining vs framework regions: for example, there are many sites in framework that experience strong diversifying selection. There is a weak correlation between selection factors and solvent accessibility. When considering evolutionary shifts down a tree of antibody evolution, affinity maturation generally shifts sites towards purifying natural selection, however this effect depends on the region, with the biggest shifts toward purifying selection happening in the third complementarity-determining region. We observe distinct evolution between gene families but a limited relationship between germline diversity and selection strength.}, }
@article {pmid40795197, year = {2025}, author = {Paturi, S and Banerjee, R}, title = {Step Count, Step Aside: Newer Physical Activity Metrics to Predict Survival in Oncology.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500197}, doi = {10.1200/CCI-25-00197}, pmid = {40795197}, issn = {2473-4276}, }
@article {pmid40795788, year = {2025}, author = {van der Heijden, MS and Powles, T and Gupta, S and Loriot, Y and Galsky, MD and Valderrama, BP and Sridhar, SS and Yu, EY and Iyer, G and Kikuchi, E and Castellano, D and Hoffman-Censits, J and Drakaki, A and Mar, N and Maroto Rey, JP and Vulsteke, C and Arafat, W and Duran, I and Dawson, NA and Swami, U and Gorla, S and Moreno, BH and Yu, X and Lu, YT and Bedke, J}, title = {Exploratory subgroup analyses of EV-302: a phase III global study to evaluate enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma.}, journal = {ESMO open}, volume = {10}, number = {8}, pages = {105544}, pmid = {40795788}, issn = {2059-7029}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration &amp; dosage/pharmacology ; Male ; Female ; Middle Aged ; Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use ; Cisplatin/administration &amp; dosage/therapeutic use ; *Urologic Neoplasms/drug therapy/pathology/mortality ; Adult ; Carboplatin/administration &amp; dosage ; *Carcinoma, Transitional Cell/drug therapy ; Aged, 80 and over ; Progression-Free Survival ; }, abstract = {BACKGROUND: In the phase III EV-302 study (NCT04223856), enfortumab vedotin (EV) plus pembrolizumab (P) demonstrated superior efficacy and safety versus platinum-based chemotherapy in patients with previously untreated locally advanced/metastatic urothelial cancer (la/mUC). We report the efficacy of EV+P in prespecified subgroups, including those defined by cisplatin eligibility status, the presence or absence of liver metastases, and metastatic disease sites.<br><br>METHODS: Patients with previously untreated la/mUC were randomly assigned 1 : 1 to receive either EV 1.25 mg/kg and pembrolizumab 200 mg, or gemcitabine plus cisplatin or carboplatin, all intravenously. The two primary endpoints were progression-free survival (PFS) and overall survival (OS). Confirmed objective response rate was one of the secondary endpoints.<br><br>RESULTS: Overall, 886 patients were randomized: 442 to EV+P and 444 to chemotherapy. Baseline characteristics were balanced across treatment groups. Efficacy and safety data for the intention-to-treat (ITT) population, along with PFS and OS data for cisplatin-eligible and -ineligible patients, were previously published (Powles et al. N Eng J Med, 2024). In this analysis, EV+P showed benefit across prespecified subgroups that was consistent with the ITT population. OS benefit in the EV+P arm versus chemotherapy was seen across all subgroups, including patients with liver metastases (OS 19.1 versus 10.1 months), patients without liver metastases [OS not estimable (NE) versus 17.9 months], patients with visceral metastases (OS 25.6 versus 13.6 months), and in patients with lymph node-only disease (OS NE versus 27.5 months). In addition, confirmed objective response rate and PFS benefit with EV+P versus chemotherapy was seen across all examined subgroups.<br><br>CONCLUSION: Along with previously published safety data, EV+P demonstrated benefit compared with chemotherapy across all prespecified subgroups, consistent with the ITT population and supporting EV+P as the standard of care for first-line treatment of la/mUC.}, }
@article {pmid40796174, year = {2026}, author = {Sevilla-González, M and Hanson, PA and Islam, J and Hsu, S and Tsoukas, MA and Marliss, EB and Reiner, AP and Gravel, M and Kooperberg, C and Clish, CB and Manning, AK and Sladek, R and Meigs, JB and Burgos, SA}, title = {Compartment-specific Metabolic Alterations to Insulin Reflect Adiposity-driven Variation and Predict Type 2 Diabetes.}, journal = {The Journal of clinical endocrinology and metabolism}, volume = {111}, number = {3}, pages = {820-831}, doi = {10.1210/clinem/dgaf454}, pmid = {40796174}, issn = {1945-7197}, support = {//Congressionally Directed Medical Research Programs/ ; 9-22-PDFPM-04//American Diabetes Association/ ; NIDDK UM1 DK078616//American Diabetes Association/ ; /HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 2/metabolism/diagnosis/epidemiology/etiology ; Female ; Middle Aged ; Glucose Clamp Technique ; Case-Control Studies ; *Adiposity/physiology ; *Insulin Resistance/physiology ; *Insulin/metabolism ; Prospective Studies ; *Hyperinsulinism/metabolism ; Male ; Aged ; Metabolomics ; Adult ; Muscle, Skeletal/metabolism ; Prognosis ; Follow-Up Studies ; }, abstract = {CONTEXT: The metabolic mechanisms underlying insulin resistance are not fully understood. Metabolomic profiling can reveal compartment-specific variations and identify individuals at risk for type 2 diabetes (T2D).<br><br>OBJECTIVE: To characterize insulin-induced metabolomic changes during a hyperinsulinemic-euglycemic clamp and evaluate a derived risk score's predictive value for T2D.<br><br>Clamp studies were conducted in 80 adults (38 with T2D, 42 without) to measure plasma and muscle metabolites in fasting and hyperinsulinemic states. An insulin resistance metabolomic score was developed and tested in a prospective case-control study (367 cases, 910 controls) from the Women's Health Initiative (28.5-year follow-up).<br><br>MAIN OUTCOME MEASURES: Metabolite changes during hyperinsulinemia and incident T2D.<br><br>RESULTS: Hyperinsulinemia altered 79.5% of plasma metabolites (notably fatty acids, lactate, and pyruvate) and 15.8% of muscle metabolites (eg, branched-chain and aromatic amino acids). T2D was associated with higher triglycerides and lower tricarboxylic acid intermediates during clamp. Adiposity amplified insulin-induced increases in plasma lipids. The risk score predicted incident T2D (hazard ratio, 1.20 per SD; 95% CI, 1.09-1.32; P = 7.4 &#xd7; 10-4).<br><br>CONCLUSION: Compartment-specific metabolic responses to insulin are shaped by adiposity and predict future T2D risk, supporting use of metabolomic signatures for early identification and prevention.}, }
@article {pmid40796223, year = {2025}, author = {Grignani, G and Rutkowski, P and Lebbé, C and Guida, M and Gaudy-Marqueste, C and Spagnolo, F and Burgess, M and Morano, F and Montaudié, H and Depenni, R and Spada, F and Yeung, CCS and Pulini, J and Cornfeld, M and Tian, C and Bhatia, S}, title = {Phase II study of retifanlimab in patients with recurrent locally advanced or metastatic Merkel cell carcinoma (POD1UM-201).}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {8}, pages = {}, pmid = {40796223}, issn = {2051-1426}, mesh = {Humans ; Male ; Female ; *Carcinoma, Merkel Cell/drug therapy/pathology/mortality ; Aged ; Middle Aged ; Aged, 80 and over ; *Skin Neoplasms/drug therapy/pathology/mortality ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology/adverse effects ; *Neoplasm Recurrence, Local/drug therapy/pathology ; Adult ; Neoplasm Metastasis ; *Immune Checkpoint Inhibitors/therapeutic use/adverse effects ; }, abstract = {BACKGROUND: POD1UM-201, an open-label, single-arm, phase II multiregional study, evaluated efficacy and tolerability of retifanlimab, a humanized monoclonal antibody targeting programmed cell death protein-1 (PD-1) in chemotherapy-naive patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC).<br><br>METHODS: Patients were enrolled across 34 sites in the USA, Canada, and Europe. Eligible patients were &#x2265;18 years with confirmed recurrent advanced locoregional or metastatic MCC not amenable to surgery or radiation therapy, had not received previous systemic treatment, had measurable disease, and Eastern Cooperative Oncology Group performance status 0-1. Retifanlimab 500&#x2009;mg was administered intravenously every 4 weeks (Q4W) for up to 2 years. The primary endpoint was objective response rate (ORR). Key secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.<br><br>RESULTS: A total of 101 patients were enrolled between February 12, 2019, and June 16, 2021, with a median duration of follow-up for response of 22.2 (range: 1.1-55.3) months. ORR was 54.5% (95% CI: 44.2% to 64.4%; n=55), including 18 patients (17.8%) with complete responses (CRs) and 37 (36.6%) with partial responses (PRs). DCR was 60.4% (95% CI: 50.2% to 70.0%; n=61). Median DOR was not reached (95%&#x2009;CI: 14.0 months to not estimable (NE)) in patients who achieved CR and was 25.3 months (95%&#x2009;CI: 14.2 months to NE) in those with PR. With a median follow-up of 9.3 (range: 0.0-57.1) months, the estimated median PFS was 16.0 months (95%&#x2009;CI: 9.0 months to 32.2). Median OS was not reached with 63% of patients alive at 3 years. The safety profile was representative of the PD-(ligand)1 inhibitor class, with grade 3 immune-related adverse events occurring in 11 patients (10.9%).<br><br>CONCLUSIONS: Retifanlimab 500&#x2009;mg Q4W led to frequent and durable responses in chemotherapy-naive patients with advanced MCC with an acceptable safety profile. Retifanlimab represents a new immunotherapy option for patients with locally advanced or metastatic MCC.<br><br>TRIAL REGISTRATION NUMBER: NCT03599713; EudraCT 2018-001627-39.}, }
@article {pmid40798950, year = {2025}, author = {Fouda, GG and Singh, A and Nelson, A and Janes, H and Martin, T and Levy, O and Wu, D and Zou, F and Jean-Philippe, P and De Paris, K and Van Rompay, KKA and Permar, SR}, title = {Integration of Preclinical and Clinical Vaccine Safety and Immunogenicity Testing for Development of a Pediatric HIV Vaccine to Achieve Protective HIV Immunity Prior to Adolescence.}, journal = {Current HIV research}, volume = {}, number = {}, pages = {}, pmid = {40798950}, issn = {1873-4251}, support = {P01 AI178377/AI/NIAID NIH HHS/United States ; R01 AI143370/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; R01 AI162245/AI/NIAID NIH HHS/United States ; P01 AI117915/AI/NIAID NIH HHS/United States ; U01 AI068614/AI/NIAID NIH HHS/United States ; U19 AI168643/AI/NIAID NIH HHS/United States ; P51 OD011107/OD/NIH HHS/United States ; }, abstract = {An optimal HIV vaccine should provide protective immunity before sexual debut to prevent infection in adolescents and young adults, including acute infections in women of childbearing age. Such a vaccine will likely require multiple sequential immunization doses and would therefore be ideally initiated in childhood. Many of the world's most successful vaccines are initiated in childhood for the induction of lifelong immunity and/or immunity that can be boosted later in life as part of the WHO Expanded Program on Immunization (EPI). Thus, the EPI vaccine framework provides an infrastructure that could be leveraged for the implementation of a multidose HIV immunization regimen. Early childhood also provides a window of time in which there is minimal HIV exposure risk, and the plasticity of the early life immune landscape may present advantages for the elicitation of broadly neutralizing Antibodies (bnAbs), a primary target for HIV vaccination. Sequential vaccination with adjuvanted immunogens targeting spe-cific bnAb lineages is a promising HIV vaccine strategy, and several vaccine candidates are cur-rently being tested in adult clinical trials. It will be critical also to evaluate the most promising immunogens and adjuvants in pediatric settings. Preclinical studies, including in vitro and in sil-ico modelling as well as studies in animal models, will be essential to guide the design of future pediatric vaccine trials. This review summarizes current advances in bnAb germline targeting immunization. It provides the rationale for a better integration of preclinical and clinical vaccine studies to facilitate the development of a vaccine that achieves protective immunity in preadoles-cence.}, }
@article {pmid40801398, year = {2025}, author = {Childers, CP and Foe, LM and Mujumdar, V and Mabry, CD and Selzer, DJ and Senkowski, CK and Ko, CY and Tsai, TC}, title = {Longitudinal Trends in Efficiency and Complexity of Surgical Procedures: Analysis of 1.7 Million Operations Between 2019 and 2023.}, journal = {Journal of the American College of Surgeons}, volume = {241}, number = {5}, pages = {741-744}, doi = {10.1097/XCS.0000000000001588}, pmid = {40801398}, issn = {1879-1190}, mesh = {Humans ; United States ; *Surgical Procedures, Operative/trends/statistics &amp; numerical data/economics ; Registries ; Male ; Female ; *Operative Time ; Aged ; Medicare/economics ; Middle Aged ; }, abstract = {BACKGROUND: The Centers for Medicare &amp; Medicaid Services has proposed reducing the work relative value unit valuations for most surgical procedures by 2.5% through an efficiency adjustment based on the assumption that surgical work and operative length have decreased over time. Whether the length and complexity of surgical procedures have decreased or increased is unknown. Empirical data on trends in surgical length and complexity are needed to guide evidence-based regulations by federal policymakers.<br><br>STUDY DESIGN: The NSQIP registry was analyzed in 2019 and 2023. Analysis was performed at the CPT level and limited to codes with at least 1,000 underlying cases. The primary outcome was surgical efficiency, defined as skin-to-skin operative time. Secondary outcomes were measures of patient complexity, including preoperative risk factors (eg age, comorbidities) and 30-day morbidity and mortality.<br><br>RESULTS: The sample included 1,704,311 operations across 249 CPT codes and 11 surgical specialties. Collectively, these codes accounted for $3.2B in fee-for-service Medicare spending in 2023. Overall, operative times increased by 3.1% (95% CI 3.0% to 3.3%, p&#x2009;<&#x2009;0.001) in 2023 compared with 2019, or 0.8% per year (95% CI 0.7% to 0.8% per year, p&#x2009;<&#x2009;0.001). At the procedure level, 90% of CPT codes had longer or similar operative times in 2023 compared with 2019. Statistically, all measures of complexity also increased during the study time period, without a change in operative mortality.<br><br>CONCLUSIONS: For the majority of surgical procedures, operative times have stayed the same or increased from 2019 to 2023. Patient complexity also correspondingly increased. The rationale for an efficiency adjustment to the Medicare physician fee schedule for surgical procedures is not supported by objective data from a national surgical registry.}, }
@article {pmid40802264, year = {2025}, author = {Turner, NA and Hamasaki, T and Doernberg, SB and Lodise, TP and King, HA and Ghazaryan, V and Cosgrove, SE and Jenkins, TC and Liu, C and Sharma, S and Zaharoff, S and Wahid, L and Renard, VJ and Cook, P and Raad, I and Hachem, R and Chaftari, AM and Sims, M and DeMarco, C and Miller, LG and McCarthy, MW and Morse, CG and Lucasti, C and Forrest, GN and Cherabuddi, K and Polk, C and Fazili, T and Rupp, ME and Thompson, GR and Kim, K and Strnad, L and Schnee, AE and McKinnell, JA and Ramesh, M and Silveira, FP and McCarty, TP and Lee, TC and McDonald, EG and Paolino, K and Wiegand, K and Wall, A and Riccobene, T and Patel, R and Rappo, U and Evans, S and Chambers, HF and Fowler, VG and Holland, TL and , }, title = {Dalbavancin for Treatment of Staphylococcus aureus Bacteremia: The DOTS Randomized Clinical Trial.}, journal = {JAMA}, volume = {}, number = {}, pages = {}, pmid = {40802264}, issn = {1538-3598}, support = {UM1 AI104681/AI/NIAID NIH HHS/United States ; }, abstract = {IMPORTANCE: Dalbavancin is a long-acting intravenous lipoglycopeptide that may be effective for treatment of complicated Staphylococcus aureus bacteremia without requiring long-term intravenous access.<br><br>OBJECTIVE: To evaluate the efficacy and safety of dalbavancin vs standard therapy for completion of treatment of complicated S aureus bacteremia.<br><br>Open-label, assessor-masked, randomized clinical trial conducted from April 2021 to December 2023 at 23 medical centers in the US (n&#x2009;=&#x2009;22) and Canada (n&#x2009;=&#x2009;1). Participant follow-up lasted 70 days (180 days for participants with osteomyelitis); date of final follow-up was December 1, 2023. Hospitalized adults with complicated S aureus bacteremia who achieved blood culture clearance following at least 72 hours but no more than 10 days of initial antibacterial therapy were included. Participants were excluded if they had central nervous system infection, retained infected prosthetic material, left-sided endocarditis, or severe immune compromise.<br><br>INTERVENTIONS: Participants were randomly assigned to receive either 2 doses of intravenous dalbavancin (n&#x2009;=&#x2009;100; 1500 mg on days 1 and 8) or 4 to 8 total weeks of standard intravenous therapy (n&#x2009;=&#x2009;100; cefazolin or antistaphylococcal penicillin if methicillin susceptible; vancomycin or daptomycin if methicillin resistant).<br><br>MAIN OUTCOMES AND MEASURES: The primary outcome was the desirability of outcome ranking (DOOR) at day 70, which involved 5 components (clinical success, infectious complications, safety complications, mortality, and health-related quality of life) and was assessed for superiority (achieved if the 95% CI for the probability of dalbavancin having a superior DOOR was >50%). Secondary outcomes included clinical efficacy at day 70 (prespecified noninferiority margin of 20%) and safety.<br><br>RESULTS: Of 200 participants randomized (mean [SD] age, 56 [16.2] years; 62 females [31%]), 167 (84%) survived to day 70 and had an efficacy assessment. Participants without a day 70 efficacy assessment were treated as clinical failures in the analyses. The probability of a more desirable day 70 outcome with dalbavancin vs standard therapy was 47.7% (95% CI, 39.8% to 55.7%). Regarding secondary outcomes, clinical efficacy was documented in 73 of 100 for dalbavancin and 72 of 100 for standard therapy (difference, 1.0% [95% CI, -11.5% to 13.5%]), meeting the noninferiority criterion. Serious adverse events were reported in 40 of 100 participants who received dalbavancin and 34 of 100 participants who received standard therapy; treatment-related adverse events were uncommon in both groups.<br><br>CONCLUSIONS AND RELEVANCE: Among adult participants with complicated S aureus bacteremia who achieved blood culture clearance, dalbavancin was not superior to standard therapy by desirability of outcome ranking. When considered with other efficacy and safety outcomes these findings may help inform use of dalbavancin in clinical practice.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04775953.}, }
@article {pmid40802741, year = {2025}, author = {Radtke, S and Fields, E and Swing, K and Kanestrom, G and Yen, JS and Pande, D and Enstrom, MR and Humbert, O and Weiss, MJ and Liu, DR and Newby, GA and Kiem, HP}, title = {Engraftment and persistence of HBB base-edited hematopoietic stem cells in nonhuman primates.}, journal = {Science translational medicine}, volume = {17}, number = {811}, pages = {eadn2601}, pmid = {40802741}, issn = {1946-6242}, support = {R01 HL136135/HL/NHLBI NIH HHS/United States ; R01 AI135953/AI/NIAID NIH HHS/United States ; R00 HL163805/HL/NHLBI NIH HHS/United States ; P51 OD011092/OD/NIH HHS/United States ; R01 HL156647/HL/NHLBI NIH HHS/United States ; P51 OD010425/OD/NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Animals ; *Hematopoietic Stem Cells/metabolism/cytology ; Macaca mulatta ; *Gene Editing ; *Hematopoietic Stem Cell Transplantation ; *beta-Globins/genetics/metabolism ; Humans ; Anemia, Sickle Cell/genetics ; }, abstract = {Sickle cell disease (SCD) is caused by a single nucleotide change in the β-globin gene that adenine base editors can convert to the nonpathogenic Makassar β-globin variant. Here, we evaluated the long-term efficiency and off-target editing potential of autologous Makassar base editing in three rhesus macaques as a step toward human translation. Base editing of CD34[+]CD90[+] hematopoietic stem cells (HSCs) at the Makassar locus reached greater than 60% efficiency using a bystander nucleotide as a proxy for the sickle cell target in cells from healthy macaques. No impact on myeloid and erythroid colony formation was seen, and clonal analysis revealed that >90% of HSCs were edited, >20% with biallelic editing. After transplantation of autologous gene-edited HSCs, all three macaques rapidly recovered neutrophils, red blood cells, and platelets with stable editing of 25.6%, on average, observed across nucleated blood cells. Similarly, the bone marrow stem cell compartment maintained over 20% of cells harboring mono- or biallelic edits. Off-target editing was assessed at over 900 candidate sites, with editing observed at eight sites, but no selection for or impact of these edits was observed throughout engraftment. These data support further translation of base editing of autologous HSCs for the treatment of patients with SCD.}, }
@article {pmid40802906, year = {2025}, author = {Roschewski, M and Kurtz, DM and Westin, JR and Lynch, RC and Gopal, AK and Alig, SK and Sworder, BJ and Cherng, HJ and Kuffer, C and Blair, D and Brown, K and Goldstein, JS and Schultz, A and Close, S and Chabon, JJ and Diehn, M and Wilson, WH and Alizadeh, AA}, title = {Remission Assessment by Circulating Tumor DNA in Large B-Cell Lymphoma.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {34}, pages = {3652-3661}, pmid = {40802906}, issn = {1527-7755}, support = {R01 CA229766/CA/NCI NIH HHS/United States ; R01 CA233975/CA/NCI NIH HHS/United States ; R01 CA254179/CA/NCI NIH HHS/United States ; R01 CA257655/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Circulating Tumor DNA/blood ; Male ; Female ; Middle Aged ; *Lymphoma, Large B-Cell, Diffuse/drug therapy/blood/genetics/mortality ; Neoplasm, Residual ; Aged ; Prospective Studies ; Adult ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Remission Induction ; *Biomarkers, Tumor/blood ; Anthracyclines/administration &amp; dosage ; Progression-Free Survival ; Aged, 80 and over ; }, abstract = {PURPOSE: Large B-cell lymphomas (LBCLs) are curable, but patients with residual disease after therapy invariably experience progression. Ultrasensitive methods to detect circulating tumor DNA (ctDNA) as minimal residual disease (MRD) may improve the determination of remission.<br><br>METHODS: We integrated data from five prospective studies of frontline anthracycline-based chemotherapy in patients with LBCL. Tumor-specific phased variants were identified from pretreatment samples and monitored at landmark time points. Serial plasma specimens were blindly analyzed for detectable ctDNA as MRD. MRD status was compared with conventional response criteria for prognosis of progression-free survival (PFS).<br><br>RESULTS: We studied ctDNA-MRD in 137 patients by monitoring 409 plasma specimens over time. Detectable ctDNA rates decreased during therapy with 55% and 78% of patients achieving undetectable ctDNA after two cycles and at the end of therapy, respectively. After a median follow-up of 37 months, the 2-year PFS for patients with detectable versus undetectable ctDNA after two cycles was 67% versus 96% (P = .0025; hazard ratio [HR], 6.9) and after therapy was 29% versus 97% (P < .0001; HR, 28.7), respectively. Ninety-two (94%) patients with undetectable ctDNA at the end of therapy remained alive without progression, while 19 (68%) patients with detectable ctDNA progressed or died. MRD status at the end of therapy had greater prognostic utility than conventional lymphoma response criteria using positron emission tomography (PET) scans (HR, 3.6 for positive PET and 28.3 for detectable ctDNA).<br><br>CONCLUSION: Ultrasensitive ctDNA detection after frontline LBCL therapy is more prognostic than conventional radiographic response criteria. A refined definition of remission with ctDNA-MRD may improve clinical and psychological outcomes for patients with LBCL.}, }
@article {pmid40803814, year = {2025}, author = {Love, JE and Naresh, KN}, title = {Splenic EBV-positive inflammatory follicular dendritic cell sarcoma with fibroblastic/myoid immunophenotype in a patient with EBV-negative diffuse large B cell lymphoma.}, journal = {Journal of clinical pathology}, volume = {78}, number = {10}, pages = {723-724}, doi = {10.1136/jcp-2025-210303}, pmid = {40803814}, issn = {1472-4146}, }
@article {pmid40803815, year = {2025}, author = {Naresh, KN and Karube, K and Borges, A and Cheuk, W and Gujral, S and Sayed, S and Sohani, A and Lazzi, S and Ott, G and Du, MQ and Leoncini, L and Chan, JKC}, title = {Fifth edition WHO classification: mature B-cell neoplasms.}, journal = {Journal of clinical pathology}, volume = {78}, number = {11}, pages = {725-739}, doi = {10.1136/jcp-2025-210260}, pmid = {40803815}, issn = {1472-4146}, mesh = {Humans ; World Health Organization ; *Lymphoma, B-Cell/classification/pathology/diagnosis/genetics ; }, abstract = {We present a review of mature B-cell neoplasms as described in the fifth edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5). Entities have expanded, and definitions are increasingly reliant on genomic and other technologies. However, the WHO-HAEM5 employs a hierarchical structure with family (class)-level definitions that group several specific entities. This approach enables the assignment of a family-level diagnosis when criteria for specific entities cannot be met due to resource constraints. To facilitate application in resource-limited settings, WHO-HAEM5 divides diagnostic criteria into 'essential' and desirable criteria for most entities. This review focuses on changes and updates in B-cell lymphoma classification, providing guidance on how to apply the WHO classification in resource-limited settings.}, }
@article {pmid40805227, year = {2025}, author = {Sarfraz, Z and Jayram, D and Ozair, A and Hodgson, L and Bellur, S and Maharaj, A and Venur, VA and Mukherjee, S and Ahluwalia, MS}, title = {Survival in Patients with Colorectal Cancer and Isolated Brain Metastases: Temporal Trends and Prognostic Factors from the National Cancer Database (2010-2020).}, journal = {Cancers}, volume = {17}, number = {15}, pages = {}, pmid = {40805227}, issn = {2072-6694}, abstract = {Background: The development of brain metastases (BM) is a relatively uncommon but significantly adverse event in the spread of colorectal cancer (CRC). Although management of CRC BM has improved with advances in imaging and systemic therapies, clinical outcomes remain poor. Methods: This retrospective cohort study used the U.S. National Cancer Database to evaluate survival outcomes, treatment patterns, and prognostic factors in CRC patients diagnosed with BM between 2010 and 2020. Patients with isolated brain-only metastases formed the primary analytic cohort, while those with additional extracranial metastases were included for descriptive comparison. Multivariable Cox proportional hazards and logistic regression models were used to assess factors associated with of survival. Proportional hazards assumptions were tested using Schoenfeld residuals. Accelerated failure time models were also employed. Results: From a cohort of 1,040,877 individuals with CRC, 795 had metastatic disease present along with relevant data, of which 296 had isolated BM. Median overall survival (mOS) in BM-only metastatic disease group was 7.82 months (95% CI: 5.82-9.66). The longest survival was observed among patients treated with stereotactic radiosurgery combined with systemic therapy (SRS+Sys), with a median OS of 23.26 months (95% CI: 17.51-41.95) and a 3-year survival rate of 35.8%. In adjusted Cox models, SRS, systemic therapy, and definitive surgery of the primary site were each independently associated with reduced hazard of death. Rectal cancer patients had longer survival than those with colon primaries (mOS: 10.35 vs. 6.08 months). Age, comorbidity burden, and insurance status were not associated with survival in adjusted analyses. Conclusions: SRS+Sys was associated with longer survival compared to other treatment strategies. However, treatment selection is highly dependent on individual clinical factors such as performance status, comorbidities, and disease extent; therefore, these findings must be interpreted with caution Future prospective studies incorporating molecular and biomarker data are warranted to better guide care in this rare and high-risk group.}, }
@article {pmid40805242, year = {2025}, author = {Amonoo, HL and Wolfe, ED and Keane, EP and Larizza, IS and Boardman, AC and Healy, BC and Traeger, LN and Cutler, C and Lee, SJ and Greer, JA and El-Jawahri, A}, title = {Medication Adherence in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.}, journal = {Cancers}, volume = {17}, number = {15}, pages = {}, pmid = {40805242}, issn = {2072-6694}, support = {K08CA251654/CA/NCI NIH HHS/United States ; n/a//Robert Wood Johnson and American Society of Hematology Harold Amos Medical Faculty Development Award/ ; n/a//Doris Duke Foundation Clinician-Scientist Development Award/ ; }, abstract = {Introduction: Medication adherence is essential for treatment and recovery following hematopoietic stem cell transplantation (HSCT). However, limited data exist on the most effective methods to measure adherence and the factors influencing it in HSCT patients. Materials and Methods: A prospective longitudinal study assessed immunosuppressant medication adherence in 150 patients with hematologic malignancies undergoing allogeneic HSCT. Adherence was assessed using pill counts, immunosuppressant medication levels, patient-reported medication logs, and the Medication Adherence Response Scale-5 (MARS-5) at 30, 100, and 180 days post-HSCT. We evaluated adherence rates, agreement between methods, and sociodemographic and clinical predictors. From patient-reported logs, we calculated dose adherence (comparing reported doses to expected doses) and timing adherence (comparing medication intake within ±3 h of the prescribed time). Kappa analysis assessed agreement among methods. Results: Of 190 eligible patients, 150 (78.9%) enrolled. The mean age was 57.5 years (SD = 13.5); 41.3% (n = 62) were female, 85.3% (n = 128) were non-Hispanic White, and 73.3% (n = 110) were married or living with a partner. Medication adherence varied across the three timepoints and by measurement type: 52-64% (pill counts), 18-24% (medication levels), 96-98% (medication log dose adherence), 83-84% (medication log timing adherence), and 97-98% (MARS-5). There was minimal agreement between measures (Kappa range: 0.008-0.12). Conclusions: Despite the feasibility of leveraging objective and patient-reported measures to assess medication adherence in HSCT patients, there was little agreement between these measures. Patient-reported measures showed high adherence, while objective measures like pill counts and medication levels revealed more modest adherence. The complexity of medication regimens likely contributes to this discrepancy. A rigorous approach to understanding medication adherence in the HSCT population may entail both objective and subjective measures of medication adherence.}, }
@article {pmid40809030, year = {2025}, author = {Garfall, AL and Banerjee, R and Frenzel, L and Khandanpour, C and Lin, Y and Ottoni, E and Rifkin, R and Rockwell, S and Rodriguez, C and Villefort, H and Zamagni, E}, title = {A roadmap to implementing outpatient administration of bispecific antibodies in multiple myeloma.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1630146}, pmid = {40809030}, issn = {2234-943X}, abstract = {INTRODUCTION: Bispecific antibodies (BsAbs) are novel immunotherapy agents for the treatment of relapsed/refractory multiple myeloma (RRMM). Currently, 3 BsAbs (teclistamab, talquetamab, and elranatamab) are approved for the treatment of RRMM. Administering BsAbs in different practice settings is crucial to improving treatment access and patient outcomes. This report provides actionable guidance to implement safe and effective administration of BsAbs for patients with RRMM in outpatient and community settings.<br><br>METHODS: Three clinician advisory workshops were held in the United States, Europe, and Latin America to discuss key factors to operationalize BsAb use in outpatient and community settings, focusing on the critical phases of practice setup, treatment initiation, and ongoing management.<br><br>RESULTS: BsAb administration in outpatient and community settings requires careful planning, a well-prepared multidisciplinary team (MDT) of healthcare professionals, and clear protocols, including MDT composition, roles/responsibilities, capacity planning, patient selection criteria, step-up dosing procedure, admission processes, patient/caregiver education requirements, and adverse event (AE) monitoring/management. Comprehensive MDT training on protocols and preparedness to manage AEs is essential. Patients initiating outpatient BsAb therapy should have a reliable caregiver, access to a hospital, controlled comorbidities, and no active infections. Ensuring patients and caregivers understand the benefits, risks, and expectations of BsAb therapy is vital for successful treatment and a positive patient experience.<br><br>CONCLUSION: Administering BsAbs in outpatient and community settings can be done safely and effectively with appropriate planning and protocols. Enabling safe and effective BsAb administration in these settings is essential to ensure more patients with RRMM have access to treatment and improved outcomes.}, }
@article {pmid40809738, year = {2025}, author = {Ye, T and He, Q and Chen, S and Zhang, B}, title = {Role of placebo samples in observational studies.}, journal = {Journal of causal inference}, volume = {13}, number = {1}, pages = {}, pmid = {40809738}, issn = {2193-3677}, support = {R35 GM155070/GM/NIGMS NIH HHS/United States ; }, abstract = {In an observational study, it is common to leverage known null effects to detect bias. One such strategy is to set aside a placebo sample - a subset of data immune from the hypothesized cause-and-effect relationship. Existence of an effect in the placebo sample raises concerns about unmeasured confounding bias while absence of it helps corroborate the causal conclusion. This paper describes a framework for using a placebo sample to detect and remove bias. We state the identification assumptions and develop estimation and inference methods based on outcome regression, inverse probability weighting, and doubly-robust approaches. Simulation studies investigate the finite-sample performance of the proposed methods. We illustrate the methods using an empirical study of the effect of the earned income tax credit on infant health.}, }
@article {pmid40810606, year = {2025}, author = {Ryser, MD and Holloway, ST and Morsomme, R and Ryan, A and Apostolidou, S and Gentry-Maharaj, A and Gogebakan, KC and Lange, J and Xu, J and Menon, U and Etzioni, R}, title = {Estimating the Opportunity for Early Detection of Ovarian Cancer Using Individual-Patient Data from a Large Randomized Controlled Trial.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {11}, pages = {2000-2006}, pmid = {40810606}, issn = {1538-7755}, support = {R35 CA274442/CA/NCI NIH HHS/United States ; R35CA274442//National Cancer Institute (NCI)/ ; MC_UU_00004/01//Medical Research Council (MRC)/ ; }, mesh = {Humans ; Female ; *Ovarian Neoplasms/diagnosis ; *Early Detection of Cancer/methods ; Middle Aged ; Aged ; }, abstract = {BACKGROUND: The UK Collaborative Trial of Ovarian Cancer Screening did not detect a reduction in ovarian cancer mortality with either multimodal screening (MMS) or transvaginal ultrasound screening (USS) compared with no screening. The trial data provide an invaluable resource to quantify the opportunity for interception in ovarian cancer.<br><br>METHODS: We used Bayesian inference to estimate ovarian cancer natural history based on individual screening and cancer diagnosis records from the UK Collaborative Trial of Ovarian Cancer Screening, a randomized controlled ovarian cancer screening trial conducted in England, Wales, and Northern Ireland. The trial included 202,638 women ages 50 to 74 years with no family history of ovarian cancer, randomized in a 1:1:2 ratio to annual MMS (serum CA125 interpreted using the risk of ovarian cancer algorithm), annual USS, or no screening. The current analysis included 199,499 women, with 674,806 screens and 2,025 cancer diagnoses.<br><br>RESULTS: Among high-grade serous cancers (HGSC), the estimated preclinical detectable phase was 1.7 years (95% credible interval, 1.3-2.2), compared with 7.8 years (95% credible interval, 5.7-10.6) for non-HGSCs. The preclinical detectable phase depended on screening modality: for HGSCs, it was longer in the MMS arm (2.2 years) compared with the USS arm (0.8 years), whereas for non-HGSCs, it was shorter in the MMS arm (2.7 years) compared with the USS arm (8.2 years).<br><br>CONCLUSIONS: The interception opportunity for ovarian cancer strongly depends on histologic subtype and screening modality.<br><br>IMPACT: Achieving a clinically significant benefit of ovarian cancer early detection will require prolonging the interception window through judicious combination of first- and second-line tests.}, }
@article {pmid40811246, year = {2025}, author = {Fang, A and Kumar, L and Creevy, KE and Promislow, DEL and Ma, J and , }, title = {Constructing the first comorbidity networks in companion dogs in the Dog Aging Project.}, journal = {PLoS computational biology}, volume = {21}, number = {8}, pages = {e1012728}, pmid = {40811246}, issn = {1553-7358}, support = {U19 AG057377/AG/NIA NIH HHS/United States ; }, mesh = {Animals ; Dogs ; *Comorbidity ; *Aging/physiology ; *Dog Diseases/epidemiology ; Female ; Male ; *Pets ; United States/epidemiology ; Computational Biology ; Cohort Studies ; }, abstract = {Comorbidity and its association with age are of great interest in geroscience. However, there are few model organisms that are well-suited to study comorbidities that will have high relevance to humans. In this light, we turn our attention to the companion dog. The companion dog shares many morbidities with humans. Thus, a better understanding of canine comorbidity relationships could benefit both humans and dogs. We present an analysis of canine comorbidity networks from the Dog Aging Project, a large epidemiological cohort study of companion dogs in the United States. We included owner-reported health conditions that occurred in at least 60 dogs (n = 160) and included only dogs that had at least one of those health conditions (n = 26,614). We constructed an undirected comorbidity network using a Poisson binomial test, adjusting for age, sex, sterilization status, breed background (i.e., purebred vs. mixed-breed), and weight. The comorbidity network reveals well-documented comorbidities, such as diabetes with cataracts and blindness, and hypertension with chronic kidney disease (CKD). In addition, this network also supports less well-studied comorbidity relationships, such as proteinuria with anemia. A directed comorbidity network accounting for time of reported condition onset suggests that diabetes precedes cataracts, elbow/hip dysplasia before osteoarthritis, and keratoconjunctivitis sicca before corneal ulcer, which are consistent with the canine literature. Analysis of age-stratified networks reveals that global centrality measures increase with age and are the highest in the Senior group compared to the Young Adult and Mature Adult groups. Only the Senior group identified the association between hypertension and CKD. Our results suggest that comorbidity network analysis is a promising method to enhance clinical knowledge and canine healthcare management.}, }
@article {pmid40811558, year = {2025}, author = {Shenoy, MK and Rico, DM and Lorant, AK and Touré, H and Gordon, S and Milburn, LJ and Schwensen, JS and Cabán, ME and Koch, MA}, title = {Breast milk IgG engages the mouse neonatal immune system to instruct responses to gut antigens.}, journal = {Science (New York, N.Y.)}, volume = {389}, number = {6761}, pages = {eado5294}, pmid = {40811558}, issn = {1095-9203}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; R01 AI173199/AI/NIAID NIH HHS/United States ; }, mesh = {Animals ; Female ; Mice ; Adaptive Immunity ; Animals, Newborn/immunology ; *Antigens, Bacterial/immunology ; Complement System Proteins/immunology ; *Gastrointestinal Microbiome/immunology ; *Immunity, Maternally-Acquired ; *Immunity, Mucosal ; *Immunoglobulin G/immunology/administration &amp; dosage ; *Intestinal Mucosa/immunology/microbiology ; Mice, Inbred C57BL ; *Milk/immunology ; *Milk, Human/immunology ; Weaning ; Mice, Inbred BALB C ; }, abstract = {Maternal antibodies fundamentally regulate gut immunity in the developing infant, yet the mechanisms underlying this process remain elusive. We found that maternal immunoglobulin G (IgG), ingested in the first week of life, restrained microbiota-dependent adaptive immune responses weeks later, after weaning. This activity was linked to maternal antibodies that could bind bacteria in the neonatal gut and the ability of microbe-IgG complexes to engage Fc and complement-dependent effector functions in offspring. Ingestion of microbiota-specific maternal IgG also limited aberrant neonatal responses to dietary antigens encountered at weaning. These discoveries suggest that maternal IgG engages the immune system of offspring in early postnatal life to tune mucosal responses and reinforce intestinal homeostasis in the face of dynamic shifts in food and bacterial antigens during development.}, }
@article {pmid40811667, year = {2026}, author = {Jatt, LP and Gillespie, KM and Van, P and Hoffman, SL and Jackson, LA and Murphy, SC and Heath, JR and Kublin, JG}, title = {Cytokines Associated With Moderate and Severe Adverse Events During a Sporozoite Malaria Vaccine Trial With Controlled Human Malaria Infection.}, journal = {The Journal of infectious diseases}, volume = {233}, number = {1}, pages = {191-196}, doi = {10.1093/infdis/jiaf435}, pmid = {40811667}, issn = {1537-6613}, support = {5T32AI007044//National Institute of Allergy and Infectious Diseases of the National Institutes of Health/ ; DMID 11-0042//National Institute of Allergy and Infectious Diseases of the National Institutes of Health/ ; HHSN272201300019I/AI/NIAID NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Female ; Humans ; Male ; Young Adult ; Biomarkers/blood ; *Cytokines/blood ; Interleukin-6/blood ; *Malaria/prevention &amp; control/immunology ; *Malaria Vaccines/adverse effects/immunology/administration &amp; dosage ; *Malaria, Falciparum/prevention &amp; control/immunology ; Plasmodium falciparum/immunology ; *Sporozoites/immunology ; }, abstract = {Ensuring the safety and efficacy of candidate vaccines is critical. Although mechanisms underpinning protective immune responses to malaria vaccines are frequently investigated, immune responses correlating with moderate and severe adverse events (AEs) are rarely examined. Here, we leverage a malaria vaccine trial with a higher-than-expected AE rate and frequent sampling to investigate cytokine profiles associated with AEs. We found that Interleukin-6 was elevated on days in which individuals experienced moderate and severe AEs. More research on immune responses associated with AEs is warranted in order to identify biomarkers associated with systemic reactogenicity and accelerate vaccine development.}, }
@article {pmid40811818, year = {2026}, author = {Greenbaum, U and Hashmi, H and Elsawy, M and Kim, S and Moskop, A and Oloyede, T and Awan, FT and Bachanova, V and Badar, T and Bar, M and Barba, P and Beitinjaneh, AM and Cashen, A and Dholaria, B and Farooq, U and Foglesong, J and Ganguly, S and Hematti, P and Hill, LC and Jain, MD and Jain, T and Kebriaei, P and Kittai, AS and Locke, FL and Lulla, PD and McGuirk, JP and Mead, E and Mussetti, A and Nishihori, T and Olson, AL and Pennisi, M and Perales, MA and Geethakumari, PR and Riedell, PA and Saber, W and Shouval, R and Shpall, EJ and Magalhaes-Silverman, M and Strouse, C and Turtle, CJ and Vallurupalli, A and Wudhikarn, K and Pasquini, MC and Ahmed, S and Sorror, M}, title = {New comorbidity index associated with survival after chimeric antigen receptor T-cell therapy for large B-cell lymphoma.}, journal = {Blood advances}, volume = {10}, number = {1}, pages = {217-227}, pmid = {40811818}, issn = {2473-9537}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; U01 AI184132/AI/NIAID NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; UG1 HL174426/HL/NHLBI NIH HHS/United States ; U24 CA233032/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Middle Aged ; Male ; Female ; Aged ; Adult ; Comorbidity ; *Immunotherapy, Adoptive/methods/adverse effects ; Aged, 80 and over ; *Lymphoma, Large B-Cell, Diffuse/therapy/mortality/epidemiology ; *Receptors, Chimeric Antigen ; Young Adult ; Treatment Outcome ; Prognosis ; }, abstract = {The cumulative impact of baseline comorbidities on outcomes of chimeric antigen receptor T-cell (CAR-T) therapy is not well established. Therefore, we developed and validated a Cellular Therapy Comorbidity Index (CT-CI) to predict outcomes following CD19-directed CAR-T therapy for large B-cell lymphoma (LBCL). Patients aged 18 or older receiving commercial CAR-T therapy for LBCL during 2017 to 2020 were selected from the Center for International Blood and Marrow Transplant Research registry. Patients were randomly assigned to training or validation cohorts. Comorbidities given weighted scores comprised the CT-CI, which was then validated for overall survival (OS) prognostication. A total of 1916 patients from 97 medical centers were included, with a median age of 64 years (19-91 years). About 70% of patients had comorbidities, such as cardiac disease (12%); diabetes (14%); hepatic dysfunction (mild, 8%; moderate to severe, 2%); psychiatric disturbance (18%); and pulmonary dysfunction (moderate, 15%; severe, 12%). The CT-CI was calculated, stratified patients in 3 categories, and was associated with increased mortality. Patients with higher CT-CI scores had worse OS (CT-CI 1: hazard ratio [HR], 1.37 [95% confidence interval [CI], 1.16-1.62; P < .001]; CT-CI 2: HR, 1.49 [95% CI, 1.17-1.89; P = .001]; CT-CI ≥ 3: HR, 2.55 [95% CI, 1.90-3.42; P< .001]). Higher CT-CI scores predicted treatment-related mortality and relapse. There was no correlation between the CT-CI score and CAR-T-related toxicities. The novel CT-CI score stratifies the effect of patient comorbidities on survival after CAR-T therapy and can be used for clinical decision-making and treatment selection in high-risk populations. However, comorbidities and fear of increased toxicity should not preclude patients from this effective therapy.}, }
@article {pmid40811854, year = {2025}, author = {Maynard, LH and Cavanaugh, EJ and Zhu, H and Starke, CE and Doherty, SM and Einhaus, T and Pérez-Osorio, AC and Stensland, L and Blair, C and Roche, AM and Everett, JK and Murnane, RD and Hoffman, M and Nelson, V and Herrin, S and Littlewood, C and Camou, K and Wilson, E and Wessel, C and Bushman, FD and Jerome, KR and Kiem, HP and Peterson, CW}, title = {Pooled CAR-T screening in pig-tailed macaques identifies designs with enhanced proliferation, trafficking, and persistence.}, journal = {Blood}, volume = {146}, number = {21}, pages = {2531-2543}, pmid = {40811854}, issn = {1528-0020}, support = {P51 OD010425/OD/NIH HHS/United States ; R01 AI167004/AI/NIAID NIH HHS/United States ; R01 AI170214/AI/NIAID NIH HHS/United States ; U42 OD011123/OD/NIH HHS/United States ; }, mesh = {Animals ; *Immunotherapy, Adoptive/methods ; Cell Proliferation ; *Receptors, Chimeric Antigen/immunology/genetics/metabolism ; Macaca nemestrina ; *T-Lymphocytes/immunology/metabolism ; Humans ; Antigens, CD20/immunology ; }, abstract = {Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies; however, >60% of patients relapse within 1 year, often due to insufficient CAR-T persistence. Although mouse and primary cell models have been instrumental in advancing CAR-T therapy, they frequently fail to predict clinical outcomes, underscoring the need for more translationally relevant models. To address this limitation, we conducted, to our knowledge, the first systematic evaluation of CAR structure-function relationships in an immunocompetent nonhuman primate (NHP) model. We engineered an array of 20 CD20-targeted CARs with distinct combinations of hinge, transmembrane, and costimulatory domains. After ex vivo characterization, we administered pooled autologous CAR-T arrays to 3 NHPs and tracked CAR abundance longitudinally using a novel digital droplet polymerase chain reaction assay. Ex vivo, CAR-T cells incorporating the MyD88-CD40 costimulatory domain exhibited markedly distinct functional profiles, including increased activation, unique cytokine secretion, tonic signaling, and resistance to exhaustion. In vivo, MyD88-CD40 CARs expanded dramatically, comprising up to 100% of peripheral CAR-T cells and significantly outperforming canonical CD28- and 4-1BB-based CARs. This expansion was associated with robust B-cell depletion across all animals. MyD88-CD40 CARs, particularly those with a CD28 hinge and transmembrane domain, demonstrated superior trafficking to secondary lymphoid tissues and persistence through study end point, unlike other CARs, which waned by day 28. Our findings highlight the value of NHP models for screening CAR designs and identify MyD88-CD40 CARs as candidates with unmatched potency. The unique functional attributes conferred by this domain may provide key insights into features that drive enhanced CAR-T activity.}, }
@article {pmid40812311, year = {2025}, author = {Jagota, M and Hsu, C and Mazumder, T and Sung, K and DeWitt, WS and Listgarten, J and Matsen Iv, FA and Ye, CJ and Song, YS}, title = {Learning antibody sequence constraints from allelic inclusion.}, journal = {Cell systems}, volume = {16}, number = {9}, pages = {101368}, doi = {10.1016/j.cels.2025.101368}, pmid = {40812311}, issn = {2405-4720}, mesh = {Humans ; *Machine Learning ; Alleles ; Animals ; Mice ; B-Lymphocytes/immunology/metabolism ; *Antibodies/genetics ; Single-Cell Analysis/methods ; Immunoglobulin Light Chains/genetics ; Immunoglobulin Heavy Chains/genetics ; }, abstract = {Although antibody sequences are highly diverse, they are constrained by requirements for expression and limited off-target reactivity. Describing which sequences violate such constraints has proven to be difficult. Here, we introduce a machine-learning framework to leverage a previously underutilized source of data for this problem. We use human single-cell sequencing data to find instances of allelic inclusion, a rare event where B cells express two different antibody light chains as mRNA. Previous studies suggest that one of these chains is either autoreactive or non-expressing as protein. We train machine-learning models to identify abnormal sequences associated with allelic inclusion. The resulting models generalize to predict antibody properties including polyreactivity, surface expression, and mutation usage, outperforming methods that do not use allelic inclusion data. We also investigate similar selection forces on the heavy chain in mice and observe that surrogate light-chain pairing has a large impact on heavy-chain diversity.}, }
@article {pmid40812337, year = {2026}, author = {Liu, C and Rosen, EA and Stohs, EJ and Imlay, H and Nigo, M and Gottesdiener, LS and So, M and Tverdek, F and Dadwal, S and Gudiol, C and Satlin, MJ and Seo, SK and Trubiano, JA and Banerjee, R and Hanson, KE and Abbo, LM}, title = {Tackling antimicrobial resistance in people who are immunocompromised: leveraging diagnostic and antimicrobial stewardship.}, journal = {The Lancet. Infectious diseases}, volume = {26}, number = {1}, pages = {e30-e48}, doi = {10.1016/S1473-3099(25)00311-1}, pmid = {40812337}, issn = {1474-4457}, support = {T32 AI007613/AI/NIAID NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Immunocompromised Host ; *Antimicrobial Stewardship/methods ; *Anti-Bacterial Agents/therapeutic use ; *Drug Resistance, Bacterial ; *Bacterial Infections/drug therapy/diagnosis ; }, abstract = {Antimicrobial resistance (AMR) disproportionately affects people who are immunocompromised due to their frequent encounters with the health-care system and repeated, prolonged exposure to antibiotics. AMR threatens to undermine continued advances in cancer care, haematopoietic cell transplantation, and solid organ transplantation by severely restricting therapeutic options. The convergence of several factors in the diagnostic evaluation of infection among individuals with immunocompromising conditions contributes to excess and inappropriate antibiotic use. Diagnostic and antimicrobial stewardship are key complementary strategies to address these challenges with shared goals of improving patient outcomes, reducing harm, and mitigating the risk of AMR. In this Series paper, we discuss opportunities to enhance use of existing diagnostic tools (eg, culture-based diagnostics, molecular diagnostics, and other tools such as antibiotic allergy delabelling), emerging diagnostic tools (eg, metagenomic sequencing and host response profiling), and digital innovation, to optimise antibiotic use, and the potential for precision medicine approaches to combat AMR in people who are immunocompromised.}, }
@article {pmid40812338, year = {2026}, author = {Pergam, SA}, title = {The smallest faith.}, journal = {The Lancet. Infectious diseases}, volume = {26}, number = {1}, pages = {11-13}, doi = {10.1016/S1473-3099(25)00355-X}, pmid = {40812338}, issn = {1474-4457}, }
@article {pmid40812340, year = {2026}, author = {Hill, JA and Boonyaratanakornkit, J and Mikulska, M and Teh, BW and Hahn, WO and Haidar, G and Liu, C and Kumar, D and Ison, MG and Halasa, N}, title = {Innovation in active and passive immunisation of people who are immunocompromised: a call to action.}, journal = {The Lancet. Infectious diseases}, volume = {26}, number = {1}, pages = {e16-e29}, doi = {10.1016/S1473-3099(25)00345-7}, pmid = {40812340}, issn = {1474-4457}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Immunocompromised Host/immunology ; *Immunization, Passive/methods ; Vaccination/methods ; Vaccines/immunology ; Antibodies, Monoclonal/immunology ; }, abstract = {The proportion of the population with immunocompromising conditions, who are at increased risk for complications from infectious diseases, continues to grow. Concurrently, outbreaks due to known and emerging pathogens are increasing. Vaccines are the foundation of infection prevention; however, attenuated immune responses in people who are immunocompromised necessitates innovation in design and delivery strategies. Passive immunisation, whereby the desired immunity is directly transferred to an individual, albeit transiently, could be valuable for patients who are unable to generate robust immune responses with vaccination or infection. However, existing therapies are insufficient. Considerable technical and conceptual advancements in the field of immunology have created unprecedented opportunities for the development of novel strategies and therapies to prevent and treat infectious diseases, and studies in people who are immunocompromised are an important setting in which to apply these developments. In this Series paper, we consider key unmet needs in the areas of vaccinology, monoclonal antibody design, study endpoints, health systems approaches, and policy considerations for people who are immunocompromised.}, }
@article {pmid40812489, year = {2026}, author = {Ellyson, AM and Mendoza, JA and Liese, AD and Tabah, A and Bekelman, TA and Rudisill, AC and Dabelea, D and Frongillo, EA and Pihoker, C and Malik, FS and Wright, DR}, title = {Healthcare and Nonhealthcare Costs: Youth With Diabetes and Food Insecurity.}, journal = {American journal of preventive medicine}, volume = {70}, number = {3}, pages = {108028}, pmid = {40812489}, issn = {1873-2607}, support = {R01 DK117461/DK/NIDDK NIH HHS/United States ; R01 DK127208/DK/NIDDK NIH HHS/United States ; UC4 DK108173/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Food Insecurity ; Male ; Female ; Adolescent ; Young Adult ; *Diabetes Mellitus, Type 2/economics/therapy ; *Diabetes Mellitus, Type 1/economics/therapy ; Prospective Studies ; *Health Care Costs/statistics &amp; numerical data ; United States ; Child ; Insurance Coverage/statistics &amp; numerical data ; *Food Supply/statistics &amp; numerical data/economics ; Adult ; }, abstract = {INTRODUCTION: This study prospectively evaluated the association of household food insecurity with acute care costs and productivity loss in youth and young adults with Type 1 and Type 2 diabetes.<br><br>METHODS: This observational cohort study included 1,256 youth and young adults with Type 1 and Type 2 diabetes from the SEARCH for Diabetes in Youth Food Security Study, with data collected at 3 time points between 2015 and 2022. Both household food insecurity (measured using the U.S. Household Food Security Survey Module) and costs (measured using survey responses on utilization and productivity losses) were self-reported by young adult participants or the caregivers of adolescents. The relationship between household food insecurity and costs was analyzed using generalized adjusted linear regression. The authors also analyzed the moderating role of continuous health insurance coverage.<br><br>RESULTS: Each additional 1-point increase in the household food insecurity score was associated with a $1,077 (95% CI=663; 1,491) increase in measured 12-month costs. Costs were $4,384 (95% CI=2,635; 6,133) higher in households that were experiencing household food insecurity than in those that were not. Youth and young adults with continuous health insurance coverage saw smaller increases in costs ($864, 95% CI=461; 1,267) than those without continuous coverage ($1,820; 95% CI=379; 3,261).<br><br>CONCLUSIONS: This study found a positive association between household food insecurity and costs for youth and young adults with diabetes, and this relationship was modified by continuous health insurance coverage. Future work should use linked claims and electronic health record data to better inform efforts aimed at reducing household food insecurity burden and improving the continuity of insurance coverage for this population.}, }
@article {pmid40813711, year = {2025}, author = {Kendra, KL and Bellasea, SL and Eroglu, Z and Hu-Lieskovan, S and Campbell, KM and Carson, WE and Wada, DA and Plaza, JA and Sosman, JA and In, GK and Ikeguchi, A and Hyngstrom, J and Brohl, AS and Khushalani, NI and Markowitz, J and Negrea, G and Kasbari, S and Doolittle, GC and Swami, U and Roberts, T and Mathew, BN and Medina, E and Baselga-Carretero, I and Gonzalez, CR and Garcilazo, IP and Vega-Crespo, A and Chen, JM and Naser Al-Deen, N and Patel, SP and Sharon, E and Moon, J and Wu, MC and Ribas, A}, title = {Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial.}, journal = {Nature medicine}, volume = {31}, number = {11}, pages = {3668-3674}, pmid = {40813711}, issn = {1546-170X}, support = {U10 CA180821/CA/NCI NIH HHS/United States ; R35 CA197633/CA/NCI NIH HHS/United States ; P01 CA244118/CA/NCI NIH HHS/United States ; U10 CA180888/CA/NCI NIH HHS/United States ; U10 CA180819/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Melanoma/drug therapy/pathology/immunology/mortality ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects/administration &amp; dosage ; Male ; Female ; Aged ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors ; Middle Aged ; Adult ; *Immune Checkpoint Inhibitors/therapeutic use/adverse effects ; *Skin Neoplasms/drug therapy/pathology ; Aged, 80 and over ; Progression-Free Survival ; Treatment Outcome ; }, abstract = {Desmoplastic melanoma is a distinct subtype of melanoma known to have preexisting immune infiltrates and high ultraviolet light damage, resulting in a high tumor mutational burden. We hypothesized that this may result in high response rates with single-agent anti-programmed death protein 1 (PD-1) therapy. SWOG S1512 was a two-cohort clinical trial testing the activity of pembrolizumab in patients with surgically resectable (cohort A) and unresectable (cohort B) desmoplastic melanoma. Here we report on the cohort B single-arm clinical trial, which enrolled 27 patients with unresectable desmoplastic melanoma receiving pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years, with the primary endpoint of complete response rate. The complete response rate was 37% (95% confidence interval: 19-58%), and the post hoc endpoint of objective response rate was 89% (95% confidence interval: 71-98%). The estimated secondary endpoints of 3-year melanoma-specific progression-free survival and overall survival were 84% and 96%, respectively, with only one patient having died from melanoma progression. Ten patients (37%) experienced grade 3 or 4 adverse events, and nine patients (33%) discontinued treatment because of adverse events. Patients with advanced desmoplastic melanoma have a high response rate to single-agent PD-1 blockade therapy, supporting single-agent anti-PD-1 as the treatment of choice, but are limited by a frequency of toxicities that is numerically higher than in other patient populations. ClinicalTrials.gov identifier: NCT02775851.}, }
@article {pmid40815487, year = {2025}, author = {Schwartz, J and Wangen, M and Odebunmi, OO and Waters, A and Ferrari, R and Marciniak, M and Brenner, AT and Wheeler, SB and Shah, PD}, title = {Patient preferences and perceived barriers to follow-up care in a pharmacy-based colorectal cancer screening program: a national survey.}, journal = {Cancer causes &amp; control : CCC}, volume = {36}, number = {11}, pages = {1563-1578}, pmid = {40815487}, issn = {1573-7225}, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/psychology/epidemiology/prevention &amp; control ; Male ; Female ; Middle Aged ; Aged ; *Early Detection of Cancer/methods/psychology ; *Patient Preference/statistics &amp; numerical data ; United States/epidemiology ; Occult Blood ; Colonoscopy ; Surveys and Questionnaires ; Mass Screening/methods ; Follow-Up Studies ; }, abstract = {BACKGROUND: Fecal immunochemical tests (FIT) are recommended for routine colorectal cancer (CRC) screening because they are cost-effective, non-invasive, and convenient. Pharmacy-based CRC screening using FIT kits could be effective to improve screening rates, particularly in medically underserved communities. However, data on follow-up procedures and barriers after positive FIT results in this context remain sparse.<br><br>METHODS: We conducted a national survey of 1,045 US adults aged 45-75 to assess preferences for follow-up care in a pharmacy-based CRC screening program we call PharmFIT&#x2122; and identify perceived barriers to follow-up colonoscopy after positive FIT results. We evaluated patient preferences and barriers using descriptive statistics. We used multinomial logistic regressions to identify correlates of patient preferences for follow-up and multiple logistic regressions to identify correlates of perceived psychosocial and structural barriers to follow-up colonoscopy.<br><br>RESULTS: Participants showed a strong preference for digital communication for negative FIT results and reminders, but favored direct, interpersonal communication from healthcare providers for positive results and follow-up. Psychosocial barriers, such as fear of colonoscopy or cancer diagnosis, were more prevalent than structural barriers like cost and transportation. Older adults, those with a regular healthcare provider, and higher-income individuals were less likely to report barriers, while non-white and Medicaid patients showed lower preferences for automated notifications.<br><br>CONCLUSION: PharmFIT should use tailored, multimodal communication strategies to address patient preferences and include strategies, like patient navigation, to address potential barriers to follow-up colonoscopy. This study reinforces the potential of pharmacy-based CRC screening programs to increase screening access and opportunities, particularly in medically underserved communities.}, }
@article {pmid40815506, year = {2025}, author = {Reddi, S and Banerjee, R}, title = {Avoid burning bridges before CAR-T therapy in myeloma.}, journal = {Blood advances}, volume = {9}, number = {16}, pages = {4232-4234}, pmid = {40815506}, issn = {2473-9537}, }
@article {pmid40815811, year = {2025}, author = {Ligon, JA and Ji, L and Dang, A and Xu, X and Rheingold, SR and Bhojwani, D and Devidas, M and Kairalla, JA and Shago, M and Heerema, NA and Carroll, AJ and Borowitz, M and Wood, BL and Winick, NJ and Carroll, WL and Hunger, SP and Raetz, EA and Loh, ML and Gupta, S and Winestone, LE}, title = {Role of race and ethnicity in survival among children/young adults with relapsed ALL: a Children's Oncology Group report.}, journal = {Blood advances}, volume = {9}, number = {22}, pages = {5738-5751}, pmid = {40815811}, issn = {2473-9537}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Young Adult ; *Ethnicity ; Hispanic or Latino ; *Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality/ethnology/therapy/epidemiology ; Prognosis ; Racial Groups ; Recurrence ; White ; Black or African American ; }, abstract = {Pediatric Hispanic and Black patients with newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL) experience worse overall survival (OS). We hypothesized that differential outcomes by race and ethnicity following relapse may contribute to disparities. We examined 2053 patients with ALL enrolled in frontline Children's Oncology Group trials from 1996 to 2014 who relapsed. We assessed the association of race and ethnicity, disease characteristics, and socioeconomic status with relapse survival predictors and postrelapse OS. For noninfant B-ALL, postrelapse OS (P = .002) and disease-related prognosticators such as time to relapse (P = .0002) differed by race and ethnicity. After adjusting for disease and patient characteristics, the OS association with overall race and ethnicity was attenuated, and lost statistical significance; Hispanic ethnicity specifically remained associated with worse OS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.01-1.41). Patients from highest annual median household income ZIP codes (>$85 000, approximately the highest quartile of patients) had better 5-year OS than those from the lowest (<$50 000; HR, 0.79; 95% CI, 0.63-0.99). Non-Hispanic Black and Hispanic patients more commonly lived in lower-income ZIP codes. For T-cell ALL, race, ethnicity, and socioeconomic status were not associated with OS. Worse postrelapse outcomes among racial and ethnic minority patients are largely driven by the prevalence of adverse disease-related factors at time of relapse, with a persistent disparity observed in Hispanic patients. The greatest impact in decreasing racial and ethnic B-ALL outcome disparities may be achieved by targeting frontline treatment interventions to address increased relapse among Black and Hispanic patients, and by developing and enabling equitable access to effective relapse treatments such as novel immunotherapies.}, }
@article {pmid40817396, year = {2026}, author = {Raggi, D and Crupi, E and Pederzoli, F and Martini, A and Briganti, A and Alhalabi, O and O'Donnell, PH and Ross, J and Gupta, S and Kamat, AM and Faltas, BM and Black, PC and Spiess, PE and Grivas, P and Gao, J and Apolo, AB and Huddart, RA and Necchi, A and Galsky, MD}, title = {HER2 and urothelial carcinoma: current understanding and future directions.}, journal = {Nature reviews. Urology}, volume = {23}, number = {2}, pages = {110-132}, pmid = {40817396}, issn = {1759-4820}, mesh = {Humans ; *Erb-b2 Receptor Tyrosine Kinases/metabolism/genetics/antagonists &amp; inhibitors ; *Carcinoma, Transitional Cell/metabolism/genetics/drug therapy ; Biomarkers, Tumor/metabolism/genetics ; *Urologic Neoplasms/metabolism/genetics/drug therapy ; *Urinary Bladder Neoplasms/metabolism/drug therapy/genetics ; }, abstract = {Human epidermal growth factor receptor 2 (HER2) has emerged as a crucial biomarker across various cancers, shaping therapeutic strategies and prognostic evaluations. In urothelial carcinoma, HER2 positivity rates can reach up to 68% when HER2-low tumours (immunohistochemistry 1+) are included in the analysis. HER2 overexpression and ERBB2 genomic alterations have been linked to advanced disease stages and poor outcomes in urothelial carcinoma. Emerging evidence suggests that HER2-low tumours might be a distinct and actionable subgroup. Accurate and consistent assessment of HER2 status is increasingly vital to identify patients likely to benefit from HER2-targeted therapies, raising interest in refining thresholds for HER2 expression, aiming to predict treatment response. HER2 heterogeneity across stages and histological subtypes complicates its evaluation, with definitions of HER2 positivity differing between clinical trials and treatments. In urothelial carcinoma, HER2-targeted therapies, such as tyrosine kinase inhibitors, monoclonal antibodies and antibody-drug conjugate (ADCs) have been explored. Unlike tyrosine kinase inhibitors and monoclonal antibodies, which act through HER2-related pathways, ADCs use HER2 as a target but achieve efficacy through additional mechanisms, enabling their activity even at low HER2 expression levels. Trastuzumab deruxtecan, a novel anti-HER2 ADC, has received FDA tumour-agnostic approval for unresectable or metastatic HER2+ solid tumours, including urothelial carcinoma, after prior therapies. Interactions between HER2 protein and putative biomarkers such as EGFR, NECTIN4, PDL1 and FGFR3 genomic alterations might influence therapeutic outcomes, offering opportunities for improved patient selection and innovative combination strategies.}, }
@article {pmid40818320, year = {2025}, author = {McElvania, E and Rao, D and Greninger, AL and Harnett, G and Larcena, A and Patel, A and Webster, B and Ulen, C and Green, DF and King, D and Patel, DR and Jandali, I and Gibson, J and Killion, J and Atwi, J and Bergmann, KR and Slade, L and Staat, MA and Faron, M and Washington, M and Patel, R and Annamalai, R and Ackerman, R and Stewart, WP and Mora Amador, Y and Raman, A and Liu, X}, title = {Evaluation of Cepheid Xpert Xpress CoV-2/Flu/RSV plus for nasal and nasopharyngeal specimens tested in CLIA-accredited and CLIA-waived settings.}, journal = {Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology}, volume = {180}, number = {}, pages = {105851}, doi = {10.1016/j.jcv.2025.105851}, pmid = {40818320}, issn = {1873-5967}, mesh = {Humans ; *Nasopharynx/virology ; *COVID-19/diagnosis ; *SARS-CoV-2/isolation &amp; purification/genetics ; *Influenza, Human/diagnosis/virology ; *Respiratory Syncytial Virus Infections/diagnosis/virology ; Influenza B virus/isolation &amp; purification/genetics ; Sensitivity and Specificity ; Respiratory Syncytial Virus, Human/isolation &amp; purification/genetics ; Influenza A virus/isolation &amp; purification/genetics ; *Molecular Diagnostic Techniques/methods ; Adult ; }, abstract = {BACKGROUND: Respiratory viruses are responsible for millions of healthcare visits annually. The unpredictable periodicity of Coronavirus disease 2019 and seasonal patterns of influenza and respiratory syncytial virus result in concurrent circulation of these viruses with non-specific and overlapping clinical symptoms.<br><br>STUDY DESIGN: This study evaluated the Cepheid Xpert Xpress CoV-2/Flu/RSV plus test using 3011 nasopharyngeal swab (NPS) and 2943 anterior nasal (NS) specimens. The assay was evaluated in CLIA-accredited (CA) laboratories with laboratory trained operators and CLIA-waived (CW) settings with non-laboratory personnel. Results were compared to the BioFire Respiratory Panel 2.1 for SARS-CoV-2 and Hologic Panther Fusion Flu A/B/RSV for influenza A, influenza B, and RSV. Cepheid Xpert Xpress CoV-2/Flu/RSV plus testing of NPS and NS specimens had high positive and negative agreement with reference testing.<br><br>RESULTS: Overall agreement for NPS was 98.8&#xa0;%, 99.1&#xa0;%, 99.9&#xa0;%, and 100&#xa0;% for SARS-CoV-2, influenza A, influenza B, and RSV, respectively. For NS, overall agreement was 98.7&#xa0;%, 99.3&#xa0;%, 99.9&#xa0;%, and 99.9&#xa0;% for SARS-CoV-2, influenza A, influenza B, and RSV, respectively. Specimen testing performed at CA and CW locations also had high positive and negative agreement with reference testing. Overall agreement for CA testing was 97.7&#xa0;%, 99.6&#xa0;%, 100&#xa0;%, and 100&#xa0;% for SARS-CoV-2, influenza A, influenza B, and RSV, respectively. For CW testing, overall agreement was 98.8&#xa0;%, 99.0&#xa0;%, 99.9&#xa0;%, and 99.9&#xa0;% for SARS-CoV-2, influenza A, influenza B, and RSV, respectively.<br><br>CONCLUSIONS: This study demonstrates that Xpert Xpress CoV-2/Flu/RSV plus provides rapid and accurate results from NPS and NS specimens in CA and CW testing facilities regardless of staff experience with molecular testing.}, }
@article {pmid40819165, year = {2025}, author = {Wu, E and Bieniosek, M and Wu, Z and Thakkar, N and Charville, GW and Makky, A and Schürch, CM and Huyghe, JR and Peters, U and Li, CI and Li, L and Giba, H and Behera, V and Raman, A and Trevino, AE and Mayer, AT and Zou, J}, title = {ROSIE: AI generation of multiplex immunofluorescence staining from histopathology images.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {7633}, pmid = {40819165}, issn = {2041-1723}, support = {P20 CA252733/CA/NCI NIH HHS/United States ; P50 CA285275/CA/NCI NIH HHS/United States ; R01 CA280639/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Fluorescent Antibody Technique/methods ; *Staining and Labeling/methods ; *Deep Learning ; Tumor Microenvironment ; Lymphocytes, Tumor-Infiltrating/immunology/pathology ; *Neoplasms/pathology ; *Image Processing, Computer-Assisted/methods ; Hematoxylin/chemistry ; Eosine Yellowish-(YS)/chemistry ; Biomarkers, Tumor/metabolism ; }, abstract = {Hematoxylin and eosin (H&amp;E) is a common and inexpensive histopathology assay. Though widely used and information-rich, it cannot directly inform about specific molecular markers, which require additional experiments to assess. To address this gap, we present ROSIE, a deep-learning framework that computationally imputes the expression and localization of dozens of proteins from H&amp;E images. Our model is trained on a dataset of over 1300 paired and aligned H&amp;E and multiplex immunofluorescence (mIF) samples from over a dozen tissues and disease conditions, spanning over 16 million cells. Validation of our in silico mIF staining method on held-out H&amp;E samples demonstrates that the predicted biomarkers are effective in identifying cell phenotypes, particularly distinguishing lymphocytes such as B cells and T cells, which are not readily discernible with H&amp;E staining alone. Additionally, ROSIE facilitates the robust identification of stromal and epithelial microenvironments and immune cell subtypes like tumor-infiltrating lymphocytes (TILs), which are important for understanding tumor-immune interactions and can help inform treatment strategies in cancer research.}, }
@article {pmid40820557, year = {2025}, author = {Cooper, N and Kruse, C and Deneen Morgan, S and Laurent, J and Arvelo-Saillant, M and Roussy, JP and Cordoba, M and Gouia, I and Schmitt, LA and Reineke, E and Gernsheimer, T}, title = {Patient survey in immune thrombocytopenia (ITP): Identifying unmet needs related to treatment and disease control in patients living in the United States.}, journal = {British journal of haematology}, volume = {207}, number = {3}, pages = {1038-1046}, pmid = {40820557}, issn = {1365-2141}, support = {//Sanofi/ ; }, mesh = {Humans ; Male ; *Purpura, Thrombocytopenic, Idiopathic/therapy/epidemiology/psychology ; United States/epidemiology ; Female ; Middle Aged ; Adult ; Cross-Sectional Studies ; Quality of Life ; Aged ; Surveys and Questionnaires ; Adolescent ; Young Adult ; Disease Management ; Aged, 80 and over ; }, abstract = {Immune thrombocytopenia (ITP) is a chronic disease with primary therapeutic goals of platelet count recovery to safe levels to minimize active/future bleeding, alongside easing additional symptoms negatively impacting overall patient well-being with consequent improvement in physical fatigue/energy levels, daily/work-related activities and social/emotional health. Documentation of this rare disease is important for evaluating real-world experiences in treatment satisfaction, expectations and unmet needs in disease management. This cross-sectional, real-world evidence survey was conducted from 9 February 2023 to 4 April 2023, by the Platelet Disorder Support Association and Sanofi in US adults diagnosed with ITP for ≥1 year. Results showed that although most patients receive and adhere to treatment, lack of sustained efficacy fuels a need for more effective therapy. Patients desired long-term ITP control and were most concerned with increasing/stabilizing platelet counts and decreasing fatigue and bleeding severity. Better treatment was needed to ease burdensome health-related quality of life symptoms, especially physical fatigue and anxiety, and decrease effects on daily life and activities. Additionally, involvement in shared decision-making and engagement in educational, digital healthcare and psychological support were preferred. Overall, ITP patients desired long-term disease management options that improved platelet counts, minimized bleeding and reduced physical fatigue and anxiety, while also engaging in patient support options.}, }
@article {pmid40820767, year = {2026}, author = {Mizuno, S and Gras, L and Baaij, LGA and Koster, L and D'Souza, A and Hari, PN and Estrada-Merly, N and Saber, W and Cowan, AJ and Iida, M and Okamoto, S and Takamatsu, H and Kawamura, K and Kodera, Y and Hamad, N and Ko, BS and Liam, C and Ho, KW and Goh, AS and Keat, TS and Elhaddad, AM and Bazarbachi, A and Chaudhry, BQUN and Alfar, R and Bekadja, MA and Benakli, M and Ortiz, CAF and Riva, E and Verburgh, E and Galeano, S and Bass, F and Mian, H and McCurdy, A and Wang, FR and Neumann, D and Koh, MBC and Snowden, JA and Schönland, S and McLornan, DP and Hayden, PJ and Balari, AMS and Greinix, HT and Aljurf, M and Atsuta, Y and Rondelli, D and Niederwieser, DW and Garderet, L}, title = {The impact of age on survival and excess mortality after autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients.}, journal = {Haematologica}, volume = {111}, number = {1}, pages = {286-299}, pmid = {40820767}, issn = {1592-8721}, mesh = {Humans ; *Multiple Myeloma/therapy/mortality/diagnosis ; *Hematopoietic Stem Cell Transplantation/adverse effects/methods/mortality ; Middle Aged ; Adult ; Male ; Female ; Aged ; Transplantation, Autologous ; Age Factors ; Young Adult ; Aged, 80 and over ; Adolescent ; Survival Rate ; Prognosis ; }, abstract = {Despite the availability of novel agents, autologous hematopoietic cell transplantation (auto-HCT) remains the standard of care in newly diagnosed multiple myeloma (MM) patients. The impact of age on overall survival (OS), progression-free survival (PFS), relapse incidence, non-relapse mortality (NRM), and excess mortality (taking account of general population mortality) was investigated using information on 61,797 MM patients transplanted between 2013 and 2017. The median age at auto-HCT was 60.8 (range, 18.1-83.2) years of whom 2.0% were 18-39 years, 68.9% 40-64 years, 21.8% 65-69 years, 6.5% 70-74 years, and 0.8% ≥75 years of age, respectively. The corresponding OS probabilities at 3 years were 85.9%, 82.8%, 81.1%, 78.4%, and 74.8%, respectively (P<0.001). Excess mortality cumulative incidences were 13.1%, 15.0%, 14.6%, 15.0%, and 14.1% at 3 years, respectively (P=0.67). In multivariable analyses, older age was a significant risk factor for OS, PFS, and NRM but not for excess mortality or relapse risk. Our results indicate that advanced age alone should not preclude the use of auto- HCT in patients with MM.}, }
@article {pmid40821852, year = {2025}, author = {Choo, S and Tong, AH and Fields, E and Mack, HM and Humbert, O and Radtke, S and Kiem, HP}, title = {A rescue fanconi anemia humanized mouse model with endogenous FA mutation and high human hematopoietic stem cell chimerism.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {33}, number = {3}, pages = {101528}, pmid = {40821852}, issn = {2329-0501}, support = {R01 HL147324/HL/NHLBI NIH HHS/United States ; T32 HL007093/HL/NHLBI NIH HHS/United States ; }, abstract = {Autologous transplantation of ex vivo gene-modified/corrected hematopoietic stem cells (HSCs) offers a definitive therapeutic approach to restore hematopoiesis in Fanconi anemia (FA) patients. However, this approach not only requires ex vivo treatment of patient HSCs in specialized facilities but also inevitably results in a loss of fragile and limited patient HSCs. In vivo correction of HSCs directly in the patient can overcome these limitations. To develop such in vivo gene therapy (GT) strategies, an appropriate in vivo model with sufficient target human HSCs carrying the disease-associated mutation is crucial. However, due to the proliferative defect imposed on FA-mutant cells, it is difficult to establish a humanized mouse model with a high engraftment of mutant HSCs. Here, we report a humanized mouse model of FA that results in high chimerism with FA-mutant human HSCs. We demonstrate successful engraftment, uncompromised proliferation, and long-term persistence of the FA-mutant HSCs facilitated by the full-length FANCA expression introduced via a lentiviral vector. This model resolves the lack of an in vivo FA disease model with human HSCs and is a promising platform for testing in vivo gene editing strategies targeting human cells.}, }
@article {pmid40823432, year = {2024}, author = {Evenson, KR and Howard, AG and Wen, F and Di, C and Lee, IM}, title = {Identifying Multicomponent Patterns and Correlates of Accelerometry-Assessed Physical Behaviors Among Postmenopausal Women: The Women's Health Accelerometry Collaboration.}, journal = {Journal for the measurement of physical behaviour}, volume = {7}, number = {1}, pages = {}, pmid = {40823432}, issn = {2575-6613}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 CA227122/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA182913/CA/NCI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; U01 CA182913/CA/NCI NIH HHS/United States ; RC1 HL099355/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 HL105065/HL/NHLBI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; R01 CA154647/CA/NCI NIH HHS/United States ; }, abstract = {Understanding the simultaneous patterning of accelerometer-measured physical activity and sedentary behavior (physical behaviors) can inform targeted interventions. This cross-sectional study described multi-component patterns and correlates of physical behaviors using accelerometry among diverse postmenopausal women. The Women's Health Accelerometry Collaboration combined two United States-based cohorts of postmenopausal women with similar accelerometry protocols and measures. Women (n=22,612) 62 to 97 years enrolled in the Women's Health Study (n=16,742) and the Women's Health Initiative Objective Physical Activity and Cardiovascular Health Study (n=5870) wore an ActiGraph GT3X+ accelerometer on their hip for one week. Awake-time accelerometry data were summarized using the accelerometer activity index into sedentary behavior, light (low, high), and moderate-to-vigorous physical activity. Latent class analysis was used to classify physical behavior hour-by-hour. Five unique patterns were identified with higher total volume of physical activity and lower sedentary behavior with each successively higher-class number based on percentage of the day in physical activity/sedentary behavior per hour over seven days. The percentage assignment was 16.3% class 1, 33.9% class 2, 20.2% class 3, 18.0% class 4, and 11.7% class 5. Median posterior probabilities ranged from 0.99-1.00. Younger age, higher education and general health, normal weight, never smokers, weekly drinking, and faster self-reported walking speed generally had higher class assignment compared to their counterparts. History of diabetes and cardiovascular disease generally had lower class assignment compared to those without these conditions. These results can inform targeted interventions based on common patterns of physical behaviors by time of day among postmenopausal women.}, }
@article {pmid40824476, year = {2025}, author = {Jones, SMW and Kent, EE and Caru, M and Arem, H and Kim, Y and Song, L and Langer, SL}, title = {Educational Targets for Patient-Reported Outcomes and Caregiver-Reported Outcomes in Psycho-oncology Research.}, journal = {Journal of cancer education : the official journal of the American Association for Cancer Education}, volume = {}, number = {}, pages = {}, pmid = {40824476}, issn = {1543-0154}, abstract = {Patient-reported outcomes (PROs) and caregiver-reported outcomes (CROs) are tools for evaluating behavioral medicine interventions and for bringing the patient voice into observational research. This study aimed to identify barriers to using PROs/CROs in behavioral cancer research and to equitably address those barriers. Forty-nine members of a cancer special interest group from a research society completed surveys in early 2023 about needs related to the use of PROs and CROs. Descriptive statistics were used to summarize results. Most participants used PROs (n = 34, 69%) but few frequently used CROs (n = 12, 24%). More than 80% of the sample were familiar with common PRO/CRO properties such as reliability and validity. Participants reported considering a wide variety of population characteristics when using PROs and CROs, including language (n = 31, 70%) and education level (n = 31, 70%). The most common barriers to using PROs/CROs in research were time, funding, and technology with many reflecting potential reasons for inequitable representation of certain groups in research. Webinars were the most preferred educational format (n = 38, 78%) for resources related to PROs/CROs. Many participants encountered barriers to using PROs in research. Creation and dissemination of educational resources to promote equitable use of PROs/CROs across underrepresented groups and overcome common barriers to use of these measurement tools are warranted.}, }
@article {pmid40826184, year = {2025}, author = {Tran, DT and Jin, R and Zhu, H and Schmidt, G and Spellman, SR and Ballen, KK}, title = {Real-world graft utilization after CTN-1101: a registry-based analysis of haploidentical graft versus umbilical cord blood trends.}, journal = {Bone marrow transplantation}, volume = {60}, number = {10}, pages = {1369-1376}, pmid = {40826184}, issn = {1476-5365}, support = {27307C0011/ES/NIEHS NIH HHS/United States ; 27305C0011/ES/NIEHS NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; 27398C0011/ES/NIEHS NIH HHS/United States ; U24CA076518//U.S. Department of Health &amp; Human Services | U.S. Public Health Service (United States Public Health Service)/ ; }, mesh = {Humans ; Male ; Female ; *Cord Blood Stem Cell Transplantation/methods ; *Registries ; Adult ; Middle Aged ; *Transplantation, Haploidentical/methods ; *Hematopoietic Stem Cell Transplantation/methods ; *Fetal Blood ; }, abstract = {Randomized clinical trials are expensive and not always practice changing. The Blood and Marrow Transplant Clinical Trials Network (CTN) 1101 trial (2012-2018) showed a lower two-year overall survival after umbilical cord blood (UCB) compared to haploidentical graft (haplo) transplants. To quantify the change in graft utilization after the trial's publication, a cohort of 11,190 U.S. adult HCT recipients selected with inclusion/exclusion criteria similar to CTN-1101's were analyzed across three time periods: 2010-2012 (pre-study), 2013-2018 (during-study), and 2019-2022 (post-study). We found a significant increase in haplo utilization compared to UCB, with the trend beginning around 2013. Compared to non-Hispanic White, Black recipients were more likely to receive haplo, Asian recipients were less likely, and Hispanic recipients had similar rates. We also expanded our analyses to 61,465 patients to assess haplo and UCB utilization compared to other allogeneic donors. In this cohort, utilization of alternative donor grafts increased when compared to HLA-matched related or unrelated donor grafts for Black, Hispanic, and Asian recipients. Our findings demonstrate practice change toward haplo transplants had begun before the CTN-1101 trial's publication and continued to significantly increase afterward. HLA-mismatched donors are vital alternative graft sources, allowing patients of all backgrounds to receive HCT.}, }
@article {pmid40827718, year = {2025}, author = {Lindsay, J and Zamora, D}, title = {Mortality Associated With Cytomegalovirus Reactivation After Umbilical Cord Blood HCT.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {27}, number = {5}, pages = {e70091}, doi = {10.1111/tid.70091}, pmid = {40827718}, issn = {1399-3062}, support = {//National Institute of Allergy and Infectious Diseases/ ; K23 AI163343/AI/NIAID NIH HHS/United States ; T32AI118690/GF/NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; K23AI163343/GF/NIH HHS/United States ; }, }
@article {pmid40828791, year = {2025}, author = {Maenetje, N and Oladimeji, M and Mlotshwa, M and Hoft, D and Lindan, C and Wallis, R and Charalambous, S and Churchyard, G and Edward, V and Fiore-Gartland, A and Shai, J and Maenetje, P}, title = {Epidemiological factors associated with immunological resistance in household contacts exposed to active tuberculosis in South Africa: A logistic regression analysis.}, journal = {PloS one}, volume = {20}, number = {8}, pages = {e0329562}, pmid = {40828791}, issn = {1932-6203}, support = {R25 MH064712/MH/NIMH NIH HHS/United States ; UM1 AI148685/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; P30 AI168034/AI/NIAID NIH HHS/United States ; INV-033558/GATES/Gates Foundation/United States ; }, mesh = {Humans ; South Africa/epidemiology ; Adult ; Male ; Female ; Family Characteristics ; Tuberculin Test ; Middle Aged ; *Tuberculosis/epidemiology/immunology ; Young Adult ; Risk Factors ; Logistic Models ; Adolescent ; *Latent Tuberculosis/epidemiology/immunology ; Contact Tracing ; }, abstract = {INTRODUCTION: Studying individuals who do not get infected with tuberculosis (TB) despite being persistently exposed to infectious TB may enable us to identify TB protective mechanisms.<br><br>METHODS: Between Apr 2015 and Apr 2017, we recruited adult household contacts (HHCs) of index TB cases (GeneXpert and sputum smear-positive) in Rustenburg, South Africa. HIV-uninfected HHCs who tested positive on both Tuberculin Skin Test (TST) and QuantiFERON-TB Gold In-tube (QFT) were defined as having latent TB infection (QFT&#x2009;+&#x2009;TST+), and those who tested double negative (QFT-TST-) were defined as uninfected with TB. The level of risk for TB infection was evaluated using an epidemiologic risk score. We compared epidemiological and clinical characteristics between the groups and used logic regression to identify factors associated with being QFT-TST-.<br><br>RESULTS: Of the 235 household contacts screened, 109 (46.3%) were QFT&#x2009;+&#x2009;TST&#x2009;+&#x2009;, 46 (19.5%) were TST-QFT-, 73 (30.1%) had discordant results, and 7 (2.9%) were excluded based on being HIV positive, already having active TB disease or had missing QFT/TST results. After 3 months, 27 (58.6%) of HHCs remained persistently negative. Younger age, higher number of household windows and habitable rooms, and relations with the index case were independently associated with being QFT-TST-. In the multivariable analysis, younger age (OR: 2.81, 95% CI, 1.23-6.47) and living in homes with more rooms (OR: 4.62, 95% CI, 1.81-11.79) remained associated with being QFT-TST-. We found no association between QFT-TST- and factors such as time spent with the index case, type of house, number of household occupants, or the risk score.<br><br>CONCLUSION: Our findings that both younger age and larger living quarters were associated with QFT-TST- status may suggest reduced exposure to TB. We found no association between the epidemiological TB risk score consisting of multiple TB infection risk factors and QFT-TST- status, suggesting other factors may play a role in remaining TB uninfected despite exposure.}, }
@article {pmid40829104, year = {2026}, author = {Tam, CS and Anderson, MA and Šimkovič, M and Ghia, P and Flinn, IW and Laribi, K and Opat, S and Cull, G and Munir, T and Österborg, A and Tedeschi, A and Wang, M and Szeto, A and Allewelt, H and Salmi, T and Li, J and Xu, L and Wu, K and Vezan, R and Shadman, M and Brown, JR}, title = {Zanubrutinib for the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies.}, journal = {Blood advances}, volume = {10}, number = {3}, pages = {694-706}, pmid = {40829104}, issn = {2473-9537}, mesh = {Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Adenine/analogs &amp; derivatives/analogs &amp; derivatives ; *Antineoplastic Agents/therapeutic use/adverse effects ; Chromosome Deletion ; Chromosomes, Human, Pair 17/genetics ; *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy/genetics/mortality ; Mutation ; *Piperidines/therapeutic use/adverse effects ; Protein Kinase Inhibitors/therapeutic use/adverse effects ; *Pyrazoles/therapeutic use/adverse effects/administration &amp; dosage ; *Pyrimidines/therapeutic use/adverse effects/administration &amp; dosage ; Treatment Outcome ; *Tumor Suppressor Protein p53/genetics ; Clinical Trials as Topic ; }, abstract = {Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N = 301; n = 132, treatment-naive [TN]; n = 169, relapsed/refractory [R/R]), data from SEQUOIA (phase 3; TN; zanubrutinib; NCT03336333), ALPINE (phase 3; R/R; zanubrutinib vs ibrutinib; NCT03734016), and AU-003 (NCT02343120) (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n = 127; median follow-up, 64.8 months), median progression-free survival (PFS) and overall survival (OS) were not reached; estimated 60-month PFS and OS were 70.7% and 82.3%, respectively. In ALPINE (n = 75, each treatment arm; median follow-up, 39.0 months), 36-month PFS rates were 59.2% among patients treated with zanubrutinib and 38.5% among those treated with ibrutinib, and OS rates were 73.6% and 72.5%, respectively. In AU-003 (n = 24; median follow-up, 69.6 months), 10 of 24 patients experienced progressive disease. Rate of response with zanubrutinib in SEQUOIA was 96.9% (95% confidence interval [CI], 95.2-98.8), and in ALPINE was 89.3% (95% CI, 80.1-95.3) with zanubrutinib vs 76.0% (95% CI, 64.7-85.1) with ibrutinib. Responses deepened over time in both TN and R/R populations. The most frequent nonhematologic treatment-emergent adverse events occurring in >20% of patients treated with zanubrutinib with del(17p) and/or TP53 mutations in SEQUOIA and ALPINE were COVID-19, upper respiratory tract infection, arthralgia, diarrhea, and contusion. In conclusion, zanubrutinib demonstrated strong efficacy in high-risk del(17p) and/or TP53 CLL/SLL, with a tolerable safety profile, further supporting use of zanubrutinib in both frontline and R/R settings.}, }
@article {pmid40829344, year = {2025}, author = {Gaspar-Maia, A and Sasamoto, N}, title = {Prevention, early detection &amp; interception: 15th biennial ovarian cancer research symposium.}, journal = {Gynecologic oncology}, volume = {201}, number = {}, pages = {83-85}, doi = {10.1016/j.ygyno.2025.08.012}, pmid = {40829344}, issn = {1095-6859}, }
@article {pmid40829691, year = {2025}, author = {Schaefer, DA and Longley, RM and Wolfe, ED and Keane, EP and Larizza, IS and Boardman, AC and Rosenberg, J and Mate-Kole, M and Waldman, LP and Majhail, N and Lee, SJ and Khera, N and Amonoo, HL}, title = {Financial Toxicity, Psychological Well-Being, and Quality of Life in Hematopoietic Stem Cell Transplantation.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {11}, pages = {936.e1-936.e10}, doi = {10.1016/j.jtct.2025.08.012}, pmid = {40829691}, issn = {2666-6367}, mesh = {Humans ; *Quality of Life ; *Hematopoietic Stem Cell Transplantation/psychology/economics ; Male ; Female ; Middle Aged ; Adult ; Prospective Studies ; Adaptation, Psychological ; Longitudinal Studies ; *Hematologic Neoplasms/therapy/psychology/economics ; Aged ; Anxiety/psychology ; Depression/psychology ; *Financial Stress/psychology ; Psychological Well-Being ; }, abstract = {BACKGROUND: Financial toxicity is a well-documented consequence of cancer care and may disproportionately impact patients with hematologic malignancies due to the high cost and intensity of hematopoietic stem cell transplant (HSCT). This population is particularly vulnerable to the psychological consequences of financial toxicity; however, the longitudinal relationship between financial toxicity and psychological well-being-particularly positive psychological well-being-remains understudied.<br><br>OBJECTIVE: To assess longitudinal associations between financial toxicity and patient-reported psychological distress (anxiety, depression, and post-traumatic stress disorder [PTSD] symptoms), positive psychological well-being (PPWB), coping, and quality of life (QOL) in patients with hematologic malignancies who received allogeneic HSCT.<br><br>STUDY DESIGN: We conducted a secondary analysis of prospective longitudinal data from 150 adult allogeneic HSCT recipients to examine the associations between financial toxicity and patient-reported psychological distress, PPWB, coping, and QOL in allogeneic HSCT survivors. Financial toxicity was measured using the Comprehensive Score for Financial Toxicity. Patient-reported psychological distress was assessed with the Hospital Anxiety and Depression Scale and the PTSD Checklist. PPWB was measured using the Revised Life Orientation Test, Positive and Negative Affect Scale, Flourishing Scale, and Satisfaction with Life Scale. Coping was assessed using the Brief-COPE, and QOL with the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation. We fitted a mixed-effects model for each outcome, adjusting for age, employment status, income, type of transplant, and transplant setting.<br><br>RESULTS: Among 150 participants (58.7% men; 94.6% non-Hispanic/Latino; 92.0% White; mean age 57.5 years [SD 13.5]), adjusted mixed-effects models indicated that lower financial toxicity was associated with lower anxiety (&#x3b2; = -0.104; P < .001), lower depression (&#x3b2; = -0.117; P < .001), and fewer PTSD symptoms (&#x3b2; = -0.280; P < .001). Lower financial toxicity was also associated with higher optimism (&#x3b2; = 0.112; P < .001), positive affect (&#x3b2; = 0.197; P < .001), flourishing (&#x3b2; = 0.201; P < .001), and life satisfaction (&#x3b2; = 0.181; P < .001), as well as lower avoidant coping (&#x3b2; = -0.043; P < .001) and improved quality of life (&#x3b2; = 0.596; P < .001).<br><br>CONCLUSION: Lower financial toxicity was significantly associated with improved psychological distress (anxiety, depression, and PTSD symptoms), positive psychological well-being (optimism, positive affect, flourishing, and satisfaction with life), avoidant coping, and QOL in allogeneic HSCT survivors. These findings suggest that supportive interventions targeting financial toxicity in the HSCT population have the potential to impact psychological well-being, coping, and QOL, warranting further study.}, }
@article {pmid40829964, year = {2025}, author = {Maughan, BL and Dyrskjøt, L and Grivas, P and Alcaraz, A and Antonarakis, ES and Bilen, MA and Bivalacqua, T and Cooperberg, MR and Cheng, L and Gupta, S}, title = {The Role of Liquid Biopsy in the Management of Patients with Genitourinary Malignancies.}, journal = {European urology}, volume = {88}, number = {5}, pages = {449-461}, doi = {10.1016/j.eururo.2025.07.016}, pmid = {40829964}, issn = {1873-7560}, mesh = {Humans ; Liquid Biopsy ; *Urogenital Neoplasms/pathology/blood/therapy/diagnosis ; *Biomarkers, Tumor/blood ; United States Food and Drug Administration ; }, abstract = {BACKGROUND AND OBJECTIVE: Liquid biopsy testing refers to the use of specific analytical methods to detect disease-related biomarkers in blood or its components. These tests can be either qualitative or quantitative. Liquid biopsy testing is increasingly used in patient care. Here, we explore all the current Food and Drug Administration (FDA)-approved indications for liquid biopsies related to genitourinary oncology. The secondary objective is to describe a few other potential uses of this technology that may become approved soon.<br><br>METHODS: We conducted a systematic review of all FDA approvals from 2015 through 2025. We interrogated multiple FDA databases to capture both tumor-specific and tissue-agnostic approvals. We limited the search to indications related to or requiring biomarker testing to assess the value of liquid biopsy testing. A total of 1119 approvals were identified. Of these, nine unique drug approvals related to genitourinary cancers require molecular testing. We then identified the registrational trials used for those approvals through PubMed and present the results here. For the secondary endpoints, we identified examples published within the past 10 yr.<br><br>KEY FINDINGS AND LIMITATIONS: The current use for liquid biopsy testing based on regulatory approval is for predicting treatment response. There are nine FDA-approved drugs or drug combinations applicable to clinical practice for patients with genitourinary malignancies. Liquid biopsy testing is currently available to identify patients for most of these indications. We highlight the limitations associated with current liquid biopsy testing.<br><br>Currently, there are multiple clinical indications for liquid biopsy in routine clinical practice. These FDA-approved indications can significantly improve the outcomes for biomarker-selected patients. All providers treating patients with a genitourinary malignancy are encouraged to use these tools regularly when indicated to improve patient care. Additional applications are expected to become available for routine clinical use in the future.}, }
@article {pmid40829965, year = {2025}, author = {Gustav, M and van Treeck, M and Reitsam, NG and Carrero, ZI and Loeffler, CML and Rabasco Meneghetti, A and Märkl, B and Boardman, LA and French, AJ and Goode, EL and Gsur, A and Brezina, S and Gunter, MJ and Murphy, N and Hönscheid, P and Sperling, C and Foersch, S and Steinfelder, R and Harrison, T and Peters, U and Phipps, A and Kather, JN}, title = {Assessing genotype-phenotype correlations in colorectal cancer with deep learning: a multicentre cohort study.}, journal = {The Lancet. Digital health}, volume = {7}, number = {8}, pages = {100891}, doi = {10.1016/j.landig.2025.100891}, pmid = {40829965}, issn = {2589-7500}, support = {001/WHO_/World Health Organization/International ; P30 CA015083/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Deep Learning ; *Colorectal Neoplasms/genetics/pathology ; Male ; Female ; Microsatellite Instability ; Biomarkers, Tumor/genetics ; Cohort Studies ; Middle Aged ; *Genetic Association Studies ; Phenotype ; Aged ; Proto-Oncogene Proteins B-raf/genetics ; }, abstract = {BACKGROUND: Deep learning-based models enable the prediction of molecular biomarkers from histopathology slides of colorectal cancer stained with haematoxylin and eosin; however, few studies have assessed prediction targets beyond microsatellite instability (MSI), BRAF, and KRAS systematically. We aimed to develop and validate a multi-target model based on deep learning for the simultaneous prediction of numerous genetic alterations and their associated phenotypes in colorectal cancer.<br><br>METHODS: In this multicentre cohort study, tissue samples from patients with colorectal cancer were obtained by surgical resection and stained with haematoxylin and eosin. These samples were then digitised into whole-slide images and used to train and test a transformer-based deep learning algorithm for biomarker detection to simultaneously predict multiple genetic alterations and provide heatmap explanations. The primary dataset comprised 1376 patients from five cohorts who underwent comprehensive panel sequencing, with an additional 536 patients from two public datasets for validation. We compared the model's performance against conventional single-target models and examined the co-occurrence of alterations and shared morphology.<br><br>FINDINGS: The multi-target model was able to predict numerous biomarkers from pathology slides, matching and partly exceeding single-target transformers. In the primary external validation cohorts, mean area under the receiver operating characteristic curve (AUROC) for the multi-target transformer was 0&#xb7;78 (SD 0&#xb7;01) for BRAF, 0&#xb7;88 (0&#xb7;01) for hypermutation, 0&#xb7;93 (0&#xb7;01) for MSI, and 0&#xb7;86 (0&#xb7;01) for RNF43; predictive performance was consistent across metrics and supported by co-occurrence analyses. However, biomarkers with high AUROCs largely correlated with MSI, with model predictions depending considerably on morphology associated with MSI at pathological examination.<br><br>INTERPRETATION: By use of morphology associated with MSI and more subtle biomarker-specific patterns within a shared phenotype, the multi-target transformers efficiently predicted biomarker status for diverse genetic alterations in colorectal cancer from slides stained with haematoxylin and eosin. These results highlight the importance of considering mutational co-occurrence and common morphology in biomarker research based on deep learning. Our validated and scalable model could support extension to other cancers and large, diverse cohorts, potentially facilitating cost-effective pre-screening and streamlined diagnostics in precision oncology.<br><br>FUNDING: German Federal Ministry of Health, Max-Eder-Programme of German Cancer Aid, German Federal Ministry of Education and Research, German Academic Exchange Service, and the EU.}, }
@article {pmid40831667, year = {2025}, author = {Gross, ME and Pike, M and Alson, J and Williams, P and Wood, ME and Marsh, E and Carey, E and Stürmer, T and Katz, R and Robinson, WR and Doll, KM}, title = {Risk factors for delayed diagnosis of endometrial cancer among black individuals: Results from the GUIDE-EC study.}, journal = {Gynecologic oncology reports}, volume = {60}, number = {}, pages = {101922}, pmid = {40831667}, issn = {2352-5789}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; }, abstract = {OBJECTIVE: Black patients with endometrial cancer (EC) experience disproportionately advanced stage at diagnosis. We aimed to identify variables, beyond race and histologic subtype, which increase risk for delayed diagnosis of EC.<br><br>METHODS: This is a retrospective study of Black individuals with EC in a large academic-affiliated healthcare system from 2014 to 2020. Primary outcome was delayed diagnosis of EC, defined as prolonged time to diagnosis (>28&#xa0;days to reach diagnosis). We used descriptive statistics, univariate regression, and factor analysis to identify variables associated with delayed diagnosis, achieve data reduction, and calculate odds ratios for delayed diagnosis.<br><br>RESULTS: Of 388 patients with EC included for analysis, one fifth (n&#xa0;=&#xa0;79, 20&#xa0;%) experienced delayed diagnosis. Ultrasound had the strongest association with delayed diagnosis in univariate regression (OR 4.4, 95&#xa0;% CI 2.4, 7.8) and factor analysis (OR 2.2, 95&#xa0;% CI 1.6, 3.0). BMI&#xa0;&#x2265;&#xa0;40 (OR 1.9, 95&#xa0;% CI 1.1, 3.3) was also associated with delayed diagnosis. Age&#xa0;&#x2265;&#xa0;50 was associated with decreased odds of delayed diagnosis (OR 0.3, 95&#xa0;% CI 0.2, 0.7). Presence of an endometrial biopsy was associated with decreased odds of delayed diagnosis on univariate regression (OR 0.4, 95&#xa0;% CI 0.2, 1.4).<br><br>CONCLUSIONS: A fifth of Black patients with EC experienced delayed diagnosis, and preoperative ultrasound was most strongly associated with delayed diagnosis. Providers should consider a tissue-sampling-first approach in Black patients at risk for EC.}, }
@article {pmid40832049, year = {2025}, author = {Ralph, DK and Bakis, AG and Galloway, J and Vora, AA and Araki, T and Victora, GD and Song, YS and DeWitt, WS and Matsen, FA}, title = {Inference of germinal center evolutionary dynamics via simulation-based deep learning.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {40832049}, issn = {2331-8422}, support = {U01 AI150747/AI/NIAID NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; R56 HG013117/HG/NHGRI NIH HHS/United States ; R01 HG013117/HG/NHGRI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {B cells and the antibodies they produce are vital to health and survival, motivating research on the details of the mutational and evolutionary processes in the germinal centers (GCs) from which mature B cells arise. It is known that B cells with higher affinity for their cognate antigen (Ag) will, on average, tend to have more offspring. However the exact form of this relationship between affinity and fecundity, which we call the "affinity-fitness response function", is not known. Here we use deep learning and simulation-based inference to learn this function from a unique experiment that replays a particular combination of GC conditions many times. All code is freely available at https://github.com/matsengrp/gcdyn, while datasets and inference results can be found at https://doi.org/10.5281/zenodo.15022130.}, }
@article {pmid40832168, year = {2025}, author = {Mout, L and Moreno-Rodriguez, T and Grillo, G and Nand, A and Keshavarzian, T and Bahl, S and Kang, K and Bootsma, M and Minnee, E and Zhou, S and Burns, KH and Corey, E and Nelson, P and Dehm, SM and Zhao, SG and Zwart, W and Feng, F and Quigley, D and Lupien, M}, title = {Genetic and Epigenetic Reprogramming of Transposable Elements Drives ecDNA-Mediated Metastatic Prostate Cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832168}, issn = {2692-8205}, support = {P50 CA275741/CA/NCI NIH HHS/United States ; R01 CA174777/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA276112/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; UG3 NS132127/NS/NINDS NIH HHS/United States ; R01 CA289390/CA/NCI NIH HHS/United States ; R01 CA240816/CA/NCI NIH HHS/United States ; }, abstract = {Extrachromosomal DNAs (ecDNAs), which replicate and segregate in a non-Mendelian manner, serve as vectors for accelerated tumor evolution. By integrating chromatin accessibility, whole-genome sequencing, and Hi-C-based genome topology data from a cohort of metastatic Castration-Resistant Prostate Cancer (mCRPC) cases, we show that epigenetically activated repeat DNA, amplified in ecDNAs, drive oncogene overexpression. Specifically, we identify a subgroup of mCRPCs (20%) characterized by clusters of accessible LINE1 repeat DNA elements flanking the androgen receptor (AR) gene. These LINE1 elements are co-amplified with AR and provide binding sites for prostate-lineage transcription factors, including AR, FOXA1 and HOXB13. Accessible LINE1 elements establish novel 3D chromatin interactions with the AR gene, forging a new regulatory plexus driving AR overexpression and confers resistance to androgen signaling inhibitors. Our findings indicate how tumor evolution is driven by the convergence of genetic and epigenetic alterations on repeat DNA, activating and amplifying them to allow oncogene overexpression.}, }
@article {pmid40832245, year = {2025}, author = {Furlong, J and Goya, S and Nawrocki, EP and Calhoun, V and Hatcher, E and Yankie, L and Greninger, AL}, title = {Automated Annotation and Validation of Human Respiratory Virus Sequences using VADR.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832245}, issn = {2692-8205}, support = {R03 LM014965/LM/NLM NIH HHS/United States ; }, abstract = {Accurate annotation of viral genomes is essential for reliable downstream analysis and public data sharing. While NCBI's Viral Annotation DefineR (VADR) pipeline provides standardized annotation and quality control, it only supports six viral groups to date. Here, we developed and validated 12 new reference sequence-based VADR models targeting key human respiratory viruses: measles virus, mumps virus, rubella virus, human metapneumovirus, human parainfluenza virus types 1-4, and seasonal coronaviruses (229E, NL63, OC43, HKU1). Model construction was guided by a comprehensive analysis of intra-species genomic and phylogenetic diversity, enabling the development of genotype-specific models associated with reference genomes that defined expected genome structure and annotation. Models were trained on 5,327 publicly available complete viral genomes and tested on 372 viral genomes not yet submitted to GenBank. VADR passed 96.3% of publicly available viral genomes and 98.1% of viral genomes not in the training set, correctly identifying overlapping ORFs, mature peptides, and transcriptional slippage as well as genome misassemblies. VADR detected novel viral biology including the first reported HCoV-OC43 NS2 knockout in a human infection and novel G and SH coding sequence lengths in human metapneumovirus. These VADR models are publicly available and are used by NCBI curators as part of the GenBank submission pipeline, supporting high-quality, scalable viral genome annotation for research and public health.}, }
@article {pmid40832333, year = {2025}, author = {Elhaw, AT and Tang, PW and Cheng, YY and Kamlapurkar, S and Javed, Z and Al-Saad, S and White, SR and Abdelnaby, AE and Khan, H and Choi, AS and Cole, AR and Kim, YS and Atiya, HI and Trebak, M and Zervantonakis, I and Buckanovich, RJ and Aird, KM and Coffman, LG and Mythreye, K and Hempel, N}, title = {RHOV is a Detachment-Responsive Rho GTPase Necessary for Ovarian Cancer Peritoneal Metastasis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40832333}, issn = {2692-8205}, support = {R01 CA230628/CA/NCI NIH HHS/United States ; P50 CA272218/CA/NCI NIH HHS/United States ; P30 CA047904/CA/NCI NIH HHS/United States ; R35 HL150778/HL/NHLBI NIH HHS/United States ; R01 CA242021/CA/NCI NIH HHS/United States ; T32 HL110849/HL/NHLBI NIH HHS/United States ; }, abstract = {All ovarian cancer subtypes spread via transcoelomic metastasis, where cells disseminate into the peritoneal fluid, resist anoikis, and form multicellular aggregates that invade the peritoneum. This represents the main driver of morbidity and mortality for peritoneal cancer patients. Mechanisms necessary for cancer cells to survive matrix detachment and initiate transcoelomic metastasis remain poorly defined. To address this, we identified a conserved detachment-sensitive gene signature activated shortly after matrix-detachment across multiple ascites-derived cancer cell lines. RHOV, an atypical, constitutively active and understudied member of the Rho GTPase family, emerged as a top upregulated transcript, which was confirmed in patient ascites-derived tumor cells. Functionally, loss of RHOV impairs anoikis resistance, multicellular aggregate integrity, migration and invasion, and completely abolishes transcoelomic tumor progression in vivo. RHOV enhances c-Jun signaling and cytoskeletal remodeling, which is dependent on both RHOV GTP-binding and membrane localization. These findings define RHOV as a novel detachment-sensitive Rho GTPase and establish RHOV as a critical regulator of peritoneal metastasis for the first time.}, }
@article {pmid40832395, year = {2025}, author = {Tran-Kiem, C and Perofsky, AC and Lessler, J and Bedford, T}, title = {Characterizing the informativeness of pathogen genome sequence datasets about transmission between population groups.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40832395}, support = {R35 GM119774/GM/NIGMS NIH HHS/United States ; }, abstract = {Pathogen genome analysis helps characterize transmission between population groups. The information carried by pathogen sequences comes from the accumulation of mutations within their genomes; thus, that the pace at which mutations accumulate should determine the granularity of transmission processes that pathogen sequences can characterize. Here, we investigate how the complex interplay between mutation, transmission, population mixing and sampling impacts the power of phylogeographic studies. First, we develop a conceptual probabilistic framework to quantify the ability of pairs of sequences in capturing migration history. This allows us to comprehensively explore the space of possible phylogeographic analyses by explicitly considering the pace at which mutations accumulate and the pace at which migration events occur. Using this framework, we identify a pathogen-intrinsic limit in the mixing scale at which their sequence data remains informative, with faster mutating pathogens enabling finer spatial characterization. Secondly, we perform a simulation study exploring a range of assumptions regarding sequencing intensity. We find that sample size further imposes a limit on the characterization of mixing processes. This work highlights inherent horizons of observability for population mixing processes that depend on the interaction between evolution, transmission, mixing and sampling. Such considerations are important for the design of phylogeographic studies.}, }
@article {pmid40833763, year = {2025}, author = {Childers, CP and Selzer, DJ and Green, ML and Sutherland, MJ and Senkowski, CK and Mabry, CD}, title = {Generating a New CPT Code Set for Adult and Pediatric Appendectomy.}, journal = {JAMA surgery}, volume = {160}, number = {10}, pages = {1076-1081}, pmid = {40833763}, issn = {2168-6262}, mesh = {Humans ; *Appendectomy/methods/classification ; Adult ; Cross-Sectional Studies ; Child ; Retrospective Studies ; *Current Procedural Terminology ; Male ; Female ; *Appendicitis/surgery ; Middle Aged ; Adolescent ; Laparoscopy ; Child, Preschool ; United States ; Young Adult ; Length of Stay/statistics &amp; numerical data ; Operative Time ; Postoperative Complications/epidemiology ; }, abstract = {IMPORTANCE: There are 3 Current Procedural Terminology (CPT) codes for appendectomy-2 codes describing open appendectomy with or without peritonitis or abscess and 1 code for laparoscopic appendectomy regardless of presentation-which have remained the same for more than 30 years. It is possible that physician work (assessed in work relative value units) for these codes will eventually need to be reassessed, and this study may provide an opportunity for modernizing the CPT codes and their descriptions.<br><br>OBJECTIVE: To provide empirical data to determine what a new code structure for appendectomy could look like.<br><br>This cross-sectional study performed a retrospective review of 2021-2023 US National Surgical Quality Improvement Program (NSQIP) adult and pediatric appendectomy-specific files among adults and children undergoing appendectomy. Data analysis was completed in May 2025.<br><br>MAIN OUTCOME AND MEASURES: We sought to identify distinct populations of patients that require different levels of surgeon work, which we measured using operative time, postoperative length of stay, and rates of complications.<br><br>RESULTS: The final sample included 110&#x202f;379 encounters for appendectomy. Approximately one-quarter (28&#x202f;583 [25.9%]) had complicated disease; only 3057 cases (2.8%) were performed open. Compared to uncomplicated appendicitis in children and adults (aged 6-64 years), we found the following factors were significantly associated with changes (generally increases) in surgeon work using our measures: complicated disease, age 5 years or younger and 65 years or older, and whether the procedure was for interval appendectomy or performed for tumor. Based on these stratifying variables, we propose 16 new codes-8 laparoscopic and 8 open-that identify unique populations of patients undergoing appendectomy with different work profiles.<br><br>CONCLUSIONS AND RELEVANCE: In this cross-sectional study, we provide the first empirical strategy for identifying new codes for appendectomy using objective measures of surgeon work. If appendectomy ever undergoes review of its relative work, this study provides a potential framework for improving the CPT codes and describing the nuances of appendectomy in the modern era.}, }
@article {pmid40833820, year = {2025}, author = {Beydoun, HA and Manson, JE and Beydoun, MA and Tsai, J and Shadyab, AH and Jung, SY and Liu, S and Allison, M and Ikramuddin, F and Mouton, CP and Nuño, T and Zonderman, AB and Tinker, LF}, title = {SARS-CoV-2 Positivity, Indicators of COVID-19 Severity, COVID-19 Hospitalization, and Diabetes Risk in the Women's Health Initiative.}, journal = {Journal of women's health (2002)}, volume = {34}, number = {11}, pages = {1416-1425}, pmid = {40833820}, issn = {1931-843X}, mesh = {Humans ; Female ; *COVID-19/epidemiology/diagnosis ; *Hospitalization/statistics &amp; numerical data ; Middle Aged ; Aged ; *Diabetes Mellitus/epidemiology ; SARS-CoV-2 ; Women's Health ; Severity of Illness Index ; Prospective Studies ; Risk Factors ; Incidence ; United States/epidemiology ; }, abstract = {Objective: To examine prospective associations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positivity, coronavirus disease 2019 (COVID-2019) symptom severity, and COVID-2019 hospitalization with incident clinical diabetes among aging women. Methods: A cohort study was conducted using data from 34,405 eligible Women's Health Initiative participants who completed ≥1 COVID-2019 surveys (Survey 1: June-December 2020; Survey 2: June 2021-February 2022) and were followed up for an average of 1.86 (±0.49) years, yielding 399 incident diabetes cases. Results: SARS-CoV-2 test positivity was associated with diabetes risk in the age-adjusted Cox regression model (hazard ratio [HR] = 1.76, 95% confidence interval [CI]: 1.10, 2.82), but not when fully adjusted (HR = 1.43, 95% CI: 0.88, 2.31). Diabetes risk was higher among those with 1-2 COVID-19 symptoms (HR = 1.39, 95% CI: 1.09, 1.77) and those with 3± COVID-2019 symptoms (HR = 1.53, 95% CI: 1.06, 2.22) compared with those without COVID-2019 symptoms in fully-adjusted models, irrespective of self-reported SARS-CoV-2 testing. COVID-2019 hospitalization was associated with 2-3 times the risk of clinical diabetes in age-adjusted (HR = 2.95, 95% CI: 1.52, 5.72) and fully-adjusted (HR = 1.90, 95% CI: 0.97, 3.72) models. Conclusions: Age-adjusted self-reported SARS-CoV-2 test positivity was associated with a higher incidence of diabetes. Reporting of COVID-2019 symptoms and being hospitalized for COVID-2019 were each associated with higher incidence of diabetes in aging women, after controlling for demographic, socioeconomic, lifestyle, and health characteristics.}, }
@article {pmid40833999, year = {2025}, author = {Singal, AG and Quirk, L and Boike, J and Chernyak, V and Feng, Z and Giamarqo, G and Kanwal, F and Ioannou, GN and Manes, S and Marrero, JA and Mehta, N and Pillai, A and Shaheen, NJ and Shaukat, A and Sirlin, CB and Verna, E and Wani, S and Wilson Woods, A and Yang, JD and Parikh, ND}, title = {Value of HCC surveillance in a landscape of emerging surveillance options: Perspectives of a multi-stakeholder modified Delphi panel.}, journal = {Hepatology (Baltimore, Md.)}, volume = {82}, number = {3}, pages = {794-809}, pmid = {40833999}, issn = {1527-3350}, support = {R01 CA212008/CA/NCI NIH HHS/United States ; U01 CA283935/CA/NCI NIH HHS/United States ; R01 CA277133/CA/NCI NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; R01 CA255621/CA/NCI NIH HHS/United States ; R01 CA233794/CA/NCI NIH HHS/United States ; R01 CA256977/CA/NCI NIH HHS/United States ; R01 CA282178/CA/NCI NIH HHS/United States ; U01 CA271887/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Liver Neoplasms/diagnosis/prevention &amp; control ; Delphi Technique ; *Carcinoma, Hepatocellular/diagnosis/prevention &amp; control ; *Early Detection of Cancer/methods ; Population Surveillance/methods ; }, abstract = {HCC surveillance is recommended by liver professional societies but lacks broad acceptance by several primary care and cancer societies due to limitations in the existing data. We convened a diverse multidisciplinary group of cancer screening experts to evaluate current and future paradigms of HCC prevention and early detection using a rigorous Delphi panel approach. The experts had high agreement on 21 statements about primary prevention, HCC surveillance benefits, HCC surveillance harms, and the evaluation of emerging surveillance modalities. The experts agreed that current data have methodologic limitations as well as unclear generalizability to Western populations. Although a randomized clinical trial of surveillance versus no surveillance is unlikely feasible, they concurred that alternative designs, such as a comparison of 2 surveillance modalities, could provide indirect evidence of surveillance efficacy. The panel acknowledged the presence of surveillance harms, but concurred the overall value of surveillance appears high, particularly given a greater emphasis on benefits over harms by both patients and clinicians. The experts underscored the importance of a framework for measuring both benefits and harms when evaluating emerging surveillance strategies. The panel acknowledged performance metrics of emerging methods may differ from other cancer screening programs given differences in populations, including higher risk of cancer development and competing risk of morality, and differences in diagnostic workflow in patients at risk of HCC. These data provide insights into the perceived value of HCC surveillance in an era of emerging blood- and imaging-based surveillance strategies.}, }
@article {pmid40835222, year = {2025}, author = {Christopher, CN and Evenson, KR and Howard, AG and Cuthbertson, CC and Di, C and Dieli-Conwright, CM and Eaton, CB and LaCroix, AZ and Lee, IM}, title = {Association of Self-Reported Walking Pace With Cancer Incidence and Mortality: The Women's Health Accelerometry Collaboration.}, journal = {Journal of physical activity &amp; health}, volume = {22}, number = {12}, pages = {1549-1556}, doi = {10.1123/jpah.2024-0839}, pmid = {40835222}, issn = {1543-5474}, mesh = {Incidence ; Self Report/statistics &amp; numerical data ; *Neoplasms/epidemiology/mortality ; *Walking/statistics &amp; numerical data ; *Walking Speed ; *Accelerometry/statistics &amp; numerical data ; Humans ; Female ; Middle Aged ; Aged ; Aged, 80 and over ; Women's Health/statistics &amp; numerical data ; Risk Assessment/methods ; Risk Factors ; United States/epidemiology ; Prospective Studies ; Follow-Up Studies ; }, abstract = {BACKGROUND: While the health benefits of walking are well-established, it is not clear if walking pace is associated with cancer-related outcomes.<br><br>PURPOSE: To investigate associations of self-reported walking pace with cancer incidence and mortality among women 62-99&#xa0;years of age in the Women's Health Accelerometry Collaboration.<br><br>METHODS: Women self-reported walking pace, classified as brisk (&#x2265;3&#xa0;mph), average (2-2.9&#xa0;mph), casual (<2&#xa0;mph), or does not walk regularly, and were followed for cancer outcomes. Multivariable stratified Cox proportional hazards models estimated hazard ratios and 95% confidence intervals.<br><br>RESULTS: There were 22,358 women in the analytic sample. During a mean 8.0&#xa0;years of follow-up, 1891 women developed cancer (n = 615 cancer deaths). Self-reported walking paces were not associated with all site cancer incidence (compared with a brisk walking pace: average walking pace hazard ratio, 1.08 (95% confidence interval, 0.95-1.23); casual walking pace, 1.15 (0.97-1.33), and does not walk regularly 1.14 (0.97-1.34) nor cancer mortality (average walking pace, 0.97 [0.76-1.25], casual walking pace, 0.98 [0.74-1.30], and does not walk regularly 1.20 [0.90-1.60]). Findings were similar when colon, endometrial, and lung cancer were examined, separately. However, casual walking pace was associated with a higher risk of a composite of inactivity-related cancers (1.21 [1.00-1.47]), and breast cancer (1.40 [1.09-1.80]) compared with a brisk walking pace.<br><br>CONCLUSIONS: Slower, compared with faster, self-reported walking paces may be related to a higher risk of some cancers in postmenopausal women. Future research is needed to confirm these findings and investigate mechanisms underlying the associations of walking pace with these cancers.}, }
@article {pmid40835749, year = {2025}, author = {Zhao, LP and Papadopoulos, GK and McFarland, BJ and Skyler, JS and Parikh, HM and Kwok, WW and Lybrand, TP and Bondinas, GP and Moustakas, AK and Wang, R and Pyo, CW and Nelson, WC and Geraghty, DE and Lernmark, &#xc5;}, title = {Profiling associations of interactive ligand-receptors (HLA class I and KIR gene products) with the progression to type 1 diabetes among seroconverted participants.}, journal = {Diabetologia}, volume = {68}, number = {12}, pages = {2743-2753}, pmid = {40835749}, issn = {1432-0428}, support = {R01 DK132406/DK/NIDDK NIH HHS/United States ; }, mesh = {Humans ; *Diabetes Mellitus, Type 1/genetics/metabolism ; *Receptors, KIR/genetics/metabolism ; Disease Progression ; Female ; Male ; Adult ; Genotype ; *Histocompatibility Antigens Class I/genetics/metabolism ; Ligands ; }, abstract = {AIMS/HYPOTHESIS: The aim of this work was to explore associations between type 1 diabetes progression from stages 1 or 2 to stage 3 and interacting ligand-receptor complexes of HLA class I (HLA-I) and KIR gene products.<br><br>METHODS: Applying next-generation sequencing technology to genotype HLA-I genes (HLA-A, -B, -C) and KIR genes (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL4, KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, KIR3DL1, KIR3DL3, KIR3DS1, KIR2DP1, KIR3DP1) from 1215 participants in the Diabetes Prevention Trial-Type 1 (DPT-1) and the Diabetes Prevention Trial (TN07), we systematically explored associations of HLA-I-KIR ligand-receptor interactions (LRIs) with disease progression via a Cox regression model. We investigated the structural properties of identified LRI complexes.<br><br>RESULTS: KIR and HLA-I genes had no or sporadic associations with disease progression. Out of all possible LRIs, nine HLA-A Ligands and 14 HLA-B ligands with corresponding receptors had modest associations with progression (p<0.05). As an example, carriers of A*03:01-KIR2DS4 had slower progression (HR 0.36, p=3.06&#xa0;&#xd7;&#xa0;10[-2]), as did B*07:02-KIR2DL3 carriers (HR 0.26, p=7.76&#xa0;&#xd7;&#xa0;10[-3]). Structural investigations of KIR-HLA-I complexes via homology modelling based on already-solved respective complex structures suggested that the respective electrostatic and van der Waals interactions encoded in the protein sequences result in strong biophysical LRIs, which could alter the progression of type 1 diabetes.<br><br>CONCLUSIONS/INTERPRETATION: These results reveal that LRIs of KIR-HLA-I gene products, rather than individual genes, contribute to type 1 diabetes progression, and such interactions are likely to be stabilised by electrostatic and van der Waals forces. As the KIR-HLA-I interactions involve part of the C-terminus of the antigen-binding groove of HLA-I, but may be affected by the respective bound peptide, this suggests a new mechanism for type 1 diabetes pathogenesis.<br><br>DATA AVAILABILITY: Clinical data on participants in DPT-1 and TN07 can be obtained from the NIDDK-Central Repository (https://repository.niddk.nih.gov/home) following the formal approval process.}, }
@article {pmid40838500, year = {2025}, author = {Ogimi, C and Waghmare, A}, title = {Risk Stratification for Seasonal Coronavirus Infections in HCT Recipients: Advances and Challenges.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {27}, number = {5}, pages = {e70096}, doi = {10.1111/tid.70096}, pmid = {40838500}, issn = {1399-3062}, }
@article {pmid40838528, year = {2025}, author = {Melchio, M and Hill, JA and Shah, M and Neofytos, D and Gambella, M and Raiola, AM and Delfino, E and Balletto, E and Angelucci, E and Bassetti, M and Mikulska, M}, title = {Old Pathogens-New Patient Types: Infections in a CAR T-Cell Recipient. Could It Get Any More Complicated?.}, journal = {Transplant infectious disease : an official journal of the Transplantation Society}, volume = {27}, number = {5}, pages = {e70093}, pmid = {40838528}, issn = {1399-3062}, mesh = {Humans ; Male ; Adult ; *Immunotherapy, Adoptive/adverse effects ; *COVID-19/complications/immunology ; *Lymphoma, Large B-Cell, Diffuse/therapy/immunology ; Cytokine Release Syndrome/etiology ; SARS-CoV-2 ; Receptors, Chimeric Antigen/immunology ; *Invasive Pulmonary Aspergillosis/drug therapy/microbiology/immunology/diagnosis ; Antifungal Agents/therapeutic use ; Aspergillus fumigatus/isolation &amp; purification ; Triazoles/therapeutic use ; *Tuberculosis, Pulmonary/drug therapy ; Nitriles/therapeutic use ; Mediastinal Neoplasms/therapy ; Pyridines/therapeutic use ; Neurotoxicity Syndromes ; Antitubercular Agents/therapeutic use ; }, abstract = {The case discussed involves a 41-year-old Italian man who was a candidate for chimeric antigen receptor T-cell therapy (CAR-T) for mediastinal diffuse large B-cell lymphoma. His CAR-T treatment was postponed several times due to prolonged relapsing COVID-19 and new onset of pulmonary Mycobacterium tuberculosis diseases. After 11 weeks of antimycobacterial treatment, CAR T-cell therapy was performed, but complicated by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Two months after CAR-T, the patient developed invasive pulmonary aspergillosis due to A. fumigatus. He was successfully treated with a 6-month course of antitubercular therapy and an 8-month course of antifungal therapy with isavuconazole. Lobectomy was performed due to episodes of severe hemoptysis. The challenging issues of diagnosis, choice, and management of treatments, including drug-drug interactions and length of therapy, are discussed.}, }
@article {pmid40838594, year = {2026}, author = {Ashby, E and Janes, H and Follmann, D and Gilbert, PB and Zhou, H and Wang, X and Girard, B and Priddy, F and Kublin, JG and Corey, L and Neuzil, KM and Baden, LR and El Sahly, HM and Zhang, B and , }, title = {Validating and leveraging non-SARS-CoV-2 respiratory infection as a negative control outcome in a phase 3 COVID-19 vaccine trial with extended observational follow-up.}, journal = {American journal of epidemiology}, volume = {195}, number = {1}, pages = {168-177}, pmid = {40838594}, issn = {1476-6256}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI148684/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; DGE-2140004//National Science Foundation Graduate Research Fellowship Program/ ; UM1 AI148684-03//Infectious Diseases Clinical Research Consortium leadership group 5/ ; UM1 AI 68636//AIDS Clinical Trials Group Leadership and Operations Center/ ; UM1 AI 68619//HIV Prevention Trials Network Leadership and Operations Center/ ; UM1 AI 68618//HVTN Laboratory Center/ ; UM1 AI 68635//Statistics and Data Management Center/ ; UM1 AI 68614HVTN//Leadership and Operations Center/ ; 75A50120C00034//Biomedical Advanced Research and Development Authority/ ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *2019-nCoV Vaccine mRNA-1273 ; *COVID-19/prevention &amp; control/epidemiology ; *COVID-19 Vaccines ; Follow-Up Studies ; *Respiratory Tract Infections/epidemiology/virology ; *Vaccine Efficacy ; }, abstract = {Negative control outcomes (NCOs) are useful tools for hidden bias detection, but empirical evidence validating NCOs for COVID-19 is lacking. To address this gap, we examined the blinded phase of the randomized, placebo-controlled Coronavirus Vaccine Efficacy (COVE; NCT04470427) trial of the mRNA-1273 COVID-19 vaccine. We confirmed that acute respiratory illness with a positive test for a non-SARS-CoV-2 respiratory pathogen on a multiplex PCR panel was a valid NCO for COVID-19, considering that it was unaffected by vaccination (vaccine efficacy, VE = 3.3% (95% CI, -22.3 to 23.6)) yet strongly associated with COVID-19 (odds ratio = 2.95 (95% CI, 2.00, 4.24)). Subsequently, we leveraged non-SARS-CoV-2 infections to detect bias in time-varying VE estimates from COVE's blinded and booster phases. Balanced incidence of non-SARS-CoV-2 infection between vaccinated and unvaccinated COVID-19-free risk sets suggested low selection bias in VE estimates of two-dose mRNA-1273 against COVID-19 during the blinded phase (VE = 92.5% (95% CI, 88.8, 94.9) 14 days post-dose-two, stable for 5 months). In COVE's booster phase, higher non-SARS-CoV-2 incidence was observed after the single booster (intensity ratio, IR = 2.38 (95% CI, 1.75, 3.25) 14 days post-boost), suggesting that booster VE estimates may underestimate the true VE against COVID-19. Our findings demonstrate the potential of off-target infections for unraveling complex biases in COVID-19 vaccine studies. Trial registration: NCT04470427, https://clinicaltrials.gov/study/NCT04470427.}, }
@article {pmid40838867, year = {2026}, author = {Major, A and Chou, J and Lam, H and Kim, KE and Turcotte, LM and Leisenring, W and Yasui, Y and Neglia, JP and Curry, M and Howell, RM and Oeffinger, KC and Hodgson, D and Nathan, PC and Armstrong, GT and Moskowitz, CS and Henderson, TO}, title = {Mortality after colorectal cancer among survivors of childhood cancer.}, journal = {Journal of the National Cancer Institute}, volume = {118}, number = {3}, pages = {545-549}, pmid = {40838867}, issn = {1460-2105}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; //American Lebanese-Syrian Associated Charities/ ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; CA55727/CA/NCI NIH HHS/United States ; CA21765//Cancer Center Support/ ; R01 CA268143/CA/NCI NIH HHS/United States ; //Memorial Sloan Kettering Cancer Center/ ; //St Jude Children's Research Hospital/ ; }, mesh = {Humans ; *Colorectal Neoplasms/mortality/epidemiology ; Female ; Male ; Adult ; SEER Program ; Middle Aged ; Child ; Adolescent ; United States/epidemiology ; *Cancer Survivors/statistics &amp; numerical data ; *Neoplasms, Second Primary/mortality/epidemiology ; Young Adult ; Child, Preschool ; Incidence ; *Survivors/statistics &amp; numerical data ; Infant ; }, abstract = {Mortality after diagnosis of colorectal subsequent malignant neoplasms (CRC-SMN) among childhood cancer survivors is understudied. Using data from the Childhood Cancer Survivor Study (CCSS) and the Surveillance, Epidemiology, and End Results (SEER) program, we compared all-cause mortality of survivors with CRC-SMN with survivors without CRC-SMN and CRC patients in the general population without a childhood cancer history. Among 25 656 childhood cancer survivors, 96 developed CRC-SMN, with 50% diagnosed before age 40 years and 19% before age 30 years. Of those diagnosed before age 40 years, 35% had no prior abdominal- or pelvic-directed radiation therapy. The cumulative incidence of CRC-SMN in CCSS survivors was 0.7% (95% CI = 0.5% to 0.9%) by age 45 years and 1.1% (95% CI = 0.8% to 1.4%) by age 50 years. There were 31 deaths after CRC-SMN. Adjusted all-cause mortality was threefold higher (hazard ratio [HR] = 3.34, 95% CI = 2.25 to 4.59) than for survivors without CRC and statistically significantly higher for survivors diagnosed younger than age 30 years compared with SEER CRC patients (HR = 2.51, 95% CI = 1.29 to 4.89).}, }
@article {pmid40839241, year = {2025}, author = {Lin, CA and Lin, C and Rhodes, CT and Moseley, MC and Wang, Y and Berger, MS}, title = {Takeaways from meta-analysis: indications of combinational treatments for glioblastoma.}, journal = {Journal of neuro-oncology}, volume = {175}, number = {3}, pages = {1199-1209}, pmid = {40839241}, issn = {1573-7373}, support = {P50CA097257//NIH/NCI/ ; }, mesh = {Humans ; *Glioblastoma/therapy/metabolism/genetics/diagnostic imaging/pathology ; *Brain Neoplasms/therapy/metabolism/genetics/diagnostic imaging/pathology ; Combined Modality Therapy ; Magnetic Resonance Imaging ; Proteomics ; Protein Processing, Post-Translational ; }, abstract = {BACKGROUND: Patients with brain cancers are diagnosed based on MRI in the clinical setting while molecular signatures offer potential therapeutic targets. The necessity to re-form molecular and imaging information motivated our meta-analysis to decipher the correlation between the MRI-classified tumor locations, gene expression, and protein signatures in GBM.<br><br>METHODS: We analyzed spatial and omics data alongside the assessment of post-translational modifications. We first utilized MRI data to classify GBM into 4 groups. We then integrated imaging groups with RNA-Seq and proteomic data to determine the association between tumor locations, gene signatures, and protein abundance. Furthermore, we scrutinized independent measurements of post-translational modifications in each group of MRI-classified GBM.<br><br>RESULTS: The coherent layer of imaging and molecular data collectively showed the dysregulation of cell cycle, ECM organization, immune infiltration or surveillance in all GBM cases regardless of tumor locations. Several neuronal and synaptic-specific genes were differentially altered, indicative of aberrant neuroactivity in GBM. These dysregulated genes and networks provided druggable targets that led to small compounds identification, possessing cytotoxicity against primary GBM and spanning histological boundaries. Our analysis also revealed lesion-specific molecular signatures in each group of GBM, suggesting pathological features uniquely in subgroups of GBM with prognostic or therapeutic potential. Moreover, alterations in post-translational modifications would be noteworthy to explore clinical applications.<br><br>CONCLUSIONS: Deliverables from our meta-analysis hold the potential to inform therapeutic intervention. Despite heterogeneity in GBM, our findings implicate new directions of emerging treatments that may be used as concomitants to chemo-, radio- or immunological therapies.}, }
@article {pmid40839355, year = {2025}, author = {McTiernan, A}, title = {Achieving Healthy Weights for Improving Breast Cancer Prognosis.}, journal = {JAMA oncology}, volume = {11}, number = {10}, pages = {1136-1138}, doi = {10.1001/jamaoncol.2025.2711}, pmid = {40839355}, issn = {2374-2445}, }
@article {pmid40839373, year = {2025}, author = {Ligibel, JA and Ballman, KV and McCall, L and Goodwin, PJ and Alfano, CM and Bernstein, V and Crane, TE and Delahanty, LM and Frank, E and Hahn, O and Hershman, DL and Hopkins, JO and Irwin, M and Mayer, EL and Minasian, L and Nebeling, L and Neuhouser, ML and Paskett, ED and Spears, PA and Stearns, V and Thomson, CA and Weiss, A and White, J and Wadden, TA and Winer, EP and Hudis, C and Partridge, AH and Carey, LA}, title = {Impact of a Weight Loss Intervention on 1-Year Weight Change in Women With Stage II/III Breast Cancer: Secondary Analysis of the Breast Cancer Weight Loss (BWEL) Trial.}, journal = {JAMA oncology}, volume = {11}, number = {10}, pages = {1194-1203}, pmid = {40839373}, issn = {2374-2445}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U10 CA180863/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Body Mass Index ; *Breast Neoplasms/pathology/therapy/complications ; Neoplasm Staging ; *Obesity/therapy/complications ; Quality of Life ; Telephone ; Treatment Outcome ; *Weight Loss ; *Weight Reduction Programs/methods ; }, abstract = {IMPORTANCE: Obesity is associated with a higher risk of recurrence, mortality, comorbidities, treatment-related adverse effects, and poor quality of life in patients with breast cancer. Scalable interventions are needed to promote weight loss in this population.<br><br>OBJECTIVE: To evaluate the impact of a remotely delivered weight loss intervention (WLI) on weight change at 1 year in patients with breast cancer and obesity and to explore factors associated with weight change.<br><br>The Breast Cancer Weight Loss trial is a phase 3, randomized clinical trial evaluating the impact of a telephone-based WLI on invasive disease-free survival and other outcomes in women with obesity and early breast cancer at 637 sites across the US and Canada. Participants were enrolled to the study between August 2016 and February 2021. Participants included women with stage II to III, ERBB2-negative breast cancer and a body mass index (BMI) of 27 or higher.<br><br>INTERVENTIONS: Participants were randomized to a 2-year, telephone-based WLI plus health education or health education alone control group.<br><br>MAIN OUTCOME AND MEASURES: The primary end point for this prespecified secondary analysis was weight change at 1 year. Weight was measured at baseline and 1 year, and changes in weight were compared between groups. Weight change was evaluated with a linear mixed-effects model including treatment group, weight over time, a time-by-group interaction, menopausal status, race and ethnicity, and hormone receptor status.<br><br>RESULTS: A total of 3180 women with breast cancer and BMI of 27 and higher were included in the study; 1591 were randomized to the WLI and 1589 to the control group. At baseline, the mean (SD) age of participants was 53.4 (10.6), and the mean (SD) BMI was 34.4 (5.6). The racial and ethnic breakdown included 406 (12.8%) Black, 231 (7.3%) Hispanic or Latino, 2906 (91.4%) non-Hispanic, and 2555 (80.3%) White participants. WLI participants lost a mean of 4.3 kg (95% CI 3.9-4.6 kg), or 4.7% (95% CI, 4.3%-5.0%) of baseline body weight at 1 year vs control participants, who gained 0.9 kg (95% CI, 0.5-1.3 kg), or 1.0% (95% CI 0.1%-1.4%) of baseline body weight (P&#x2009;<&#x2009;.001). Participants randomized to WLI experienced significant weight loss (vs control group participants) across demographic and tumor factors. WLI effect differed significantly by menopausal status, with postmenopausal participants having greater weight loss than premenopausal participants, and by race and ethnicity, with Black and Hispanic participants having less weight loss compared to other races and ethnicities.<br><br>CONCLUSIONS AND RELEVANCE: In this secondary analysis of a randomized clinical trial, a telephone-based WLI induced significant weight loss in patients with breast cancer with overweight and obesity across demographic and treatment factors. Further follow-up of the Breast Cancer Weight Loss trial will evaluate whether the WLI improves disease outcomes.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02750826.}, }
@article {pmid40841141, year = {2025}, author = {Ng, N and Molina-Molina, M and Adegunsoye, A and Borie, R and Newton, CA and Raby, B and Zhang, D and Padilla, M and Crestani, B and Horwitz, MS and Keel, S and Murray, MF and Stergachis, AB and Knight, S and Garcia, CK and Wain, LV and Raghu, G}, title = {Genetics of interstitial lung diseases: a state-of-the-art review.}, journal = {The European respiratory journal}, volume = {66}, number = {3}, pages = {}, doi = {10.1183/13993003.00788-2025}, pmid = {40841141}, issn = {1399-3003}, mesh = {Humans ; *Lung Diseases, Interstitial/genetics/diagnosis ; Genetic Predisposition to Disease ; Gene-Environment Interaction ; Risk Factors ; }, abstract = {Advancements in genetics and genomics continue to further our understanding of their contributions to the development of interstitial lung diseases (ILDs). This state-of-the-art clinical review synthesises current knowledge of the contribution of genetics when evaluating patients suspected to have ILD. We consider highly penetrant Mendelian disorders as well as common variants conferring smaller risk that act in concert with other genetic and acquired risk factors. Additionally, gene-by-environment and pharmacogenomic interactions are discussed to highlight their impact on disease course. Lastly, the approach to genetic ILDs is reviewed from available testing to future directions.}, }
@article {pmid40844776, year = {2025}, author = {Hill, JA and Pergam, SA and Halasa, NB and Kumar, D and Baden, LR and Boeckh, MJ}, title = {A Network for Advancing Prevention and Treatment of Infections Among Immunocompromised Individuals.}, journal = {JAMA network open}, volume = {8}, number = {8}, pages = {e2528383}, doi = {10.1001/jamanetworkopen.2025.28383}, pmid = {40844776}, issn = {2574-3805}, mesh = {Humans ; *Immunocompromised Host ; United States ; Clinical Trials as Topic ; Public-Private Sector Partnerships ; *Communicable Diseases/therapy ; }, abstract = {IMPORTANCE: Immunocompromised individuals are a large and growing population who are at increased risk for infectious diseases. There has and continues to be a lack of focus on clinical trials to establish the safety and efficacy of therapies for infectious diseases in immunocompromised patients. The establishment of a US-based clinical trial network to improve the study and subsequent implementation of therapies and strategies to treat and prevent infections in immunocompromised individuals would address this gap in research infrastructure and jumpstart public and private investment.<br><br>OBSERVATIONS: A national interdisciplinary meeting was convened on September 10, 2024, in Bethesda, Maryland, to discuss the outsized impact of infectious diseases in immunocompromised individuals and to identify the primary gaps and opportunities for clinical trials in this population. Approaches to achieve this goal include obtaining dedicated funding and support through public-private partnerships to establish alignment and feasibility for high-priority areas of research. This article outlines the relevance of this work; ongoing efforts to collaborate with the National Institutes of Health, US Congress, industry, and philanthropy to obtain funding for mutually beneficial outcomes; the network structure; and perspectives from clinicians, regulatory agencies, the pharmaceutical industry, and patients.<br><br>CONCLUSIONS AND RELEVANCE: There is a dearth of evidence to support the use of many therapies for infectious diseases in immunocompromised individuals, which has substantial impact at the individual and societal level. A multipronged approach to improve integration of, and funding for, rigorous research in this population into the core priorities of the public and private sectors could address important public health gaps by developing evidence-based guidance to protect a vulnerable community.}, }
@article {pmid40845137, year = {2025}, author = {Nazha, A and Elemento, O and Ahuja, S and Lam, B and Miles, M and Shouval, R and McWeeney, S and Sirhan, S and Srisuwananukorn, A and Haferlach, T}, title = {Artificial intelligence in hematology.}, journal = {Blood}, volume = {146}, number = {19}, pages = {2283-2292}, doi = {10.1182/blood.2025029876}, pmid = {40845137}, issn = {1528-0020}, mesh = {Humans ; *Hematology/methods ; *Artificial Intelligence ; *Hematologic Diseases/diagnosis/therapy ; Machine Learning ; Clinical Decision-Making ; }, abstract = {Artificial intelligence (AI) and its subdiscipline, machine learning (ML), have the potential to revolutionize health care, including hematology. The diagnosis and treatment of hematologic disorders depend on the integration of diverse data sources, such as imaging, pathology, omics, and laboratory parameters. The increasing volume and complexity of patient data have made clinical decision-making more challenging. AI/ML hold significant potential for enhancing diagnostic accuracy, risk stratification, and treatment response prediction through advanced modeling techniques. Generative AI, a recent advancement within the broader field of AI, is poised to have a profound impact on health care and hematology. Generative AI can enhance the development of novel therapeutic strategies, improve diagnostic workflows by generating high-fidelity images or pathology reports, and facilitate more personalized approaches to patient management. Its ability to augment clinical decision-making and streamline research represents a significant leap forward in the field. However, despite this potential, few AI/ML tools have been fully implemented in clinical practice due to challenges related to data quality, equity, advanced infrastructure, and the establishment of robust evaluation metrics. Despite its promise, AI implementation in hematology faces critical challenges, including bias, data quality issues, and a lack of regulatory frameworks and safety standards that keep pace with rapid technological advancements. In this review, we provide an overview of the current state of AI/ML in hematology as of 2025, identify existing gaps, and offer insights into future developments.}, }
@article {pmid40847340, year = {2025}, author = {Vu, K and Sánchez, H and Cabello, R and Hidalgo, J and Dasgupta, S and Duerr, A and Lankowski, A}, title = {Sexual behaviors and access to HIV services during the COVID-19 pandemic among cisgender men who have sex with men in Lima, Peru.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {2888}, pmid = {40847340}, issn = {1471-2458}, support = {K23MH126781/MH/NIMH NIH HHS/United States ; NIH U54CA132381//Fred Hutchinson Cancer Center Summer Undergraduate Research Program/ ; K23 MH126781/MH/NIMH NIH HHS/United States ; U54 CA132381/CA/NCI NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; NIH P30AI027757//University of Washington / Fred Hutch Center for AIDS Research/ ; D43TW009345/TW/FIC NIH HHS/United States ; D43 TW009345/TW/FIC NIH HHS/United States ; }, abstract = {BACKGROUND: The COVID-19 pandemic significantly impacted sexual behaviors, access to health services, and other factors related to HIV vulnerability among sexual and gender minority populations globally. This study investigates such changes among men who have sex with men (MSM) in Lima, Peru.<br><br>METHODS: We analyzed data from a cross-sectional survey that was conducted initially in 2018&#x2013;2019 (&#x2018;pre-pandemic&#x2019; period, n&#x2009;=&#x2009;382) and then repeated in 2020&#x2013;2021 (&#x2018;mid-pandemic&#x2019; period, n&#x2009;=&#x2009;387). The survey asked about participants&#x2019; sexual behaviors in the previous three months, including attendance of sex-on-premises venues (SOPVs) and the use of online platforms to meet partners, as well as their knowledge and behaviors related to HIV testing and prevention. We assessed for differences in sexual behaviors and HIV testing/prevention knowledge between the mid-pandemic period and the pre-pandemic period using robust Poisson regression, including in multivariable models adjusting for age and educational attainment. The mid-pandemic survey included additional questions asking about access to HIV services and changes in perceived health status during the pandemic, which we analyzed descriptively.<br><br>RESULTS: Participants in the mid-pandemic period were significantly less likely to report they had attended an SOPV, met a sex partner online, engaged in group sex, or had three or more partners in the past three months. However, the prevalence of other HIV-related sexual risk behaviors, including condomless anal sex and substance use in a sexual context, was unchanged compared to pre-pandemic. Among mid-pandemic survey participants, SOPV attendance and meeting a partner online were both associated with a range of sexual risk behaviors, similar to the relationship observed between these behaviors during the pre-pandemic period.<br><br>CONCLUSIONS: We observed relatively modest differences in the prevalence of sexual risk behaviors during, versus prior to, the COVID-19 pandemic. These findings underscore the importance of minimizing disruptions to HIV prevention and sexual health services for vulnerable populations such as MSM in Peru.<br><br>SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-025-23886-8.}, }
@article {pmid40848024, year = {2025}, author = {Shetty, NS and Gaonkar, M and Pampana, A and Patel, N and Carson, AP and Haring, B and Psaty, BM and Kooperberg, C and Boerwinkle, E and Rotter, JI and Lima, JAC and Kizer, JR and Martin, LW and Taylor, KD and Hall, ME and Fornage, M and Shah, SJ and Rich, SS and Vasan, RS and Nassir, R and Li, P and Arora, G and Arora, P}, title = {Association of Pathogenic/Likely Pathogenic Inherited Cardiomyopathy Variants With Heart Failure: A TOPMed Multiancestry Analysis.}, journal = {Mayo Clinic proceedings}, volume = {100}, number = {11}, pages = {1948-1955}, pmid = {40848024}, issn = {1942-5546}, support = {HHSN268201100037C/HL/NHLBI NIH HHS/United States ; U01 HL130114/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201800015I/HB/NHLBI NIH HHS/United States ; UL1 TR000040/TR/NCATS NIH HHS/United States ; N01 HC085081/HL/NHLBI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; 75N92020D00002/HL/NHLBI NIH HHS/United States ; N01 HC085080/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; HHSN268201500003C/HL/NHLBI NIH HHS/United States ; HHSN268201800012I/HB/NHLBI NIH HHS/United States ; HHSN268201800012C/HL/NHLBI NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; 75N92020D00005/HL/NHLBI NIH HHS/United States ; N01 HC095168/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U54 HG003067/HG/NHGRI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268201800004I/HL/NHLBI NIH HHS/United States ; 75N92022D00002/HL/NHLBI NIH HHS/United States ; UL1 TR001079/TR/NCATS NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; N01 HC085082/HL/NHLBI NIH HHS/United States ; HHSN268201800014I/HB/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; N01 HC085086/HL/NHLBI NIH HHS/United States ; 75N92020D00001/HL/NHLBI NIH HHS/United States ; N01 HC085083/HL/NHLBI NIH HHS/United States ; T32 HL007457/HL/NHLBI NIH HHS/United States ; HHSN268201800014C/HL/NHLBI NIH HHS/United States ; N01 HC095159/HL/NHLBI NIH HHS/United States ; 75N92020D00003/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92022D00004/HL/NHLBI NIH HHS/United States ; HHSN268201800003I/HL/NHLBI NIH HHS/United States ; P30 DK063491/DK/NIDDK NIH HHS/United States ; HHSN268201800007I/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201800013I/MD/NIMHD NIH HHS/United States ; N01 HC055222/HL/NHLBI NIH HHS/United States ; HHSN268201600033C/ES/NIEHS NIH HHS/United States ; N01 HC085079/HL/NHLBI NIH HHS/United States ; UL1 TR001420/TR/NCATS NIH HHS/United States ; 75N92020D00004/HL/NHLBI NIH HHS/United States ; R01 HL163852/HL/NHLBI NIH HHS/United States ; 75N92020D00007/HL/NHLBI NIH HHS/United States ; N01 HC095163/HL/NHLBI NIH HHS/United States ; HHSN268201800011C/HL/NHLBI NIH HHS/United States ; R01 HL163081/HL/NHLBI NIH HHS/United States ; 75N92022D00003/HL/NHLBI NIH HHS/United States ; HHSN268201500003I/HL/NHLBI NIH HHS/United States ; 75N92021D00006/HL/NHLBI NIH HHS/United States ; 75N92022D00005/HL/NHLBI NIH HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; HHSN268201800010I/HB/NHLBI NIH HHS/United States ; 75N92020D00006/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; N01 HC095162/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; HHSN268201800011I/HB/NHLBI NIH HHS/United States ; HHSN268201800005I/HL/NHLBI NIH HHS/United States ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; 75N92022D00001/HL/NHLBI NIH HHS/United States ; HHSN268201800006I/HL/NHLBI NIH HHS/United States ; R01 HL160982/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; *Heart Failure/genetics/epidemiology ; Female ; Male ; Middle Aged ; Retrospective Studies ; *Cardiomyopathies/genetics/epidemiology/complications ; United States/epidemiology ; Adult ; Aged ; Genetic Predisposition to Disease ; Prevalence ; }, abstract = {OBJECTIVE: To evaluate the prevalence of pathogenic/likely pathogenic inherited cardiomyopathy variants and their association with heart failure in the (TOPMed) TransOmic for Precision of Medicine cohorts.<br><br>METHODS: A retrospective cohort study using the TOPMed cohorts, including multi-ancestry US adults (&#x2265;18 years of age) with sequencing data, was conducted. Pathogenic/likely pathogenic inherited cardiomyopathy variant carrier status was determined based on ClinVar variants classified with two or more stars of evidence. Individuals without pathogenic/likely pathogenic variants were used as the reference group. The primary outcome was heart failure , adjudicated by an expert panel. Cox proportional hazards models assessed the association between carrier status and heart failure risk, adjusting for sex, study cohort, coronary artery disease, and genetic ancestry. Age was used as the timescale to account for the effect of variants since birth, and interval censoring was used to handle the uncertainty in the timing of heart failure events.<br><br>RESULTS: Among 30,977 individuals (median age, 61.0 years; 71.3% female; 37.0% non-European ancestry), 229 (0.7%) were identified as pathogenic/likely pathogenic inherited cardiomyopathy variant carriers. There were 3,298 events of heart failure (35 in carriers and 3,263 in non-carriers). The heart failure incidence rate was higher in variant carriers (2.06 per 1000 person-years) compared with noncarriers (1.40 per 1000 person-years), with an adjusted hazard ratio of 1.68 (95% CI, 1.29-2.22).<br><br>CONCLUSION: Approximately 1 in 140 US adults carry a cardiomyopathy variant, which increases heart failure risk. Targeted genetic screening may facilitate early identification and preventive interventions to reduce heart failure risk in carriers.}, }
@article {pmid40848054, year = {2025}, author = {Yang, J and Roy, I and Hunter, H}, title = {Prehabilitation for muscle wasting in cancer: do definitions matter?.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {9}, pages = {807}, pmid = {40848054}, issn = {1433-7339}, mesh = {Humans ; *Neoplasms/complications ; Quality of Life ; Body Composition ; Frailty/etiology ; *Preoperative Exercise ; *Muscular Atrophy/etiology/rehabilitation ; *Exercise Therapy/methods ; Aged ; }, abstract = {Frailty in older patients with cancer has been associated with functional impairments, decline in quality of life, and increased risk of mortality. There is growing interest in prehabilitation interventions designed to optimize function prior to cancer treatment to mitigate functional decline and to optimize post-treatment outcomes. This review aims to describe the heterogeneity in muscle wasting definitions, modalities used for body composition analysis, and functional outcomes investigated in exercise prehabilitation trials in cancer patients. Defining muscle loss among patients with cancer is needed to better diagnose, treat, and prevent functional decline. Utilization of a consensus on definitions for muscle wasting syndromes is critical to evaluate the efficacy of prehabilitation and exercise interventions in cancer care.}, }
@article {pmid40849364, year = {2025}, author = {O'Connor, TE and Lin, C and Roloff, GW and Zhang, A and Miller, K and Aldoss, I and Kopmar, NE and Dekker, SE and Gupta, VK and Jeyakumar, N and Muhsen, IN and Valtis, Y and Ahmed, N and Sutherland, K and Dykes, KC and Ahmed, M and Chen, E and Zambrano, H and Bradshaw, D and Mercadal, S and Schwartz, M and Tracy, S and Connor, MP and Kubiak, M and Mukherjee, A and Majhail, N and Battiwalla, M and Mountjoy, L and Malik, SA and Mathews, J and Shaughnessy, P and Blunk, B and Logan, AC and Ladha, A and Advani, AS and Stefan, M and Guzowski, C and Hoeg, RT and Hilal, T and Moore, J and O'Dwyer, KM and Hill, LC and Sasine, J and Oliai, C and Solh, MM and Lee, CJ and Kota, VK and Koura, D and Kumaran, MV and Leonard, JT and Frey, NV and Park, JH and Luskin, MR and Bachanova, V and Galal, A and Pullarkat, V and Bishop, MR and Stock, W and Cassaday, RD and Shah, BD and Faramand, R and Muffly, LS and Tsai, SB and Dholaria, B}, title = {The impact of social determinants of health on outcomes of brexucabtagene autoleucel in adults with relapsed/refractory B-cell acute lymphoblastic leukemia.}, journal = {Bone marrow transplantation}, volume = {60}, number = {11}, pages = {1465-1471}, pmid = {40849364}, issn = {1476-5365}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Adult ; Middle Aged ; Retrospective Studies ; *Social Determinants of Health ; Aged ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/mortality ; *Immunotherapy, Adoptive/methods ; Recurrence ; Young Adult ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy ; Adolescent ; }, abstract = {Brexucabtagene autoleucel (brexu-cel) is a chimeric antigen receptor T (CAR T) cell therapy approved for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We studied the impact of social determinants of health (SDoH) on outcomes of adults with B-ALL receiving brexu-cel. This retrospective analysis included adults (≥18 years) with R/R B-ALL treated with brexu-cel between 2021 and 2023. Cox proportional hazards models evaluated the association of race, ethnicity, and SDoH with progression-free survival (PFS) and overall survival (OS). 189 patients received brexu-cel and 57% were male. 55% were non-Hispanic White, 30% Hispanic, 7% non-Hispanic Black, 6% Asian/Pacific Islander, and 2% other/unknown. 43% were referred from private/community-based practices and 35% lived 50 miles or greater from the CAR T center. Health insurance included public (47%) and private (41%). 31% had a high social deprivation index (SDI, 76-99th percentile). Black race was associated with worse OS (HR 3.48; 95% CI 1.01-12.03). There was no difference in PFS (HR 1.03, 95% CI 0.50-2.10) or OS (HR 1.43; 95% CI 0.56-3.65) in Hispanic patients. Outcomes appear independent of SDoH and SDoH did not impact OS. We observed comparable outcomes to non-Hispanic patients.}, }
@article {pmid40849910, year = {2025}, author = {Weis, AM and Bauer, KM and Tang, WW and Stephen-Victor, E and Bell, R and Brown, DG and Ekiz, HA and Tran, V and Klag, KA and Swanson, EA and Barrios, L and Harwood, M and Hill, JH and Ost, KS and Gigic, B and Schneider, M and Ose, J and Hardikar, S and Toriola, AT and Shibata, D and Li, CI and Figueiredo, JC and Byrd, DA and Siegel, EM and Arnolds, K and Lozupone, C and Ulrich, CM and O'Connell, RM and Stephens, WZ and Round, JL}, title = {A capsular polysaccharide from a healthy human microbiota member activates a Lag-3-NK cell axis to restrain colon cancer and augment immunotherapy.}, journal = {Cell reports}, volume = {44}, number = {9}, pages = {116172}, doi = {10.1016/j.celrep.2025.116172}, pmid = {40849910}, issn = {2211-1247}, support = {F32 CA243501/CA/NCI NIH HHS/United States ; K22 CA289144/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Killer Cells, Natural/immunology/drug effects ; Animals ; *Immunotherapy/methods ; Mice ; *Colonic Neoplasms/immunology/therapy/microbiology/pathology ; Lymphocyte Activation Gene 3 Protein ; *Antigens, CD/metabolism ; Female ; Mice, Inbred C57BL ; *Polysaccharides, Bacterial/pharmacology ; *Microbiota ; Male ; Gastrointestinal Microbiome ; }, abstract = {Colorectal cancer (CRC) is increasing globally, making identification of preventative measures necessary. Transplantation of the microbiota from CRC and non-CRC patients into mice demonstrates that non-diseased individuals possess organisms that reduce tumor formation and highlights Bacteriodes uniformis as protective. B. uniformis is reduced in humans with CRC, and proactive treatment with B. uniformis slows tumor growth in mice. Natural killer (NK) cells, but not T cells, are required for B. uniformis-mediated protection. CRC is recalcitrant to immunotherapies; however, addition of B. uniformis restores response to α-CTLA-4 treatment in an NK cell-dependent manner. We report that high Lag-3 expression is associated with greater survival in CRC patients and that B. uniformis-mediated protection is reliant on Lag-3 in innate cells. Induction of NK cell activity and reduced tumor growth is dependent on a specific B. uniformis capsular polysaccharide. Thus, healthy individuals possess tumor suppressor microbes that prevent cancer development and can be harnessed therapeutically.}, }
@article {pmid40850015, year = {2025}, author = {Kenny, A and van Duijn, J and Dintwe, O and Heptinstall, J and Burnham, R and Sawant, S and Zhang, L and Mielke, D and Khuzwayo, S and Omar, FL and Stanfield-Oakley, S and Keyes, T and Dunn, B and Goodman, D and Fong, Y and Benkeser, D and Zou, R and Hural, J and Hyrien, O and Juraska, M and Luedtke, A and van der Laan, L and Giorgi, EE and Magaret, C and Carpp, LN and Pattacini, L and van de Kerkhof, T and Korber, B and Willems, W and Fisher, LH and Schuitemaker, H and Swann, E and Kublin, JG and Pau, MG and Buchbinder, S and Tomaka, F and Nijs, S and Lavreys, L and Gelderblom, HC and Corey, L and Mngadi, K and Gray, GE and Borducchi, E and Hendriks, J and Seaton, KE and Zolla-Pazner, S and Barouch, DH and Ferrari, G and De Rosa, SC and McElrath, MJ and Andersen-Nissen, E and Stieh, DJ and Tomaras, GD and Gilbert, PB and , }, title = {Corrigendum to 'Immune correlates analysis of the Imbokodo (HVTN 705/HPX2008) efficacy trial of a mosaic HIV-1 vaccine regimen evaluated in Southern African people assigned female sex at birth: a two-phase case-control study'. EBioMedicine 2024;108: 105320.}, journal = {EBioMedicine}, volume = {119}, number = {}, pages = {105874}, doi = {10.1016/j.ebiom.2025.105874}, pmid = {40850015}, issn = {2352-3964}, support = {UM1 AI068635/AI/NIAID NIH HHS/United States ; }, }
@article {pmid40852372, year = {2025}, author = {Huang, TJ and Liu, Z and McKeague, IW}, title = {Post-selection inference for high-dimensional mediation analysis with survival outcomes.}, journal = {Scandinavian journal of statistics, theory and applications}, volume = {52}, number = {2}, pages = {756-776}, pmid = {40852372}, issn = {0303-6898}, support = {R01 AG062401/AG/NIA NIH HHS/United States ; R01 AG086379/AG/NIA NIH HHS/United States ; }, abstract = {It is of substantial scientific interest to detect mediators that lie in the causal pathway from an exposure to a survival outcome. However, with high-dimensional mediators, as often encountered in modern genomic data settings, there is a lack of powerful methods that can provide valid post-selection inference for the identified marginal mediation effect. To resolve this challenge, we develop a post-selection inference procedure for the maximally selected natural indirect effect using a semiparametric efficient influence function approach. To this end, we establish the asymptotic normality of a stabilized one-step estimator that takes the selection of the mediator into account. Simulation studies show that our proposed method has good empirical performance. We further apply our proposed approach to a lung cancer dataset and find multiple DNA methylation CpG sites that might mediate the effect of cigarette smoking on lung cancer survival.}, }
@article {pmid40853264, year = {2025}, author = {Bolier, M and Pluimakers, VG and Broer, L and Neggers, SJCMM and de Winter, DTC and Wang, F and Baedke, JL and Uitterlinden, AG and Petrykey, K and Kremer, LCM and Loonen, JJ and Louwerens, M and van der Pal, HJ and Feijen, ELAM and Oeffinger, KC and Howell, RM and Chow, EJ and Leisenring, WM and Gramatges, MMM and Morton, LM and Robison, LL and Hudson, MM and Ness, KK and Sapkota, Y and Armstrong, GT and Bhatia, S and Yasui, Y and van den Heuvel-Eibrink, MM}, title = {Genetic Contribution to Treatment-Related Dyslipidemia in Adult Survivors of Childhood Cancer: Findings from the CCSS, SJLIFE, and DCCSS-LATER Cohorts.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {11}, pages = {2068-2076}, pmid = {40853264}, issn = {1538-7755}, support = {U24 CA055727/CA/NCI NIH HHS/United States ; U01 CA301480/CA/NCI NIH HHS/United States ; DCOG2011-5027 and UVA2012-5517//KWF Kankerbestrijding (DCS)/ ; U24 CA55727//National Cancer Institute (NCI)/ ; NA//ODAS Stichting (ODAS Foundation)/ ; P30 CA21765//National Cancer Institute (NCI)/ ; U01 CA195547/CA/NCI NIH HHS/United States ; SKION LATER registry. 2006-2010//Stichting Kinderen Kankervrij (KiKa)/ ; NA//Division of Intramural Research (DIR)/ ; P30 CA021765/CA/NCI NIH HHS/United States ; NA//American Lebanese Syrian Associated Charities (ALSAC)/ ; }, mesh = {Humans ; *Dyslipidemias/genetics/chemically induced/epidemiology ; *Cancer Survivors/statistics &amp; numerical data ; Male ; Female ; Adult ; *Neoplasms/therapy ; Genome-Wide Association Study ; Child ; Cohort Studies ; Adolescent ; }, abstract = {BACKGROUND: Dyslipidemia can occur as a long-term side effect of childhood cancer treatment. The difference in prevalence among children receiving comparable treatment suggests a role for genetic variation. We conducted the first genome-wide association study on dyslipidemia in a large childhood cancer survivor cohort, using three additional cohorts for replication.<br><br>METHODS: Discovery analysis was performed in the original Childhood Cancer Survivor Study (CCSS) cohort (N = 4,332). Replication analyses were carried out in the CCSS expansion (N = 2,212), St. Jude Lifetime (N = 2,829), and Dutch Childhood Cancer Survivor Study (DCCSS-LATER) (N = 1,814) cohorts. In the CCSS cohorts, dyslipidemia was defined as Common Terminology Criteria for Adverse Events grade 2 self-reported high cholesterol or high triglycerides, whereas in the St. Jude Lifetime and DCCSS-LATER cohorts, it was assessed by serum lipid measurements. Association analysis was performed in the entire cohort and stratified by cancer treatment.<br><br>RESULTS: The initial discovery analysis yielded one genome-wide significant (p < 5 &#xd7; 10-8) and 16 suggestive (p < 5 &#xd7; 10-6) loci associated with dyslipidemia risk. Of these, one genome-wide significant and eight suggestive loci with biological plausibility were selected for replication analysis, but none replicated. Additionally, treatment-stratified analysis revealed six significant (p < 5 &#xd7; 10-8) loci, none of which replicated in meta-analysis.<br><br>CONCLUSIONS: Further research with clinically assessed data and larger sample sizes is needed to explore the genetic contributions to dyslipidemia risk in childhood cancer survivors.<br><br>IMPACT: The establishment of larger, internationally collaborative consortia of childhood cancer survivors is critical for generating more robust findings, which will help the identification of those survivors at risk for dyslipidemia and subsequently cardiovascular disease.}, }
@article {pmid40854613, year = {2025}, author = {Ferris, RL and Leidner, RS and Chung, CH and Jimeno, A and Lee, SM and Sukari, A and Nieva, JJ and Grilley-Olson, JE and Redman, R and Wong, SJ and Villaflor, VM and Misleh, J and Finckenstein, FG and Chou, J and Gastman, B and Fiaz, R and Catlett, M and Yi, M and Cohen, EEW}, title = {Efficacy and safety of one-time autologous tumor-infiltrating lymphocyte cell therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {8}, pages = {}, pmid = {40854613}, issn = {2051-1426}, mesh = {Humans ; Male ; Female ; Middle Aged ; *Lymphocytes, Tumor-Infiltrating/immunology/transplantation ; *Squamous Cell Carcinoma of Head and Neck/therapy/immunology/pathology ; Aged ; *Head and Neck Neoplasms/therapy/immunology/pathology ; *Neoplasm Recurrence, Local/therapy/immunology ; Adult ; Neoplasm Metastasis ; Treatment Outcome ; }, abstract = {BACKGROUND: Recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) has a high recurrence rate after first-line immunotherapy or chemoimmunotherapy. The presence of a high density of tumor-infiltrating lymphocytes (TILs) in HNSCC tumors was shown to be associated with improved clinical outcomes. One-time autologous TIL cell therapy was evaluated in patients with recurrent and/or metastatic HNSCC.<br><br>METHODS: C-145-03 (NCT03083873) was a phase 2 study of TIL in patients with recurrent and/or metastatic HNSCC assigned to 1 of 4 treatment cohorts: cohort 1, non-cryopreserved TIL; cohort 2, cryopreserved lifileucel (22-day manufacturing); cohort 3, cryopreserved lifileucel (16-day manufacturing); cohort 4, cryopreserved LN-145-S1 programmed cell death protein-1 (PD-1) selected. Patients underwent tumor resection for TIL generation. After preparative non-myeloablative lymphodepletion, patients received a single infusion of TIL followed by interleukin-2 (IL-2) infusion(s). The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation Criteria for Solid Tumors (RECIST) V.1.1. Secondary endpoints were investigator-assessed duration of response (DOR), disease control rate (DCR), progression-free survival, overall survival, and incidence of treatment-emergent adverse events.<br><br>RESULTS: Overall, 53 patients received TIL: cohort 1 (n=8), cohort 2 (n=17), cohort 3 (n=16), cohort 4 (n=12). Median age was 57 years and most patients were males (87%; 46/53) with stage IV disease (98%; 52/53). Patients had a median of two prior lines of systemic therapy; 87% (46/53) of patients had prior anti-PD-1/programmed cell death ligand-1 therapy and 72% (38/53) had prior chemotherapy. The ORR was 11% (6/53) with six patients achieving partial response (cohort 1, n=3; cohort 2, n=1; cohort 4, n=2). At median follow-up of 17.9 months, the median DOR was 7.6 months. The DCR was 76% (40/53); 64% (34/53) of patients had stable disease. The safety profile was consistent with known toxicities associated with non-myeloablative lymphodepletion and IL-2 administration.<br><br>CONCLUSIONS: This study demonstrated the feasibility of consistently generating sufficient TIL from HNSCC tumors. Results from this study suggest TIL cell therapy may serve as a potential treatment option for patients with HNSCC and support further development, including TIL cell therapy combined with immune checkpoint inhibitors or other agents or with other TIL products.<br><br>TRIAL REGISTRATION NUMBER: NCT03083873.}, }
@article {pmid40854792, year = {2025}, author = {Naik, A and Kanzaria, A and Chen, X and Kaur, N and Ho, CJ and Smith, SD and Gopal, AK and Shadman, M and Naresh, KN}, title = {Digital pathology and image analysis of p53 biomarker in lymphomas using two algorithms: correlation with genotype and visual inspection.}, journal = {Journal of clinical pathology}, volume = {78}, number = {11}, pages = {792-797}, doi = {10.1136/jcp-2025-210280}, pmid = {40854792}, issn = {1472-4146}, mesh = {Humans ; *Algorithms ; *Tumor Suppressor Protein p53/genetics/analysis/metabolism ; *Biomarkers, Tumor/genetics/analysis ; Immunohistochemistry ; Genotype ; *Lymphoma/genetics/pathology/metabolism ; *Image Interpretation, Computer-Assisted/methods ; Mutation ; Predictive Value of Tests ; Reproducibility of Results ; }, abstract = {p53 immunohistochemistry (IHC) is widely used as a rapid surrogate for detecting TP53 mutations, with TP53 mutations being a key biomarker for poor outcomes in lymphomas. We developed two algorithms using digital quantification tools to assess p53 expression from whole slide images of 77 lymphoma samples. An experienced pathologist visually evaluated the p53 slides, classifying cases as likely wild-type or mutated TP53 genotype. We correlated the results of the algorithms and visual inspection with the actual TP53 genotype. For cases with p53 overexpression (likely missense mutations), the algorithms achieved 86.7% sensitivity and 98.2% specificity (visual inspection: 80% and 95.2%). For cases with reduced p53 expression (likely 'other' mutations), the algorithms showed 92.7% sensitivity and 100% specificity (visual inspection: 40% and 95.8%). This study demonstrates that combining digital pathology with digital quantification tools-based algorithms can reliably predict TP53 genotype from p53 IHC patterns, with comparable or slightly superior performance to an experienced pathologist.}, }
@article {pmid40857002, year = {2025}, author = {Bhatt, NS and Voutsinas, J and Winters, M and Leisenring, WM and Ballard, S and Jenssen, K and Baker, KS}, title = {Work Status, Absenteeism, Presenteeism, and Quality of Life in Young Adult Cancer Survivors.}, journal = {JAMA network open}, volume = {8}, number = {8}, pages = {e2528882}, pmid = {40857002}, issn = {2574-3805}, mesh = {Humans ; *Quality of Life/psychology ; Male ; Female ; Adult ; *Cancer Survivors/psychology/statistics &amp; numerical data ; Cross-Sectional Studies ; *Absenteeism ; Young Adult ; *Presenteeism/statistics &amp; numerical data ; Adolescent ; *Neoplasms/psychology ; Unemployment/statistics &amp; numerical data/psychology ; *Employment/statistics &amp; numerical data/psychology ; Washington ; }, abstract = {IMPORTANCE: Current literature lacks information on the association between the work status and performance of young adult cancer survivors and their quality of life (QOL).<br><br>OBJECTIVE: To assess self-reported work status, missed time at work (absenteeism), and performance (presenteeism) and their associations with QOL among young adult cancer survivors.<br><br>This cross-sectional survey study was performed from October 18, 2020, to September 17, 2022, at a single cancer center in Seattle, Washington. Participants included young adult cancer survivors (aged 18 to 39 years at diagnosis) who were 1 year or more from completion of cancer therapy. Data were analyzed from May 1, 2023, to February 1, 2025.<br><br>EXPOSURES: Cancer therapy.<br><br>MAIN OUTCOMES AND MEASURES: Unemployment rate compared with the age-, sex-, and calendar year-matched general population; standardized absolute and relative absenteeism and presenteeism scores; standardized scores for domains of anxiety, depression, physical function, fatigue, sleep disturbance, pain, social role, and cognition; and adjusted linear regressions to study factors associated with higher QOL scores.<br><br>RESULTS: A total of 198 survivors, with a median age at diagnosis of 31 (IQR, 26-35) years and a median age at survey of 39 (IQR, 35-44) years were included (142 [71.7%] female). The unemployment rate (14 [7.1%]) did not differ from that of the general population (4.7%) (P&#x2009;=&#x2009;.13). Compared with employed survivors, unemployed survivors reported significantly higher depression scores (coefficient, 5.11; 95% CI, 0.92-9.30) and lower scores for satisfaction with social roles and activities (coefficient, -6.59; 95% CI, -11.34 to -1.84) and physical function (coefficient, -6.63; 95% CI, -11.38 to -1.87). Higher absolute presenteeism score was associated with lower scores for anxiety (coefficient, -0.19; 95% CI, -0.26 to -0.11), depression (coefficient, -0.17; 95% CI, -0.24 to -0.10), fatigue (coefficient, -0.20; 95% CI, -0.30 to -0.10), pain interference (coefficient, -0.11; 95% CI, -0.21 to -0.02), and sleep disturbance (coefficient, -0.12; 95% CI, -0.21 to -0.03) and higher scores for physical function (coefficient, 0.08; 95% CI, 0.008-0.17), cognitive function (coefficient, 0.19; 95% CI, 0.11-0.27), and satisfaction in social roles and activities scores (coefficient, 0.16; 95% CI, 0.08-0.24). Additionally, a higher absolute absenteeism score was associated with a higher anxiety (coefficient, 0.03; 95% CI, 0.004-0.07) and lower cognitive function (coefficient, -0.04; 95% CI, -0.07 to -0.004).<br><br>CONCLUSIONS AND RELEVANCE: In this cross-sectional study of young adult cancer survivors, associations were found between survivors' self-reported work status and performance and their QOL affecting their mental, physical, and social health. These findings call for the development of effective communication strategies with employers to balance work expectations with survivors' treatment-related complications to achieve better performance and in turn higher QOL.}, }
@article {pmid40857092, year = {2025}, author = {Nagana Gowda, GA and Zhu, W and Pascua, V and McMillen, T and Tian, R and Raftery, D}, title = {Identification and Distribution of the Dietary Antioxidant Ergothioneine in Humans and Animal Models Combining NMR, RANSY, and MS Methods.}, journal = {Analytical chemistry}, volume = {97}, number = {35}, pages = {19313-19320}, pmid = {40857092}, issn = {1520-6882}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 AR074990/AR/NIAMS NIH HHS/United States ; R01 GM138465/GM/NIGMS NIH HHS/United States ; P30 DK035816/DK/NIDDK NIH HHS/United States ; P30 DK056350/DK/NIDDK NIH HHS/United States ; P30 AG013280/AG/NIA NIH HHS/United States ; }, mesh = {*Ergothioneine/analysis/blood/metabolism ; Animals ; Humans ; Mice ; *Antioxidants/analysis/metabolism ; Mass Spectrometry ; Magnetic Resonance Spectroscopy ; Erythrocytes/chemistry ; Male ; Chromatography, Liquid ; }, abstract = {Ergothioneine (ERG), a unique, naturally occurring antioxidant of dietary origin, is gaining increasing attention due to its crucial roles in human health and diseases. Despite its significance, ERG is rarely detected in biospecimens by mass spectrometry (MS) and, to date, has not been characterized by nuclear magnetic resonance (NMR) spectroscopy, two widely used analytical techniques in metabolomics. In this study, we investigated human plasma, whole blood (WB), and red blood cells (RBC), as well as mouse blood and tissues, combining NMR, LC-MS, and ratio analysis techniques. The results demonstrate the ability of simple 1D [1]H NMR to routinely identify and quantify ERG in various biological samples. The levels of ERG vary widely and depend on the type of biological sample, with human RBC exhibiting remarkably high concentrations, often exceeding 1.5 mM. The average levels of ERG in human plasma, WB, and RBC were in ratios of 1:70:140, respectively. Moreover, ERG levels showed a linear correlation between plasma and WB (R[2] = 0.59), plasma and RBC (R[2] = 0.75), and WB and RBC (R[2] = 0.98). In mice, ERG levels exhibit a distinct whole-body distribution, with average levels in the mouse skeletal muscle, brain, heart, kidney, and liver in ratios of 0:1:10:35:45, respectively. The demonstration of surprisingly high levels of ERG in biological samples using [1]H NMR opens new avenues for its analysis using both NMR and MS methods to explore its roles in human health and diseases, as part of routine global or targeted metabolomics studies.}, }
@article {pmid40857443, year = {2025}, author = {O'Connor, TM and Garza, T and Alam, U and Vadathya, AK and Moreno, JP and Beltran, A and Haidar, S and Haidar, N and Hughes, SO and Thompson, D and Musaad, SMA and Baranowski, T and Mendoza, JA and Young, J and Sano, A and Veeraraghavan, A}, title = {The feasibility of passively tracking children's TV viewing and mobile device use in naturalistic settings.}, journal = {Behaviour &amp; information technology}, volume = {}, number = {}, pages = {}, pmid = {40857443}, issn = {0144-929X}, support = {P01 HD109876/HD/NICHD NIH HHS/United States ; R01 DK113269/DK/NIDDK NIH HHS/United States ; }, abstract = {Research on children's technology and digital media (TDM) is hampered by a lack of robust approaches for assessing TDM use. This study assessed the feasibility of passively measuring children's TV screens and mobile devices (TDM) in a naturalistic setting. In the three-day feasibility study, FLASH-TV was set up on one to two TVs the child (5-12 year olds) typically used in the home (n=20). Children's mobile device use was assessed with either the Chronicle App or ScreenTime screenshots. Parents completed three TDM diaries. An exit interview with the parent explored their perceptions of the assessments and the child's TDM use report. Complete data were obtained on 86.7% of days for passive assessment of TV viewing and 84.3% of days for mobile device use. Fifteen parents reviewed complete TDM use reports for their child, with most stating the reports appeared correct for TV (80%) and mobile device (80%). Almost two-thirds had no concerns about having the FLASH-TV installed in their home, while some reported issues about feeling observed. Parents described high burden and frustration with the TDM diaries. Data provided preliminary evidence that passive measurement is feasible for assessing children's TV and mobile device use, with reduced burden for parents.}, }
@article {pmid40857688, year = {2025}, author = {Orellana, MA and Pike, M and Katz, R and Robinson, W and Doll, KM}, title = {Risk Factors Impacting Endometrial Thickness Visibility and Information Availability in Black Patients.}, journal = {Journal of women's health (2002)}, volume = {34}, number = {12}, pages = {1472-1483}, doi = {10.1177/15409996251371097}, pmid = {40857688}, issn = {1931-843X}, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Black or African American/statistics &amp; numerical data ; *Endometrial Neoplasms/diagnostic imaging/ethnology/diagnosis ; *Endometrium/diagnostic imaging/pathology ; Hysterectomy ; Retrospective Studies ; Risk Factors ; Ultrasonography/methods ; }, abstract = {Background: Black patients experience worse endometrial cancer outcomes compared to white patients. Endometrial thickness (ET) measures from transvaginal ultrasound (TVUS) are used in diagnostic triage to determine if further endometrial tissue sampling is needed. However, recent work suggests that TVUS may disproportionately underdiagnose Black patients and those over 60 years old, contributing to Black patients' lower survival. Our study aimed to identify risk factors that impact ET measurement quality [visibility, missing data] from TVUS and result in nondiagnostic TVUS results. Methods: A retrospective analysis was conducted in a cohort of Black patients undergoing hysterectomy from 2014 to 2020. ET visibility documentation was categorized as visible or "compromised" (partially visible or nonvisible). The presence or absence of endometrial information was also assessed. Results: Of 2,705 patients with ultrasound information, 78% (N = 1,838) had documented ET visibility. Of those with visibility, 1,301 (71%) had complete ET visibility. Among those with compromised visibility (n = 537), 271 (50.5%) had partially visible ET, while 266 (49.5%) had nonvisible ET. Significant risk factors associated with compromised visibility included an enlarged uterus (OR: 2.89, 95% CI: 2.32-3.61) and fibroids (OR: 3.78, 95% CI: 1.94-7.39). Of 2,032 patients with ultrasound reports, 9.5% (N = 194) lacked endometrial information. Fibroids (OR: 1.81, 95% CI: 1.19-2.76) and enlarged uterus (OR: 2.61, 95% CI: 1.53-4.45) were also significantly associated with missing endometrial information. Conclusion: These findings suggest that a substantial proportion of TVUS examinations may not yield definitive data for diagnostic triage in Black women, potentially contributing to diagnostic delays and worse survival. Improved diagnostic approaches are needed in this population.}, }
@article {pmid40858099, year = {2025}, author = {Oehler, VG and Walter, RB}, title = {Biology-Directed Therapy for Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangements.}, journal = {NEJM evidence}, volume = {4}, number = {9}, pages = {EVIDe2500196}, doi = {10.1056/EVIDe2500196}, pmid = {40858099}, issn = {2766-5526}, }
@article {pmid40858972, year = {2025}, author = {Kendra, KL and Bellasea, SL and Eroglu, Z and Hu-Lieskovan, S and Campbell, KM and Carson, WE and Wada, DA and Plaza, JA and Sosman, JA and In, GK and Ikeguchi, A and Hyngstrom, J and Brohl, AS and Khushalani, NI and Markowitz, J and Negrea, G and Kasbari, S and Doolittle, GC and Swami, U and Roberts, T and Mathew, BN and Medina, E and Baselga-Carretero, I and Gonzalez, CR and Garcilazo, IP and Vega-Crespo, A and Chen, JM and Naser Al-Deen, N and Patel, SP and Sharon, E and Moon, J and Wu, MC and Ribas, A}, title = {Publisher Correction: Anti-PD-1 therapy in unresectable desmoplastic melanoma: the phase 2 SWOG S1512 trial.}, journal = {Nature medicine}, volume = {31}, number = {11}, pages = {3933}, doi = {10.1038/s41591-025-03975-2}, pmid = {40858972}, issn = {1546-170X}, }
@article {pmid40859413, year = {2025}, author = {Lu, G and Han, F and Wang, Y and Yuan, C and Zhu, Q and Xia, T and Chen, L and Dong, X and Ding, Y and Xiao, W and Zhang, Y and Pan, J and Xu, H and Chen, W and Tu, B and Li, W and Wang, F and Gong, W and Hu, L}, title = {Src Reduces Neutrophil Extracellular Traps Generation and Resolves Acute Organ Damage.}, journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)}, volume = {12}, number = {41}, pages = {e06028}, pmid = {40859413}, issn = {2198-3844}, support = {82070668//National Natural Science Foundation/ ; 82241043//National Natural Science Foundation/ ; 82270680//National Natural Science Foundation/ ; 82270679//National Natural Science Foundation/ ; 82400763//National Natural Science Foundation/ ; BK20240028//Natural Science Foundation of Jiangsu Province/ ; BK20240500//Natural Science Foundation of Jiangsu Province/ ; ZD2022011//The Medical research Project of Jiangsu Provincial Health Commission/ ; YZ2022080//Yangzhou key research and development plan/ ; YZ2022207//Yangzhou Policy guidance Program/ ; SZS2023001//Suzhou Innovation Platform Construction Projects- Municipal Key Laboratory Construction/ ; }, mesh = {*Extracellular Traps/metabolism ; Animals ; Humans ; *Neutrophils/metabolism ; Mice ; *src-Family Kinases/metabolism ; Reactive Oxygen Species/metabolism ; *Pancreatitis/metabolism ; *Sepsis/metabolism ; Male ; Mice, Inbred C57BL ; }, abstract = {Neutrophil extracellular traps (NETs) are key factors mediating acute inflammatory injury. However, the underlying mechanisms and potential therapeutic targets remain unclear. Previous results suggest Src may be involved in regulating the NETs formation. Here, Src is found activated in the NETs model in vitro, in the murine- and human-derived neutrophils (acute pancreatitis and sepsis). Moreover, p-Src expression correlates with the clinical prognosis of acute pancreatitis and sepsis patients. Meanwhile, the inhibition of Src activity (gene silencing or inhibitors) inhibits NETs formation in vitro. Mechanistically, Src directly activates RAF1 by regulating phosphorylation at the Ser 621 site and mediates the RAF/MEK/ERK pathway, thereby affecting the intracellular ROS production. Alternatively, Src activates the RAF/MEK/ERK pathway by mediating PKC phosphorylation. In vivo, neutrophil Src - specific defect significantly reduces acute inflammatory response, organ damage, and the NETs formation in damaged tissue. Eventually, Src inhibitors are used and validated their pharmacological effects. These results identify Src as a key mediator in intracellular ROS production, NETs formation, and acute organ injury. Hence, Src inhibition may represent a promising therapeutic strategy for treating acute organ injury.}, }
@article {pmid40860163, year = {2025}, author = {Westover, T and Walsh, MP and Abdelhamed, S and Xiong, E and Ma, J and Song, G and Thomas, ME and Umeda, M and Maciaszek, JL and Wong, JC and Wintering, A and Wang, L and Emanuel, PD and Loh, ML and Tasian, SK and Stieglitz, E and Schwartz, JR and Shannon, KM and Klco, JM}, title = {Genomic landscape and clonal architecture in pediatric myeloid neoplasms with chromosome 7 deletions.}, journal = {Blood neoplasia}, volume = {2}, number = {2}, pages = {100093}, pmid = {40860163}, issn = {2950-3280}, support = {R01 CA216352/CA/NCI NIH HHS/United States ; R01 HL144653/HL/NHLBI NIH HHS/United States ; }, }
@article {pmid40863730, year = {2025}, author = {Lai, Y-T and Dingens, AS and DeMouth, M and Helmold Hait, S and O'Dell, S and Schon, A and Olia, AS and Wang, T and Shrader, HR and Lovelace, SE and Pegu, A and Doria-Rose, NA and Mascola, JR and Bloom, JD and Kwong, PD}, title = {Fostemsavir analog BMS-818251 has enhanced viral neutralization potency and similar escape mutation profile.}, journal = {Antimicrobial agents and chemotherapy}, volume = {69}, number = {10}, pages = {e0191024}, pmid = {40863730}, issn = {1098-6596}, support = {109861-61-RKNT//amfAR, The Foundation for AIDS Research/ ; }, mesh = {*Organophosphates/pharmacology ; *Piperazines/pharmacology ; Humans ; Virus Internalization/drug effects ; *Anti-HIV Agents/pharmacology ; HIV-1/drug effects ; HIV Infections/drug therapy/virology ; Neutralization Tests ; env Gene Products, Human Immunodeficiency Virus ; HIV Envelope Protein gp120/genetics/metabolism ; Binding Sites ; Mutation ; }, abstract = {BMS-818251, a fostemsavir analog, is a next-generation HIV-1 attachment inhibitor with enhanced potency and a similar resistance profile. By using ex vivo viral outgrowth assays with HIV+ donor samples, we demonstrate here that BMS-818251 exhibits superior viral suppression compared to temsavir, the active form of fostemsavir. To map potential resistance pathways, we employed deep mutational scanning and pseudotyped virus neutralization assays to identify escape mutations within the HIV-1 envelope glycoprotein (Env). These mutations were largely clustered around the BMS-818251 binding site, with key resistance mutations reducing drug-binding affinity. Several of the enriched mutations, such as S375I/N, M426L, and M475I, have been previously observed in fostemsavir-treated patients, highlighting their clinical relevance. Isothermal titration calorimetry revealed reduced binding affinity as the primary mechanism of resistance, though with notable exceptions, such as R429G, suggesting additional factors to influence viral escape. Ex vivo Env sequencing confirmed selection of resistance mutations under BMS-818251 pressure, reinforcing the predictive value of deep mutational scanning for in vivo resistance monitoring. Compared to fostemsavir, BMS-818251 achieved more effective viral suppression at lower concentrations, even in donor samples harboring preexisting resistance mutations. These findings support the continued development of BMS-818251 as a promising alternative to fostemsavir, with potential benefits for patients with multidrug-resistant HIV-1.}, }
@article {pmid40864016, year = {2025}, author = {Ezzat, D and Uddin, MM and Xue, L and Pershad, Y and Zhang, S and Collins, JM and Kitzman, JO and Jaiswal, S and Desai, P and Kooperberg, C and Bick, AG and Natarajan, P and Manson, JE and Whitsel, EA and Reiner, AP and Honigberg, MC}, title = {Clonal Hematopoiesis and Cardiovascular Outcomes in Older Women.}, journal = {Journal of the American College of Cardiology}, volume = {86}, number = {15}, pages = {1093-1106}, pmid = {40864016}, issn = {1558-3597}, support = {75N92021D00002/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; R01 HL148565/HL/NHLBI NIH HHS/United States ; R01 HL173028/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Clonal Hematopoiesis/physiology/genetics ; *Cardiovascular Diseases/genetics/epidemiology ; Aged ; Aged, 80 and over ; Dioxygenases ; DNA Methyltransferase 3A ; DNA-Binding Proteins/genetics ; Proto-Oncogene Proteins/genetics ; Janus Kinase 2/genetics ; Incidence ; Repressor Proteins ; }, abstract = {BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) is an emerging aging-related risk factor for cardiovascular disease (CVD). However, previous studies suggest that CHIP's relevance to CVD may diminish with advancing age.<br><br>OBJECTIVES: This study aimed to test the association of CHIP and its key subtypes with incident CVD in an older population.<br><br>METHODS: Participants in the Women's Health Initiative Long Life Study completed study assessments in 2012-2013 and underwent high-coverage sequencing (median depth 4,580&#xd7;). The co-primary exposures were composite CHIP and TET2 CHIP. DNMT3A, ASXL1, JAK2, and non-DNMT3A CHIP were examined as secondary exposures. The primary outcome was incident coronary heart disease. Secondary outcomes were incident heart failure with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF), ischemic stroke, venous thromboembolism, and cardiovascular death. Multivariable-adjusted Cox models tested associations between CHIP and incident CVD.<br><br>RESULTS: Among 6,677 women (median age 80 years; median follow-up 10.1 years), 2,176 (32.6%) had any CHIP. TET2 CHIP was independently associated with incident coronary heart disease (aHR: 1.36 [95% CI: 1.05-1.77]; P = 0.02), whereas composite CHIP was not (aHR: 1.07 [95% CI: 0.89-1.28]; P = 0.49). Secondarily, TET2 CHIP was associated with HFpEF (aHR: 1.40 [95% CI: 1.03-1.90]; P = 0.03), ASXL1 CHIP with HFrEF (aHR: 3.16 [95% CI: 1.53-6.55]; P = 0.002), and JAK2 CHIP with ischemic stroke (aHR: 2.49 [95% CI: 1.17-5.30]; P = 0.02), venous thromboembolism (aHR: 2.71 [95% CI: 1.11-6.65]; P = 0.03), and cardiovascular death (aHR: 2.62 [95% CI: 1.68-4.11]; P < 0.001). No other significant associations were observed for composite or DNMT3A CHIP.<br><br>CONCLUSIONS: In an older female cohort, key CHIP subtypes (TET2, ASXL1, and JAK2) were associated with incident CVD, with associations that appeared to differ by CVD outcome. These findings suggest that CHIP remains associated with cardiovascular health into later life. (Women's Health Initiative [WHI]; NCT00000611).}, }
@article {pmid40864714, year = {2025}, author = {Craig, E and Keyes, TJ and Sarno, J and D'Silva, JP and Domizi, P and Zaslavsky, M and Tsai, A and Glass, D and Nolan, GP and Hastie, T and Tibshirani, R and Davis, KL}, title = {Annotation-free discovery of disease-relevant cells in single-cell datasets.}, journal = {Science advances}, volume = {11}, number = {35}, pages = {eadv5019}, pmid = {40864714}, issn = {2375-2548}, support = {U54 CA209971/CA/NCI NIH HHS/United States ; R01 CA251858/CA/NCI NIH HHS/United States ; F31 CA239365/CA/NCI NIH HHS/United States ; U19 AI100627/AI/NIAID NIH HHS/United States ; R01 GM134483/GM/NIGMS NIH HHS/United States ; R01 EB001988/EB/NIBIB NIH HHS/United States ; }, mesh = {Humans ; *Single-Cell Analysis/methods ; *Leukemia/pathology ; Neoplasm, Residual/pathology ; Algorithms ; }, abstract = {In single-cell datasets, patient labels indicating disease status (e.g., "sick" or "not sick") are typically available, but individual cell labels indicating which of a patient's cells are associated with their disease state are generally unknown. To address this, we introduce mixture modeling for multiple-instance learning (MMIL), an expectation-maximization approach that trains cell-level binary classifiers using only patient-level labels. Applied to primary samples from patients with acute leukemia, MMIL accurately separates leukemia from nonleukemia baseline cells, including rare minimal residual disease (MRD) cells; generalizes across tissues and treatment time points; and identifies biologically relevant features with accuracy approaching that of a hematopathologist. MMIL can also incorporate cell labels when they are available, creating a robust framework for leveraging both labeled and unlabeled cells. MMIL provides a flexible modeling framework for cell classification, especially in scenarios with unknown gold-standard cell labels.}, }
@article {pmid40867077, year = {2025}, author = {Ebadi, M and Reddi, S and Senyshyn, L and Minot, SS and Gooley, T and Kabage, AJ and Lee, SJ and Hill, GR and Khoruts, A and Rashidi, A}, title = {Effect of fecal microbiota transplantation on gut microbiota functional profile in recipients of allogeneic hematopoietic cell transplantation.}, journal = {Gut microbes}, volume = {17}, number = {1}, pages = {2551882}, pmid = {40867077}, issn = {1949-0984}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Fecal Microbiota Transplantation ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Gastrointestinal Microbiome ; Male ; Middle Aged ; Female ; Adult ; Bacteria/classification/genetics/isolation &amp; purification/metabolism ; *Dysbiosis/therapy/microbiology ; Transplantation, Homologous ; Feces/microbiology ; Aged ; }, abstract = {Intestinal dysbiosis has been associated with both the effectiveness and toxicity of immunotherapy in cancer patients, inspiring multiple trials investigating fecal microbiota transplantation (FMT) in these patients. FMT restores microbial community structures damaged by antibiotics and enriches the microbiota with beneficial bacteria. However, the precise mechanism through which FMT exerts its effects and provides clinical benefits remains incompletely understood. Efforts to date have primarily focused on characterizing taxonomic changes following FMT. We hypothesized that FMT may also modify the functional pathways and metabolic capabilities of the gut microbiota, with possible clinical impact. To investigate this, we conducted a study involving 17 patients with blood disorders who received prophylactic FMT from one of the three healthy donors shortly after hematopoietic cell transplantation (HCT). By analyzing shotgun metagenomic profiles of the baseline, pre-FMT, and post-FMT gut microbiota, we demonstrate that FMT effectively restored pathways that had been depleted following HCT. However, it did not significantly reduce pathways that had expanded, indicating that FMT operates primarily through a restorative mechanism, reestablishing lost functional capabilities in the microbiota rather than suppressing overactive pathways. These findings highlight the potential for optimizing FMT protocols and identifying patient populations where FMT may be particularly beneficial.}, }
@article {pmid40870354, year = {2025}, author = {Han, Z and Li, T and You, J and Balakrishnan, N}, title = {Varying-Coefficient Additive Models with Density Responses and Functional Auto-Regressive Error Process.}, journal = {Entropy (Basel, Switzerland)}, volume = {27}, number = {8}, pages = {}, pmid = {40870354}, issn = {1099-4300}, support = {21YJA910001//Humanities and Social Science Fund of Ministry of Education of China/ ; 11971291//National Natural Science Foundation of China (NSFC)/ ; }, abstract = {In many practical applications, data collected over time often exhibit autocorrelation, which, if unaccounted for, can lead to biased or misleading statistical inferences. To address this issue, we propose a varying-coefficient additive model for density-valued responses, incorporating a functional auto-regressive (FAR) error process to capture serial dependence. Our estimation procedure consists of three main steps, utilizing spline-based methods after mapping density functions into a linear space via the log-quantile density transformation. First, we obtain initial estimates of the bivariate varying-coefficient functions using a B-spline series approximation. Second, we estimate the error process from the residuals using spline smoothing techniques. Finally, we refine the estimates of the additive components by adjusting for the estimated error process. We establish theoretical properties of the proposed method, including convergence rates and asymptotic behavior. The effectiveness of our approach is further demonstrated through simulation studies and applications to real-world data.}, }
@article {pmid40873297, year = {2025}, author = {Duong, VA and Pan, E and Dabral, P and Utzschneider, KM and Lampe, JW and Chen, R and A J Hullar, M}, title = {Metaproteomic Analysis to Assess the Impact of Storage Media on Human Gut Microbiome in Fecal Samples.}, journal = {Proteomics}, volume = {25}, number = {19}, pages = {39-49}, pmid = {40873297}, issn = {1615-9861}, support = {R01 CA211892/CA/NCI NIH HHS/United States ; R01 CA276173/CA/NCI NIH HHS/United States ; R01CA211892//National Institutes of Health (NIH)/ ; R01CA276173//National Institutes of Health (NIH)/ ; }, mesh = {Humans ; *Feces/microbiology ; *Gastrointestinal Microbiome ; *Proteomics/methods ; *Specimen Handling/methods ; *Proteome/analysis ; Buffers ; Bacterial Proteins/analysis ; }, abstract = {The human gut microbiome is a diverse community of microorganisms residing in the gastrointestinal tract. The storage condition of fecal samples may impact the taxonomic and protein compositions of microbiomes in these samples. Here, we performed a mass spectrometry-based metaproteomic study to assess the impact of storage media on human gut microbiome in fecal samples. We evaluated FDA-authorized OMNIgene·GUT (OG), phosphate-buffered saline (PBS), and RNALater (RNAL) buffers and identified 38,185 microbial peptides corresponding to 7348 microbial proteins, which matched 16 phyla, 20 classes, 50 orders, 104 families, 332 genera, and 453 species. We found a high similarity among the fecal microbiomes preserved in OG, PBS, and RNAL in terms of the identification of proteins, taxa, and functional annotations. Both alpha and beta diversity suggested the high similarity among samples stored in the three media. Nonetheless, we also found some notable differences among buffers regarding the abundances of a few taxon groups. A partial human proteome (over 400 proteins) was identified in the fecal samples, with most of these proteins associated with the membrane and extracellular regions. The findings indicate the similarity among microbiomes in the fecal samples stored in OG, PBS, and RNAL regarding proteome profile, taxa, and functional capacity. SUMMARY: This study thoroughly analyzed and compared the metaproteomes of fecal samples preserved at -80°C in PBS, RNALater, and OMNIgene·GUT Dx buffers, offering novel insights into the effectiveness of these buffers in maintaining the stability and composition of the human gut microbiome. We found a high similarity in the identification and quantification of proteins, taxa, and functional annotations across the three buffers, with notable quantitative differences highlighting subtle yet important variations in preservation efficacy. The unique datasets and findings could offer valuable revelations into the impact of fecal sample preservation on translational and clinical analyses of the human gut microbiome.}, }
@article {pmid40875480, year = {2025}, author = {Friedland, BA and Browne, EN and Roberts, ST and Ngure, K and Nakalega, R and Macdonald, P and Mpongo, CN and Tenza, S and Mhlanga, N and Szydlo, D and Johnson, S and McClure, T and Nair, G and Celum, C and Hillier, SL and van der Straten, A and , }, title = {Higher Acceptability of the Monthly Dapivirine Ring Versus Daily Oral Pre-Exposure Prophylaxis Among Adolescent Girls and Young Women in Sub-Saharan Africa in the REACH Trial.}, journal = {Journal of acquired immune deficiency syndromes (1999)}, volume = {100}, number = {5}, pages = {415-424}, pmid = {40875480}, issn = {1944-7884}, support = {UM1 AI068633/AI/NIAID NIH HHS/United States ; UM1 AI068615/AI/NIAID NIH HHS/United States ; UM1AI068615//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1 AI106707/AI/NIAID NIH HHS/United States ; UM1AI106707//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1AI068633//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; }, mesh = {Adolescent ; Female ; Humans ; Young Adult ; Administration, Oral ; Africa South of the Sahara ; *Anti-HIV Agents/administration &amp; dosage ; Contraceptive Devices, Female ; *HIV Infections/prevention &amp; control ; *Patient Acceptance of Health Care/statistics &amp; numerical data ; *Pre-Exposure Prophylaxis/methods ; *Pyrimidines/administration &amp; dosage ; Uganda ; Zimbabwe ; Delayed-Action Preparations/administration &amp; dosage ; Administration, Intravaginal ; }, abstract = {BACKGROUND: Oral pre-exposure prophylaxis (PrEP) is effective for HIV prevention , yet use has been inconsistent in adolescent girls and young women (AGYW). We compared PrEP with the dapivirine vaginal ring (ring) among AGYW in MTN-034 (REACH).<br><br>METHODS: We randomized 247 16-21-yr-old AGYW (South Africa, Uganda, Zimbabwe) to the sequence of using the ring and oral PrEP for 6 m each (February 2019-September 2021). Participants rated overall product acceptability (1, dislike very much to 5, like very much) after 3 m and 6 m, and product characteristics/use attributes after 3 m. We compared proportions of participants rating each product a "5" (binomial model with generalized estimating equations). We assessed associations between product characteristics/use attribute ratings at 3 m and overall acceptability after 6 m (&#x3c7; 2).<br><br>RESULTSOVERALL,: 65% and 41% of participants rated the ring versus PrEP a "5" (adjusted risk difference [aRD] 24%, 95% CI: 15%, 32%; P < 0.001). For both products, high overall acceptability was associated with "excellent" self-rated adherence (ring, P < 0.001; PrEP, P = 0.03), product appearance (ring, P = 0.005; PrEP, P < 0.001), and ease of use (ring, P = 0.001; PrEP, P = 0.003). Not worrying about/or experiencing side effects were also associated with high acceptability of oral PREP.<br><br>CONCLUSIONS: The dapivirine ring was highly acceptable to substantially more individuals than oral PrEP, although a significant minority rated oral PrEP highly, even after using the ring. As has been found in the contraceptive field, offering AGYW a choice of PrEP products is likely to increase the use of any HIV prevention method in this vulnerable population.}, }
@article {pmid40875591, year = {2026}, author = {Hall, K and Lazaryan, A and van der Laan, M and Lee, C and Logan, AC and Gruber, S and Kabadi, S and Khan, I and Nicholls, C and Rota, L and Nikai, E and Ponomareva, E and Koumas, A and Waller, EK}, title = {Efficacy and safety of belumosudil as compared with best available therapy for the treatment of cGVHD in the United States.}, journal = {Blood advances}, volume = {10}, number = {3}, pages = {682-693}, pmid = {40875591}, issn = {2473-9537}, mesh = {Humans ; Male ; Female ; United States ; Middle Aged ; *Graft vs Host Disease/drug therapy/mortality/etiology ; Treatment Outcome ; Adult ; Aged ; Retrospective Studies ; Chronic Disease ; *Protein Kinase Inhibitors/therapeutic use/adverse effects ; Young Adult ; }, abstract = {Belumosudil was approved by the Food and Drug Administration in the United States for the treatment of relapsed/refractory chronic graft-versus-host disease (cGVHD) based on a randomized phase 2 trial comparing 2 belumosudil doses. The efficacy and safety of belumosudil vs the best available therapy (BAT) has not been studied. Applying rigorous statistical methodology to real-world data, this study estimated the efficacy of belumosudil vs BAT in cGVHD patients whose disease failed to respond to 2 to 5 prior lines of therapy (LOTs). Retrospective data between March 2015 and 2024 were collected across 8 US sites for 196 patients, contributing 113 belumosudil and 245 BAT LOTs. The primary outcome was 6-month overall response rate (ORR), defined as the proportion of complete or partial responses based on 2014 National Institutes of Health consensus criteria, physician assessment, or corticosteroid dose taper of ≥50% without cGVHD progression. Death, relapse, and beginning a new LOT were considered a lack of response. Targeted maximum likelihood estimation (TMLE) was used to estimate the 6-month ORR following belumosudil vs BAT (38.7% vs 26.8%, respectively) or 44.2% improvement with belumosudil (1-sided 95% confidence interval [CI], [4.4 to ∞]; P = .031). TMLE was also used to estimate 1-year failure-free survival when treated with belumosudil (61.2%) or BAT (47.8%), a 13.5% difference (95% CI, 1.5-100; P = .032). Descriptive assessment of safety showed adverse events recorded in 27% of belumosudil and 36% of BAT LOTs. Findings demonstrated that belumosudil improved clinical outcomes compared to BAT in cGVHD patients with 2 to 5 prior LOTs, and safety was consistent with belumosudil's established profile.}, }
@article {pmid40875887, year = {2025}, author = {Galarza Fortuna, GM and Peres, L and Nazarenko, E and De Menezes Silva Corraes, A and Hovanky, VN and Shune, L and McGuirk, J and De Avilla, G and Khouri, J and Dima, D and Gaballa, M and Dhakal, B and Forsberg, P and Godara, A and Afrough, A and Anderson, LD and Herr, MM and Davis, JA and Mann, H and Purvey, S and Clark, W and Htut, M and Beitinjaneh, A and Pereira, DL and Kocoglu, MH and Ferreri, CJ and Atrash, S and Voorhees, PM and Rossi, A and Shambavi, R and Hashmi, H and Patel, K and Sidana, S and Lin, Y and Hansen, DK and Sborov, DW}, title = {Safety and efficacy of BCMA-directed chimeric antigen receptor T-cell therapy for the treatment of plasma cell leukemia.}, journal = {Blood advances}, volume = {9}, number = {23}, pages = {6009-6018}, pmid = {40875887}, issn = {2473-9537}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; Middle Aged ; Aged ; *B-Cell Maturation Antigen/immunology ; *Immunotherapy, Adoptive/adverse effects/methods ; *Receptors, Chimeric Antigen/immunology ; *Leukemia, Plasma Cell/therapy/mortality/immunology ; Adult ; Retrospective Studies ; Treatment Outcome ; Aged, 80 and over ; }, abstract = {Despite significant therapeutic advances in multiple myeloma (MM), outcomes in patients with plasma cell leukemia (PCL) remain dismal. We conducted a multicenter retrospective analysis of patients with PCL who were treated with the B-cell maturation antigen-directed chimeric antigen receptor T-cell (CAR-T) products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We identified 34 patients; 19 patients received ide-cel and 15 received cilta-cel. With a median follow-up of 11.9 months, the overall median progression-free survival (mPFS) was 9.0 months (95% confidence interval [CI], 4-15) and the median overall survival (mOS) was 13.0 months (95% CI, 8 to not estimable [NE]). The 1-year cumulative incidence of progression or death was 72%, and the 1-year cumulative incidence of death was 47%. Patients who received cilta-cel had a longer mPFS (19.0 months vs 6.0 months) and mOS (>23 months [NE] vs 9.0 months) when compared with those treated with ide-cel. Similarly, the 1-year cumulative incidence of disease progression or death was 37.5% (95% CI, 17.4-68.5) with cilta-cel, whereas all patients treated with ide-cel progressed or died within 12 months of infusion. The rates of hematologic and nonhematologic toxicities were similar between patients treated with cilta-cel and those treated with ide-cel and were consistent with those reported in patients with MM. In this first multicenter study that evaluated patients with PCL who were treated with standard-of-care CAR-T products, we show that CAR-T is safe, feasible, and associated with improved outcomes when compared with historic standards.}, }
@article {pmid40876913, year = {2025}, author = {Sandmaier, BM}, title = {Profile of a Pioneer: Rainer F. Storb.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {9}, pages = {599-604}, doi = {10.1016/j.jtct.2025.08.001}, pmid = {40876913}, issn = {2666-6367}, }
@article {pmid40879300, year = {2025}, author = {Nieto, C and Kadan-Lottick, NS and Ross, WL and Santiago-Rivera, Y and Sandbo, C and Hild, M and Bryant, S and Barnhorst, M and Appel, B and Mendoza, JA}, title = {Increasing Physical Activity in Children During Cancer Treatment: A Qualitative Study of Parents' Perspectives.}, journal = {Pediatric blood &amp; cancer}, volume = {72}, number = {11}, pages = {e31961}, doi = {10.1002/pbc.31961}, pmid = {40879300}, issn = {1545-5017}, support = {//Georgetown Lombardi Comprehensive Cancer Center/ ; //Fred Hutchinson Cancer Research Center/ ; }, mesh = {Humans ; Child ; *Parents/psychology ; *Exercise ; *Neoplasms/therapy/psychology ; Child, Preschool ; Female ; Male ; Adolescent ; Qualitative Research ; Adult ; Social Support ; Follow-Up Studies ; }, abstract = {This qualitative study explored barriers, facilitators, and preferences for promoting physical activity (PA) in children undergoing cancer therapy by interviewing 36 parents of children aged 4-15 years, on-therapy or less than 1 year post-therapy at three hospitals. Key barriers included safety concerns, risk of infection, and treatment side effects. Facilitators included social support and oncologist recommendations for PA. Parents preferred interventions that were flexible, varied, gamified, low-burden, and tailored to the child. Parents also expressed a desire for family involvement, connection to other parents, online social media groups, and activity trackers. These findings can inform PA interventions for children undergoing cancer therapy.}, }
@article {pmid40879331, year = {2025}, author = {Sung, K and Johnson, MM and Dumm, W and Simon, N and Haddox, H and Fukuyama, J and Matsen, FA}, title = {Thrifty wide-context models of B cell receptor somatic hypermutation.}, journal = {eLife}, volume = {14}, number = {}, pages = {}, pmid = {40879331}, issn = {2050-084X}, support = {2919.02//Gordon and Betty Moore Foundation/ ; S10 OD028685/OD/NIH HHS/United States ; R01 AI146028/AI/NIAID NIH HHS/United States ; S10OD028685/NH/NIH HHS/United States ; PHY-2309135//National Science Foundation/ ; R01-AI146028/NH/NIH HHS/United States ; }, mesh = {*Somatic Hypermutation, Immunoglobulin ; *Receptors, Antigen, B-Cell/genetics ; Humans ; }, abstract = {Somatic hypermutation (SHM) is the diversity-generating process in antibody affinity maturation. Probabilistic models of SHM are needed for analyzing rare mutations, understanding the selective forces guiding affinity maturation, and understanding the underlying biochemical process. High-throughput data offers the potential to develop and fit models of SHM on relevant data sets. In this article, we model SHM using modern frameworks. We are motivated by recent work suggesting the importance of a wider context for SHM; however, assigning an independent rate to each k-mer leads to an exponential proliferation of parameters. Thus, using convolutions on 3-mer embeddings, we develop 'thrifty' models of SHM of various sizes; these can have fewer free parameters than a 5-mer model and yet have a significantly wider context. These offer a slight performance improvement over a 5-mer model, and other modern model elaborations worsen performance. We also find that a per-site effect is not necessary to explain SHM patterns given nucleotide context. Also, the two current methods for fitting an SHM model-on out-of-frame sequence data and on synonymous mutations-produce significantly different results, and augmenting out-of-frame data with synonymous mutations does not aid out-of-sample performance.}, }
@article {pmid40880210, year = {2025}, author = {Dahlberg, A and Milano, F}, title = {Targeted GVL through HLA mismatch in double cord blood transplant.}, journal = {Blood advances}, volume = {9}, number = {17}, pages = {4470-4471}, pmid = {40880210}, issn = {2473-9537}, }
@article {pmid40883483, year = {2025}, author = {Urgessa, F and Jenkins, I and Tsegaye, A and Nigussie, H and Kuru, T and Gebremedhin, A and Abdela, F and Tadesse, F and Radich, J}, title = {MicroRNAs as prognostic and predictive biomarkers among chronic myeloid leukemia patients in Addis Ababa, Ethiopia.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {31844}, pmid = {40883483}, issn = {2045-2322}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/drug therapy/diagnosis/blood ; *MicroRNAs/genetics/blood ; Male ; Female ; Ethiopia ; *Biomarkers, Tumor/genetics/blood ; Adult ; Middle Aged ; Prognosis ; Imatinib Mesylate/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Young Adult ; Aged ; Gene Expression Regulation, Leukemic ; Adolescent ; }, abstract = {Approximately 1.5 million people worldwide suffer from chronic myeloid leukemia (CML). MicroRNAs (miRs) are important regulators of gene expression and offer an attractive option as biomarkers for cancer detection, diagnosis, and prognosis assessment in solid and liquid tumors. To assess miRs as prognostic and predictive biomarkers among CML patients at the Tikur Anbessa Specialized Hospital (TASH), Addis Ababa, Ethiopia from April 2021 to May 2023. Blood samples were collected from newly diagnosed CML patients before initiation of tyrosine kinase inhibitor (TKI), imatinib treatment, and while on therapy. The expression level of miRs were determined using the NanoString platform. LIMMA analysis was used to identify differentially expressed miR between TKI response groups and disease phases. Fifty-two study participants were enrolled in the study. From each sample, 798 hsa-miRs included on the Nanostring assay were measured. Comparing TKI naive new CML patients (n = 14) with those progressed or had blast crisis (BC) on TKI therapy (n = 12), 97 miRs were differentially expressed (|log2FC|, FDR, and P-value at > 1, < 0.001, and < 0.0001, respectively). Most miRs showed upregulation in BC CML patients compared to new CML cases except miR-223-3p, miR-4454, miR-7975, and miR-630 which were downregulated in patients with BC. In addition, eight miRs were differentially expressed comparing poor molecular responder (n = 12) with good molecular responder (n = 28) patients (P < 0.05). MiR-223-3p, miR-4454, miR-7975, and miR-630 were commonly deregulated in BC and poor molecular response groups. MiRs have significant potential as prognostic and predictive biomarkers for CML patients. MiR-223-3p, miR-4454, miR-7975 and miR-630 could be considered as prognostic and predictive biomarkers for disease progression and treatment response if validated by other large studies.}, }
@article {pmid40884418, year = {2025}, author = {Yu, N and Panch, S and Mepani, K and Stanworth, S and Bonet-Bub, C and Gragert, L and Menard, V and Mangiola, M and Maiers, M and Berka, N}, title = {"Epitope-based matching for platelet transfusion overview: Is it time?"-Insights and future directions from the 2024 American Red Cross symposium on platelet component selection.}, journal = {Transfusion}, volume = {65}, number = {10}, pages = {1954-1965}, doi = {10.1111/trf.18392}, pmid = {40884418}, issn = {1537-2995}, }
@article {pmid40884510, year = {2025}, author = {Bhole, S and Grimm, LJ and Parikh, JR and Dontchos, BN and Reig, B and Jacobs, SA and Coffey, K and Dashevsky, BZ and Mullen, LA and Daly, C and Dodelzon, K}, title = {Breast Imaging Staffing Shortages: Defining the Problem and Addressing Root Causes.}, journal = {Journal of breast imaging}, volume = {7}, number = {6}, pages = {676-684}, doi = {10.1093/jbi/wbaf031}, pmid = {40884510}, issn = {2631-6129}, mesh = {Humans ; Female ; Surveys and Questionnaires ; *Radiologists/supply &amp; distribution ; Workforce ; *Mammography ; *Breast Neoplasms/diagnostic imaging ; United States ; *Personnel Staffing and Scheduling ; Attitude of Health Personnel ; }, abstract = {OBJECTIVE: To assess the current perceptions of breast imaging staffing shortages and contributing factors among breast imaging radiologists.<br><br>METHODS: A survey assessing current perception of breast radiologists regarding breast imaging-specific staffing shortages and contributing factors was developed by the Patient Care and Delivery Committee of the Society of Breast Imaging (SBI) and emailed to SBI active physician members. Bivariable analysis (chi-squared, t test) was performed between the survey demographics and survey response questions of interest.<br><br>RESULTS: There were 309 responses (response rate of 15.7%). Most respondents perceived their practices to be short-staffed for breast radiologists (79%, 239/302), US technologists (74%, 216/290), mammography technologists (70%, 211/301), and support staff (66%, 201/302). Of the respondents who indicated they were short-staffed for breast imaging radiologists, 92% (226/246) believed it was due to insufficient number of radiologists, 67% (164/246) thought it was due to increase in volume, and 63% (154/246) attributed it to both increase in volume and insufficient number of breast imaging radiologists. Practices were more likely to be short-staffed if they had more practice sites (mean, 8.2&#x2009;&#xb1;&#x2009;7.1 vs 6.4&#x2009;&#xb1;&#x2009;8.4; P&#x2009;=&#x2009;.002), had fewer breast imaging radiologists (mean, 10.1&#x2009;&#xb1;&#x2009;9.6 vs 11.3&#x2009;&#xb1;&#x2009;11.5; P&#x2009;=&#x2009;.009), and were academic practices (35.1% vs 25.7%; P&#x2009;=&#x2009;.028).<br><br>CONCLUSIONS: Most breast imaging radiologists perceive their current breast imaging practices to be short-staffed for radiologists, mammography technologists, US technologists, and support staff. Understanding contributing factors is crucial to addressing root causes and mitigating impact on patient care and burnout across breast imaging team members.}, }
@article {pmid40885198, year = {2026}, author = {von Lilienfeld-Toal, M and Khawaja, F and Compagno, F and Robin, C and Piñana, JL and Cesaro, S and Einsele, H and Ljungman, P and Navarro, D and Boeckh, M and Chemaly, RF and Hirsch, HH}, title = {Community-acquired respiratory virus infections in patients with haematological malignancies or undergoing haematopoietic cell transplantation: updated recommendations from the 10th European Conference on Infections in Leukaemia.}, journal = {The Lancet. Infectious diseases}, volume = {26}, number = {3}, pages = {e193-e206}, doi = {10.1016/S1473-3099(25)00365-2}, pmid = {40885198}, issn = {1474-4457}, mesh = {Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Respiratory Tract Infections/prevention &amp; control/virology/diagnosis/drug therapy ; *Hematologic Neoplasms/complications/virology ; Antiviral Agents/therapeutic use ; *Community-Acquired Infections/prevention &amp; control/diagnosis/virology/drug therapy ; Europe ; *Virus Diseases/diagnosis/prevention &amp; control ; *Leukemia/complications ; Immunocompromised Host ; }, abstract = {To update recommendations of the 4th European Conference on Infections in Leukaemia (ECIL-4) on community-acquired respiratory virus (CARV) infections published in 2013, we reviewed publications from between Jan 1, 2014, and June 30, 2024 on adenovirus, bocavirus, coronavirus, influenzavirus, metapneumovirus, parainfluenzavirus, respiratory syncytial virus (RSV), and rhinovirus in patients with haematological malignancies or undergoing haematopoietic cell transplantation (HCT), or both. In the current ECIL recommendations (ECIL-10), we outline a common approach to infection control, laboratory testing, and diagnosis for all CARVs (including SARS-CoV-2) and specific management and deferral strategies for CARVs other than SARS-CoV-2. For influenzavirus, seasonal inactivated-vaccines and early antivirals are recommended, whereas routine antiviral prophylaxis is discouraged for immunocompromised patients. For RSV, licensed vaccines can be considered according to local approval, despite scarce evidence for patients with haematological malignancies and those undergoing HCT. Passive immunisation with palivizumab or nirsevimab is recommended for children younger than 2 years, but data are insufficient for pre-exposure or post-exposure prophylaxis, or treatment of older children and adults. Oral ribavirin or intravenous immunoglobulins, or a combination of the two, are recommended for patients undergoing HCT with severe immunodeficiency scores. For other CARVs, recommendations include only supportive care, improving immune functions, correcting hypogammaglobulinaemia, and judicious lowering of corticosteroids. We highlight unmet needs in immunisation and antivirals for reducing CARV-associated morbidity and mortality in patients with haematological malignancies and those undergoing HCT.}, }
@article {pmid40885199, year = {2025}, author = {Necchi, A and Guerrero-Ramos, F and Crispen, PL and Herrera-Imbroda, B and Garje, R and Powles, T and Peyton, CC and Pradere, B and Ku, JH and Shore, N and Bögemann, M and Preston, MA and Xylinas, E and Sanchez de Llano, C and Hasan, M and Stitou, H and Bhanvadia, S and Sweiti, H and Psutka, SP}, title = {TAR-200 plus cetrelimab versus cetrelimab monotherapy as neoadjuvant therapy in patients with muscle-invasive bladder cancer who are ineligible for or decline neoadjuvant cisplatin-based chemotherapy (SunRISe-4): interim analysis of a randomised, open-label phase 2 trial.}, journal = {The Lancet. Oncology}, volume = {26}, number = {10}, pages = {1312-1322}, doi = {10.1016/S1470-2045(25)00358-4}, pmid = {40885199}, issn = {1474-5488}, mesh = {Humans ; *Urinary Bladder Neoplasms/drug therapy/pathology ; *Neoadjuvant Therapy ; Male ; Female ; Aged ; Middle Aged ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects ; Cisplatin/administration &amp; dosage ; *Antibodies, Monoclonal, Humanized/administration &amp; dosage/adverse effects ; *Deoxycytidine/analogs &amp; derivatives/administration &amp; dosage/adverse effects ; Neoplasm Invasiveness ; Gemcitabine ; Cystectomy ; }, abstract = {BACKGROUND: Effective treatments are needed for patients with muscle-invasive bladder cancer scheduled for radical cystectomy who are ineligible for or decline to receive neoadjuvant cisplatin-based chemotherapy. We aimed to evaluate neoadjuvant TAR-200 plus cetrelimab (anti-PD-1) versus cetrelimab monotherapy in this setting.<br><br>METHODS: SunRISe-4 is a randomised, open-label, phase 2 trial being conducted at 109 investigative centres in ten countries worldwide. Eligible patients were aged 18 years or older, were newly diagnosed with histologically confirmed muscle-invasive bladder cancer (stage cT2-cT4 N0M0), had an Eastern Cooperative Oncology Group performance status of 0-1, were scheduled to undergo radical cystectomy, and were deemed ineligible for or declined platinum-based neoadjuvant chemotherapy. Patients were randomly assigned (5:3) in blocks of eight using an interactive web response system to receive four cycles of intravesical TAR-200 (225 mg gemcitabine) plus intravenous cetrelimab (360 mg) every 21 days or four cycles of intravenous cetrelimab (360 mg) monotherapy every 21 days. Randomisation was stratified by results of transurethral resection of bladder tumour (visibly complete vs incomplete and &#x2264;3 cm) and tumour stage (cT2 vs cT3-4a at initial diagnosis). The primary endpoint was centrally confirmed pathological complete response in the efficacy-evaluable set. As this was a prespecified interim analysis and all patients had not completed treatment, efficacy-evaluable set was defined as all patients who had radical cystectomy or progressive disease or death before radical cystectomy. Safety was analysed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04919512, and is ongoing.<br><br>FINDINGS: From July 7, 2022, to May 31, 2024, 196 patients were assessed for eligibility and 122 were randomly assigned (TAR-200 plus cetrelimab n=80, cetrelimab monotherapy n=42). 120 patients received at least one dose of study drug. Mean age was 70&#xb7;7 years (SD 7&#xb7;9); 102 (85%) participants were male, 18 (15%) were female, 81 (68%) were White, 28 (23%) were Asian, and 11 (9%) were other races. In the efficacy-evaluable set (TAR-200 plus cetrelimab n=53, cetrelimab monotherapy n=31), at a median follow up of 23&#xb7;5 weeks (IQR 8&#xb7;6-42&#xb7;0), pathological complete response rates were 42% (22 of 53 patients; 95% CI 28-56) in the TAR-200 plus cetrelimab cohort and 23% (seven of 31 patients; 10-41) in the cetrelimab monotherapy cohort. In the safety set, at a median follow-up of 10&#xb7;2 weeks (IQR 1&#xb7;1-36&#xb7;9), treatment-related adverse events occurred in 57 (72%) of 79 patients in the TAR-200 plus cetrelimab cohort and in 18 (44%) of 41 patients in the cetrelimab monotherapy cohort. Grade 3 or worse treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and two (5%) in the cetrelimab monotherapy cohort, the most common being haematuria (two [3%] in the TAR-200 plus cetrelimab cohort). Serious treatment-related adverse events occurred in nine (11%) patients in the TAR-200 plus cetrelimab cohort and one (2%) patient in the cetrelimab monotherapy cohort. In the TAR-200 plus cetrelimab cohort, seven (9%) patients had treatment-related adverse events leading to discontinuation of TAR-200 and six (8%) had treatment-related adverse events leading to discontinuation of cetrelimab; there were no treatment related deaths. In the cetrelimab monotherapy cohort, no patients discontinued due to treatment-related adverse events; there was one death from a treatment-related adverse event due to hyperglycaemic, hyperosmolar, non-ketotic syndrome.<br><br>INTERPRETATION: Neoadjuvant TAR-200 plus cetrelimab showed a high pathological complete response rate with a manageable safety profile. These results support continued investigation of TAR-200 in patients with muscle-invasive bladder cancer planned for radical cystectomy.<br><br>FUNDING: Johnson &amp; Johnson.}, }
@article {pmid40886051, year = {2026}, author = {Li, R and Gagliano Taliun, SA and Liao, K and Flickinger, M and Sobell, JL and Genovese, G and Locke, AE and Chiu, RR and LeFaive, J and Wang, J and Martins, T and Chapman, S and Neumann, A and Handsaker, RE and Arnett, DK and Barnes, KC and Boerwinkle, E and Braff, D and Cade, BE and Fornage, M and Gibbs, RA and Hoth, KF and Hou, L and Kooperberg, C and Loos, RJF and Metcalf, GA and Montgomery, CG and Morrison, AC and Qin, ZS and Redline, S and Reiner, AP and Rich, SS and Rotter, JI and Taylor, KD and Viaud-Martinez, KA and ,  and ,  and Bigdeli, TB and Gabriel, S and Zollner, S and Smith, AV and Abecasis, G and McCarroll, SA and Pato, MT and Pato, CN and Boehnke, M and Knowles, J and Kang, HM and Ophoff, RA and Ernst, J and Scott, LJ}, title = {Whole-genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.}, journal = {HGG advances}, volume = {7}, number = {1}, pages = {100499}, pmid = {40886051}, issn = {2666-2477}, support = {R01 MH115676/MH/NIMH NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; *Bipolar Disorder/genetics ; *Black or African American/genetics ; Case-Control Studies ; Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; *Schizophrenia/genetics ; *Whole Genome Sequencing ; }, abstract = {In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole-genome sequencing (∼27X) of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls (∼37X). To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of the association of BD with single variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD genome-wide association study loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole-genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.}, }
@article {pmid40887511, year = {2025}, author = {Cimino, PJ and Keiser, DJ and Parrish, AG and Holland, EC and Szulzewsky, F}, title = {C-terminal fusion partner activity contributes to the oncogenic functions of YAP1::TFE3.}, journal = {Scientific reports}, volume = {15}, number = {1}, pages = {32013}, pmid = {40887511}, issn = {2045-2322}, support = {R35 CA253119/CA/NCI NIH HHS/United States ; R35 CA253119-01A1//National Institutes of Health,United States/ ; U54 CA243125/NH/NIH HHS/United States ; U54 CA243125/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; Start-up funds//University of Utah Department of Neurosurgery and Huntsman Cancer Institute/ ; }, mesh = {*Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics/metabolism/chemistry ; YAP-Signaling Proteins ; Humans ; Animals ; Mice ; *Adaptor Proteins, Signal Transducing/genetics/metabolism ; *Transcription Factors/genetics/metabolism ; *Oncogene Proteins, Fusion/genetics/metabolism ; Cell Line, Tumor ; Carcinogenesis/genetics ; Protein Domains ; *Phosphoproteins/genetics/metabolism ; }, abstract = {YAP1 gene fusions are found in a multitude of human tumors and are the likely tumor-initiating events in these tumors. We have previously shown that YAP1 fusion proteins exert TEAD-dependent oncogenic YAP1 activity. However, the contributions of the C-terminal fusion partners to the oncogenic functions of YAP1 fusion proteins are understudied. Here, we expressed eight different YAP1 gene fusions in vivo. Tumors induced by YAP1::TFE3 displayed a significantly different histomorphology compared to tumors induced by other YAP1 fusions or activated non-fusion YAP1. To assess the extent to which TFE3 activity and the functional TFE3 domains (DNA binding: leucine zipper (LZ) and basic-helix-loop-helix (bHLH); activation domain (AD)) contribute to the oncogenic functions of YAP1::TFE3, we generated several mutant variants and performed functional in vitro and in vivo assays. In vitro, mutation or deletion of the TFE3 DNA binding domains (LZ, bHLH) resulted in reduced TFE3 activity but increased YAP1 activity of YAP1::TFE3. In vivo, deletion of the LZ and bHLH domains did not result in a decrease in tumor incidence but induced the formation of more YAP1-like tumors that lacked prominent features of YAP1::TFE3-driven tumors. By contrast, loss of the TFE3 AD almost completely abrogated tumor formation. Our results suggest that the TFE3 domains significantly contribute to the oncogenic activity of YAP1::TFE3.}, }
@article {pmid40888442, year = {2025}, author = {Grivas, P and Tagawa, ST and Jain, RK and Bupathi, M and Balar, A and Rezazadeh Kalebasty, A and George, S and Palmbos, P and Nordquist, L and Petrylak, DP and Davis, N and Sternberg, CN and Agarwal, N and Park, C and Tonelli, J and Zhou, H and Bangs, R and Loriot, Y}, title = {A plain language summary of the TROPHY-U-01 study (Cohort 2): use of sacituzumab govitecan after immunotherapy in people with metastatic urothelial cancer who cannot take cisplatin-based chemotherapy.}, journal = {Future oncology (London, England)}, volume = {21}, number = {23}, pages = {2941-2954}, doi = {10.1080/14796694.2025.2548757}, pmid = {40888442}, issn = {1744-8301}, }
@article {pmid40889272, year = {2025}, author = {Kazemian, E and Mo, Q and Matejcic, M and Tsai, YY and Sobieski, D and Li, X and Hoogland, AI and Crowder, SL and Gonzalez, BD and Oswald, LB and Sleight, AG and Nguyen, N and Loroña, NC and Damerell, V and Komrokji, KR and Mooney, K and Playdon, MC and Ulrich, CM and Li, CI and Shibata, D and Toriola, AT and Ose, J and Peoples, AR and Hardikar, S and Kahlert, C and Siegel, EM and Bower, JE and Schmit, SL and Gigic, B and Jim, HSL and Figueiredo, JC}, title = {Genetic predisposition to persistent fatigue after a diagnosis of colorectal cancer.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {12}, pages = {2513-2525}, pmid = {40889272}, issn = {1460-2105}, support = {KL2TR00-2539/NH/NIH HHS/United States ; //University of Utah/ ; //Cancer Control and Population Health Sciences/ ; R01 CA189184/CA/NCI NIH HHS/United States ; //Stiftung LebensBlicke/ ; //Core and Molecular Genomics Core Facilities/ ; //German Cancer Research Center/ ; R01 CA254108/CA/NCI NIH HHS/United States ; //Matthias Lackas Stiftung/ ; R01 CA211705/CA/NCI NIH HHS/United States ; R01 CA254108/NH/NIH HHS/United States ; //Claussen-Simon Stiftung/ ; P30-CA076292/CA/NCI NIH HHS/United States ; R01 AG083580/AG/NIA NIH HHS/United States ; R03 CA270473/CA/NCI NIH HHS/United States ; T32CA009168/CA/NCI NIH HHS/United States ; KL2 TR002539/TR/NCATS NIH HHS/United States ; //German Consortium of Translational Cancer Research/ ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA211705/NH/NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; T32 HG008962/HG/NHGRI NIH HHS/United States ; T32 CA009168/CA/NCI NIH HHS/United States ; R01 NR018762/NR/NINR NIH HHS/United States ; //H. Lee Moffitt Cancer Center &amp; Research Institute/ ; R01 CA207371/NH/NIH HHS/United States ; 1A1 R01 CA189184/CA/NCI NIH HHS/United States ; R03CA270473/NH/NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; //Tissue Core, Participant Research, Interventions, &amp; Measurements/ ; T32 HG008962/NH/NIH HHS/United States ; //Huntsman Cancer Foundation, Immunology, Inflammation, and Infectious Disease Initiative/ ; //H. Lee Moffitt Cancer Center and Research Institute/ ; U01 CA206110/NH/NIH HHS/United States ; R2 U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA189184/NH/NIH HHS/United States ; R01NR018762/NR/NINR NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/complications/genetics/diagnosis ; *Fatigue/genetics/etiology/epidemiology ; Male ; *Genetic Predisposition to Disease ; Female ; Middle Aged ; Prospective Studies ; Genome-Wide Association Study ; Aged ; Polymorphism, Single Nucleotide ; Quality of Life ; Adult ; }, abstract = {BACKGROUND: Cancer-related fatigue (fatigue) is a common and persistent symptom after cancer treatment, yet the role of genetic susceptibility remains unclear.<br><br>METHODS: We used data from a prospective cohort study called the ColoCare Study, conducted over 5 US sites and Germany. Fatigue was assessed at 5 time points using the European Organisation for the Research and Treatment of Cancer Core Quality of Life Questionnaire fatigue subscale and analyzed as (1) a binary summary measure of the trajectory from diagnosis into survivorship (defined as severe: yes/no), (2) a mean score across all time points, and (3) the highest (ie, worst) score across all time points. We genotyped samples using the Illumina Infinium Global Diversity Array kit with imputation using the National Institutes of Health TOPMed reference panel to conduct a genome-wide association study. The Sum of Single Effects was used to identify independent secondary signals. Transcriptome-wide association studies using the S-PrediXcan and MultiXcan methods were conducted to examine genetic regulation of gene expression. The COLOC package assessed whether variants identified in the genome-wide association study influence gene expression through colocalization analysis.<br><br>RESULTS: Among 1219 participants, 31.0% experienced severe fatigue over the course of their disease. A locus near LINC02505 on chromosome 4 was associated with severe fatigue (rs6531463; odds ratio&#x2009;=&#x2009;3.25, P&#x2009;=&#x2009;3.88&#x2009;&#xd7;&#x2009;10-8). When modeling mean fatigue levels, strongly associated variants were identified in or near NEK10 and SLC4A7. Integrative analyses linked the predicted expression of NEK10 in liver tissue to risk of fatigue (P&#x2009;<&#x2009;4.36&#x2009;&#xd7;&#x2009;10-6). Colocalization analysis identified genetic loci and gene expression near NEK10 (posterior probabilities >0.9).<br><br>CONCLUSIONS: This study identified novel genetic loci associated with fatigue in patients with colorectal cancer and may be useful for identifying high-risk individuals for preventative strategies.}, }
@article {pmid40890722, year = {2025}, author = {Henderson, V and Carnahan, L and Cohn, EB and Waite, AW and Mersha, T and Block, R and Kolpack, M and Sommers, J and Salum, K and Hoskins, KF and Nguyen, R}, title = {"The more I know, the more you know" Using culturally responsive marketing strategies to develop tools that increase awareness about clinical trials among Black communities.}, journal = {BMC public health}, volume = {25}, number = {1}, pages = {3003}, pmid = {40890722}, issn = {1471-2458}, mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; *Black or African American/psychology/statistics &amp; numerical data ; *Clinical Trials as Topic ; *Cultural Competency ; Focus Groups ; *Marketing/methods ; Neoplasms/ethnology/therapy ; }, abstract = {BACKGROUND: Ineffective dissemination of cancer research and information among the public contributes to cancer inequities. Dissemination rarely involves efforts to engage non-research audiences and end-users in developing effective messaging. Efforts to promote equity in clinical trial participation may benefit from marketing strategies traditionally applied in the business sector. Black Americans suffer the highest death rates from most cancers than any other race/ethnicity, yet only 5% of patients enrolled in cancer clinical trials are Black. Our team used a marketing strategy framework to create a culturally responsive public service announcement (PSA) video to increase awareness of clinical trials among Black audiences.<br><br>METHODS: We partnered with a marketing recruitment firm and a marketing agency to conduct six focus groups (n&#x2009;=&#x2009;54) with social support networks of Black cancer survivors and Black community members. Maximum variation sampling was used to recruit a national sample of eligible participants that varied in age, education, geographic region, and gender. Focus groups were conducted over three phases that informed script development, script and storyline testing, and sought feedback on the PSA video post-production. We used the Marketing and Clinical Trials Reference Model to guide marketing strategies, data collection, video content development and production. We used rapid qualitative data analysis techniques to identify themes for each phase to guide PSA development.<br><br>RESULTS: Partnered with a film production company, we produced a 2-min PSA video that uses professional actors and storytelling and marketing techniques to describe clinical trials, provide relevant statistics, address barriers to participation expressed by participants, and provide credible resources to seek further information. We also produced 30&#xa0;s and 60&#xa0;s versions of the PSA to accommodate different marketing media outlets. Participants felt the videos were engaging and relatable and that the messaging was clear. The videos ignited meaningful discussions about clinical trial participation and motivated participants to share the information learned.<br><br>CONCLUSIONS: Using marketing communication strategies is a low-tech, pragmatic approach to effectively produce health information that is meaningful, can be tailored for specific audiences, and disseminated to broader audiences.}, }
@article {pmid40891586, year = {2025}, author = {Velloza, J and Ortblad, KF and Kemp, CG}, title = {"Measuring the gap": advances and practical considerations in assessment of adoption, penetration, and sustainment of HIV prevention services.}, journal = {Current opinion in HIV and AIDS}, volume = {20}, number = {6}, pages = {587-593}, doi = {10.1097/COH.0000000000000979}, pmid = {40891586}, issn = {1746-6318}, mesh = {Humans ; *HIV Infections/prevention &amp; control ; *Pre-Exposure Prophylaxis/methods ; Anti-HIV Agents/administration &amp; dosage ; *Disease Transmission, Infectious/prevention &amp; control ; }, abstract = {PURPOSE OF REVIEW: Prior reviews have documented lack of consistency around implementation outcome measurement and gaps in assessing adoption, penetration or reach, and sustainment in HIV research. Our review sought to summarize approaches to measuring adoption, penetration, and sustainment in the HIV research literature, with a focus on the preexposure prophylaxis (PrEP) field which is ripe for exploration as long-acting PrEP formulations become available and oral PrEP programs become increasingly sustained.<br><br>RECENT FINDINGS: Our literature search of adoption, penetration, and sustainment measurement in HIV research identified 250 manuscripts. We developed a conceptual heuristic of latent and manifest measures for HIV implementation research. Few PrEP studies measured adoption according to our heuristic and latent adoption measurements were often conflated with acceptability, while manifest measurements were conflated with penetration. Most PrEP studies measuring penetration focused on the client level, with fewer measuring penetration among organizations or providers. Sustainment measurement across studies was diverse and included mixed methods assessment at organization, provider, and client levels.<br><br>SUMMARY: Heterogeneity persists in operationalizing adoption, penetration, and sustainment. Future work is needed to develop and validate pragmatic and robust measures of these constructs that can be used in evolving HIV implementation contexts.}, }
@article {pmid40892436, year = {2025}, author = {Nguyen, E and Korolkova, A and Ahmed, A and Meanley, S and Dee, L and Hussain, M and Wan, F and Hoh, R and Rodriguez, A and Figueroa, T and Cohn, LB and Deeks, SG and Peluso, MJ and Eskaf, S and Sugarman, J and Sauceda, JA and Dubé, K}, title = {Participant Perspectives in an HIV Treatment Interruption Study in San Francisco, United States.}, journal = {AIDS research and human retroviruses}, volume = {41}, number = {11}, pages = {505-516}, pmid = {40892436}, issn = {1931-8405}, support = {INV-002707/GATES/Gates Foundation/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; R01 MH126768/MH/NIMH NIH HHS/United States ; UM1 AI164560/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *HIV Infections/drug therapy/psychology ; Male ; San Francisco ; Female ; Adult ; Middle Aged ; *Anti-HIV Agents/therapeutic use/administration &amp; dosage ; Motivation ; *Withholding Treatment ; Treatment Interruption ; }, abstract = {HIV cure-related clinical research studies often include analytical treatment interruptions (ATIs), in which participants pause antiretroviral treatment (ART). During ATIs, researchers closely monitor laboratory values and adverse events. We assessed and compared the perspectives of two distinct groups of participants: HIV noncontrollers and controllers in a San Francisco-based ATI study focused on identifying biomarkers predicting HIV viral rebound. Data were collected from 2021 to 2024 over five study time points to assess motivations, understanding of the study, decisional regret, and partner protections. All participants (n = 16) endorsed the goal of helping advance HIV research as a motivator, about half were also driven by interest in their body's response to the ATI, and some indicated monetary compensation as a key motivator. Most participants (6 of 10 noncontrollers and 4 of 6 controllers) did not view personal health benefit as a primary study goal. All understood the option for an extended ATI if they had not met ART restart criteria after 28 days. At the study's onset, all sexually active participants (n = 14) were informed about the risk of transmission to sex partners and the need for partner protections during ATIs. Among noncontrollers, 2 of 5 reported using condoms, being abstinent or partner use of pre-exposure prophylaxis (PrEP) during sexual activity. Among controllers, 3 of 5 reported sexual activity: one with a partner on PrEP, one with a partner on ART, and one using other protection methods. Decisional regret about study participation, measured on a scale of 0-100, was low among both noncontrollers (range 1.67-13.57), and controllers (range 8.33-10) during the ATI, and remained low following it (noncontroller M = 5.07, SD = 4.52; controller M = 10.00, SD = 11.31). Participants generally understood the study, highlighted the need for partner protection support during ATI, and reported low decisional regret.}, }
@article {pmid40892926, year = {2025}, author = {Willcox, AC and Gobillot, TA and Kikawa, C and Baumgarten, NE and Stoddard, CI and Sung, K and Bhattacharya, T and Freeman, TS and Marceau, J and Humes, D and Overbaugh, J}, title = {Identification of AMOTL2 as an antiviral factor that enhances the human type I interferon response against Zika virus.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {36}, pages = {e2507955122}, pmid = {40892926}, issn = {1091-6490}, support = {K99 AI171000/AI/NIAID NIH HHS/United States ; F30 AI142870/AI/NIAID NIH HHS/United States ; F30 AI181359/AI/NIAID NIH HHS/United States ; T32 AI083203/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; *Zika Virus/immunology/physiology ; *Interferon Type I/metabolism/immunology ; *Zika Virus Infection/immunology/virology/genetics ; Virus Replication ; Signal Transduction ; Angiomotins ; STAT1 Transcription Factor/metabolism/genetics ; HEK293 Cells ; Animals ; Immunity, Innate ; Antigens, Differentiation ; }, abstract = {Zika virus (ZIKV) has caused multiple human outbreaks, with more recent epidemics associated with severe outcomes in infants. Today, ZIKV is endemic to many countries and presents a persistent threat for future epidemics. The host innate immune proteins that regulate ZIKV replication are incompletely defined. We developed a CRISPR knockout screen to identify host factors that impact ZIKV replication, resulting in the finding of angiomotin-like protein 2 (AMOTL2), a protein that inhibits ZIKV by regulating the host type I interferon (IFN) response. AMOTL2 affects IFN signaling by modulating STAT1 levels and activation in response to type I IFN. Thus, AMOTL2, which has largely been studied for its role in cancer, represents an antiviral protein that interacts with the IFN signaling pathway to promote downstream expression of IFN stimulated genes, resulting in restriction of ZIKV.}, }
@article {pmid40894770, year = {2025}, author = {Dadonaite, B and Harari, S and Larsen, BB and Kampman, L and Harteloo, A and Elias-Warren, A and Chu, HY and Bloom, JD}, title = {Spike mutations that affect the function and antigenicity of recent KP.3.1.1-like SARS-CoV-2 variants.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40894770}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; P01 AI167966/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; }, abstract = {SARS-CoV-2 is under strong evolutionary selection to acquire mutations in its spike protein that reduce neutralization by human polyclonal antibodies. Here we use pseudovirus-based deep mutational scanning to measure how mutations to the spike from the recent KP.3.1.1 SARS-CoV-2 strain affect cell entry, binding to ACE2 receptor, RBD up/down motion, and neutralization by human sera and clinically relevant antibodies. The spike mutations that most affect serum antibody neutralization sometimes differ between sera collected before versus after recent vaccination or infection, indicating these exposures shift the neutralization immunodominance hierarchy. The sites where mutations cause the greatest reduction in neutralization by post-vaccination or infection sera include receptor-binding domain (RBD) sites 475, 478 and 487, all of which have mutated in recent SARS-CoV-2 variants. Multiple mutations outside the RBD affect sera neutralization as strongly as any RBD mutations by modulating RBD up/down movement. Some sites that affect RBD up/down movement have mutated in recent SARS-CoV-2 variants. Finally, we measure how spike mutations affect neutralization by three clinically relevant SARS-CoV-2 antibodies: VYD222, BD55-1205, and SA55. Overall, these results illuminate the current constraints and pressures shaping SARS-CoV-2 evolution, and can help with efforts to forecast possible future antigenic changes that may impact vaccines or clinical antibodies.}, }
@article {pmid40895774, year = {2025}, author = {Malik, NH and Plastaras, JP and Corradini, S and Dawson, LA and Hawkins, MA and Salerno, KE and Mayo, CS and Dunne, EM and Gabryś, D and Grassberger, C and Lawrence, TS and Sharma, M and Bergman, AM and Owen, D and Zaila, A and Rudra, S and Velec, M and Murrell, DH}, title = {Reirradiation clinical practice in gastrointestinal abdominal malignancies: an international reirradiation collaborative group (ReCOG) systematic review.}, journal = {Clinical and translational radiation oncology}, volume = {55}, number = {}, pages = {101033}, pmid = {40895774}, issn = {2405-6308}, abstract = {PURPOSE: Reirradiation in abdominal malignancies has grown more common with advanced radiotherapy techniques. However, clinical use and implementation varies, and there remains limited consensus on best practices for reirradiation. In this systematic review, a multidisciplinary team treating gastrointestinal and hepatobiliary malignancies within the Reirradiation Collaborative Group (ReCOG) convened to review published literature on reirradiation in the abdomen to offer insights into patient selection, radiotherapy planning, risk management, and assessing knowledge gaps for future development of guidelines.<br><br>METHODS AND MATERIALS: A systematic search of Cochrane Central, CINAHL Plus, EMBASE, and PubMed up to August 30, 2024, was conducted as per Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) framework. Data on patient characteristics, radiation doses, dose constraints, treatment outcomes, and toxicities were extracted. Where feasible, pooled weighted analyses were performed.<br><br>RESULTS: Thirty-three studies involving 1,264 patients met inclusion criteria: 30 were retrospective and 3 prospective. The median number of patients reported per study was 26 (range 2-245). Of the reported tumor sites, 718 patients had liver tumors and 277 pancreas, with smaller numbers of mixed/lymph node targets. Reirradiation doses, fractionation schemes, and dose constraints varied widely; only half of the studies provided explicit organ-at-risk constraints. Three studies included patients treated with palliative intent. Median overall survival ranged from 5.9 to 44&#xa0;months, with a pooled weighted median OS of 19.6&#xa0;months across 20 studies that reported it. One-year local control rates ranged from 19&#xa0;% to 93&#xa0;%, with severe (grade&#xa0;&#x2265;&#xa0;3) toxicities typically reported in 5-15&#xa0;% of patients, although one study reported 25&#xa0;% lethal RILD in liver reirradiation.<br><br>CONCLUSION: Reirradiation in abdominal malignancies appears to be able to achieve meaningful local control and survival in select patients, though heterogeneity in planning, dosing, and toxicity reporting remains a major challenge for establishing best practices. Standardized reporting of doses, constraints, and dose-volume relationships are needed to guide safe and effective reirradiation in this setting.}, }
@article {pmid40899409, year = {2026}, author = {Johnson, T and Spieler, BO and Toskich, BB and Wang, DS and Folkert, MR and Russo, S and Sharma, NK and Kim, CY and Wright, CL and Kappadath, SC and Farsad, K and Muzahir, S and Chundury, A and Parent, EE and Sio, TT and Mercier, GA and Ghesani, MV and Subramaniam, RM and Caplin, D and Small, W and Schechter, NR}, title = {ACR-ABS-ACNM-ARS-SIR-SNMMI Practice Parameter for Radioembolization of Liver Malignancies.}, journal = {American journal of clinical oncology}, volume = {49}, number = {1}, pages = {10-24}, doi = {10.1097/COC.0000000000001234}, pmid = {40899409}, issn = {1537-453X}, mesh = {Humans ; *Liver Neoplasms/radiotherapy/therapy/diagnostic imaging ; *Embolization, Therapeutic/methods/standards ; *Yttrium Radioisotopes/therapeutic use ; Brachytherapy/methods ; Nuclear Medicine/standards ; Societies, Medical ; }, abstract = {OBJECTIVES: The practice parameter was revised collaboratively by the American College of Radiology (ACR), the American Brachytherapy Society (ABS), the American College of Nuclear Medicine (ACNM), the American Radium Society (ARS), the Society of Interventional Radiology (SIR), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). This document summarizes current evidence-based guidelines for the administration of Yttrium radioembolic therapy to the liver, including training requirements, evidence-based guidelines for administration, and safe practice for administration.<br><br>METHODS: This practice parameter was revised according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters-Interventional and Cardiovascular Radiology of the ACR Commission on Interventional and Cardiovascular, Committee on Practice Parameters and Technical Standards-Nuclear Medicine and Molecular Imaging of the ACR Commission on Nuclear Medicine and Molecular Imaging and the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ABS, the ACNM, the ARS, the SIR, and the SNMMI.<br><br>RESULTS: This review seeks not to be a comprehensive discussion of radiotherapy to the liver, but rather, seeks to provide a parameter for safe and effective therapy. We discuss the qualifications of physicians involved in this therapy, basic indications, contraindications, procedural work-up, safe-handling, and regulatory requirement for the administration of selective internal radiation therapy to patients that are likely to benefit. The goal of this document is not to define which patients are best treated by these therapies, as this is best determined for individual patients after multidisciplinary review. A consistent and evidence-based approach to therapy, however, would benefit all patients who are offered this therapy. This document seeks to provide a framework for current best practices for the administration of the 2 currently available radioembolization devices.<br><br>CONCLUSIONS: As Yttrium-90 radiotherapy to the liver occupies a growing role in the treatment of primary and metastatic liver cancer, this review seeks to assist clinicians of all involved specialties to optimize the efficacy and safety of these procedures.}, }
@article {pmid40902330, year = {2025}, author = {Colbert, CM and Kruse, E and Jacqmin, D and Pichardo, JC and Wang, C and Schubert, LK and Bennett, S and Lin, MH and Olsen, L and Li, B and Kim, M}, title = {Virtual radiotherapy plan quality education: Perspectives from a global setting.}, journal = {Physica medica : PM : an international journal devoted to the applications of physics to medicine and biology : official journal of the Italian Association of Biomedical Physics (AIFB)}, volume = {137}, number = {}, pages = {105069}, doi = {10.1016/j.ejmp.2025.105069}, pmid = {40902330}, issn = {1724-191X}, mesh = {Humans ; *Radiotherapy Planning, Computer-Assisted ; *Education, Distance ; *Internationality ; Quality Control ; *Radiation Oncology/education ; }, abstract = {PURPOSE: Evaluation of treatment plan quality is a critical element of training for radiotherapy professionals. With the increased adoption of intensity modulated radiotherapy internationally, this training is crucial to address patient care inequity. We aim to evaluate learning outcomes from a 14-session remote training course targeting critical elements of plan quality with advanced modalities.<br><br>METHODS: The virtual training course was delivered to over 500 radiotherapy professionals in North Africa. Attendees completed online pre- and post-course knowledge assessments, and surveys of their confidence in core competencies. Paired t-tests, general linear regression, and ANOVA were used to evaluate learning outcomes.<br><br>RESULTS: On the pre-course knowledge assessment, attendees scored a mean of 3.97&#xa0;&#xb1;&#xa0;1.54 out of 10. After the course, remaining attendees' scores increased to a mean of 4.88&#xa0;&#xb1;&#xa0;1.86 (p&#xa0;<&#xa0;0.001). Mean confidence scores increased from 2.28&#xa0;&#xb1;&#xa0;1.22 to 3.70&#xa0;&#xb1;&#xa0;0.76 out of 5. Confidence scores varied significantly with enrollees' years of experience, clinical role, and involvement in treatment planning (p&#xa0;<&#xa0;0.05). However, pre-course knowledge scores only varied based on clinicians' current involvement in advanced treatment planning (p&#xa0;<&#xa0;0.01). The improvement in knowledge score from baseline increased significantly with course attendance (p&#xa0;=&#xa0;0.02).<br><br>CONCLUSIONS: This course produced positive overall learning outcomes, particularly with advanced treatment planning modalities. Attendees gained practical experience applying rigorous plan quality criteria. The study results support the crucial importance of continuing education and hands-on experience in the rapidly advancing technological environment of radiation oncology.}, }
@article {pmid40903320, year = {2025}, author = {Bakaloudi, DR and Koehne, EL and Voutsinas, JM and Diamantopoulos, L&#x39d; and Makrakis, D and Grivas, P and True, LD and Tretiakova, MS and Vakar-Lopez, F and Psutka, SP and Holt, SK and Gore, JL and Lin, DW and Schade, GR and Nyame, YA and Hsieh, AC and Yezefski, T and Hawley, JE and Schweizer, MT and Cheng, HH and Yu, EY and Montgomery, RB and Wu, QV and Wright, JL}, title = {Agreement between transurethral resection of bladder tumor and radical cystectomy pathology in patients with bladder cancer subtype histology: A retrospective cohort study.}, journal = {Urologic oncology}, volume = {43}, number = {12}, pages = {695.e21-695.e29}, doi = {10.1016/j.urolonc.2025.07.024}, pmid = {40903320}, issn = {1873-2496}, mesh = {Humans ; *Urinary Bladder Neoplasms/surgery/pathology ; *Cystectomy/methods ; Retrospective Studies ; Male ; Female ; Aged ; Middle Aged ; Cohort Studies ; Aged, 80 and over ; Transurethral Resection of Bladder ; }, abstract = {INTRODUCTION AND OBJECTIVES: Transurethral Resection of Bladder Tumor (TURBT) is a diagnostic staging procedure for bladder cancer (BC). Its pathologic interpretation may be limited by cautery artifact, lack of spatial orientation of tumor specimens, inter-pathologist variance in identifying subtypes, and sampling bias. Accurately identifying subtype histology (SH) on TURBT is critical for clinical decisions. We compared the agreement between TURBT and radical cystectomy (RC) pathology in patients with SH BC.<br><br>METHODS: We examined TURBT and RC pathology of patients who underwent RC at our institution. We included patients with pure SH and mixed histologies in either TURBT or RC specimens. Cohen's kappa coefficient was used to determine the degree of agreement between TURBT and RC.<br><br>RESULTS: From 1135 RC performed, 650 (57%) patients had SH in either TURBT or RC; 225 patients were (y)pT0 at the time of RC and 36 patients had rare histologies, leaving 389 patients for analysis. 172 (44%) patients had an exact match between TURBT and RC. We found a high level of agreement between TURBT and RC in pure non-UC histology (kappa range: 0.82-0.98). In contrast, we found substantial (sarcomatoid; kappa 0.70), moderate (squamous, glandular, plasmacytoid, small cell/neuroendocrine; kappa range: 0.42-0.55) and fair (micropapillary; kappa 0.38) concordance between TURBT and RC in patients with UC mixed with SH.<br><br>CONCLUSIONS: We found variable levels of agreement of SH detection between TURBT and RC. Agreement was high in pure non-UC histology. Further, we found that NAT, completeness of TURBT, and >50% SH at TURBT are associated with the persistence of SH at RC. Future efforts are needed to develop reproducible diagnostic tools for accurate characterization of SH in UC.}, }
@article {pmid40904946, year = {2025}, author = {Cho, Y and Zheng, C and Qi, L and Prentice, RL and Zhang, MJ}, title = {Causal effect estimation for competing risk data in randomized trial: adjusting covariates to gain efficiency.}, journal = {Journal of applied statistics}, volume = {52}, number = {11}, pages = {2094-2112}, pmid = {40904946}, issn = {0266-4763}, support = {HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; U54 GM115458/GM/NIGMS NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; R01 CA119171/CA/NCI NIH HHS/United States ; }, abstract = {The double-blinded randomized trial is considered the gold standard to estimate the average causal effect (ACE). The naive estimator without adjusting any covariate is consistent. However, incorporating the covariates that are strong predictors of the outcome could reduce the issue of unbalanced covariate distribution between the treated and controlled groups and can improve efficiency. Recent work has shown that thanks to randomization, for linear regression, an estimator under risk consistency (e.g. Random Forest) for the regression coefficients could maintain the convergence rate even when a nonparametric model is assumed for the effect of covariates. Also, such an adjusted estimator will always lead to efficiency gain compared to the naive unadjusted estimator. In this paper, we extend this result to the competing risk data setting and show that under similar assumptions, the augmented inverse probability censoring weighting (AIPCW) based adjusted estimator has the same convergence rate and efficiency gain. Extensive simulations were performed to show the efficiency gain in the finite sample setting. To illustrate our proposed method, we apply it to the Women's Health Initiative (WHI) dietary modification trial studying the effect of a low-fat diet on cardiovascular disease (CVD) related mortality among those who have prior CVD.}, }
@article {pmid40905099, year = {2026}, author = {Gem, H and Ebadi, M and Sebastian, G and Abasaeed, R and Lloid, M and Minot, SS and Dean, DR and Rashidi, A}, title = {Dental plaque microbiota following allogeneic hematopoietic cell transplantation and risk of chronic graft-versus-host disease.}, journal = {Haematologica}, volume = {111}, number = {2}, pages = {620-631}, pmid = {40905099}, issn = {1592-8721}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Graft vs Host Disease/etiology/diagnosis/microbiology ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Female ; Male ; Middle Aged ; Adult ; *Dental Plaque/microbiology ; *Microbiota ; Transplantation, Homologous ; Chronic Disease ; Aged ; Young Adult ; }, abstract = {Microbiota disruptions have been associated with short-term complications after allogeneic hematopoietic cell transplantation (alloHCT). However, only a few studies have examined the relationship between dysbiosis and chronic graft-versus-host disease (cGvHD), the main long-term immunologic toxicity of alloHCT. Considering the role of oral microbiota in systemic inflammatory diseases, we evaluated whether oral microbiota at day 28 post HCT corresponding to clinical recovery from the acute events after transplantation is associated with subsequent cGvHD. Shotgun metagenomic sequencing of 207 saliva and supragingival plaque samples collected longitudinally at baseline (pre-conditioning), day +28, and day +84 from 37 patients (11 with subsequent moderate/severe cGvHD) revealed a significant association between day +28 plaque microbiota composition and cGvHD. Two orthogonal statistical approaches demonstrated Streptococcus sanguinis and Prevotella loescheii in day +28 plaque to be associated with cGvHD. Metagenome-based functional analysis identified 4 microbial metabolic pathways associated with future cGvHD, 2 of which were highly attributed to S. sanguinis. These pathways - ethanolamine utilization and glycerol metabolism - increase bacterial fitness by providing an alternative carbon/nitrogen source and improving survival in inflamed tissues. Our findings propose a novel mechanism by which the early post-transplant dental biofilm may contribute to cGvHD months later, offering a potential target for early prophylactic intervention.}, }
@article {pmid40905566, year = {2025}, author = {Merli, P and Masetti, R and Pigazzi, M and Girardi, K and Miele, E and Bresolin, S and Baccelli, F and Peplinski, JH and Becilli, M and Paganelli, V and Strocchio, L and Buldini, B and Pagliara, D and Meshinchi, S and Locatelli, F}, title = {Sensitivity of Pediatric Myelodysplastic Syndromes With Excess of Blasts With UBTF -TD to Venetoclax/Azacitidine.}, journal = {American journal of hematology}, volume = {100}, number = {11}, pages = {2160-2164}, doi = {10.1002/ajh.70056}, pmid = {40905566}, issn = {1096-8652}, support = {//Fondazione Umberto Veronesi (F.L.)/ ; AIRCIG26039//Fondazione AIRC/ ; }, mesh = {Adolescent ; Child ; Humans ; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Azacitidine/administration &amp; dosage ; Bridged Bicyclo Compounds, Heterocyclic/administration &amp; dosage/therapeutic use ; Hematopoietic Stem Cell Transplantation ; *Myelodysplastic Syndromes/genetics/drug therapy/therapy ; Sulfonamides/administration &amp; dosage ; }, abstract = {UBTF-TD has been reported in a significant percentage of childhood MDS-EB and has been associated with inferior survival compared to that of patients with the wild-type gene. We treated three consecutive pediatric patients affected by UBTF-TD MDS-EB with venetoclax and azacitidine (ven/aza) in combination as 28-day cycles on a compassionate use basis three consecutive pediatric patients affected by UBTF-TD MDS-EB as a bridge to allogeneic HSCT. Treatment with ven/aza was well-tolerated, and all patients responded to the ven/aza course, achieving CR with flow-cytometry negativity. All three patients were bridged to myeloablative HSCT. All patients are disease-free and graft-versus-host disease-free at last follow-up. Comprehensive biological characterization of the disease showed (i) high expression of the BCL2 gene, paralleled by a low expression of BCL2A1 and MCL1; (ii) overexpression of both HOXA and HOXB; and (iii) a distinct methylation signature of patients with UBTF-TD myeloid neoplasms.}, }
@article {pmid40905821, year = {2025}, author = {Lawson-Michod, KA and Johnson, CE and Barnard, ME and Davidson, NR and Collin, LJ and Nix, DA and Huff, CD and Berchuck, A and Salas, LA and Greene, CS and Marks, JR and Peres, LC and Doherty, JA and Schildkraut, JM}, title = {Homologous Recombination Deficiency and Survival in Ovarian High-Grade Serous Carcinoma by Self-Reported Race.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {11}, pages = {2007-2014}, pmid = {40905821}, issn = {1538-7755}, support = {R01 CA188943/CA/NCI NIH HHS/United States ; R01 CA188943-01A1//National Institutes of Health (NIH)/ ; R00 CA277580/CA/NCI NIH HHS/United States ; R01 CA142081/CA/NCI NIH HHS/United States ; P20 GM130454/GM/NIGMS NIH HHS/United States ; R01 CA237170/CA/NCI NIH HHS/United States ; R01 CA200854/CA/NCI NIH HHS/United States ; R01 CA076016/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; Black or African American/genetics/statistics &amp; numerical data ; *Cystadenocarcinoma, Serous/genetics/mortality/pathology/ethnology ; *Homologous Recombination ; *Ovarian Neoplasms/genetics/mortality/pathology/ethnology ; Self Report ; White/genetics/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Half of ovarian high-grade serous carcinomas (HGSC) have homologous recombination deficiency (HRD). However, HRD is not well characterized in Black individuals who experience worse survival after a diagnosis of HGSC. The objective of this study was to characterize ovarian HGSC HRD and examine its association with survival by self-reported race.<br><br>METHODS: HRD features were identified using matched tumor-normal whole-exome and RNA sequencing in an HGSC cohort. We calculated age- and stage-adjusted HR and 95% confidence intervals (CI) for survival, comparing individuals with a feature to those without, separately by self-reported race.<br><br>RESULTS: Any HRD was associated with a 32% reduced risk of death in Black individuals compared with a 62% reduction in White individuals (Black HR = 0.68; 95% CI, 0.43-1.09; White HR = 0.38; 95% CI, 0.14-1.04). More of the germline and somatic variants detected among Black individuals were unannotated or variants of uncertain significance (VUS; germline 65% vs. 45%; somatic 62% vs. 50%). Black individuals with germline unannotated/VUS were more likely to have tumors with HRD scarring and a first-degree family history of breast or ovarian cancer compared with those without (HRD scar 71.4% vs. 49.6%; family history 68.4% vs. 34.6%).<br><br>CONCLUSIONS: HRD testing informs precision-based medicine approaches that improve outcomes, but a higher proportion of VUS among Black individuals may complicate referral for such care leading to worse outcomes for Black individuals.<br><br>IMPACT: Our findings emphasize the importance of recruiting diverse individuals in genomics research and better characterizing VUS.}, }
@article {pmid40906320, year = {2025}, author = {Ilozumba, MN and Gomez, MF and Lin, T and Himbert, C and Round, JL and Zac Stephens, W and Warby, CA and Hardikar, S and Li, CI and Figueiredo, JC and Damerell, V and Fillmore, GC and Pickron, B and Toriola, AT and Shibata, D and Holowatyj, AN and Kahlert, C and Sankar, K and Siegel, EM and Jedrzkiewicz, J and Gigic, B and Byrd, DA and Ose, J and Ulrich, CM}, title = {Pre-surgery gut microbial diversity and abundance are associated with post-surgery onset of cachexia in colorectal cancer patients: the ColoCare Study.}, journal = {Cancer causes &amp; control : CCC}, volume = {36}, number = {12}, pages = {1795-1812}, pmid = {40906320}, issn = {1573-7225}, support = {01KD2101D//the German Ministry of Education and Research project PerMiCCion/ ; R01 AG083580/AG/NIA NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA206110/CA/NCI NIH HHS/United States ; R01 CA207371/CA/NCI NIH HHS/United States ; R01 CA254108/CA/NCI NIH HHS/United States ; R01 CA211705/CA/NCI NIH HHS/United States ; U01 CA206110, R01 CA189184, R01 CA207371, R01 CA211705, R01 CA254108//National Institutes of Health/ National Cancer Institute/ ; }, mesh = {Humans ; Male ; *Cachexia/etiology/microbiology ; Female ; *Colorectal Neoplasms/surgery/microbiology/complications/pathology ; *Gastrointestinal Microbiome/genetics ; Middle Aged ; Aged ; Feces/microbiology ; *Postoperative Complications/etiology ; RNA, Ribosomal, 16S/genetics ; }, abstract = {BACKGROUND: Cachexia accounts for about 20% of all cancer-related deaths and it is indicative of poor prognosis and progressive functional impairment. The role of the gut microbiome in the development of cachexia in colorectal cancer (CRC) patients has not been established.<br><br>METHODS: Pre-surgical stool samples from n&#x2009;=&#x2009;103 stage I-III CRC patients in the ColoCare Study were analyzed using 16S rRNA gene sequencing (Illumina) to characterize fecal bacteria. We calculated estimates of alpha- and beta-diversity and a priori- and exploratory-selected bacterial relative abundance. Using Fearon criteria, cachexia onset at 6&#xa0;months post-surgery was defined as >&#x2009;5% weight loss over the past 6&#xa0;months and/or body mass index (BMI) of <&#x2009;20&#xa0;kg/m[2] and weight loss of >&#x2009;2%. Associations of microbial metrics with cachexia onset were estimated using multivariable logistic regression models.<br><br>RESULTS: Higher alpha-diversity was positively associated with cachexia onset, with stronger associations in females, patients&#x2009;<&#x2009;65&#xa0;years, those receiving adjuvant treatment, consuming high fiber, or with energy intake outside USDA recommendations (p&#x2009;<&#x2009;0.05). Porphyromonas (OR&#x2009;=&#x2009;0.51, 95% CI 0.26-0.89, p&#x2009;=&#x2009;0.03) and Actinomyces (OR&#x2009;=&#x2009;0.72, 95% CI 0.48-1.03, p&#x2009;=&#x2009;0.08) were inversely associated with cachexia, although the association for Actinomyces did not reach statistical significance. Stratified analyses revealed a stronger inverse association between Porphyromonas and cachexia onset in males, patients with rectal or stage III tumors, those receiving neoadjuvant treatment, physically inactive individuals, and those consuming low fiber. However, these associations did not reach statistical significance (0.05&#x2009;&#x2264;&#x2009;p&#x2009;<&#x2009;0.10).<br><br>CONCLUSION: Higher gut microbial alpha-diversity and lower relative abundances of the genera Porphyromonas and Actinomyces in pre-surgery stool samples were associated with onset of cachexia in CRC patients six months post-surgery. This is the first study to explore a link between the gut microbiome and cachexia in CRC patients, providing novel insights into the biology of cachexia and potential clinical interventions.}, }
@article {pmid40906475, year = {2025}, author = {Issaka, RB and Matrajt, L and de Lima, PN and Rutter, CM}, title = {Modeled Cost-Effectiveness of a Rideshare Program to Facilitate Colonoscopy Completion.}, journal = {JAMA network open}, volume = {8}, number = {9}, pages = {e2530515}, pmid = {40906475}, issn = {2574-3805}, support = {R01 MD017599/MD/NIMHD NIH HHS/United States ; U01 CA199335/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colonoscopy/economics/statistics &amp; numerical data ; *Cost-Benefit Analysis ; *Colorectal Neoplasms/diagnosis/economics/prevention &amp; control ; Male ; Female ; Middle Aged ; *Early Detection of Cancer/economics/methods/statistics &amp; numerical data ; Aged ; Occult Blood ; *Mass Screening/economics ; }, abstract = {IMPORTANCE: In colorectal cancer (CRC) screening, too many patients fail to receive follow-up colonoscopy after an abnormal fecal immunochemical test (FIT), and transportation is a frequently reported barrier.<br><br>OBJECTIVE: To determine the outcomes and cost-effectiveness of providing a rideshare intervention to patients with abnormal FIT results.<br><br>The CRC-Simulated Population Model for Incidence and Natural History microsimulation model was used to simulate the outcomes and cost-effectiveness of a rideshare intervention to improve colonoscopy completion in a population-based CRC screening program. Cohorts were adherent to annual FIT-based screening; baseline analyses assumed that 35% would complete a follow-up colonoscopy. Data were analyzed from November 14, 2023, to July 8, 2025.<br><br>INTERVENTION: A $40 or $100 rideshare to increase completion of follow-up colonoscopy.<br><br>MAIN OUTCOMES AND MEASURES: Lifetime outcomes included the number of CRC cases, deaths, and life-years gained (LYG) per 1000 people screened and costs associated with improved completion of a colonoscopy after an abnormal FIT result.<br><br>RESULTS: Four single-age cohorts (ages 45, 55, 65, and 70 years on January 1, 2024) of 10 million people each were simulated. In cohorts with similar sex distribution as the US population (aged 45 years, 50.0% male; aged 55 years, 49.4% male); aged 65 years, 48.0% male; and aged 70 years, 46.9% male), compared with no intervention, using a rideshare intervention starting at age 45 years that costs $100 per ride to increase colonoscopy completion from 35% to 70% was associated with a reduction in CRC cases per 1000 by 26.3% (30.7 vs 41.6 cases per 1000), CRC deaths per 1000 by 32.5% (9.8 vs 14.6 cases per 1000), 24.9 LYG per 1000, and at $100 per ride cost $43&#x202f;308 per 1000 people screened and saved $330&#x202f;587 per 1000 people screened.<br><br>CONCLUSIONS AND RELEVANCE: In a microsimulation model, increasing colonoscopy completion in a population with abnormal FIT results via a rideshare intervention was cost saving up to $100 per ride due to the combined outcome of cancer prevention and early detection.}, }
@article {pmid40906481, year = {2025}, author = {Osazuwa-Peters, N and Gao, MZ and Kahmke, RR and Ramkumar, SP and Bates, NE and Scherrer, JF}, title = {Preexisting Psychiatric Risk Factors and Any and Long-Term Opioid Use in Head and Neck Cancer.}, journal = {JAMA otolaryngology-- head &amp; neck surgery}, volume = {151}, number = {12}, pages = {1166-1174}, pmid = {40906481}, issn = {2168-619X}, support = {R21 DE032531/DE/NIDCR NIH HHS/United States ; }, mesh = {Humans ; Male ; Female ; *Analgesics, Opioid/therapeutic use ; *Head and Neck Neoplasms/psychology/complications ; Middle Aged ; Retrospective Studies ; Risk Factors ; Longitudinal Studies ; *Mental Disorders/complications/epidemiology ; Aged ; Adult ; United States/epidemiology ; }, abstract = {INTRODUCTION: Head and neck cancer (HNC), one of the most emotionally distressing cancers, carries a significant burden of psychiatric comorbidities. While opioids are commonly prescribed in cancer care, the association between preexisting psychiatric risk factors and prescription opioid use in HNC remains unclear.<br><br>OBJECTIVE: To test the hypothesis that preexisting psychiatric risk factors are associated with any opioid prescription and long-term opioid therapy in patients with HNC.<br><br>This retrospective longitudinal cohort study used deidentified data from the Optum electronic health record database, comprising a random sample of 5 million patients across the US between January 2010 and December 2018. Eligible patients were adults diagnosed with HNC. Using a 2-year look-back prior to the index date of HNC diagnosis, patients who used prescription opioids prior to HNC diagnosis were excluded. The data analysis was conducted between July 2022 and July 2023.<br><br>MAIN OUTCOMES AND MEASURES: Outcomes of interest were receipt of any prescription opioid within 12 months of index HNC and long-term opioid therapy (LTOT), defined as 10 or more opioid prescriptions within 12 months of index HNC. Psychiatric risk factors included anxiety disorders, depression, smoking/nicotine dependence, substance use disorders, and benzodiazepine prescription. Multivariate logistic regression estimated the odds of opioid use based on preexisting psychiatric factors.<br><br>RESULTS: Of 20&#x202f;286 patients with an HNC diagnosis, 11&#x202f;335 met all eligibility criteria. Patients in the analytic cohort had a mean (SD) age of 57.1 (15.5) years, and 55.4% were female. Within 12 months of HNC diagnosis, 23.4% received an opioid prescription, and 4.9% received LTOT. In fully adjusted models, depression (adjusted odds ratio [aOR], 1.21; 95% CI, 1.01-1.45), nicotine dependence (aOR, 1.56; 95% CI, 1.40-1.73), and benzodiazepine comedication (aOR, 1.44; 95% CI, 1.22-1.70) were associated with increased odds of receiving any opioid prescription. Furthermore, male patients had 49% greater odds of receiving opioid prescriptions (aOR, 1.49; 95% CI, 1.36-1.64). Only smoking/nicotine dependence was associated with increased odds of LTOT (aOR, 1.77; 95% CI, 1.21-2.61).<br><br>CONCLUSIONS AND RELEVANCE: Preexisting psychiatric comorbidities, especially depression and smoking/nicotine dependence, were associated with increased odds of prescription opioid use and LTOT in patients with HNC in this longitudinal cohort study. Screening for these comorbidities during the management of patients with HNC can be impactful in informing clinical decisions that contribute to safer opioid prescribing.}, }
@article {pmid40907068, year = {2025}, author = {Beckers, F and Karkada, N and Yang, Y and Scott, J and Huang, L and Klinglmüller, F and Fay, MP and Englert, S and Spiessens, B and Van Dromme, I and Shekar, T and Zhou, H and Deng, Q and Casula, D and Janes, H and Moulton, LH}, title = {Adopting the estimand framework in prophylactic vaccine trials.}, journal = {Vaccine}, volume = {64}, number = {}, pages = {127645}, pmid = {40907068}, issn = {1873-2518}, support = {FD999999/ImFDA/Intramural FDA HHS/United States ; }, mesh = {Humans ; *Vaccines/immunology/administration &amp; dosage ; *Clinical Trials as Topic/methods ; Vaccination ; Research Design ; Immunization Schedule ; }, abstract = {The estimand framework as outlined in ICH E9(R1) has been extensively discussed and implemented in clinical trials of therapeutic products. However, there is limited literature on the application of the framework in preventive vaccine trials, which has many unique characteristics, including emphasis on estimating the per-protocol or "biological" effect. We provide a comprehensive review of the application of the framework to preventive vaccine trials evaluating clinical outcome and immunogenicity, focusing on commonly encountered intercurrent events including but not limited to: noncompliance with vaccination schedule and blood sampling window, infection not meeting protocol definition, death, and use of prohibited products. We discuss various considerations in choosing strategies to handle intercurrent events in terms of their utility in addressing the scientific questions. Finally, we provide considerations and examples for summarizing study estimands and data handling which may be incorporated into the protocol and statistical analysis plan.}, }
@article {pmid40907516, year = {2025}, author = {Gui, C and Wang, JZ and Patil, V and Landry, AP and Singh, O and Castelo-Branco, P and Tabori, U and Aldape, K and Behling, F and Barnholtz-Sloan, JS and Horbinski, C and Tabatabai, G and Ajisebutu, A and Liu, J and Patel, Z and Yakubov, R and Kaloti, R and Ellenbogen, Y and Wilson, C and Cohen-Gadol, A and Tatagiba, M and Holland, EC and Sloan, AE and Chotai, S and Chambless, LB and Gao, A and Makarenko, S and Yip, S and Nassiri, F and Zadeh, G and , }, title = {Analysis of TERT association with clinical outcome in meningiomas: a multi-institutional cohort study.}, journal = {The Lancet. Oncology}, volume = {26}, number = {9}, pages = {1191-1203}, doi = {10.1016/S1470-2045(25)00267-0}, pmid = {40907516}, issn = {1474-5488}, mesh = {Humans ; *Telomerase/genetics ; *Meningioma/genetics/pathology/mortality/surgery ; Male ; Female ; Middle Aged ; Promoter Regions, Genetic ; Mutation ; Retrospective Studies ; *Meningeal Neoplasms/genetics/pathology/mortality/surgery ; Aged ; Adult ; Prognosis ; Progression-Free Survival ; *Biomarkers, Tumor/genetics ; Canada ; Cohort Studies ; }, abstract = {BACKGROUND: TERT promoter mutation is a rare biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival. Although high TERT expression is characteristic of tumours with TERT promoter mutations, it has also been observed in tumours with wildtype TERT promoters. This study aimed to investigate the prevalence and prognostic association of TERT expression in meningiomas.<br><br>METHODS: This multi-institutional cohort study retrospectively collected clinical and molecular data from 1241 meningiomas surgically resected between Jan 1, 2000, and Dec 31, 2024, at Toronto Western Hospital, Canada (n=380; discovery cohort) and external institutions in Canada, Germany, and the USA (n=861; validation cohort). All patients were aged 18 years and older. TERT promoter mutation and TERT expression were determined by Sanger and bulk RNA sequencing. The primary outcomes were TERT expression (presence or absence) in meningiomas with and without TERT promoter mutations, and the difference in progression-free survival between tumours expressing TERT and those not expressing TERT. Survival analysis was assessed using Cox regression and Kaplan-Meier analysis.<br><br>FINDINGS: Between Jan 1, 2000, and Dec 31, 2024, clinical demographics and tumour characteristics were collected. Median follow-up was 6&#xb7;2 years (IQR 1&#xb7;7-12&#xb7;5) in the discovery cohort and 3&#xb7;3 years (1&#xb7;3-3&#xb7;8) in the validation cohort. 777 (65&#xb7;8%) of 1181 patients with sex data in the overall cohort were female; 404 (34&#xb7;2%) were male. TERT was expressed in 157 (28&#xb7;7%) of 547 wildtype TERT promoter meningiomas and in 193 (32&#xb7;0%) of 604 overall with RNA data. TERT expression overall conferred an intermediate progression-free survival, shorter than that in patients with TERT-negative tumours but longer than in those with TERT promoter mutations. In the discovery cohort, median progression-free survival was 3&#xb7;2 years (95% CI 1&#xb7;7-6&#xb7;5) in patients with wildtype TERT promoter tumours expressing TERT, 16&#xb7;0 years (7&#xb7;1 to not reached; p=0&#xb7;0021) in patients with TERT-negative wildtype TERT promoter tumours, and 1&#xb7;6 years (0&#xb7;9 to not reached; p=0&#xb7;039) in patients with TERT promoter mutations. These findings were replicated in the validation cohort. Within each WHO grade, TERT expression conferred a progression-free survival equivalent to TERT-negative meningiomas of one grade higher. Grade 1 tumours with TERT expression had a progression-free survival similar to TERT-negative grade 2 tumours (median not reached [95% CI 16&#xb7;0 to not reached] vs 8&#xb7;2 years [95% CI 4&#xb7;5 to not reached]; p=0&#xb7;59). Grade 2 tumours with TERT expression had a similar progression-free survival to TERT-negative grade 3 tumours (median 3&#xb7;6 years [2&#xb7;4 to 5&#xb7;3] vs 3&#xb7;8 years [2&#xb7;3 to not reached]; p=0&#xb7;42). Multivariable regression showed that TERT expression remained associated with shorter progression-free survival even after adjusting for TERT promoter mutations, CDKN2A/B loss, chromosome 1p/22q status, and WHO grade (hazard ratio 1&#xb7;85 [95% CI 1&#xb7;33-2&#xb7;57]; p=0&#xb7;0002).<br><br>INTERPRETATION: TERT expression in meningiomas predicted earlier disease progression, independent of TERT promoter mutation and other markers, and might warrant reclassification of meningiomas that express TERT to a higher WHO grade.<br><br>FUNDING: Canadian Institutes of Health Research, Brain Tumour Charity UK, University Health Network Foundation, Mary Hunter Meningioma Research Fund, V Foundation, and National Institutes of Health.}, }
@article {pmid40907772, year = {2026}, author = {Ali, M and Correa, RJM and Pryor, D and Higgs, B and Sridharan, S and Sidhom, M and Muacevic, A and Onishi, H and Swaminath, A and Grubb, W and Yang, DX and Grant, A and Morgan, SC and Ponsky, L and Cury, FL and Teh, BS and Lo, SS and Mahadevan, A and Kaplan, ID and Chu, W and Hannan, R and Staehler, M and Zaorsky, NG and Warner, A and Louie, AV and Siva, S}, title = {Efficacy of SABR in Uncommon Subtypes of Primary Kidney Cancer: An Analysis From the International Radiosurgery Oncology Consortium of the Kidney.}, journal = {International journal of radiation oncology, biology, physics}, volume = {125}, number = {1}, pages = {146-153}, doi = {10.1016/j.ijrobp.2025.08.043}, pmid = {40907772}, issn = {1879-355X}, mesh = {Humans ; *Kidney Neoplasms/radiotherapy/pathology/mortality ; *Radiosurgery/methods/adverse effects/mortality ; Male ; Female ; Aged ; Middle Aged ; *Carcinoma, Renal Cell/radiotherapy/pathology/mortality ; Aged, 80 and over ; Treatment Outcome ; Adult ; Kaplan-Meier Estimate ; }, abstract = {PURPOSE: While SABR is associated with excellent local control of primary renal cell carcinoma (RCC), outcomes based on clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) histologies are not well defined. This retropsective study's objective is to report the outcomes following SABR for uncommon subtypes of primary RCC.<br><br>METHODS AND MATERIALS: Individual data of adult patients with biopsy-confirmed primary RCC receiving SABR between 2007 and 2021 from 16 institutions in Australia, Canada, Germany, Japan, and the USA were pooled. Patients with metastatic disease or upper tract urothelial carcinoma were excluded. The primary outcome was local failure (LF), based on the Response Evaluation Criteria in Solid Tumors version 1.1. Distant failure (DF), cancer-specific survival (CSS), treatment-related toxicity, and renal function changes following SABR were defined as secondary outcomes. Kaplan-Meier estimates were generated for LF, DF, and CSS stratified by ccRCC versus nccRCC histology, and compared using the log-rank test (for CSS) or Gray's test (for LF and DF).<br><br>RESULTS: Two hundred eleven patients with a biopsy-confirmed ccRCC (n = 167) or nccRCC (n = 44) were included. In the nccRCC group, 59% (n = 26/44) and 11% (n = 5/44) were papillary and chromophobe histologies, respectively. Patients with nccRCC were more likely to be older (median age at SABR, 77.2 years vs 71.5; p = .009) and to be treated with multifraction SABR (82% [n = 36/44] vs 38% [n = 63/167]; p < .001) than the ccRCC group. The median follow-up was 4.02 years (IQR, 3.43-4.94) and 4.25 years (IQR, 3.02-5.00) for the ccRCC and nccRCC groups, respectively. The 5-year cumulative incidence of LF was 1.5% (95% CI, 0.3%-4.8%) in the ccRCC group versus 2.4% (95% CI, 0.2%-11.0%) in the nccRCC group (hazard ratio [HR], 0.90; 95% CI, 0.10-8.31; p = .922). The corresponding cumulative incidence of DF at 5 years was 6.0% in the ccRCC group versus 2.9% in the nccRCC group (HR, 0.34; 95% CI, 0.04-2.68; p = .304). The 5-year estimated CSS was 96.4% in the ccRCC group versus 96.4% in the nccRCC group (HR, 2.04; p = .561). From baseline, the mean &#xb1; SD estimated glomerular filtration rate reduced by 11.4 &#xb1; 13.4 mL/min at 3 years and by 12.2 &#xb1; 14.0 mL/min at 5 years. Sixteen patients (7.6%) experienced grade 2 or higher toxicities, with grade 2 fatigue (5.7%) being the most common.<br><br>CONCLUSIONS: SABR provides excellent oncologic outcomes, irrespective of ccRCC or nccRCC histology.}, }
@article {pmid40908355, year = {2025}, author = {Chu, HY and Janes, H and Carone, M and Gilbert, PB and Plotkin, S}, title = {Improving the evidence base for COVID-19 vaccines.}, journal = {Nature medicine}, volume = {31}, number = {11}, pages = {3595-3596}, pmid = {40908355}, issn = {1546-170X}, }
@article {pmid40909525, year = {2025}, author = {Jena, S and Lawore, D and Briones, JM and Birse, K and Lamont, A and Mackelprang, RD and Noel-Romas, L and Perner, M and Hou, X and Irungu, E and Mugo, N and Knodel, S and Brubaker, SD and Muwonge, TR and Katabira, E and Hughes, SM and Calienes, FL and Krajci, R and Liu, R and Nemecio, D and Hladik, F and Lingappa, J and Burgener, AD and Berard, AR and Green, LN and Brubaker, DK}, title = {Identifying a Vaginal Microbiome-Derived Selective Antibiotic Metabolite via Microbiome Pharmacology Analysis.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909525}, issn = {2692-8205}, support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 AI111738/AI/NIAID NIH HHS/United States ; R01 HD110367/HD/NICHD NIH HHS/United States ; }, abstract = {The vaginal microbiome plays a critical role in maintaining immune and epithelial homeostasis in the female reproductive tract. Bacterial Vaginosis (BV) is deleterious to female health, causing the loss of beneficial Lactobacillus species, overgrowth of anaerobic taxa, changes in vaginal pH, breakdown of protective mucins and epithelial barriers, and activation of the immune system. Treatment with gel-based antibiotics (Metronidazole or Clindamycin) resolves BV for 85% of patients, but 50% of those cases recur, indicating a need to identify strategies for overcoming antibiotic resistance and achieving a more durable response. Here, we developed a systems biology approach termed Microbiome Pharmacology Analysis to characterize the antibiotic potential of vaginal microbes, their metabolites and functions, via computational fusion of human cohort multi-omics and post-drug perturbation transcriptomic profiles. We focused on Clindamycin and Metronidazole as candidate drugs and screened 780 vaginal microbiome-drug mimicry candidates to identify candidate taxa and metabolites with antibiotic potential. We demonstrate experimentally that Lactobacillus crispatus-derived Hydroxyisocaproate (HICA) selectively kills Gardnerella vaginalis and that HICA enhances epithelial barrier integrity in a human vagina-on-a-chip system. Our work demonstrates the first use of Pharmacobiome Analysis, for discovering novel, selective antibiotic metabolites for BV with implications for charting the full pharmacologic potential of the vaginal microbiome.}, }
@article {pmid40909540, year = {2025}, author = {Ockerman, F and Chen, B and Sun, Q and Kharitonova, EV and Chen, W and Zhou, LY and Loos, RJF and Kooperberg, C and Peters, U and Haessler, J and Reiner, A and Jung, SY and Manson, JE and Nassir, R and North, KE and Buyske, S and Haiman, CA and Conti, DV and Wilkens, LR and Lange, EM and Cox, NJ and Cao, H and Raffield, LM and Li, Y and Tao, R}, title = {An Efficient Lasso Framework for Admixture-Aware Polygenic Scores.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909540}, issn = {2692-8205}, support = {HHSN268201300003I/HL/NHLBI NIH HHS/United States ; N01 HC065233/HL/NHLBI NIH HHS/United States ; N01 HC065236/HL/NHLBI NIH HHS/United States ; N01 HC065235/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; N01 HC065234/HL/NHLBI NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; R01 AR083790/AR/NIAMS NIH HHS/United States ; U01 HG011715/HG/NHGRI NIH HHS/United States ; HHSN268201300005C/HL/NHLBI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; U01 HG007419/HG/NHGRI NIH HHS/United States ; HHSN268201300004C/HL/NHLBI NIH HHS/United States ; 75N92021D00005/WH/WHI NIH HHS/United States ; HHSN268201300001C/HL/NHLBI NIH HHS/United States ; U01 HG011720/HG/NHGRI NIH HHS/United States ; U24 AR076730/AR/NIAMS NIH HHS/United States ; HHSN268201300003C/HG/NHGRI NIH HHS/United States ; R01 HL146500/HL/NHLBI NIH HHS/United States ; N01 HC065237/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, abstract = {Polygenic scores (PGS) have promising clinical applications for risk stratification, disease screening, and personalized medicine. However, most PGS are trained on predominantly European ancestry cohorts and have limited portability to external populations. While cross-population PGS methods have demonstrated greater generalizability than single-ancestry PGS, they fail to properly account for individuals with recent admixture between continental ancestry groups. GAUDI is a recently proposed PGS method which overcomes this gap by leveraging local ancestry to estimate ancestry-specific effects, penalizing but allowing ancestry-differential effects. However, the modified fused LASSO approach used by GAUDI is computationally expensive and does not readily accommodate more than two-way admixture. To address these limitations, we introduce HAUDI, an efficient LASSO framework for admixed PGS construction. HAUDI re-parameterizes the GAUDI model as a standard LASSO problem, allowing for extension to multi-way admixture settings and far superior computational speed than GAUDI. In extensive simulations, HAUDI compares favorably to GAUDI while dramatically reducing computation time. In real data applications, HAUDI uniformly out-performs GAUDI across 18 clinical phenotypes, including total triglycerides (TG), C-reactive protein (CRP), and mean corpuscular hemoglobin concentration (MCHC), and shows substantial benefits over an ancestry-agnostic PGS for white blood cell count (WBC) and chronic kidney disease (CKD).}, }
@article {pmid40909667, year = {2025}, author = {Ju, X and Hannon, WW and Kaszuba, T and Radford, CE and Larsen, BB and Nelson, SS and Nelson, CA and Baltazar-Perez, I and Zimmerman, O and Fremont, DH and Diamond, MS and Bloom, JD}, title = {Determinants of human versus mosquito cell entry by the Chikungunya virus envelope proteins.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909667}, issn = {2692-8205}, support = {75N93022C00035/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R01 AI143673/AI/NIAID NIH HHS/United States ; U19 AI181960/AI/NIAID NIH HHS/United States ; R01 AI141707/AI/NIAID NIH HHS/United States ; }, abstract = {Chikungunya virus (CHIKV) infects both humans and mosquitoes during its transmission cycle. How the virus's envelope proteins mediate entry in cells from such different species is unclear. MXRA8 is a receptor for CHIKV in mammalian cells, but the receptor(s) in mosquito cells remains unknown. Here we use pseudovirus deep mutational scanning to measure how nearly all amino-acid mutations to the CHIKV envelope proteins affect entry in MXRA8-expressing human and mosquito cells. Most mutations similarly affect entry in both types of cells, and our comprehensive measurements of these effects define functional constraints related to protein folding and fusion activity. However, some mutations differentially affect entry in MXRA8-expressing human cells versus mosquito cells. Sites where mutations specifically impair entry in MXRA8-expressing human cells are often involved in MXRA8 binding, and we hypothesize sites where mutations specifically impair entry in mosquito cells are involved in binding the unknown mosquito receptor(s). We use the deep mutational scanning data to design loss-of-tropism mutant viruses that are impaired in their ability to infect either mosquito cells or MXRA8-expressing human cells. Our findings provide insights into the species-specific determinants of CHIKV cell entry that can help guide receptor identification and vaccine development.}, }
@article {pmid40909710, year = {2025}, author = {Gautier, O and Blum, JA and Nguyen, TP and Klemm, S and Yamakawa, M and Sinnott-Armstrong, N and Zeng, Y and Davis, CO and Bombosch, J and Nakayama, L and Guttenplan, KA and Chen, D and Kathira, A and Zhao, L and Rexach, JE and Greenleaf, WJ and Gitler, AD}, title = {An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909710}, issn = {2692-8205}, support = {R01 AG075802/AG/NIA NIH HHS/United States ; R01 NS128028/NS/NINDS NIH HHS/United States ; RF1 NS128800/NS/NINDS NIH HHS/United States ; U54 NS123743/NS/NINDS NIH HHS/United States ; R01 AG064690/AG/NIA NIH HHS/United States ; S10 RR025518/RR/NCRR NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; R35 NS137159/NS/NINDS NIH HHS/United States ; }, abstract = {To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named 'disease-associated motor neurons' (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.}, }
@article {pmid40909725, year = {2025}, author = {Hong, A and Liu, M and Truta, A and Talaie, A and Smith, GR and Bondy-Denomy, J}, title = {Gabija restricts phages that antagonize a conserved host DNA repair complex.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909725}, issn = {2692-8205}, support = {R01 AI167412/AI/NIAID NIH HHS/United States ; R35 GM118120/GM/NIGMS NIH HHS/United States ; }, abstract = {Anti-bacteriophage systems like restriction-modification and CRISPR-Cas have DNA substrate specificity mechanisms that enable identification of invaders. How Gabija, a highly prevalent nuclease-helicase anti-phage system, executes self- vs. non-self-discrimination remains unknown. Here, we propose that phage-encoded DNA end-binding proteins that antagonize host RecBCD sensitize phages to Gabija. When targeting a temperate Lambda-like phage in Pseudomonas aeruginosa, Gabija protects the cell by preventing phage genome circularization and subsequent replication. Phage and plasmid sensitivity to Gabija is licensed by DNA end-binding complexes such as a phage exonuclease together with a ssDNA-annealing protein or GamMu dimers, which prevent loading of host repair complex RecBCD. Escape phages lacking these end-binding proteins become protected from Gabija by RecBCD translocation activities. RecBCD activity on the bacterial genome also prevents Gabija from targeting self-DNA. Therefore, we propose that Gabija antagonizes circularization of linear DNA devoid of RecBCD as a mechanism to identify foreign invaders.}, }
@article {pmid40909728, year = {2025}, author = {Romero, EV and Clyde, AE and Giorgi, EE and Westfall, DH and Azam, W and Taylor, ML and Caskey, M and Feder, AF and Cohn, LB}, title = {Distinct modes of evolution drive HIV escape from two broadly neutralizing antibodies.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909728}, issn = {2692-8205}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; }, abstract = {Broadly neutralizing antibodies (bNAbs) show promise for HIV treatment and prevention, but are vulnerable to resistance evolution. Comprehensively understanding in vivo viral escape from individual bNAbs is necessary to design bNAb combinations that will provide durable responses. We characterize viral escape from two such bNAbs, 10-1074 and 3BNC117, using deep, longitudinal sequencing of full length HIV envelope (env) genes from study participants treated with bNAb monotherapy. Improved sequencing depth and computational evolutionary analyses permit us to identify in vivo routes and parallelism underlying HIV escape from each bNAb, providing new insights into this evolutionary process: 10-1074 escape is restricted to a small number of previously documented pathways, but these escape mutations 1) pre-exist in intra-host viral populations before therapy, 2) are not all equally preferred, and 3) emerge with a high degree of genetic parallelism within and across viral populations. In contrast, 3BNC117 escape follows background-specific patterns in which specific escape mutations present in one population rarely emerge or spread in other populations, but often still exhibit parallel evolutionary responses within their host. That bNAbs elicit starkly different in vivo escape profiles depending on their Env target exposes the limitations of generalizing escape patterns across therapies and highlights the substantial challenges in predicting a viral population's bNAb susceptibility from genetic diversity alone.}, }
@article {pmid40909752, year = {2025}, author = {Gieselmann, L and DeLaitsch, AT and Rohde, M and Gruell, H and Kreer, C and Ercanoglu, MS and Gristick, HB and Schommers, P and Ahmadov, E and Radford, C and Mazzolini, A and Zhang, L and West, AP and Worczinski, J and Momot, A and Reichwein, ML and Knüfer, J and Stumpf, R and Mkhize, NN and Kaldine, H and Bhebhe, S and Deshpande, S and Giovannoni, F and Stefanutti, E and Benigni, F and Havenar-Daughton, C and Corti, D and Kroidl, A and Adhikari, A and Nanfack, AJ and Ambada, GE and Duerr, R and Maganga, L and William, W and Ntinginya, NE and Wolf, T and Geldmacher, C and Hoelscher, M and Lehmann, C and Moore, PL and Mora, T and Walczak, AM and Gilbert, PB and Doria-Rose, NA and Huang, Y and Bloom, JD and Seaman, MS and Bjorkman, PJ and Klein, F}, title = {Profiling a large HIV-1 elite neutralizer cohort reveals remarkable CD4bs bNAb for HIV-1 prevention and therapy.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40909752}, issn = {2692-8205}, support = {INV-036842/GATES/Gates Foundation/United States ; U54 AI170856/AI/NIAID NIH HHS/United States ; INV-002143/GATES/Gates Foundation/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; P01 AI100148/AI/NIAID NIH HHS/United States ; R01 AI140891/AI/NIAID NIH HHS/United States ; }, abstract = {Administration of HIV-1 neutralizing antibodies can suppress viremia and prevent infection in vivo. However, clinical use is challenged by broad envelope sequence diversity and rapid emergence of viral escape[1-9]. Here, we performed single B cell profiling of 32 top HIV-1 elite neutralizers to identify broadly neutralizing antibodies (bNAbs) with highest potency and breadth for clinical application. From 831 expressed monoclonal antibodies, we identified 04_A06, a new VH1-2-encoded CD4 binding site bNAb with remarkable breadth and potency against extended multiclade pseudovirus panels (GeoMean IC50 = 0.059 μg/ml, breadth = 98.5%, 332 virus strains). Moreover, 04_A06 was not susceptible to classic viral CD4bs escape variants and maintained full viral suppression in HIV-1-infected humanized mice. Structural analyses revealed that antiviral activity is mediated by an unusually long 11-amino acid heavy chain insertion. This insertion facilitates inter-protomer contacts and interactions with highly conserved residues on the adjacent gp120 protomer. Finally, 04_A06 demonstrated high activity against contemporaneously circulating viruses from the Antibody Mediated Prevention (AMP) trials (GeoMean IC50 = 0.082 μg/ml, breadth = 98.4%, 191 virus strains) and in silico modeling for 04_A06LS predicted HIV-1 prevention efficacy of >93%. Thus, 04_A06 will provide unique opportunities for effective treatment and prevention strategies of HIV-1 infection.}, }
@article {pmid40909820, year = {2025}, author = {Lim, R and O'Connor, C and Pan, J and Tang, TT and Castelo, AH and He, Y and Titt, U and Mohan, R and Liao, Z and Brock, KK}, title = {Weekly changes in ventilation response for photon and proton lung cancer patients during radiotherapy.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40909820}, support = {P01 CA261669/CA/NCI NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; R01 HL157273/HL/NHLBI NIH HHS/United States ; }, abstract = {PURPOSE: Conformal dose distributions in proton radiotherapy promise to reduce normal tissue toxicity such as radiation-induced pneumonitis, but this has not been fully realized in clinical trials. To further investigate dose and toxicity, we employ voxel-based normal tissue evaluation techniques such as ventilation maps throughout treatment. We hypothesize that ventilation change after 1 week of treatment (WK1) predicts for ventilation change at the end of treatment (EOT).<br><br>METHODS: For 48 photon and 23 proton lung cancer patients, 4DCT-based ventilation maps were generated using stress-based methods at planning, WK1, and EOT. Voxel-wise ventilation change from planning to WK1 and EOT was calculated and binned by planned dose, and median ventilation change at WK1 and EOT was calculated across all patients in each dose bin. Patients were stratified into 6 groups based on modality and increased, decreased, or stable ventilation at WK1. Mann-Whitney U tests were performed to determine if median ventilation change at WK1 and EOT in each dose bin was significantly different from zero. Univariate analysis was performed to correlate ventilation change at EOT with change at WK1 and other clinical factors. A linear regression model was developed to predict ventilation at EOT using a variety of input features including ventilation at planning, ventilation at WK1, tumor response information, and tumor location. Accuracy of the model was assessed through R[2].<br><br>RESULTS: For patients that decreased in ventilation at WK1, 90% of photon patients and 92% of proton patients were stratified similarly at EOT. Patients that were stratified as increased ventilation at WK1 were stratified similarly (72% for photon, 80% for proton) at EOT. These patients were more likely to develop Grade 2+ pneumonitis though the difference was not significant when computing a Fisher's exact test. Univariate analysis indicated that only ventilation change at WK1 was correlated with ventilation change at EOT. The linear regression model achieved R[2] of 0.65.<br><br>CONCLUSION: Ventilation changes at EOT can be predicted using ventilation information from planning and WK1. Patients that increased in ventilation at WK1 were more likely to develop pneumonitis. Further work is needed to characterize the relationship between ventilation change with pneumonitis development.}, }
@article {pmid40910475, year = {2026}, author = {Moore, A and Kane, E and Teras, LR and Machiela, MJ and Arias, J and Panagiotou, OA and Monnereau, A and Doo, NW and Wang, Z and Slager, SL and Vermeulen, RCH and Vajdic, CM and Smedby, KE and Spinelli, JJ and Vijai, J and Giles, GG and Link, BK and Arslan, AA and Nieters, A and Bracci, PM and Camp, NJ and Salles, G and Cozen, W and Hjalgrim, H and De Vivo, I and Adami, HO and Albanes, D and Becker, N and Benavente, Y and Bisanzi, S and Boffetta, P and Brennan, P and Brooks-Wilson, AR and Canzian, F and Clavel, J and Conde, L and Cox, DG and Curtin, K and Foretova, L and Ghesquières, H and Glimelius, B and Habermann, TM and Hofmann, JN and Lan, Q and Liebow, M and Lincoln, A and Maynadie, M and McKay, J and Melbye, M and Miligi, L and Milne, RL and Molina, TJ and Morton, LM and North, KE and Offit, K and Padoan, M and Piro, S and Patel, AV and Purdue, MP and Ravichandran, V and Riboli, E and Severson, RK and Southey, MC and Staines, A and Tinker, LF and Travis, RC and Wang, SS and Weiderpass, E and Weinstein, S and Zheng, T and Chanock, SJ and Rothman, N and Birmann, BM and Cerhan, JR and Berndt, SI}, title = {Genetically determined body mass index is associated with diffuse large B-cell lymphoma in polygenic and Mendelian randomization analyses.}, journal = {International journal of cancer}, volume = {158}, number = {1}, pages = {45-59}, pmid = {40910475}, issn = {1097-0215}, support = {HHSN268201100001I/HL/NHLBI NIH HHS/United States ; HHSN268201100046C/HL/NHLBI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; U58 DP000807/DP/NCCDPHP CDC HHS/United States ; HHSN261201000034C/CA/NCI NIH HHS/United States ; R01 CA134674/CA/NCI NIH HHS/United States ; P30 CA016087/CA/NCI NIH HHS/United States ; HHSN261201000140C/CA/NCI NIH HHS/United States ; R01 CA098122/CA/NCI NIH HHS/United States ; U01 HG007033/HG/NHGRI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; HHSN261201000035C/CA/NCI NIH HHS/United States ; R01 CA134958/CA/NCI NIH HHS/United States ; R21 CA165923/CA/NCI NIH HHS/United States ; HHSN268201100004I/HL/NHLBI NIH HHS/United States ; P30 CA086862/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; HHSN268201100003C/WH/WHI NIH HHS/United States ; R01 CA148690/CA/NCI NIH HHS/United States ; HHSN261201800016C/CA/NCI NIH HHS/United States ; P30 ES000260/ES/NIEHS NIH HHS/United States ; R01 CA154643/CA/NCI NIH HHS/United States ; R01 CA062006/CA/NCI NIH HHS/United States ; K08 CA134919/CA/NCI NIH HHS/United States ; UL1 TR000135/TR/NCATS NIH HHS/United States ; HHSN271201100004C/AG/NIA NIH HHS/United States ; R01 CA098661/CA/NCI NIH HHS/United States ; HHSN261201800016I/CA/NCI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; HHSN268201100002C/WH/WHI NIH HHS/United States ; P30 CA015083/CA/NCI NIH HHS/United States ; R01 CA092153/CA/NCI NIH HHS/United States ; HHSN261201000035I/CA/NCI NIH HHS/United States ; P50 CA097274/CA/NCI NIH HHS/United States ; HHSN268201100003I/HL/NHLBI NIH HHS/United States ; R01 CA049449/CA/NCI NIH HHS/United States ; HHSN268201100002I/HL/NHLBI NIH HHS/United States ; R01 CA149445/CA/NCI NIH HHS/United States ; U01 CA257679/CA/NCI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; HHSN268201100001C/WH/WHI NIH HHS/United States ; HHSN268201100004C/WH/WHI NIH HHS/United States ; U01 CA118444/CA/NCI NIH HHS/United States ; P30 CA042014/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lymphoma, Large B-Cell, Diffuse/genetics/epidemiology ; *Body Mass Index ; Mendelian Randomization Analysis ; Genome-Wide Association Study ; Female ; Male ; Middle Aged ; *Obesity/genetics/complications ; *Multifactorial Inheritance ; Case-Control Studies ; Polymorphism, Single Nucleotide ; Waist-Hip Ratio ; Genetic Predisposition to Disease ; Adiposity/genetics ; Lymphoma, Follicular/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Risk Factors ; }, abstract = {Obesity has been associated with non-Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome-wide association studies of European ancestry (N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05-1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (ORper SD = 1.12, 95% CI: 1.02-1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.}, }
@article {pmid40911901, year = {2026}, author = {Dela Cruz, FS and Stewart, EA and Surdez, D and Daley, JD and Soragni, A and Tomazou, EM and Alvarez-Perez, J and Feinberg, TY and Amatruda, JF and Ganapathi, SS and Ohm, JE and Heske, CM and Cohen-Gogo, S and Pesic, D and Nash, JO and Shlien, A and Roundhill, EA and Burchill, SA and Crompton, BD and Lawlor, ER and Loeb, DM and Delattre, O and Mora, J and Scotlandi, K and Reed, DR and Grohar, PJ and Grünewald, TGP and Kovar, H and Bailey, KM}, title = {Advancing Preclinical Biology for Ewing Sarcoma: An International Effort.}, journal = {Molecular cancer therapeutics}, volume = {25}, number = {1}, pages = {48-70}, pmid = {40911901}, issn = {1538-8514}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; U10 CA180886/CA/NCI NIH HHS/United States ; }, mesh = {*Sarcoma, Ewing/pathology ; Humans ; Animals ; *Bone Neoplasms/pathology ; Mice ; Disease Models, Animal ; Xenograft Model Antitumor Assays ; }, abstract = {Ewing sarcoma is an aggressive bone and soft-tissue cancer affecting adolescents and young adults. In vitro and in vivo models of Ewing sarcoma have been instrumental in advancing our understanding of Ewing sarcoma biology and essential in evaluating potential therapies, particularly for metastatic or relapsed disease for which effective treatment options remain limited. Through an international collaborative effort between the Children's Oncology Group Bone Tumor Committee and the Euro Ewing Consortium, we review the current landscape of preclinical modeling used in Ewing sarcoma research encompassing both in vitro (cell lines and tumor organoids) and in vivo (mouse and nonmammalian xenografts) model systems. We discuss factors that can influence experimental results, provide testing considerations for both in vitro and in vivo studies, and descriptions of existing preclinical data repositories. We highlight current needs in Ewing sarcoma modeling and the importance of enhanced international cooperative research and patient advocacy efforts which will be critical in expanding our resources of biologically relevant Ewing sarcoma models to enable translation of preclinical findings into effective therapeutic strategies for patients with Ewing sarcoma.}, }
@article {pmid40914571, year = {2025}, author = {Vuong, W and Lo, SS}, title = {A Case for Widening the Window of Opportunity.}, journal = {International journal of radiation oncology, biology, physics}, volume = {123}, number = {2}, pages = {331-332}, doi = {10.1016/j.ijrobp.2025.03.089}, pmid = {40914571}, issn = {1879-355X}, }
@article {pmid40914661, year = {2025}, author = {de la Calle, CM and Jing, Y and Fountain, J and Fletcher, SA and Mamawala, MM and Landis, P and Macura, KJ and Lotan, TL and Trock, BJ and Isaacs, WB and Pavlovich, CP}, title = {Family History of Prostate, Breast, Ovarian, and/or Pancreatic Cancer and Associations with Grade Reclassification in a Large Prostate Cancer Active Surveillance Cohort.}, journal = {European urology oncology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.euo.2025.07.008}, pmid = {40914661}, issn = {2588-9311}, abstract = {BACKGROUND AND OBJECTIVE: The effect of family history (FH) on prostate cancer active surveillance outcomes is unknown. Our objective is to evaluate FH of prostate, breast, ovarian, and/or pancreatic cancer in a large prospective active surveillance cohort.<br><br>METHODS: Patients with recorded FH data (N&#xa0;=&#xa0;1421) were selected. Association between grade reclassification to Gleason grade (GG) &#x2265;2 and GG &#x2265;3, and FH of prostate cancer (FH-Pr); FH of breast, ovarian, and/or pancreatic cancer (FH-BOPa); and FH-Pr and/or FH-BOPa in first-degree relatives was evaluated by a competing risk analysis. Association with adverse pathologic features (APFs; GG &#x2265;3, seminal vesicle, and/or lymph node involvement) at radical prostatectomy was assessed with multivariable logistic regression.<br><br>KEY FINDINGS AND LIMITATIONS: Of the 1421 patients, 41/362 (11.3%) with FH-Pr, 37/336 (11.0%) with FH-BOPa, and 67/600 (11.2%) with FH-Pr and/or FH-BOPa were reclassified to GG &#x2265;3. FH-Pr was associated with reclassification to GG &#x2265;2 and GG &#x2265;3 (adjusted hazard ratio [HR] 1.49 for GG &#x2265;3 [95% confidence interval {CI} 1.02-2.17], p&#xa0;=&#xa0;0.039), as was FH-Pr and/or FH-BOPa (HR 1.52 for GG &#x2265;3 [95% CI 1.07-2.17], p&#xa0;=&#xa0;0.020). FH-BOPa however was not associated with any grade reclassification (HR 1.30 for GG &#x2265;3 [95% CI 0.88-1.94], p&#xa0;=&#xa0;0.190). In the 349 patients who underwent radical prostatectomy, no FH status was associated with APFs. Our study is limited by having information on first-degree relatives only.<br><br>Patients with FH-Pr had a higher risk of grade reclassification, including extreme grade reclassification (GG &#x2265;3), but no FH status led to more APFs at radical prostatectomy. Patients with FH can safely be managed on surveillance, but might benefit from closer monitoring.}, }
@article {pmid40914769, year = {2025}, author = {Upreti, M and Petrosyan, A and Thornton, ME and Hovsepyan, A and Fernandez, GE and Koos, DS and Byrum, SD and Mackintosh, SG and Al-Husseini, JK and Porras, T and Ha, J and Tackett, AJ and Zhang, M and Johal, MS and Erdreich-Epstein, A and Durham, S and Krieger, MD and Margol, AS and Grubbs, BH and Chambers, TC and Asgharzadeh, S and Moats, RA and Chiarelli, PA}, title = {Multicellular tumor-stromal interactions recapitulate aspects of therapeutic response and human oncogenic signaling in a 3D disease model for H3K27M-altered DIPG.}, journal = {Oncogene}, volume = {44}, number = {39}, pages = {3694-3712}, pmid = {40914769}, issn = {1476-5594}, support = {R25 CA225513/CA/NCI NIH HHS/United States ; CDMRP RA210290//United States Department of Defense | United States Army | Army Medical Command | Congressionally Directed Medical Research Programs (CDMRP)/ ; R24GM137786//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; K08 NS125175/NS/NINDS NIH HHS/United States ; K08NS125175-01A1//U.S. Department of Health &amp; Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; R24 GM137786/GM/NIGMS NIH HHS/United States ; }, mesh = {Humans ; Tumor Microenvironment ; *Glioma/pathology/genetics/metabolism/drug therapy ; Signal Transduction ; Cell Line, Tumor ; *Histones/genetics/metabolism ; *Brain Stem Neoplasms/pathology/genetics/metabolism/drug therapy ; Stromal Cells/pathology/metabolism ; Spheroids, Cellular/pathology/metabolism ; }, abstract = {It has become evident from decades of clinical trials that multimodal therapeutic approaches with focus on cell intrinsic and microenvironmental cues are needed to improve understanding and treat the rare, inoperable, and ultimately fatal diffuse intrinsic pontine glioma (DIPG), now categorized as a diffuse midline glioma. In this study we report the development and characterization of an in vitro system utilizing 3D Tumor Tissue Analogs (TTA), designed to replicate the intricate DIPG microenvironment. The innate ability of fluorescently labeled human brain endothelial cells, microglia, and patient-derived DIPG cell lines to self-assemble has been exploited to generate multicellular 3D TTAs that mimic tissue-like microstructures, enabling an in- depth exploration of the spatio-temporal dynamics between neoplastic and stromal cells. The 3D-TTA model recapitulates clinical patterns of DIPG growth, evidenced by resistance to chemotherapy, HDAC and proteasome inhibitors, as well as sensitization to the antibody-activated innate immune microenvironment including complement proteins and surrounding microglia. Multimodal fluorescence imaging platforms integrated with high-throughput omics revealed that alterations in tumor cell motility and growth in the 3D-TTA model compared to tumor cell only spheroids correlated with specific transcriptomic and proteomic changes. STAT3, ITGA5, LGALS1, SOD2, MVP, and CLIC1, associated with microenvironment signaling, DNA replication, and immune regulation, were identified as potential novel targets in the 3D model. The results indicate that the 3D TTA platform developed here represents a powerful tool for preclinical studies, paving the way for identification/validation of tissue specific biomarkers and novel drug targets, thus advancing disease management strategies for DIPG in children.}, }
@article {pmid40915872, year = {2025}, author = {MacKay, EJ and Zhang, B and Beaty, JM and Devine, KA and O'Reilly-Shah, V and Mathis, MR and Szeto, WY and Groeneveld, PW and Augoustides, JG}, title = {Practice Pattern Variability in the Use of Pulmonary Arterial Catheters in Cardiac Surgery.}, journal = {Journal of cardiothoracic and vascular anesthesia}, volume = {39}, number = {12}, pages = {3268-3276}, pmid = {40915872}, issn = {1532-8422}, support = {K23 HL166964/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; Cross-Sectional Studies ; Male ; Female ; *Catheterization, Swan-Ganz/statistics &amp; numerical data/methods/trends ; *Cardiac Surgical Procedures/methods/trends ; Middle Aged ; Aged ; *Monitoring, Intraoperative/methods/statistics &amp; numerical data ; *Practice Patterns, Physicians'/statistics &amp; numerical data ; Registries ; Adult ; }, abstract = {OBJECTIVES: To quantify intraoperative pulmonary arterial catheter (PAC) use during cardiac surgery and identify hospital-, anesthesiologist-, and patient-level factors associated with PAC utilization.<br><br>DESIGN: A cross-sectional, observational study using generalized logistic mixed models to examine variations in PAC use.<br><br>SETTING: Fifty-three US academic hospitals participating in the Multicenter Perioperative Outcomes Group (MPOG) national registry PARTICIPANTS: 145,343 adult patients undergoing cardiac surgery between January 1, 2016, and December 31, 2022.<br><br>INTERVENTION(S): Receipt of intraoperative PAC, defined by &#x2265;60 minutes of physiologically plausible pulmonary arterial pressures.<br><br>The primary outcome was PAC utilization. Mixed-effects logistic regression quantified fixed-effect predictors, and variation attributable to anesthesiologists and then to anesthesiologists nested within a hospital was characterized using median odds ratio (MOR). Of the 145,343 cardiac surgeries performed across 53 hospitals, 104,626 (72%) included PAC monitoring. PAC use varied widely across hospitals (0-98%) and across anesthesiologists (0-100%). PAC was used most frequently in heart transplants (94%) and lung transplants (87%) and least frequently in pulmonic valve procedures (30%). A patient's likelihood of receiving a PAC was influenced most strongly by hospital (MOR, 15.00; 95% confidence interval [CI], 8.98-28.32), with substantially less variation attributable to an anesthesiologist within the same hospital (MOR, 1.70; 95% CI, 1.61-1.81).<br><br>CONCLUSIONS: Intraoperative PAC monitoring is used in nearly three-quarters of cardiac surgeries at US academic centers, with hospital practice pattern the factor most closely associated with PAC utilization.}, }
@article {pmid40916416, year = {2025}, author = {Giorgi, EE and Abrahams, MR and Fouda, G and John-Stewart, G and Goga, A and Mullins, JI and Permar, SR and Janes, HE and Martin, TM}, title = {Characterization of Early Viral Populations in Infants Acquiring HIV Through Perinatal and Breastmilk Transmission: A Review of what is Currently Known and the Gaps that Need to be Addressed to Guide Passive HIV Immunization of Breastfeeding Infants.}, journal = {Current HIV research}, volume = {}, number = {}, pages = {}, doi = {10.2174/011570162X357975250902104402}, pmid = {40916416}, issn = {1873-4251}, abstract = {Newborns represent only 1% of the population. Yet, HIV vertical transmissions represent 10% of all new infections globally, even though antiretroviral therapy (ART) has been shown to reduce the risk of vertical transmission to less than 2%. While vaccines still represent the most efficient and cost-effective intervention to eradicate new infections, HIV immunogens that can effectively elicit broad-spectrum protection are still at least a decade away. In contrast, passive immunization with broadly neutralizing antibody (bnAb) combinations has the potential to provide a more immediate pathway to HIV prophylaxis. Early-phase infant trials are underway to establish the safety and pharmacokinetics of bnAb combinations selected for their potency against viruses acquired via adult transmissions. However, the specific characteristics and phenotypic differences of vertically transmitted viruses in infants compared to those in adults remain uncertain, including their susceptibility to known broadly neutralizing antibodies (bnAbs). We review the current knowledge of vertically transmitted HIV viruses, including their genetics and phenotypic features. Differences in immunity between adults and infants lead us to hypothesize that distinct selection and evolutionary pressures act on the virus at the time of transmission and during the early phases of infection, and these may in turn affect the choice of bnAb combinations needed for protection against vertical transmission of HIV.}, }
@article {pmid40917113, year = {2025}, author = {Chakraborty, H and Sun, Q and Bhupathiraju, SN and Schenk, JM and Mishchuk, DO and Bain, JR and He, X and Sun, J and Harnly, J and Simmons, W and Raftery, D and Liang, L and Newman, JW and Fiehn, O and Clish, CB and Lampe, JW and Bennett, BJ and Navarro, SL and Wang, Y and Zheng, C and Mossavar-Rahmani, Y and McCullough, ML and Huang, Y and Shojaie, A and Zhu, W and Djukovic, D and Sacks, F and Williams, J and Steinberg, FM and Adams, SH and Hu, FB and Neuhouser, ML and Slupsky, CM and Maruvada, P}, title = {Corrigendum to "The Dietary Biomarkers Development Consortium: An Initiative for Discovery and Validation of Dietary Biomarkers for Precision Nutrition. [Current Developments in Nutrition, Volume 9, Issue 5, May 2025, 107435]".}, journal = {Current developments in nutrition}, volume = {9}, number = {8}, pages = {107517}, doi = {10.1016/j.cdnut.2025.107517}, pmid = {40917113}, issn = {2475-2991}, support = {P30 ES007033/ES/NIEHS NIH HHS/United States ; U24 DK129557/DK/NIDDK NIH HHS/United States ; }, abstract = {[This corrects the article DOI: 10.1016/j.cdnut.2025.107435.].}, }
@article {pmid40918924, year = {2025}, author = {Nriagu, BN and Rosario, KF and Hansen, S and Luciano, PD and Joshi, P and Mehta, A and Khera, AV and Kaplan, R and Sofer, T and McClelland, RL and Rodriguez, CJ}, title = {Hispanic/Latino ethnic background and genetic ancestry in relation to atherosclerotic cardiovascular disease risk estimation: Findings from the Multi-Ethnic Study of Atherosclerosis (MESA).}, journal = {American journal of preventive cardiology}, volume = {23}, number = {}, pages = {101268}, pmid = {40918924}, issn = {2666-6677}, abstract = {BACKGROUND: Hispanics/Latinos are a heterogenous population with no validated atherosclerotic cardiovascular disease (ASCVD) risk estimation tool. We examined performance of the pooled cohort equation (PCE) across Hispanic/Latino background groups and quantiles of African, Amerindian, and European genetic ancestry.<br><br>METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) was used to evaluate the performance of the non-Hispanic Black (NHB) and non-Hispanic White (NHW) PCE defined by predicted to observed (P/O) ratios of 10-year ASCVD events. Risk calibration was expressed as P/O ratios and risk discrimination was assessed with Harrell's C-statistic based on Cox models.<br><br>RESULTS: Our study included 966 Hispanics/Latinos [age 58 years at baseline (SD=9); 52 % females], comprising 504 Hispanics/Latinos of Mexican descent (MX), 284 Hispanics/Latinos of Caribbean descent (CA) and 178 Other Hispanics (O). At 10-years, there were 54 ASCVD events: MX (33); CA (13) and O (8). The PCE overestimated ASCVD risk across disaggregated Hispanic/Latino background groups. Both NHW and NHB PCE models performed best with increasing European genetic ancestry (NHW PCE: P/O ratio decreasing from 1.5 to 1.0; NHB PCE: from 2.4 to 1.5 between the 20th and 80th quantile threshold of European genetic ancestry). In contrast, PCE performance worsened with increasing African genetic ancestry (NHW PCE: P/O ratio increasing from 1.5 to 2.6; NHB PCE: from 1.5 to 2.9 between the 20th and 80th quantile threshold of African genetic ancestry).<br><br>CONCLUSIONS: Disaggregating Hispanics/Latinos by background and ancestry led to variability in PCE performance with greater overestimation of ASCVD risk for those of Caribbean background and those with increasing quantiles of African genetic ancestry.}, }
@article {pmid40919233, year = {2025}, author = {Wallace, M and Mathey, B and Yeung, CCS and Appelbaum, JS and Wallace, M}, title = {Coexistence of Essential Thrombocythemia and Waldenström Macroglobulinemia: A Case Report.}, journal = {Case reports in hematology}, volume = {2025}, number = {}, pages = {3390770}, pmid = {40919233}, issn = {2090-6560}, abstract = {Waldenström macroglobulinemia (WM) and essential thrombocythemia (ET) are distinct hematologic malignancies that have only been reported to co-occur in one previous patient. We present a 64-year-old man with a significant family history for WM who was found to have both ET and WM. He had symptomatic ET, diagnosed by elevated platelets and a positive JAK2 V617F mutation, and asymptomatic WM was found on serum electrophoresis done for screening due to family history. Genomic evaluation of the myeloid and lymphoid cells suggested independent neoplastic transformation. This is the second reported case of a patient with both WM and ET. There was no evidence for a shared mechanism in these dual malignancies.}, }
@article {pmid40919994, year = {2025}, author = {Choe, M and Kirkey, D and Lira, I and Hawkins, G and Blankenfeld, M and Menashe, S and Ries, RE and Wrightson, B and Root, C and McKay, CN and Peplinski, JH and Glabman, R and Davis, LE and Malhotra, SV and Gorlick, R and Loggers, ET and Meshinchi, S}, title = {Preclinical Evaluation of Folate Receptor-α Chimeric Antigen Receptor T Cells Exhibits Highly Efficient Antitumor Activity against Osteosarcoma.}, journal = {Cancer research communications}, volume = {5}, number = {9}, pages = {1701-1713}, pmid = {40919994}, issn = {2767-9764}, support = {//Sam Day Foundation/ ; T32 CA009351/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; //Wipe Out Kids' Cancer (WOKC)/ ; //Kuni Foundation/ ; SR-20221337//M.J. Murdock Charitable Trust (MJMCT)/ ; K12 CA076930/CA/NCI NIH HHS/United States ; S10 OD026919/OD/NIH HHS/United States ; }, mesh = {*Osteosarcoma/therapy/immunology/pathology/genetics ; Humans ; Animals ; Mice ; Xenograft Model Antitumor Assays ; *Folate Receptor 1/genetics/immunology/metabolism ; *Immunotherapy, Adoptive/methods ; *Bone Neoplasms/therapy/immunology/pathology/genetics ; *Receptors, Chimeric Antigen/immunology/metabolism ; Cell Line, Tumor ; Female ; Male ; *T-Lymphocytes/immunology ; }, abstract = {UNLABELLED: Metastatic and relapsed osteosarcoma remains difficult to treat despite advanced surgical techniques, intensified chemotherapy, and targeted therapies. Adoptive immunotherapies such as chimeric antigen receptor (CAR) T cells are in their nascent stage but remain a viable therapeutic strategy for patients with aggressive solid tumors such as osteosarcoma. Folate receptor-α (FOLR1) has been functionally implicated in osteosarcoma pathophysiology, providing rationale as a potential therapeutic target. We recently advanced a FOLR1-specific CAR T-cell product (FH FOLR1-CART) into a trial in infant acute myeloid leukemia (NCT06609928) and now evaluate this CAR construct against osteosarcoma. We provide comprehensive FOLR1 transcript and protein expression profile in patients with osteosarcoma, cell lines, and patient-derived xenografts, substantiating its significance as a therapeutic target. We further evaluate the in vitro and in vivo efficacy of FH FOLR1-CART in both standard and patient-derived osteosarcoma cell lines and xenograft models. FOLR1 transcript is expressed in the overwhelming majority of osteosarcoma primary patient specimens, osteosarcoma cell lines, and patient-derived models. FH FOLR1-CART exhibits robust in vitro activation and potent cytotoxicity against FOLR1-expressing osteosarcoma cell lines and primary osteosarcoma patient samples. More importantly, FH FOLR1-CART demonstrates potent antitumor activity in both localized and metastatic in vivo cell-derived and patient-derived xenograft models, with complete tumor eradication. These results demonstrate a potential therapeutic option for patients with advanced osteosarcoma. FH FOLR1-CART is advancing to an early-phase trial in relapsed/refractory osteosarcoma at Fred Hutchinson Cancer Center and Seattle Children's Hospital.<br><br>SIGNIFICANCE: FOLR1 expression has previously been implicated in the pathogenesis of treatment-resistant osteosarcoma. This report demonstrates FOLR1 expression by most osteosarcoma tumors and provides preclinical evidence of robust antitumor activity both in vitro and in vivo against xenograft osteosarcoma models exhibited by FH FOLR1-CART. These data support ongoing efforts for clinical translation of FH FOLR1-CART to an early-phase clinical trial for patients with aggressive osteosarcoma.}, }
@article {pmid40920226, year = {2025}, author = {Wang, LH and Sonbas Cobb, B and Riem, L and DuCharme, O and Shaw, DW and Walker, M and Eichinger, K and Lewis, L and Tawil, R and Hamel, JI and Mul, K and Blemker, SS and Tapscott, SJ and Friedman, SD and Rutkove, SB and Statland, JM}, title = {Electrical impedance myography captures features of muscle structure measured by MRI and transcriptomic analysis in facioscapulohumeral muscular dystrophy.}, journal = {Journal of neuromuscular diseases}, volume = {}, number = {}, pages = {22143602251369246}, doi = {10.1177/22143602251369246}, pmid = {40920226}, issn = {2214-3602}, abstract = {BACKGROUND: Electrical impedance myography (EIM) has been proposed as an efficient, non-invasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD).<br><br>OBJECTIVE: We investigate whether EIM parameters are associated with muscle structure measured by magnetic resonance imaging (MRI), muscle histology, and transcriptomic analysis as well as strength at the individual leg muscle level.<br><br>METHODS: We performed a multi-center cross-sectional study enrolling 33 patients with FSHD. EIM measurements were recorded from bilateral vastus lateralis, tibialis anterior (TA), and medial gastrocnemius muscles and compared to quantitative muscle volume measures by MRI as well as knee extension and ankle dorsiflexion strength by quantitative muscle testing. EIM measurements of the bilateral TA were further compared to histology and transcriptomic analysis (RNAseq) of muscle and fat content.<br><br>RESULTS: EIM phase at multiple frequencies was positively associated to the amount of muscle measured by MRI (&#x3c1;&#x2009;=&#x2009;0.48 to 0.70, p&#x2009;&#x2264;&#x2009;0.001) and negatively associated to the amount of fat replacement of muscle (&#x3c1;&#x2009;=&#x2009;-0.53 to -0.73, p&#x2009;&#x2264;&#x2009;0.001). EIM phase of the vastus lateralis and TA was positively associated with knee extension and ankle dorsiflexion strength normalized to age and sex (&#x3c1;&#x2009;=&#x2009;0.45 to 0.60, p&#x2009;<&#x2009;0.0001). The bilateral TA muscles were analyzed at the histopathological and molecular (transcriptomic) levels and showed that EIM phase was positively associated with amount of muscle (&#x3c1;&#x2009;=&#x2009;0.33 to 0.35, p&#x2009;<&#x2009;.01) and negatively associated with amount of fat (&#x3c1;&#x2009;=&#x2009;-0.36 to -0.56, p&#x2009;<&#x2009;.001) by transcriptomic analysis.<br><br>CONCLUSIONS: This study supports the hypothesis that the amount and quality of muscle tissue as assessed by EIM is associated with the amount and quality of muscle tissues as assessed by MRI and muscle biopsy, with all measures ultimately being strongly associated with muscle strength. These data provide further convergent validity for the use of EIM as a potential non-invasive biomarker to assess muscle health in FSHD.}, }
@article {pmid40920378, year = {2025}, author = {Lee, JR and Morehead, D and Young, B and Tolbert, V and Masembe, J and Britt, G and Neuenschwander, L and Schuppe, K and Pelman, R and Johnson, D and Henderson, V and Darst, BF and Egwuatu, P and Kim, SM and Wolff, EM and Gore, JL and Nyame, YA}, title = {Patient and Physician Perceptions of Prostate-Specific Antigen Testing Among Black Individuals.}, journal = {JAMA network open}, volume = {8}, number = {9}, pages = {e2530946}, pmid = {40920378}, issn = {2574-3805}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Aged ; Humans ; Male ; Middle Aged ; *Attitude of Health Personnel ; *Black or African American/psychology/statistics &amp; numerical data ; *Early Detection of Cancer/psychology ; *Health Knowledge, Attitudes, Practice ; *Prostate-Specific Antigen/blood ; *Prostatic Neoplasms/diagnosis/ethnology ; Qualitative Research ; United States ; }, abstract = {IMPORTANCE: Black individuals have a twofold higher rate of prostate cancer death in the US compared with the average population with prostate cancer. Few guidelines support race-conscious screening practices among at-risk Black individuals.<br><br>OBJECTIVE: To examine structural factors that facilitate or impede access to prostate cancer screening among Black individuals in the US.<br><br>This qualitative, mixed-methods study was conducted between September 1, 2021, and December 31, 2023, in clinical and community settings across Washington, Wyoming, Alaska, Montana, Idaho, and Oregon. It included semistructured interviews with Black adults (aged &#x2265;18 years) at risk for prostate cancer with or without a history of prostate-specific antigen (PSA) testing and a survey of primary care practitioners (PCPs) and urologists.<br><br>MAIN OUTCOMES AND MEASURES: Patient and physician experiences, knowledge, attitudes, and practices of PSA testing and prostate cancer screening were evaluated. Consensus coding and thematic analysis were used to analyze interviews; surveys were analyzed using descriptive statistics.<br><br>RESULTS: A total of 29 Black men (median [range] age, 59 [32-72] years) participated in the interviews, and 31 PCPs (including 30 phyicians and 1 physician assistant) and 32 urologists (45 of 63 aged 30-59 years [71.4%]; 40 male [63.5%]) participated in the survey. Interview participants perceived that PCPs function as gatekeepers in accessing PSA testing but may lack knowledge specific to Black men's risk for prostate cancer and hold attitudes about PSA testing that do not support its use. Interview participants also reported a lack of trusted relationships with PCPs to support shared decision-making. While both urologists and PCPs were highly aware of US Preventive Services Task Force guidelines, PCPs were much less likely than urologists to believe in the value of PSA testing or the role of early detection to prevent prostate cancer-related mortality (2 [6.5%] vs 24 [75.0%], respectively).<br><br>CONCLUSIONS AND RELEVANCE: In this qualitative study examining structural factors associated with access to prostate cancer screening among Black individuals, findings from the survey supported participants' perceptions that PCPs do not value PSA testing for prostate cancer early detection or appreciate its role in reducing the risk of prostate cancer-related mortality. Primary care practitioner reliance on USPSTF guidelines, which currently do not provide guideline recommendations for screening high-risk groups, including Black individuals, suggests that incorporating evidence-driven guidance for PSA screening among Black individuals into these guidelines may substantially improve prostate cancer early detection among this high-risk population.}, }
@article {pmid40920992, year = {2025}, author = {Bashore, L and Peterson, RK and Li, C and Liu, W and Wang, M and Jiwani, ZM and McDonald, AJ and Lupo, PJ and King, A and Srivastava, D and Leisenring, WM and Howell, RM and Gibson, TM and Oeffinger, K and Armstrong, GT and Bowman, WP and Krull, KR and Edelstein, K}, title = {Chronic Health Conditions and Academic Achievement: A Childhood Cancer Survivor Study Report.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500414}, pmid = {40920992}, issn = {2688-1535}, support = {P30 CA021765/CA/NCI NIH HHS/United States ; U24 CA055727/CA/NCI NIH HHS/United States ; }, abstract = {PURPOSE: To examine associations between special education, chronic health conditions (CHCs), and college graduation in survivors of childhood cancer and their siblings.<br><br>METHODS: Childhood Cancer Survivor Study participants included 23,082 5-year survivors (53.7% male; median [IQR] age at diagnosis, 6 [3-13] years; age at evaluation, 31.0 [24-39] years; treated between 1970 and 1999) and 5,037 siblings (47.7% male; 36.0 [28-44] years at evaluation). Special education use, reasons for special education, CHCs, and college graduation were self-reported. Primary cancer diagnosis and treatment exposures were abstracted from medical records. Comparisons between survivors and siblings were made using chi-square statistics; demographic and treatment factors associated with outcomes were examined using modified Poisson regression models.<br><br>RESULTS: More survivors reported special education use than siblings (26.5% v 8.6%; relative risk [RR], 2.55 [95% CI, 2.32 to 2.80]). Of those survivors and siblings who had special education services, use was highest between kindergarten and fifth grade (64.4% of survivors and 71.9% of siblings in kindergarten-fifth grade, 14.4% of survivors and 12.5% of siblings in sixth-eighth grade, and 9.2% of survivors and 9.0% of siblings in ninth-12th grade), and primarily attributable to learning and concentration problems. Despite receiving special education, survivors were less likely to graduate college compared with siblings requiring special education (RR, 0.76 [95% CI, 0.66 to 0.88]). Risk for not graduating college included history of CNS tumor (RR, 1.47 [95% CI, 1.40 to 1.55]), cranial irradiation (20-29 Gy, RR, 1.16 [95% CI, 1.09 to 1.25]; 30-49 Gy, RR, 1.37 [95% CI, 1.26 to 1.49]; &#x2265;50 Gy, RR, 1.35 [95% CI, 1.28 to 1.42]), or the presence of a severe, disabling or life-threatening CHC (Common Terminology Criteria for Adverse Events grade 3-4, RR, 1.15 [95% CI, 1.07 to 1.24]).<br><br>CONCLUSION: Cognitive problems and CHCs increase risk for not graduating college; these problems are not alleviated by special education.}, }
@article {pmid40920995, year = {2025}, author = {Thakur, R and Al Hadidi, S}, title = {From Physician-Driven to Patient-Centered: Transforming Multiple Myeloma Care Decisions.}, journal = {JCO oncology practice}, volume = {}, number = {}, pages = {OP2500712}, doi = {10.1200/OP-25-00712}, pmid = {40920995}, issn = {2688-1535}, }
@article {pmid40923286, year = {2025}, author = {Malik, H}, title = {The viral arms race: an interview with Harmit Malik.}, journal = {Disease models &amp; mechanisms}, volume = {18}, number = {9}, pages = {}, doi = {10.1242/dmm.052591}, pmid = {40923286}, issn = {1754-8411}, }
@article {pmid40923321, year = {2025}, author = {Song, Q and Zheng, M and Li, Q and Wu, X and Lin, B and Kang, TH and Qin, H and Kujawski, M and Pillai, RK and Lin, JL and Nakamura, R and Shively, J and Martin, PJ and Zeng, D}, title = {Intestinal epithelial Ceacam1 deficiency prevents steroid-refractory acute gut graft-versus-host disease.}, journal = {JCI insight}, volume = {10}, number = {17}, pages = {}, pmid = {40923321}, issn = {2379-3708}, support = {P30 CA033572/CA/NCI NIH HHS/United States ; R01 HL162847/HL/NHLBI NIH HHS/United States ; R01 HL170099/HL/NHLBI NIH HHS/United States ; }, mesh = {*Graft vs Host Disease/immunology/prevention &amp; control/genetics ; Animals ; Mice ; Humans ; *Intestinal Mucosa/immunology/metabolism/pathology ; Disease Models, Animal ; *Cell Adhesion Molecules/genetics ; Hematopoietic Stem Cell Transplantation/adverse effects ; *Antigens, CD/genetics/metabolism ; Interleukin-22 ; Male ; Mice, Inbred C57BL ; Interleukins/metabolism ; Female ; Epithelial Cells/metabolism/immunology ; Mice, Knockout ; Steroids ; T-Lymphocytes, Regulatory/immunology ; CEACAM1 Protein ; Carcinoembryonic Antigen ; }, abstract = {Steroid-refractory gut acute graft-versus-host disease (SR-Gut-aGVHD) is the major cause of nonrelapse death after allogeneic hematopoietic cell transplantation. High numbers of donor-type IL-22+ T cells, IL-22-dependent dysbiosis, and loss of antiinflammatory CX3CR1hi mononuclear phagocytes (MNPs) play critical roles in SR-Gut-aGVHD pathogenesis. CEACAM1 on intestinal epithelial cells (IECs) is proposed to regulate bacterial translocation and subsequent immune responses in the intestine. Here, with imaging mass cytometry (IMC), combined scRNA-Seq with ATAC-Seq, and high-dimensional flow cytometry analysis, we show that CEACAM1 expression was enhanced on IECs in murine and human SR-Gut-aGVHD. Ceacam1 deficiency on host IECs effectively prevented SR-Gut-aGVHD in murine models. Ceacam1 deficiency on IECs resulted in (i) higher numbers of IL-22+IL-10+Foxp3+CD4+ peripheral Tregs (pTregs) and lower numbers of conventional IL-22+CD4+ T (Tcon), Th/Tc1, and Th17 cells in the intestine; (ii) higher prevalence of beneficial commensal bacteria that augment colonic pTreg expansion, with lower prevalence of pathogenic bacteria; and (iii) higher numbers of antiinflammatory CD103-CX3CR1hi MNPs that produce indoleamine 2,3-dioxygenase (IDO) and IL-10, with lower numbers of proinflammatory CD103+CX3CR1lo MNPs that produce IL-6. Thus, specifically targeting IEC CEACAM1 represents a promising approach for prevention of SR-Gut-aGVHD.}, }
@article {pmid40923785, year = {2025}, author = {Rossenkhan, R and Giorgi, EE and Shao, D and Ludwig, J and Labuschagne, P and Magaret, CA and Ndung'u, T and Muema, D and Gounder, K and Dong, KL and Walker, BD and Rolland, M and Robb, ML and Eller, LA and Sawe, F and Nitayaphan, S and Grebe, E and Busch, MP and Delaney, KP and Facente, S and Carpp, LN and deCamp, AC and Huang, Y and Korber, B and Juraska, M and Rudnicki, E and Kosmider, E and Reeves, DB and Mayer, BT and Hural, J and Deng, W and Westfall, DH and Yssel, A and Matten, D and Bhattacharya, T and Corey, L and Gilbert, PB and Williamson, C and Mullins, JI and Edlefsen, PT}, title = {Bayesian estimation of HIV acquisition dates for prevention trials.}, journal = {mBio}, volume = {16}, number = {10}, pages = {e0188125}, pmid = {40923785}, issn = {2150-7511}, support = {K25 AI155224/AI/NIAID NIH HHS/United States ; R37AI054165//National Institute of Allergy and Infectious Diseases/ ; W81XWH-18-2-0040//Henry M. Jackson Foundation for the Advancement of Military Medicine/ ; INV-016189/GATES/Gates Foundation/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; UM1AI068635//National Institute of Allergy and Infectious Diseases/ ; K25 AI155224/AI/NIAID NIH HHS/United States ; INV-016189/GATES/Gates Foundation/United States ; }, mesh = {Humans ; *HIV Infections/prevention &amp; control/immunology/diagnosis/virology ; Bayes Theorem ; Male ; Female ; Time Factors ; South Africa/epidemiology ; HIV Antibodies/immunology ; Kenya/epidemiology ; *HIV-1/genetics/immunology ; Adult ; Young Adult ; Thailand/epidemiology ; Prospective Studies ; }, abstract = {Accurate timing estimates of when participants acquire HIV in HIV prevention trials are necessary for determining antibody levels at acquisition. The Antibody-Mediated Prevention (AMP) Studies showed that a passively administered broadly neutralizing antibody can prevent the acquisition of HIV from a neutralization-sensitive virus. We developed a pipeline for estimating the date of detectable HIV acquisition (DDA) in AMP Study participants using diagnostic and viral sequence data. Using a Bayesian strategy that combines three streams of data (REN [rev/vpu/env/Δnef] sequence, GP [gag/Δpol] sequence, and diagnostic) where their 95% credible intervals overlap based on pre-specified criteria and decision rules. We evaluated the performance of our AMP pipeline using PacBio viral sequence data from 41 participants across two prospective acute HIV acquisition cohort studies, FRESH and RV217, with twice-weekly sampling. These cohort studies enrolled young women in South Africa and men and women in Kenya and Thailand, respectively, with a high likelihood of HIV acquisition. In evaluating performance, "true DDA" was the center of bounds between last-negative and first-positive RNA diagnostic tests (median time 4 days, range 2-7 days); bias was the mean difference between estimated and true DDA. Using diagnostic data alone yielded timing estimates with a bias of 2.4 days and root mean square error (RMSE) of 7.9 days. These results were improved using sequence + diagnostic data (bias 1.5 days, RMSE 6.9 days), as well as by restricting sequence-based estimation to samples from ≤5 weeks post-DDA (bias 0.2 days, RMSE 7.8 days).IMPORTANCEIn HIV prevention trials, accurate timing estimates of when individual participants acquire HIV can be used to estimate antibody levels at the time of acquisition, which is useful for projecting antibody levels needed for prevention. The results we report here suggest that if sequence-based estimation of acquisition timing is used in future clinical trials of combination broadly neutralizing antibody (bnAb) regimens or multispecific bnAbs for HIV prevention, a sampling frequency of at least monthly is needed. Moreover, in the samples analyzed here, we observed less bias in sequence-based timing estimation for samples taken <5 weeks post-DDA. This observation is consistent with the timing of immune-driven selective pressures that may negatively impact the power to detect acquisition sieve effects.}, }
@article {pmid40924543, year = {2025}, author = {Baele, G and Carvalho, LM and Brusselmans, M and Dudas, G and Ji, X and McCrone, JT and Lemey, P and Suchard, MA and Rambaut, A}, title = {HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X.}, journal = {Bioinformatics (Oxford, England)}, volume = {41}, number = {10}, pages = {}, pmid = {40924543}, issn = {1367-4811}, support = {//Research Foundation-Flanders/ ; }, mesh = {*Software ; *Phylogeny ; *SARS-CoV-2/genetics/classification ; Bayes Theorem ; *Ebolavirus/genetics/classification ; Algorithms ; Humans ; *Computational Biology/methods ; COVID-19/virology ; }, abstract = {SUMMARY: In Bayesian phylogenetic and phylodynamic studies, it is common to summarize the posterior distribution of trees with a time-calibrated summary phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel summary tree method-the highest independent posterior subtree reconstruction, or (HIPSTR)-contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both summary trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the summary tree.<br><br>RESULTS: HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 datasets show that HIPSTR yields summary trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (&#x2265;0.95) as well as a large number of clades with moderate to high posterior probability (&#x2265;50%), whereas HIPSTR-in particular its majority-rule extension MrHIPSTR-achieves near-perfect performance in this respect. HIPSTR and MrHIPSTR also exhibit favourable computational performance over MCC in TreeAnnotator X. Comparison to the recent CCD0-MAP algorithm yielded mixed results and requires a more in-depth investigation in follow-up studies.<br><br>TreeAnnotator X is available as part of the BEAST X (v10.5.0) software package, available at https://github.com/beast-dev/beast-mcmc/releases, and on Zenodo (DOI: https://doi.org/10.5281/zenodo.4895234).}, }
@article {pmid40924642, year = {2025}, author = {Blinka, S and Yu, EY}, title = {Drug Targets in Prostate Cancer: An Appetite for KLK2-Mediated Destruction.}, journal = {Clinical cancer research : an official journal of the American Association for Cancer Research}, volume = {31}, number = {21}, pages = {4393-4395}, pmid = {40924642}, issn = {1557-3265}, support = {T32 CA009515/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/drug therapy/metabolism ; Receptors, Androgen/metabolism ; Signal Transduction ; Molecular Targeted Therapy ; *Kallikreins/metabolism ; *Tissue Kallikreins/metabolism ; }, abstract = {Human kallikrein (KLK) 2 is a prostate cancer tissue-specific protein that is regulated by androgen receptor signaling. KLK2 was not previously recognized as a therapeutic target as it was shown to be a secreted serine protease with no evidence for localization to the cell surface. It has now been demonstrated that KLK2 is expressed on the cell surface and is targetable by various methodologies. See related article by Shen et al., p. 4543.}, }
@article {pmid40924774, year = {2025}, author = {Mugwanya, KK and Saina, M and Mugo, NR and MaWhinney, S and Morrow, M and Schaafsma, TT and Donnell, D and Glidden, DV and Ngure, K and Brown, CE and Rechkina, EA and Chohan, BH and Wu, L and Hill, E and Koome, E and Akelo, N and Mbaire, S and Morrison, SA and Kibatha, M and Njeru, I and Muriithi, M and Coppinger, C and Bushman, L and Baeten, JM and Anderson, PL and , }, title = {Adherence thresholds for emtricitabine-tenofovir disoproxil fumarate preexposure prophylaxis against HIV acquisition in cisgender women: A randomized directly observed dosing study.}, journal = {PLoS medicine}, volume = {22}, number = {9}, pages = {e1004732}, pmid = {40924774}, issn = {1549-1676}, support = {R01 AI155086/AI/NIAID NIH HHS/United States ; }, mesh = {Humans ; Female ; *HIV Infections/prevention &amp; control ; Adult ; *Pre-Exposure Prophylaxis/methods ; *Anti-HIV Agents/administration &amp; dosage ; *Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination/administration &amp; dosage/pharmacokinetics ; Kenya ; Young Adult ; *Medication Adherence ; *Tenofovir/administration &amp; dosage ; *Emtricitabine/administration &amp; dosage ; Male ; Middle Aged ; Adenine/analogs &amp; derivatives ; Organophosphates ; }, abstract = {BACKGROUND: Oral emtricitabine/tenofovir disoproxil fumarate (F/TDF) preexposure prophylaxis (PrEP) effectiveness against HIV acquisition highly depends on adherence. For men who have sex with men, a dosing study in the United States (US) population defined clinically meaningful tenofovir diphosphate (TFV-DP) thresholds in dried blood spots (DBS) based on the rounded 25th percentile for 2, 4, and 7 doses/week as 350, 700, and 1,250 fmol/punch. However, divergent efficacy results in the first generation randomized clinical trials of F/TDF PrEP among African women led to several hypotheses to question whether the pharmacology and adherence requirement for oral F/TDF PrEP may be different in cisgender women compared to what is already established for men.<br><br>METHODS AND FINDINGS: We conducted an open-label, parallel, randomized directly observed dosing (DOD) study of oral F/TDF PrEP among women without HIV who were not pregnant or breastfeeding in Kenya. Participants were randomly assigned to 2, 4, or 7 DOD F/TDF doses/week for 8 weeks. Blood was collected weekly, and TFV-DP and emtricitabine triphosphate (FTC-TP) concentrations in DBS and peripheral blood mononuclear cells (PBMCs) were quantified using validated liquid chromatography-tandem mass spectrometry. For DBS, concentrations were quantified from a 3-mm punch using the 70% methanol/30% water (70:30) extraction method as the primary process-the same method used for the original TFV-DP benchmarks derived in US adults, and additionally with 50% methanol/50% water (50:50) extraction using punches from the same DBS spot to compare the extraction performance of 70:30 versus 50:50 methods. The primary outcome was the steady-state fitted concentrations of TFV-DP and dose proportionality in DBS and the observed PBMC TFV-DP levels by study dosing groups. Secondary outcomes included the quantitative concentrations of FTC-TP in DBS, TFV-DP half-life in DBS, and the relative TFV-DP recovery from DBS using the 70:30 versus 50:50 extraction method. One-compartment population pharmacokinetic models were fit to estimate steady-state DBS concentrations. Descriptive statistics were summarized as range, means, and medians with interquartile range (IQR) for continuous outcomes and proportions for categorical variables.&#xa0;Fifty-four women were enrolled and randomized. Median age was 22 (IQR, 20-25) years. The observed median (IQR) week 8 TFV-DP concentrations in DBS were 359 (266-464), 749 (596-923), and 1,389 (1,151-1,551) fmol/punch after 2, 4, and 7 doses/week, respectively. At week 8, FTC-TP was quantifiable in 71%, 19%, and 0% DBS samples for 7, 4, and 2 doses/week groups, respectively. Fitted median (IQR) steady-state DBS TFV-DP concentrations were 416 (316, 516), 832 (631, 1,033), and 1,457 (1,106, 1,808) fmol/punch for 2, 4, and 7 doses/week, respectively, similar to previous estimates in US adults. TFV-DP exhibited a mean half-life of 17.5 days (95%CI: 16.7, 18.4) in DBS and steady-state TFV-DP concentrations varied in direct proportion to the dosing frequency [slope: 1.02 90% confidence interval 0.84, 1.20]. The 50:50 DBS extraction method yielded 1.27 (95% CI 1.25, 1.28) higher TFV-DP concentrations compared to the 70:30 method. When the 1.27 conversion factor was applied to the original 70:30 method-derived TFV-DP thresholds, the updated TFV-DP adherence interpretation benchmarks based on the 50:50 extraction were:&#x2009;<450 for <2 dose/week, 450-899 for 2-3 doses/week, 900-1,599 for 4-6 doses/week, and &#x2265;1,600&#x2009;fmol/punch for 7 doses/week. The observed mean (standard deviation) steady-state PBMC TFV-DP concentrations was 11.99&#x2009;&#xb1;&#x2009;8.47, 31.81&#x2009;&#xb1;&#x2009;15.66, and 63.1&#x2009;&#xb1;&#x2009;28.97&#x2009;fmol/106 cells after 2, 4, and 7 doses/week, respectively. Overall, oral F/TDF PrEP was well tolerated. No grade 3 or higher adverse events were observed during the dosing phase. The primary study limitation was dosing for 8 weeks, but population pharmacokinetic modeling enabled steady-state estimates.<br><br>CONCLUSIONS: Steady-state DBS TFV-DP concentrations from directly observed F/TDF PrEP dosing in African cisgender women participants are similar to previous estimates defined from US-based participants. These data demonstrate that cisgender women achieve similar DBS and PBMC TFV-DP concentrations as men for the same adherence level and validate the original TFV-DP benchmarks to interpret F/TDF adherence in HIV prevention studies and PrEP programs among cisgender women.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov: NCT05057858.}, }
@article {pmid40925936, year = {2025}, author = {Lawrenson, K and Kar, S and McCue, K and Kuchenbaeker, K and Michailidou, K and Tyrer, J and Beesley, J and Ramus, SJ and Li, Q and Delgado, MK and Lee, JM and Aittomäki, K and Andrulis, IL and Anton-Culver, H and Arndt, V and Arun, BK and Arver, B and Bandera, EV and Barile, M and Barkardottir, RB and Barrowdale, D and Beckmann, MW and Benitez, J and Berchuck, A and Bisogna, M and Bjorge, L and Blomqvist, C and Blot, W and Bogdanova, N and Bojesen, A and Bojesen, SE and Bolla, MK and Bonanni, B and Børresen-Dale, AL and Brauch, H and Brennan, P and Brenner, H and Bruinsma, F and Brunet, J and Buhari, SA and Burwinkel, B and Butzow, R and Buys, SS and Cai, Q and Caldes, T and Campbell, I and Cannioto, R and Chang-Claude, J and Chiquette, J and Choi, JY and Claes, KBM and ,  and Cook, LS and Cox, A and Cramer, DW and Cross, SS and Cybulski, C and Czene, K and Daly, MB and Damiola, F and Dansonka-Mieszkowska, A and Darabi, H and Dennis, J and Devilee, P and Diez, O and Doherty, JA and Domchek, SM and Dorfling, CM and Dörk, T and Dumont, M and Ehrencrona, H and Ejlertsen, B and Ellis, S and ,  and Engel, C and Lee, E and Evans, DG and Fasching, PA and Feliubadalo, L and Figueroa, J and Flesch-Janys, D and Fletcher, O and Flyger, H and Foretova, L and Fostira, F and Foulkes, WD and Fridley, BL and Friedman, E and Frost, D and Gambino, G and Ganz, PA and Garber, J and García-Closas, M and Gentry-Maharaj, A and Ghoussaini, M and Giles, GG and Glasspool, R and Godwin, AK and Goldberg, MS and Goldgar, DE and González-Neira, A and Goode, EL and Goodman, MT and Greene, MH and Gronwald, J and Guénel, P and Haiman, CA and Hall, P and Hallberg, E and Hamann, U and Hansen, TVO and Harrington, PA and Hartman, M and Hassan, N and Healey, S and ,  and Heitz, F and Herzog, J and Høgdall, E and Høgdall, CK and Hogervorst, FBL and Hollestelle, A and Hopper, JL and Hulick, PJ and Huzarski, T and Imyanitov, EN and ,  and ,  and Isaacs, C and Ito, H and Jakubowska, A and Janavicius, R and Jensen, A and John, EM and Johnson, N and Kabisch, M and Kang, D and Kapuscinski, M and Karlan, BY and Khan, S and Kiemeney, LA and Kjaer, SK and Knight, JA and Konstantopoulou, I and Kosma, VM and Kristensen, V and Kupryjanczyk, J and Kwong, A and de la Hoya, M and Laitman, Y and Lambrechts, D and Le, N and De Leeneer, K and Lester, J and Levine, DA and Li, J and Lindblom, A and Long, J and Lophatananon, A and Loud, JT and Lu, K and Lubinski, J and Mannermaa, A and Manoukian, S and Le Marchand, L and Margolin, S and Marme, F and Massuger, LFAG and Matsuo, K and Mazoyer, S and McGuffog, L and McLean, C and McNeish, I and Meindl, A and Menon, U and Mensenkamp, AR and Milne, RL and Montagna, M and Moysich, KB and Muir, K and Mulligan, AM and Nathanson, KL and Ness, RB and Neuhausen, SL and Nevanlinna, H and Nord, S and Nussbaum, RL and Odunsi, K and Offit, K and Olah, E and Olopade, OI and Olson, JE and Olswold, C and O'Malley, D and Orlow, I and Orr, N and Osorio, A and Park, SK and Pearce, CL and Pejovic, T and Peterlongo, P and Pfeiler, G and Phelan, CM and Poole, EM and Pylkäs, K and Radice, P and Rantala, J and Rashid, MU and Rennert, G and Rhenius, V and Rhiem, K and Risch, HA and Rodriguez, G and Rossing, MA and Rudolph, A and Salvesen, HB and Sangrajrang, S and Sawyer, EJ and Schildkraut, JM and Schmidt, MK and Schmutzler, RK and Sellers, TA and Seynaeve, C and Shah, M and Shen, CY and Shu, XO and Sieh, W and Singer, CF and Sinilnikova, OM and Slager, S and Song, H and Soucy, P and Southey, MC and Stenmark-Askmalm, M and Stoppa-Lyonnet, D and Sutter, C and Swerdlow, A and Tchatchou, S and Teixeira, MR and Teo, SH and Terry, KL and Terry, MB and Thomassen, M and Tibiletti, MG and Tihomirova, L and Tognazzo, S and Toland, AE and Tomlinson, I and Torres, D and Truong, T and Tseng, CC and Tung, N and Tworoger, SS and Vachon, C and van den Ouweland, AMW and van Doorn, HC and van Rensburg, EJ and Van't Veer, LJ and Vanderstichele, A and Vergote, I and Vijai, J and Wang, Q and Wang-Gohrke, S and Weitzel, JN and Wentzensen, N and Whittemore, AS and Wildiers, H and Winqvist, R and Wu, AH and Yannoukakos, D and Yoon, SY and Yu, JC and Zheng, W and Zheng, Y and Khanna, KK and Simard, J and Monteiro, AN and French, JD and Couch, FJ and Freedman, ML and Easton, DF and Dunning, AM and Pharoah, PD and Edwards, SL and Chenevix-Trench, G and Antoniou, AC and Gayther, SA}, title = {Author Correction: Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus.}, journal = {Nature communications}, volume = {16}, number = {1}, pages = {8237}, doi = {10.1038/s41467-025-63507-x}, pmid = {40925936}, issn = {2041-1723}, support = {001/WHO_/World Health Organization/International ; R01 CA248288/CA/NCI NIH HHS/United States ; }, }
@article {pmid40926209, year = {2025}, author = {Selvaraj, MS and Li, X and Li, Z and Van Buren, E and Haidermota, S and Postupaka, D and Hornsby, W and Bis, JC and Brody, JA and Cade, BE and Chung, RH and Curran, JE and Damrauer, SM and de Las Fuentes, L and de Vries, PS and Duggirala, R and Freedman, BI and Graff, M and Guo, X and Hidalgo, BA and Hou, L and Irvin, R and Judy, R and Kalyani, RR and Kelly, TN and Konigsberg, IR and Kral, BG and Kwee, LC and Levy, D and Li, C and Manichaikul, AW and Martin, LW and Montasser, ME and Morrison, AC and Naseri, T and North, KE and O'Connell, JR and Palmer, ND and Peyser, PA and Reiner, AP and Shah, SH and Smit, RAJ and Smith, JA and Taylor, KD and Tiwari, H and Tsai, MY and Viali, S and Wang, Z and Wang, Y and Zhao, W and Arnett, DK and Blangero, J and Boerwinkle, E and Bowden, DW and Carlson, JC and Chen, YI and Ellinor, PT and Fornage, M and He, J and Heard-Costa, N and Kaplan, RC and Kardia, SLR and Kooperberg, C and Kraus, WE and Lange, LA and Loos, RJF and Mitchell, BD and Psaty, BM and Rader, DJ and Redline, S and Rich, SS and Yanek, LR and Gibbs, R and Gabriel, S and Viaud-Martinez, KA and Dutcher, SK and Germer, S and Kim, R and Rotter, JI and Lin, X and Peloso, GM and ,  and Natarajan, P}, title = {Whole genome sequence analysis of low-density lipoprotein cholesterol across 246 K individuals.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {273}, pmid = {40926209}, issn = {1474-760X}, support = {R01HL142711//National Institutes of Health (NIH)/ ; R01 EB015611/EB/NIBIB NIH HHS/United States ; P50 HL118006/HL/NHLBI NIH HHS/United States ; R01 HL163560/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; R01 HL172803/HL/NHLBI NIH HHS/United States ; R01 HL173044/HL/NHLBI NIH HHS/United States ; 75N92021F00229//NHLBI TOPMed fellowship/ ; R01 HL142302/HL/NHLBI NIH HHS/United States ; }, mesh = {Humans ; *Cholesterol, LDL/genetics/blood ; *Whole Genome Sequencing ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Genome, Human ; Genetic Variation ; }, abstract = {BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability.<br><br>RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246&#xa0;K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86&#xa0;K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate.<br><br>CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.}, }
@article {pmid40926591, year = {2025}, author = {Shaik, F and Uldrick, TS and Mazinu, M and Gwebushe, N and Mosam, A}, title = {Cytokine biomarkers and their relationship to symptoms and quality of life in people with HIV-associated Kaposi sarcoma.}, journal = {HIV medicine}, volume = {26}, number = {12}, pages = {1983-1993}, pmid = {40926591}, issn = {1468-1293}, support = {//South African Medical Research Council/ ; }, mesh = {Humans ; *Quality of Life ; *Sarcoma, Kaposi/immunology/blood/psychology ; Female ; Male ; Adult ; *Cytokines/blood ; *Biomarkers/blood ; *HIV Infections/complications ; Middle Aged ; Herpesvirus 8, Human ; }, abstract = {INTRODUCTION: Quality of life (QOL) is an essential component of care in people with HIV-associated Kaposi sarcoma (HIV-KS). Kaposi sarcoma herpes virus (KSHV) promotes cytokine expression and a dysfunctional inflammatory environment, contributing to KS pathogenesis and progression. However, disease-related inflammatory factors influencing QOL and symptoms remain underexplored. This study examines the relationship between baseline QOL parameters and inflammatory cytokine biomarkers in treatment-naïve Africans with HIV-KS participating in the randomized controlled KAART study. We hypothesized that inflammatory cytokines are linked with reduced QOL and symptom burden.<br><br>METHODS: Twenty-eight cytokines were measured from stored baseline serum using the Milliplex&#xae; multiplex assay. QOL was assessed using the validated EORTC QLQ-C30. Spearman Rho-Rank correlation was used to assess relationships between cytokine levels and QOL parameters, with p&#x2009;&#x2264;&#x2009;0.01 considered statistically significant.<br><br>RESULTS: Paired cytokine and QOL data were available for 68 participants. IL-8 showed significant negative correlations with summary scores, a reliable indicator of overall QOL (rs&#x2009;=&#x2009;-0.35, p&#x2009;=&#x2009;0.005). Increased IL-8 also correlated significantly with reduced emotional functioning scales (rs&#x2009;=&#x2009;-0.33, p&#x2009;=&#x2009;0.01) and increased pain (rs&#x2009;=&#x2009;0.32, p&#x2009;=&#x2009;0.01). By contrast, increased IL-10 correlated significantly with reduced pain (rs&#x2009;=&#x2009;-0.31, p&#x2009;=&#x2009;0.01). VEGF and MCP-1 levels correlated negatively with role functioning (rs&#x2009;=&#x2009;-0.32, p&#x2009;=&#x2009;0.01; rs&#x2009;=&#x2009;-0.30, p&#x2009;=&#x2009;0.01).<br><br>CONCLUSION: IL-8 is a key cytokine affecting QOL in HIV-KS. Elevations have a negative impact on pain, emotional functioning and overall QOL. IL-10, VEGF and MCP-1 perturbations also impact QOL. These findings enhance understanding of cytokine involvement in KS pathogenesis.}, }
@article {pmid40927245, year = {2025}, author = {Wilson, MH and Krantz, EM and Pergam, SA and Mielcarek, M and Elgar, S and Rosen, E and Swetky, M and Liu, C and Hill, JA and Cohen, S and McCulloch, DJ}, title = {Limited yield of SARS-CoV-2 screening in asymptomatic hematopoietic cell transplant and chimeric antigen receptor T-cell therapy patients.}, journal = {Antimicrobial stewardship &amp; healthcare epidemiology : ASHE}, volume = {5}, number = {1}, pages = {e195}, pmid = {40927245}, issn = {2732-494X}, abstract = {Early in the COVID-19 pandemic, screening was initiated in several settings to mitigate asymptomatic transmission of SARS-CoV-2. However, this practice was later discouraged by the Society for Healthcare Epidemiology of America. This single-center retrospective study demonstrates limited utility of SARS-CoV-2 screening tests in asymptomatic HCT and CAR T-cell patients.}, }
@article {pmid40928768, year = {2025}, author = {Gunnell, L and Hippe, DS and Park, SY and Fu, A and Akaike, T and Lachance, K and Cahill, K and Doolittle-Amieva, C and Nghiem, P}, title = {Polyomavirus Antibodies for Merkel Cell Carcinoma Recurrence Detection.}, journal = {JAMA dermatology}, volume = {161}, number = {11}, pages = {1132-1139}, pmid = {40928768}, issn = {2168-6084}, support = {K24 CA139052/CA/NCI NIH HHS/United States ; P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Carcinoma, Merkel Cell/diagnosis/virology/immunology/blood/pathology ; Male ; Female ; Aged ; Middle Aged ; *Neoplasm Recurrence, Local/diagnosis/immunology/virology/blood ; Prospective Studies ; *Merkel cell polyomavirus/immunology ; *Skin Neoplasms/diagnosis/virology/immunology/blood/pathology ; *Antibodies, Viral/blood ; *Polyomavirus Infections/diagnosis/immunology ; }, abstract = {IMPORTANCE: Merkel cell carcinoma (MCC) is typically caused by the Merkel cell polyomavirus (MCPyV) and recurs in 40% of patients. Half of patients with MCC produce antibodies to MCPyV oncoproteins, the titers of which rise with disease recurrence and fall after successful treatment.<br><br>OBJECTIVE: To assess the utility of MCPyV oncoprotein antibodies for early detection of first recurrence of MCC in a real-world clinical setting.<br><br>This prospective cohort study used a data and specimen repository from 2008 to 2020 in Seattle, Washington. Patients with MCC with locoregional disease underwent serum antibody testing at diagnosis. Statistical analysis was conducted between 2020 and 2025.<br><br>MAIN OUTCOMES AND MEASURES: The first posttreatment titer was necessary to establish a trend and was not used to assess risk (deferred). Subsequent titers were defined as (1) falling or negative, (2) rising, or (3) stable compared with the preceding titer.<br><br>RESULTS: Among the 503 patients in the cohort (median [IQR] age at diagnosis, 70 [62-77] years; 40% female), 1402 tests were performed; 247 (49%) were seropositive. A total of 877 were falling or negative, 62 were rising, 317 were stable, and 146 were deferred. Median (IQR) follow-up was 4.2 (1.8-7.4) years. On average, antibody titers fell by half every 3 months among patients not experiencing a recurrence. After a falling or negative titer, the likelihood that a given patient would remain recurrence-free for 3 months was 99.3% (95% CI, 98.6%-99.8%). In contrast, after a single rising titer, the risk of recurrence over the next 3 months was 36% (95% CI, 22%-52%), increasing to 58% (95% CI, 40%-78%) by 12 months and 68% (95% CI, 48%-86%) by 24 months. A rising titer preceded clinical or radiographic evidence of recurrence in 57% of cases (20/35). The median (IQR) interval between a rising titer and clinical disease detection was 3.7 (1.1-7.5) months, with 90% of recurrences (18/20) occurring within 14 months of the rising titer. Recurrences and antibody titers were analyzed in 196 patients with multiple blood draws.<br><br>CONCLUSIONS AND RELEVANCE: In this prospective cohort study, given a negative predictive value of 99.3%, a falling or negative titer may obviate the need for imaging, reducing radiation and contrast dye exposure. Conversely, a rising antibody titer should trigger closer follow-up, as it may lead to earlier detection of clinical recurrence and initiation of therapy.}, }
@article {pmid40929058, year = {2025}, author = {Haas, JS and Todd, KW and Mclerran, D and Tiro, JA and Vachani, A and Kobrin, S and Saia, C and Sugg Skinner, C and Zheng, Y and Chubak, J and Corley, DA and Greenlee, RT and Halm, EA and Li, CI}, title = {Gaps in care across the cancer screening continuum for cervical, colorectal, and lung cancers.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {12}, pages = {2556-2570}, pmid = {40929058}, issn = {1460-2105}, support = {UM1 CA221939/CA/NCI NIH HHS/United States ; UM1 CA221940/CA/NCI NIH HHS/United States ; U24CA221936/NH/NIH HHS/United States ; CRP-22-080-01-CTPS//American Cancer Society/ ; UM1CA221940/NH/NIH HHS/United States ; UM1CA221939/NH/NIH HHS/United States ; UM1CA222035/NH/NIH HHS/United States ; UM1 CA222035/CA/NCI NIH HHS/United States ; U24 CA221936/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Colorectal Neoplasms/diagnosis/epidemiology/therapy ; *Lung Neoplasms/diagnosis/epidemiology/therapy ; Female ; *Early Detection of Cancer/statistics &amp; numerical data/methods ; *Uterine Cervical Neoplasms/diagnosis/epidemiology ; Middle Aged ; Retrospective Studies ; Male ; Aged ; *Continuity of Patient Care/statistics &amp; numerical data ; Adult ; United States/epidemiology ; Mass Screening/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Screening for cervical, colorectal, and lung cancers reduces cancer-specific mortality, but the full benefits of screening are realized only when they are coupled with timely care across the subsequent "screening continuum" steps, including surveillance (results warranting frequent monitoring), diagnostic evaluation (results that require additional testing), and treatment (detected cancers). Our goal was to describe the proportion of individuals receiving timely cervical, colorectal, and lung cancer care at each step in the screening continuum.<br><br>METHODS: This retrospective cohort study used data from the 10 health-care settings that participate in the Population-based Research to Optimize the Screening Process, 2018 to present, consortium and included individuals who were eligible for a step along the cancer screening continuum in 2018. Proportions of individuals who received timely testing were calculated for screening, surveillance, and diagnostic tests for each of the 3 cancers and treatment (colorectal cancer only), and we evaluated the association of these outcomes with patient characteristics using multivariate logistic regression.<br><br>RESULTS: The overall proportions of timely screening, surveillance, and diagnostic testing were 41.8%, 37.3%, and 61.2% for cervical cancer; 82.4%, 45.5%, and 73.5% for colorectal cancer (94.1% for timely treatment); and 73.8%, 80.5%, and 80.7% for lung cancer. Across all 3 cancers, there were differences across the screening continuum by insurance status, race and ethnicity, and socioeconomic status.<br><br>CONCLUSIONS: There are important gaps in care across the screening continuum beyond common metrics for screening uptake. Comparison across organ types may facilitate the identification of interventions and policies that could broadly improve cancer prevention and promote health equity.}, }
@article {pmid40929164, year = {2025}, author = {Colegrove, HL and Monnat, RJ and Feder, AF}, title = {Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk.}, journal = {PLoS computational biology}, volume = {21}, number = {9}, pages = {e1012915}, pmid = {40929164}, issn = {1553-7358}, support = {DP2 CA280623/CA/NCI NIH HHS/United States ; }, mesh = {*Fanconi Anemia/therapy/genetics/complications ; Humans ; *Mouth Neoplasms/genetics/therapy/prevention &amp; control ; *Genetic Therapy/methods ; Computational Biology ; Mouth Mucosa ; Models, Biological ; Squamous Cell Carcinoma of Head and Neck/genetics ; }, abstract = {Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction in situ to FA cells and determine the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer [Formula: see text]) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of TP53 mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a TP53-dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.}, }
@article {pmid40929264, year = {2025}, author = {Hollis, JA and Chan, MC and Malik, HS and Campbell, MG}, title = {Molecular exaptation by the integrin αI domain.}, journal = {Science advances}, volume = {11}, number = {37}, pages = {eadx9567}, pmid = {40929264}, issn = {2375-2548}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 GM147414/GM/NIGMS NIH HHS/United States ; T32 GM008268/GM/NIGMS NIH HHS/United States ; }, mesh = {Cryoelectron Microscopy ; Protein Domains ; Animals ; Humans ; Protein Binding ; Ligands ; Evolution, Molecular ; Models, Molecular ; *Integrin alpha Chains/chemistry/metabolism ; Binding Sites ; }, abstract = {Integrins bind ligands between their alpha (α) and beta (β) subunits and transmit signals through conformational changes. Early in chordate evolution, some α subunits acquired an "inserted" (I) domain that expanded integrin's ligand-binding repertoire but obstructed the ancestral ligand pocket, seemingly blocking conventional integrin activation. Here, we compare cryo-electron microscopy structures of apo and ligand-bound states of the I domain-containing αEβ7 integrin and the I domain-lacking α4β7 integrin to illuminate how the I domain intrinsically mimics an extrinsic ligand to preserve integrin function. We trace the I domain's evolutionary origin to an ancestral collagen-collagen interaction domain, identifying an ancient molecular exaptation that facilitated integrin activation immediately upon I domain insertion. Our analyses reveal the evolutionary and biochemical basis of expanded cellular communication in vertebrates.}, }
@article {pmid40929366, year = {2025}, author = {Goya, S and Greninger, AL}, title = {Distinct Evolutionary Signatures of Human Parainfluenza Viruses 2 and 4 Reveal Host Antagonism Divergence and Phylogenetic Discordance.}, journal = {Molecular biology and evolution}, volume = {42}, number = {10}, pages = {}, pmid = {40929366}, issn = {1537-1719}, mesh = {Humans ; Phylogeny ; *Evolution, Molecular ; *Parainfluenza Virus 2, Human/genetics ; *Parainfluenza Virus 4, Human/genetics ; Genome, Viral ; Viral Proteins/genetics ; }, abstract = {Human parainfluenza virus 2 (HPIV-2) and human parainfluenza virus 4 (HPIV-4) are significant but underappreciated respiratory pathogens, particularly among high-risk populations including children, the elderly, and immunocompromised individuals. In this study, we sequenced 101 HPIV-2 and HPIV-4 genomes from respiratory samples collected in western Washington State and performed comprehensive evolutionary analyses using both new and publicly available sequences. Phylogenetic and phylodynamic analyses revealed that both HPIV-2 and HPIV-4 evolve at significantly faster rates compared to the mumps virus, a reference human orthorubulavirus. Notably, while HPIV-2 demonstrated the highest evolutionary rates in the surface glycoprotein HN, consistent with humoral immune-driven selection, the innate immune antagonist V/P gene evolved fastest in HPIV-4. We identified a hypervariable region within the HPIV-4V/P protein (residues 35 to 75), which structural modeling placed in a loop overlapping a known interferon antagonism domain in other paramyxovirus V proteins, though HPIV-4 is functionally incompetent in this activity. Expanded phylogenetic analysis across the Paramyxoviridae family uncovered a striking evolutionary discordance: while the HN glycoprotein and L polymerase of HPIV-4 and its 2 closest bat-derived viruses clustered within the Orthorubulavirus genus, their nucleoprotein (N), phosphoprotein (P), matrix (M), and fusion (F) proteins formed a distinct lineage outside the Rubulavirinae subfamily. Together, these findings highlight the distinct evolutionary trajectories of HPIV-2 and HPIV-4, raise hypotheses around complex Paramyxoviridae zoonotic events including recombination-like patterns, and demonstrate limitations of current L protein-based taxonomic classification schemes.}, }
@article {pmid40930044, year = {2025}, author = {Diemert, DJ and Graciaa, DS and Zhang, B and Rouphael, NG and Branche, AR and Martin, TCS and Jackson, LA and Presti, RM and Kamidani, S and Mahgoub, SM and Babu, TM and Magaret, CA and Simon, V and van Bakel, H and Roberts, PC and Beigel, JH and Gilbert, PB and Follmann, D and , }, title = {Effect of Omicron BA.1-based compared to prototype booster mRNA vaccination on incidence of COVID-19 in the COVAIL trial.}, journal = {Vaccine}, volume = {64}, number = {}, pages = {127718}, doi = {10.1016/j.vaccine.2025.127718}, pmid = {40930044}, issn = {1873-2518}, mesh = {Humans ; *COVID-19/prevention &amp; control/epidemiology/immunology ; Female ; Male ; *Immunization, Secondary/methods ; Middle Aged ; Adult ; Incidence ; *SARS-CoV-2/immunology ; *COVID-19 Vaccines/immunology/administration &amp; dosage ; Antibodies, Viral/blood/immunology ; 2019-nCoV Vaccine mRNA-1273/immunology ; BNT162 Vaccine/immunology ; Antibodies, Neutralizing/blood/immunology ; Aged ; Immunogenicity, Vaccine ; Vaccination ; }, abstract = {BACKGROUND: Covid-19 vaccines are updated to match circulating strains based on reasoning that better strain-matched immunogenicity should provide better protection. Randomized evidence with disease endpoints to support strain matching is lacking. We evaluated COVID-19 incidence among adults randomized to a second booster of Prototype or Omicron-based vaccines.<br><br>METHODS: COVAIL was a four-stage Phase 2 clinical trial; results from Stages 1 (mRNA-1273 [Moderna]) and 2 (BNT162b2 [Pfizer/BioNTech]) are described here. Adults who had received a primary series and one booster of an authorized COVID-19 vaccine were eligible. Participants received one dose of either Prototype vaccine or a monovalent or bivalent Omicron BA.1 vaccine. SARS-CoV-2 neutralization titers (ID50) were measured pre- and post-vaccination. Covariate-adjusted cumulative COVID-19 incidence and Cox regression analyses were conducted separately for each stage.<br><br>RESULTS: 706 participants with pre- and day 15 post-vaccination ID50 titers (n&#xa0;=&#xa0;503 in Stage 1, n&#xa0;=&#xa0;203 in Stage 2) were included. Within stages, participant characteristics and baseline ID50 titers were similar between Prototype and Omicron-based arms. There was no difference in cumulative COVID-19 incidence for Prototype vs. Omicron-based vaccine in Stage 1 (RR 1.04, 95&#xa0;% CI 0.73-1.48), while incidence was higher among Prototype recipients in Stage 2 (RR 2.56, 1.44-4.52). Cox regression analysis showed no difference in Stage 1 (HR 1.04, 0.68-1.58), but higher incidence for Prototype recipients in Stage 2 (HR 2.95, 1.52-5.72).<br><br>CONCLUSIONS: Omicron-based vaccines as second boosters were more protective against COVID-19 relative to Prototype among those receiving BNT162b2 but not mRNA-1273. Differences between stages such as force of infection, antigen matching, and vaccine differences may explain this finding.<br><br>CLINICALTRIALS: govRegistry Number: NCT05289037.}, }
@article {pmid40930223, year = {2025}, author = {Portuguese, AJ and Tuazon, SA and Pont, MJ and Cole, GO and Sather, BD and Song, X and Thomas, S and Wood, BL and Blake, M and Works, MG and Shadman, M and Liang, EC and Wu, VQ and Voutsinas, JM and Gooley, TA and Turtle, CJ and Till, BG and Coffey, DG and Maloney, DG and Libby, EN and Chapuis, AG and Milano, F and Riddell, SR and Green, DJ and Cowan, AJ}, title = {Impact of Gamma-Secretase Inhibition on Outcomes Following BCMA CAR-T Therapy in Multiple Myeloma: A Comparison of Two Phase 1 Trials.}, journal = {Transplantation and cellular therapy}, volume = {31}, number = {12}, pages = {1002.e1-1002.e9}, doi = {10.1016/j.jtct.2025.09.003}, pmid = {40930223}, issn = {2666-6367}, mesh = {Humans ; *Multiple Myeloma/therapy/drug therapy/mortality ; Male ; Middle Aged ; Female ; *B-Cell Maturation Antigen/metabolism ; *Amyloid Precursor Protein Secretases/antagonists &amp; inhibitors ; Aged ; *Immunotherapy, Adoptive/methods ; *Receptors, Chimeric Antigen ; Treatment Outcome ; Adult ; }, abstract = {BACKGROUND: BCMA-directed chimeric antigen receptor (CAR)-T cell therapy represents a major therapeutic breakthrough for relapsed/refractory multiple myeloma (RRMM), offering deep and durable responses in heavily pretreated patients. However, a subset of patients experiences early relapse or fail to respond, highlighting the need for strategies to enhance efficacy. Gamma-secretase inhibitors (GSIs) have been shown to increase surface BCMA expression on malignant plasma cells and may potentiate the activity of BCMA CAR-T cells, particularly in patients with low baseline BCMA antigen density. Two contemporaneous phase 1 trials (FH9952 and FH9762) evaluated the fully human BCMA-targeted CAR-T product FCARH143, with FH9952 incorporating GSI co-administration.<br><br>OBJECTIVE: To determine whether GSI use improves clinical outcomes following FCARH143 CAR-T therapy in RRMM, with particular focus on overall survival (OS), progression-free survival (PFS), and subgroup differences based on prior BCMA-targeted therapy and baseline tumor BCMA levels.<br><br>STUDY DESIGN: This retrospective analysis compared outcomes from two single-arm, single-center phase 1 trials of the fully human BCMA-targeted CAR-T cell product FCARH143 in RRMM: FH9952 (n = 18), which incorporated the GSI crenigacestat, and FH9762 (n = 25), which did not. Both studies had extended follow-up beyond previously published reports. Eligible patients had measurable RRMM with &#x2265;10% bone marrow plasma cell involvement and confirmed BCMA expression. BCMA-na&#xef;ve patients were defined as those without prior exposure to BCMA-targeted therapies (e.g., BCMA CAR-T, bispecific antibodies, or antibody-drug conjugates); BCMA-exposed patients had received at least one such therapy. All participants received lymphodepletion with fludarabine and cyclophosphamide followed by infusion of FCARH143. In FH9952, crenigacestat (25 mg orally, three times weekly) was administered from day 0 through day +18. Outcomes included response rates, adverse events, OS, and PFS. Cox proportional hazards models were used for survival analysis.<br><br>RESULTS: With extended follow-up (median 5.8 years), the overall cohort (n = 43) had a median OS of 2.7 years (95% CI 1.9-4.8) and median PFS of 1.1 years (95% CI 0.72-2.2). Baseline characteristics were generally similar, though BCMA-exposed status was more frequent in FH9952 (39% versus 8%). Rates of cytokine release syndrome, immune effector cell-associated neurotoxicity, and early immune effector cell-associated hematotoxicity were comparable between trials. Among BCMA-na&#xef;ve patients (n = 34), GSI use was associated with improved OS (not reached versus 2.3 years; adjusted HR 0.30, 95% CI 0.10-0.88, P = .028) and a trend toward improved PFS (2.6 versus 1.3 years; adjusted HR 0.47, 95% CI 0.22-1.04, P = .062). No benefit was observed among BCMA-exposed patients. Exploratory spline modeling suggested GSI mitigated the adverse impact of low tumor BCMA levels, with inferior outcomes at low BCMA expression observed only in the non-GSI cohort.<br><br>CONCLUSIONS: Co-administration of a GSI with BCMA CAR-T therapy was associated with improved survival in BCMA-na&#xef;ve RRMM patients, particularly those with low baseline tumor BCMA levels. These findings suggest GSI modulation of BCMA surface expression may enhance CAR-T efficacy in select patients and support further prospective investigation.}, }
@article {pmid40930249, year = {2025}, author = {Newsom, OJ and Zheng, E and Sullivan, LB}, title = {Defined media reveal the essential role of lipid scavenging in supporting cancer cell proliferation.}, journal = {The Journal of biological chemistry}, volume = {301}, number = {10}, pages = {110693}, pmid = {40930249}, issn = {1083-351X}, support = {R35 GM147118/GM/NIGMS NIH HHS/United States ; T32 GM153182/GM/NIGMS NIH HHS/United States ; }, mesh = {*Cell Proliferation ; Humans ; *Lipid Metabolism ; Animals ; *Culture Media/chemistry/pharmacology ; *Lipids/chemistry ; *Neoplasms/metabolism/pathology ; Lipidomics ; Cell Line, Tumor ; Cattle ; }, abstract = {Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS. Here, we use a combination of live-cell imaging and quantitative lipidomics to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation, with serum metal and lipid components serving as crucial metabolic resources. Despite access to a wide range of lipid classes available in serum, we find albumin-bound lipids are the primary species consumed by cancer cells. Furthermore, we find that supplementing with additives that contain necessary metals and any of the albumin-associated lipid classes can obviate the FBS requirement for cancer cell proliferation. Using this defined system, we investigated cancer cell lipid consumption dynamics, finding that albumin-associated lipids are primarily consumed through a mass-action mechanism with minimal competition within or amongst lipid classes. We also find that lipid scavenging is a dominant lipid acquisition route and is necessary for cancer cell proliferation. This work therefore identifies metabolic contributions of serum and provides a framework for building defined culture systems that sustain cell proliferation without the undefined contributions of serum.}, }
@article {pmid40931081, year = {2025}, author = {Wen, L and Miyagi, H and Spiess, PE and Yu, A and Mendelsohn, CL and Tan, WS and Psutka, SP and Lerner, SP and Cheng, L and Dyrskjøt, L and Meeks, JJ and Shariat, SF and Gontero, P and Pradere, B and Steinberg, GD and Kamat, AM and Li, R}, title = {Low-grade non-muscle-invasive bladder cancer: molecular landscape, treatment strategies and emerging therapies.}, journal = {Nature reviews. Urology}, volume = {22}, number = {12}, pages = {846-861}, pmid = {40931081}, issn = {1759-4820}, support = {I01 BX005599/BX/BLRD VA/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/therapy/pathology/genetics/diagnosis ; Neoplasm Invasiveness ; Neoplasm Grading ; Non-Muscle Invasive Bladder Neoplasms ; }, abstract = {Low-grade non-muscle invasive bladder cancer is a specific category of bladder cancer with a favourable prognosis; however, its management presents several challenges. The risk of stage progression is very low, but approximately half of patients will experience recurrence within the first 5 years after diagnosis. This high propensity for recurrence, coupled with the threat of progression, mandates ongoing surveillance. However, the optimal frequency and duration of follow-up monitoring remain undefined. Current management strategies for low-grade non-muscle invasive bladder cancer rely heavily on routine office cystoscopy, with few advances in diagnostic and treatment options over the past 25 years. Our basic understanding of disease biology has substantially advanced. However, at present, considerable variations in clinical practice exist, with implications for increased financial and treatment burden for patients and health care systems. Molecular signatures and biomarker discoveries are crucial to understand disease behaviour and inform novel treatment strategies. Emerging therapies, such as advanced drug-delivery systems, immunomodulatory agents and targeted therapies, offer the potential to improve patient outcomes, streamline management and reduce the need for surveillance cystoscopies. Actionable avenues for future research in the field include prospective validation of novel biomarkers and therapies with the ultimate aim of optimizing patient care and reducing health care costs.}, }
@article {pmid40931545, year = {2025}, author = {Poh, C and Chen, X and Voutsinas, J and Naresh, K and Dizon, JJ and Shadman, M and Lynch, RC and Till, BG and Ujjani, CS and Di, M and Raghunathan, V and Warren, EH and Smith, SD and Wu, QV and Cherian, S and Gopal, AK}, title = {Impact of immunophenotype on clinical disease characteristics and outcomes in T-cell prolymphocytic leukaemia.}, journal = {British journal of haematology}, volume = {207}, number = {5}, pages = {2143-2146}, doi = {10.1111/bjh.70113}, pmid = {40931545}, issn = {1365-2141}, }
@article {pmid40931630, year = {2025}, author = {Ball-Burack, M and Menssen, A and Eidenschink Brodersen, L and Nalla, A and Loken, M and Pardo, L and Dahlberg, A and Hudson, C and Meshinchi, S and Tarlock, K}, title = {A Case of Blinatumomab Efficacy in RAM Immunophenotype/CBFA2T3::GLIS2 Fusion AML.}, journal = {Pediatric blood &amp; cancer}, volume = {72}, number = {12}, pages = {e32035}, doi = {10.1002/pbc.32035}, pmid = {40931630}, issn = {1545-5017}, }
@article {pmid40932993, year = {2025}, author = {Repele, A and Pande, D and Enstrom, MR and Perez, AM and Cui, M and Madhu, R and Nelson, V and Kiem, HP and Radtke, S}, title = {GroβT rapidly and reliably mobilizes primitive hematopoietic stem and progenitor cells in nonhuman primates.}, journal = {Molecular therapy. Methods &amp; clinical development}, volume = {33}, number = {3}, pages = {101558}, pmid = {40932993}, issn = {2329-0501}, support = {P51 OD010425/OD/NIH HHS/United States ; P51 OD011092/OD/NIH HHS/United States ; R01 AI135953/AI/NIAID NIH HHS/United States ; R01 HL136135/HL/NHLBI NIH HHS/United States ; }, abstract = {Autologous hematopoietic stem cell (HSC) gene therapy has gone through remarkable advancements in recent years, especially for the treatment of sickle cell disease (SCD). However, the collection of HSCs from SCD patients requires unique considerations, as granulocyte colony-stimulating factor (G-CSF)-mediated mobilization is contraindicated, and plerixafor-only mobilization is highly variable. Consequently, alternative mobilization regimens that are safe for SCD patients and generate better cell yields are desirable for SCD HSC gene therapy. Here, we evaluated a combination of plerixafor (AMD3100, a CXCR4 antagonist) with GroβT (MGTA-145/GroβT, a CXCR2 agonist) against the current gold-standard G-CSF for HSC gene therapy in nonhuman primates (NHPs) for HSC mobilization, leukapheresis, ex vivo gene editing to reactivate fetal hemoglobin, and transplantation. AMD3100/GroβT rapidly and reliably mobilized phenotypically primitive HSCs within hours even in a G-CSF non-responder. Average CD34/CD90 frequency in the blood and yields after enrichment were comparable in both mobilization regimens. Rapid recovery and robust multilineage long-term engraftment of gene-modified HSCs was achieved in the bone marrow and blood of animals. In summary, AMD3100/GroβT allows highly efficient and reliable mobilization of HSCs, providing a G-CSF-free regimen specifically for SCD but also any other hematological disease or disorder treatable with HSC gene therapy.}, }
@article {pmid40934109, year = {2025}, author = {Azhideh, A and Haseli, S and Schaub, SK and Amini, B and Hosseini, N and Mansoori, B and Chalian, H and Mirghaderi, P and Hall, ET and Chalian, M}, title = {Musculoskeletal Complications of Radiation Therapy and Immunotherapy.}, journal = {Radiographics : a review publication of the Radiological Society of North America, Inc}, volume = {45}, number = {10}, pages = {e250014}, doi = {10.1148/rg.250014}, pmid = {40934109}, issn = {1527-1323}, mesh = {Humans ; *Immunotherapy/adverse effects ; *Musculoskeletal Diseases/etiology/diagnostic imaging ; *Radiation Injuries/diagnostic imaging/etiology ; *Radiotherapy/adverse effects ; }, abstract = {Radiation therapy (RT) and immunotherapy are widely used in modern oncologic care and are both associated with a broad spectrum of musculoskeletal complications. These adverse effects can be acute or delayed and include bone fragility, insufficiency fractures, osteoradionecrosis, cartilage degeneration, inflammatory arthritis, myositis, and tendinopathy. Many of these complications can closely mimic metastatic disease or infection, creating diagnostic challenges. RT-induced musculoskeletal injuries are influenced by factors such as total dose, fractionation, and technique, with newer modalities such as stereotactic body RT and proton beam therapy associated with specific imaging appearances and complication profiles. Immunotherapy, particularly immune checkpoint inhibitor medication, has introduced a distinct set of immune-related adverse events affecting the musculoskeletal system, including inflammatory arthropathy, myositis, and enthesitis, often occurring in seronegative patterns and overlapping with other systemic toxicities. The authors provide an in-depth overview of the radiobiologic principles underlying RT, the evolving landscape of immunotherapy, and the diverse musculoskeletal complications that arise from both therapies. Emphasis is placed on the clinical context and imaging features that aid in recognizing and differentiating these conditions from neoplastic or infectious processes. A thorough understanding of these complications is essential for accurate diagnosis, timely management, and improved patient outcomes. [©]RSNA, 2025 Supplemental material is available for this article.}, }
@article {pmid40934225, year = {2025}, author = {Mkhize, NN and Li, SS and Hu, J and Robinson, ST and Hoosain, Z and Garrett, N and Chirenje, ZM and Fleurs, L and Kaldine, H and Modise, T and Moore, PL and Randhawa, AK and Sholukh, AM and Hutter, J and Polakowski, L and Corey, L and Gill, K and Montefiori, DC and Janes, H and Karuna, S and , }, title = {Neutralizing antibody responses over time in a demographically and clinically diverse cohort of individuals recovered from SARS-CoV-2 acquisition in Africa: A cohort study.}, journal = {PLOS global public health}, volume = {5}, number = {9}, pages = {e0005156}, pmid = {40934225}, issn = {2767-3375}, support = {UM1 AI068614/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; }, abstract = {COVID-19 has affected millions worldwide. Research characterized immune responses of individuals who acquired SARS-CoV-2 and identified co-factors, such as HIV, associated with greater likelihood of poor clinical outcomes. SARS-CoV-2-specific neutralizing antibodies (nAbs) are a strong correlate of protection but their elicitation in people living with HIV (PLWH), and particularly in southern Africa, is less well characterized. HVTN 405/HPTN 1901 was an observational cohort study of individuals recently recovered from SARS-CoV-2. We describe 323 participants enrolled early in the pandemic (June 2020 to January 2021) in Zambia (n = 12), Malawi (n = 13), Zimbabwe (n = 59), and South Africa (n = 239), profiling their SARS-CoV-2-specific nAb responses and associations with demographics, comorbidities, disease severity, and time since diagnosis based on linear and logistic regression. Participants' median age was 39 years, 63.5% were assigned female sex at birth, 71.2% were black African, and 39 (12.1%) were PLWH. Approximately one in four participants (25.7%) had asymptomatic SARS-CoV-2, 47.4% were symptomatic but not hospitalized, and 26.9% were hospitalized with COVID-19. Participants in these groups were enrolled at a median of 51.5 days, 53 days, and 60 days post-SARS-CoV-2 diagnosis, respectively. SARS-CoV-2 nAbs were measured in serum using one of two calibrated assays. Most (291/322, 90.4%) participants had positive nAb responses at enrollment. Across all participants, nAb responses generally declined in magnitude between enrollment and 2-3 months thereafter, then increased through month 12 coincident with epidemiologically observed new waves of acquisition. In a multivariate model adjusted for potentially confounding factors, PLWH had a 65% lower geometric mean (GM) nAb ID50 titer compared to people without HIV (PWOH) (GMR: 0.35, p = 0.003, q = 0.006). Greater disease severity, older age (>55 years), high BMI (≥30) and diabetes were associated with higher nAb ID50 titers (all p < 0.05, all q < 0.20).These findings are important, as nAb titers are predictive of vulnerability to COVID-19.}, }
@article {pmid40934429, year = {2025}, author = {Esmaeili, S and Owens, K and de Leon, UA and Standing, JF and Lowe, DM and Zhang, S and Watson, JA and Schilling, WH and Wagoner, J and Polyak, SJ and Schiffer, JT}, title = {Molnupiravir clinical trial simulation suggests that polymerase chain reaction underestimates antiviral potency against SARS-CoV-2.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {21}, pages = {}, pmid = {40934429}, issn = {1558-8238}, support = {R01 AI177512/AI/NIAID NIH HHS/United States ; T32 AI118690/AI/NIAID NIH HHS/United States ; }, mesh = {*SARS-CoV-2/genetics/drug effects ; Humans ; *Hydroxylamines/therapeutic use/pharmacology ; *Cytidine/analogs &amp; derivatives/therapeutic use/pharmacology ; *COVID-19 Drug Treatment ; *Antiviral Agents/therapeutic use/pharmacology ; RNA, Viral/genetics ; COVID-19/virology ; Ribonucleotides ; Mutation ; Virus Replication/drug effects ; Computer Simulation ; }, abstract = {Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggested lower antiviral potency against pre-Omicron SARS-CoV-2 variants than against Omicron. We estimated that in vitro assays underestimated in vivo potency by 6- to 7-fold against Omicron variants. Our model suggested that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA was underestimated by approximately 0.4 log10 in the two trials conducted while Omicron variants dominated. Viral area under the curve estimates differed significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.}, }
@article {pmid40934451, year = {2025}, author = {Necchi, A and Galsky, MD and Dizman, N and Aggen, DH and Agarwal, N and Al-Ahmadie, H and Apolo, AB and Ballas, L and Bangs, R and Black, PC and Brausi, M and Brembilla, G and Cheng, L and Chiti, A and Cimadamore, A and Colecchia, M and Daneshmand, S and Di Stasi, S and Efstathiou, JA and Filicevas, A and Geynisman, DM and Grivas, P and Gupta, S and Iasonos, A and James, ND and Lerner, SP and Loriot, Y and Makaroff, LE and Maluf, F and Moschini, M and Ostrovnaya, I and Pal, SK and Plimack, ER and Prakash, G and Psutka, SP and Rosenberg, JE and Sadeghi, S and Schmidt, B and Schwartz, LH and Sonpavde, GP and St Laurent, MP and Ye, D and Spiess, PE and Kamat, AM}, title = {End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {32}, pages = {3536-3544}, pmid = {40934451}, issn = {1527-7755}, support = {P30 CA008748/CA/NCI NIH HHS/United States ; ZIA BC011351/ImNIH/Intramural NIH HHS/United States ; }, mesh = {Humans ; *Urinary Bladder Neoplasms/pathology/surgery/therapy ; *Organ Sparing Treatments/methods ; Neoplasm Invasiveness ; Clinical Trials as Topic ; Perioperative Care/methods ; Endpoint Determination ; }, abstract = {PURPOSE: The evolving treatment landscape of muscle-invasive bladder cancer (MIBC) increasingly warrants novel trial design to evaluate perioperative strategies aimed at bladder preservation. To establish standardized outcome measures for evaluating organ preservation strategies in MIBC, the International Bladder Cancer Group (IBCG) and the Global Society of Rare Genitourinary Tumors (GSRGT) assembled an international, multidisciplinary consensus panel.<br><br>METHODS: The IBCG and GSRGT gathered global bladder cancer experts and patient advocates to establish a framework for risk-adapted bladder-sparing treatment approaches for MIBC. Working groups reviewed the literature and developed draft recommendations, which were discussed at a live meeting in December 2024 in Milan. This was followed by voting by the members using a modified Delphi process. Recommendations achieving &#x2265;75% agreement during the meeting were further refined and presented.<br><br>RESULTS: Clinical complete response (cCR) definition should encompass the absence of high-grade malignancy on pathology and malignant cells on urine cytology and no evidence of local or metastatic disease on cross-sectional imaging. Although cCR remains immature as a primary or coprimary end point in registrational trials, it could serve as a suitable end point in early-phase studies and risk-adapted investigations. Event-free survival (EFS) remains the preferred primary end point as it could reliably capture the durability of clinically meaningful benefit after omittance of surgical consolidation or chemoradiation. Given the composite nature of EFS, events should be prespecified, evaluated in an intention-to-treat approach, and meticulously collected. Continuous assessment of individual patient preferences should begin at the outset of perioperative therapy discussions, with informed decision making prioritized throughout.<br><br>CONCLUSION: The consensus definition of cCR and the framework presented in this study can serve as a foundation for thorough testing of risk-adapted bladder-sparing treatment paradigms for MIBC.}, }
@article {pmid40935610, year = {2025}, author = {Uribe, C and Iravani, A and Savir-Baruch, B and Jacene, H and Graves, SA and Dewaraja, YK and Heath, CL and Hope, TA}, title = {Summary: SNMMI/ACNM Procedure Standard for Posttreatment Imaging of [177]Lu-Based Radiopharmaceuticals.}, journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine}, volume = {66}, number = {10}, pages = {1528-1537}, doi = {10.2967/jnumed.125.270979}, pmid = {40935610}, issn = {1535-5667}, }
@article {pmid40935830, year = {2025}, author = {Granadier, D and Cooper, K and Acenas, D and Kousa, A and Warren, M and Hernandez, V and Iovino, L and deRoos, P and Lederer, EE and Shannon-Sevillano, S and Kinsella, S and Evandy, C and van den Brink, MRM and Lemarquis, A and Dudakov, JA}, title = {Damage-induced IL-18 stimulates thymic NK cells limiting endogenous tissue regeneration.}, journal = {Nature immunology}, volume = {26}, number = {10}, pages = {1699-1711}, pmid = {40935830}, issn = {1529-2916}, support = {F30-HL165761//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01 HL145276/HL/NHLBI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30-CA015704//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; R35-HL171556//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-HL145276//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; R35 HL171556/HL/NHLBI NIH HHS/United States ; U01-AI70035//Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID)/ ; F30 HL165761/HL/NHLBI NIH HHS/United States ; R01 HL165673/HL/NHLBI NIH HHS/United States ; P01-AG052359//U.S. Department of Health &amp; Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P01 AG052359/AG/NIA NIH HHS/United States ; T32 GM007270/GM/NIGMS NIH HHS/United States ; U01 AI170035/AI/NIAID NIH HHS/United States ; R01-HL165673//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; }, mesh = {*Interleukin-18/metabolism/immunology/genetics ; Animals ; *Thymus Gland/immunology/physiology ; *Killer Cells, Natural/immunology ; *Regeneration/immunology ; Mice ; Mice, Inbred C57BL ; Epithelial Cells/immunology ; Mice, Knockout ; Mice, Transgenic ; }, abstract = {Interleukin-18 (IL-18) is an acute-phase proinflammatory molecule crucial for mediating viral clearance by activating T helper 1 CD4[+] T cells, cytotoxic CD8[+] T cells and natural killer (NK) cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18-stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures the restoration of immune competence after acute insults such as stress, infection, chemotherapy and radiation. NK cells suppress thymus recovery by aberrantly targeting thymic epithelial cells, which act as the master regulators of organ function and regeneration. Together, our data reveal a new pathway regulating tissue regeneration in the thymus and suggest IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy due to its capacity to elicit a type 1 immune response, these findings also offer insight into potential off-target effects.}, }
@article {pmid40936721, year = {2025}, author = {Parrish, AG and Holland, EC}, title = {Seq-ing answers: exploring meningioma biology utilizing bulk RNA-seq-based reference landscapes.}, journal = {Frontiers in oncology}, volume = {15}, number = {}, pages = {1631573}, pmid = {40936721}, issn = {2234-943X}, abstract = {Meningiomas are the most common primary brain tumors, accounting for 40% of all central nervous system neoplasms. While usually benign, these tumors can vary in aggressiveness. Traditional classification and grading systems, which primarily rely on histopathological features, are not always reliable in capturing tumor behavior and predicting patient outcomes. In contrast, modern systems-based on factors such as copy number alterations, DNA methylation, and gene expression-offer a more accurate framework for identifying distinct biological signatures and aggressive subtypes, as well as for predicting recurrence. Transcriptomic profiling using bulk whole-genome RNA sequencing (RNA-seq), which provides insights into alternative splicing, gene expression, fusion events, non-coding RNAs, and pathway activity, further enhances our understanding of meningioma tumorigenesis, enables the projection of new samples onto dimension-reduced reference landscapes, and helps accurately predict recurrence. As bulk RNA-seq becomes more accessible, it holds great potential for refining prognostic tools, informing personalized treatment approaches, and ultimately improving outcomes for meningioma patients.}, }
@article {pmid40938106, year = {2025}, author = {Matsubara, T and Miller, CP and Min, C and Su, CY and Choi, JS and Lim, CT and Phillip, JM and Kim, JW and Kim, DH}, title = {Topographic cues regulate collective cell dynamics in curved nano/microgrooved tubular microchannels.}, journal = {Lab on a chip}, volume = {25}, number = {20}, pages = {5255-5267}, pmid = {40938106}, issn = {1473-0189}, support = {R01 CA279948/CA/NCI NIH HHS/United States ; R35 GM157099/GM/NIGMS NIH HHS/United States ; }, mesh = {Cell Movement ; Animals ; Surface Properties ; Epithelial Cells/cytology ; *Lab-On-A-Chip Devices ; Madin Darby Canine Kidney Cells ; }, abstract = {Physical properties of the extracellular matrix, such as topography and curvature, regulate collective epithelial behaviors. However, the interplay between these geometric factors on collective migration is not well understood. In this study, we investigate the effects of topographic cues on a curved surface on collective epithelial migration within tubular microchannels with an inner diameter of 100 μm. These tubular microchannels feature circumferential or longitudinal micro- and nano-grooves fabricated by two-photon polymerization three-dimensional printing and micro-molding techniques. Live cell microscopy records the collective migration of GFP-labeled epithelial cells into the microchannel with each topographical design. We utilized a single-cell behavior analysis for the tracked time-dependent cell position data to visualize and quantify complex cell migration. Results show that longitudinal grooves (800 nm and 4 μm) enhanced cell migration, but circumferential grooves did not significantly enhance cell migration. This indicates that curvature rather than topography dominates migration at the microtube scale. These findings provide insights into the interplay between curvature, microscale structure, and cell behaviors and suggest the potential to control cell behaviors by manipulating the structure and topographic cues with their local microenvironments.}, }
@article {pmid40938896, year = {2025}, author = {Estrella, F and Lewin, J and Schuessler, A}, title = {Establishing the clinical IDS pharmacist role in a phase 1 clinic.}, journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners}, volume = {}, number = {}, pages = {10781552251376302}, doi = {10.1177/10781552251376302}, pmid = {40938896}, issn = {1477-092X}, abstract = {BackgroundPhase 1 oncology clinical trials are complex and prioritize patient safety. Clinical pharmacists-experts in pharmacotherapy and patient-centered care-can enhance these trials by managing drug regimens and interactions. Despite demonstrated benefits, their integration into trial teams remains inconsistent. To address this, the Fred Hutch Phase 1 Clinical Trials Program embedded a clinical Investigational Drug Services (IDS) pharmacist into the clinic. This study assessed pharmacist utilization, intervention types, time spent, and inquiry sources.MethodsA retrospective review compared a pilot phase (Apr 2021-Apr 2022) and a follow-up (Apr-Sept 2023). Intervention type, frequency, duration, and communication modality were descriptively analyzed.ResultsDuring the pilot phase, 311 interventions were documented, primarily related to concomitant medication reviews (77%) and drug information (16%). In the 6-month follow-up period, 302 interventions were recorded, demonstrating an increased reliance on pharmacist services. Concomitant medication reviews remained high at 83%, indicating the pharmacist's critical role in medication management. Total intervention time was 93 h (pilot) compared to 72 h (follow-up), with a consistent median time per intervention. Over 85% of inquiries originated from study coordinators and nurses. The adoption of digital communication tools supported streamlined workflows and timely responses, aligning with broader clinic operational enhancements.ConclusionsThe integration of clinical IDS pharmacists enhanced the management of phase 1 trials while maintaining high safety and compliance standards. This study demonstrates the important contributions of pharmacists in supporting early-phase clinical trial research and highlights opportunities for expanding their role to meet growing trial complexities.}, }
@article {pmid40939575, year = {2025}, author = {Krishnan, M and Anwar, MY and Justice, AE and Chittoor, G and Chen, HH and Roshani, R and Scartozzi, A and Dickerson, RR and Smit, RAJ and Preuss, MH and Chami, N and Hadad, BS and Parra, EJ and Cruz, M and Hui, Q and Wilson, PWF and Sun, YV and Zhang, X and Linchangco, GV and Kardia, SLR and Faul, JD and Weir, DR and Bielak, LF and Highland, HM and Young, KL and Qi, B and Wang, Y and Fornage, M and Haiman, C and Cheng, I and Peters, U and Kooperberg, C and Buyske, S and McCormick, JB and Fisher-Hoch, SP and Lona-Durazo, F and Peralta, J and Gomez-Zamudio, J and Rich, SS and Ferrier, KR and Lange, EM and Gignoux, CR and Kenny, EE and Wojcik, GL and Cho, K and Gaziano, MJ and Djousse, L and Liu, S and Vaidya, D and de Mutsert, R and Josyula, NS and Bauer, CR and Zhao, W and Walker, RW and Smith, JA and Lange, LA and Meyer, MC and Liu, CT and Yanek, LR and Lee, M and Raffield, LM and Loos, RJF and Gordon-Larsen, P and Below, JE and North, KE and Graff, M}, title = {Genome-wide association study provides novel insight into the genetic architecture of severe obesity.}, journal = {PLoS genetics}, volume = {21}, number = {9}, pages = {e1011842}, pmid = {40939575}, issn = {1553-7404}, support = {RC4 AG039029/AG/NIA NIH HHS/United States ; I01 BX004821/BX/BLRD VA/United States ; U01 AG009740/AG/NIA NIH HHS/United States ; R01 HL163262/HL/NHLBI NIH HHS/United States ; R01 HL087660/HL/NHLBI NIH HHS/United States ; R01 DK107786/DK/NIDDK NIH HHS/United States ; R01 DK075787/DK/NIDDK NIH HHS/United States ; R01 HL119443/HL/NHLBI NIH HHS/United States ; U01 HG004729/HG/NHGRI NIH HHS/United States ; KL2 TR002490/TR/NCATS NIH HHS/United States ; R01 DK124097/DK/NIDDK NIH HHS/United States ; I01 BX005831/BX/BLRD VA/United States ; R01 DK122503/DK/NIDDK NIH HHS/United States ; R01 HL143885/HL/NHLBI NIH HHS/United States ; U01 CA288325/CA/NCI NIH HHS/United States ; R01 HL142302/HL/NHLBI NIH HHS/United States ; R01 DK110113/DK/NIDDK NIH HHS/United States ; R01 HL151152/HL/NHLBI NIH HHS/United States ; U01 HL054457/HL/NHLBI NIH HHS/United States ; R01 EY036258/EY/NEI NIH HHS/United States ; RC2 AG036495/AG/NIA NIH HHS/United States ; R01 HD057194/HD/NICHD NIH HHS/United States ; R01 DK137968/DK/NIDDK NIH HHS/United States ; R01 HL087641/HL/NHLBI NIH HHS/United States ; R01 HG010297/HG/NHGRI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; }, mesh = {Adult ; Female ; Humans ; Male ; Middle Aged ; Body Mass Index ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Multifactorial Inheritance/genetics ; *Obesity, Morbid/genetics ; Phenotype ; Polymorphism, Single Nucleotide ; }, abstract = {Severe obesity (SevO) is a primary driver of cardiovascular diseases (CVD), cardiometabolic diseases (CMD) and several cancers, with a disproportionate impact on marginalized populations. SevO is an understudied global health disease, limiting knowledge about its mechanisms and impacts. In genome-wide association study (GWAS) meta-analyses of the tail end of the BMI distribution (≥95th percentile BMI) and two SevO phenotypes [Obesity Class III BMI ≥ 40 kg/m2 and Obesity Class IV BMI ≥ 50 kg/m2] in 159,359 individuals across eleven ancestrally diverse population-based studies followed by replication in 480,897 individuals across six ancestrally diverse studies, we identified and replicated three novel signals in known loci of BMI [TENM2, PLCL2, ZNF184], associated with SevO traits. We confirmed a large overlap in the genetic architecture of continuous BMI and severe obesity phenotypes, suggesting little genetic heterogeneity in common variants, between obesity subgroups. Systematic analyses combining functional mapping, polygenic risk scores (PRS), phenome wide association studies (PheWAS) and environmental risk factors further reinforce shared downstream comorbidities associated with continuous measures of BMI and the importance of known lifestyle factors in interaction with genetic predisposition to SevO. Our study expands the number of SevO signals, demonstrates a strong overlap in the genetic architecture of SevO and BMI and reveals a remarkable impact of SevO on the clinical phenome, affording new opportunities for clinical prevention and mechanistic insights.}, }
@article {pmid40939933, year = {2026}, author = {Wernli, KJ and Anderson, ML and Palazzo, L and Luce, C and Bezman, N and Chin, M and Gao, H and Ralston, JD and Rogers, K and Su, YR and Triplette, M and Carter-Bawa, L and Vasavada, A and Jordan, M and West, M and Boler, S and Green, BB}, title = {Effectiveness of Health Communication Intervention to Improve Knowledge on Timeliness to Return for Annual Lung Cancer Screening: The Larch Trial.}, journal = {Chest}, volume = {169}, number = {2}, pages = {550-561}, pmid = {40939933}, issn = {1931-3543}, support = {R01 CA262015/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Lung Neoplasms/diagnosis ; Middle Aged ; Male ; Female ; Aged ; *Early Detection of Cancer/methods ; *Health Communication/methods ; *Health Knowledge, Attitudes, Practice ; Self Efficacy ; Time Factors ; }, abstract = {BACKGROUND: Many patients are unaware of the need to repeat lung cancer screening (LCS) annually despite shared decision-making. A health communication intervention was tested to improve patient knowledge, tobacco-related stigma, and self-efficacy in LCS.<br><br>RESEARCH QUESTION: Does additional health communication improve patient knowledge of LCS timeliness?<br><br>STUDY DESIGN AND METHODS: Trial participants aged 50 to 78 years with a normal LCS scan were randomized to the intervention or control arm. The intervention was delivered 3 weeks following an LCS scan. Intervention participants received health communication (print plus video) with 3 key messages to normalize routine LCS; a reminder of when due for screening; and encouraging social connection. Interventions were primarily delivered through the electronic health record patient portal. Eight weeks following the scan, all participants were invited to complete an online or telephone survey about knowledge, tobacco-related stigma, and self-efficacy. Modified Poisson and linear regression was used to test association of the intervention on secondary trial outcomes, using weights to account for survey nonresponse. Heterogeneity of the intervention effect was tested by using tobacco and LCS histories.<br><br>RESULTS: The survey participation rate was 38.9% with 714 respondents (n = 363 intervention; n = 351 control). Knowledge to return in 1 year improved by 13% in the intervention arm vs the control arm (relative risk, 1.13; 95% CI, 1.05-1.22; P < .001). Intervention increased the proportion by 21.9% who knew to return in 1 year from 62.0% to 83.9% (relative risk, 1.35; 95% CI, 1.16-1.58) in first-time screeners but no difference in those screened 2 or more times. No other statistically significant differences in knowledge were detected. In the control arm, both tobacco-related stigma (mean, 13.9; 95% CI, 13.6-14.2) and self-efficacy (mean, 29.0; 95% CI, 28.6-29.4) were high and unchanged by the intervention.<br><br>INTERPRETATION: A multiformat LCS intervention was shown to improve short-term knowledge of LCS timeliness to return. This finding suggests that additional health communication beyond shared decision-making might encourage repeat screening, especially in first-time screeners.<br><br>CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT05747443; URL: www.<br><br>CLINICALTRIALS: gov.}, }
@article {pmid40940539, year = {2025}, author = {Glasscock, CJ and Pecoraro, RJ and McHugh, R and Doyle, LA and Chen, W and Boivin, O and Lonnquist, B and Na, E and Politanska, Y and Haddox, HK and Cox, D and Norn, C and Coventry, B and Goreshnik, I and Vafeados, D and Lee, GR and Gordân, R and Stoddard, BL and DiMaio, F and Baker, D}, title = {Computational design of sequence-specific DNA-binding proteins.}, journal = {Nature structural &amp; molecular biology}, volume = {32}, number = {11}, pages = {2252-2261}, pmid = {40940539}, issn = {1545-9985}, support = {P30 GM124169/GM/NIGMS NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; S10 OD021832/OD/NIH HHS/United States ; S10 OD028581/OD/NIH HHS/United States ; T32 GM136627/GM/NIGMS NIH HHS/United States ; R01 GM135658/GM/NIGMS NIH HHS/United States ; }, mesh = {*DNA-Binding Proteins/chemistry/metabolism/genetics ; *DNA/chemistry/metabolism ; Escherichia coli/metabolism/genetics ; Models, Molecular ; Binding Sites ; Humans ; Protein Binding ; *Protein Engineering/methods ; Crystallography, X-Ray ; *Computational Biology/methods ; Animals ; }, abstract = {Sequence-specific DNA-binding proteins (DBPs) have critical roles in biology and biotechnology and there has been considerable interest in the engineering of DBPs with new or altered specificities for genome editing and other applications. While there has been some success in reprogramming naturally occurring DBPs using selection methods, the computational design of new DBPs that recognize arbitrary target sites remains an outstanding challenge. We describe a computational method for the design of small DBPs that recognize short specific target sequences through interactions with bases in the major groove and use this method to generate binders for five distinct DNA targets with mid-nanomolar to high-nanomolar affinities. The individual binding modules have specificity closely matching the computational models at as many as six base-pair positions and higher-order specificity can be achieved by rigidly positioning the binders along the DNA double helix using RFdiffusion. The crystal structure of a designed DBP-target site complex is in close agreement with the design model and the designed DBPs function in both Escherichia coli and mammalian cells to repress and activate transcription of neighboring genes. Our method provides a route to small and, hence, readily deliverable sequence-specific DBPs for gene regulation and editing.}, }
@article {pmid40940860, year = {2025}, author = {Nasrollahi, E and Wang, S and Yanes, R and Gonzalez Gomez, C and Magge, T and Overacre, A and Hsieh, R and Mcfarquhar, A and Tatsuoka, C and Singhi, A and Saeed, A and Sahin, IH}, title = {A Comprehensive Molecular and Clinical Study of Patients with Young-Onset Colorectal Cancer.}, journal = {Cancers}, volume = {17}, number = {17}, pages = {}, pmid = {40940860}, issn = {2072-6694}, abstract = {Background: Young-onset colorectal cancer (YO-CRC) has emerged as a distinct clinical entity, often presenting at advanced stages. Despite the increasing incidence, the molecular and clinical underpinnings of YO-CRC remain underexplored. This study aims to characterize the clinical and molecular features of YO-CRC and to evaluate their impact on OS. Methods: We reviewed 110 patients diagnosed with YO-CRC at our institution who underwent next-generation sequencing. Demographic, clinical, and molecular data, including age, gender, race, tumor location, cancer stage, and mutation status (KRAS, NRAS, BRAF, POLE, ERBB-2/HER2, microsatellite status), were collected by reviewing electronic medical records. For OS analysis, we focused on patients diagnosed with de novo stage IV. Cox proportional hazards regression and Kaplan-Meier survival analysis were utilized to assess the association of these factors with OS, with statistical significance determined by a p-value threshold of <0.05. Results: Among 110 patients, n = 44 (40%) presented with local disease (stage 1-3), while n = 66 (60%) presented with de novo metastatic disease at the time of diagnosis. The median age at diagnosis was 44.5 years. The cohort consisted of 64% males and 36% females, with 84% of patients identified as White. Most tumors were left-sided (77%), including the distal colon/sigmoid (44%) and rectum (33%). KRAS and BRAF mutations were present in 36% and 5.5%, respectively. ERBB-2/HER2 amplification and microsatellite instability were observed in 4.5% and 6.4%, respectively. Tumor mutation burden (TMB) was <10 in 57% of patients, with 14% having TMB > 20. CNV analysis revealed that 14% of patients had copy gains, 12% had concurrent gains/losses, and 31% had copy losses. Among 66 patients with de novo metastatic disease, 44% had died by the time of analysis, with a median overall survival (OS) of 43.6 months (95% CI, 28.7-not reached). KRAS mutations were found to be significantly associated with worse survival outcomes. Cox regression analysis reveals the prognostic significance of KRAS status, with a hazard ratio (HR) of 3.52 (95% CI: 1.59-7.76, p = 0.002), indicating a significantly higher risk of death for KRAS-mutant YO-CRC patients. Conclusions: Patients with YO-CRC are more likely to present with de novo metastatic disease and left-sided tumors with distinct molecular characteristics. KRAS mutations are a key prognostic factor in YO-CRC, highlighting the need for therapeutic interventions to improve outcomes in this high-risk group.}, }
@article {pmid40947766, year = {2025}, author = {Tran, L and Nickens, R and Luu, V and Petersdorf, EW and Mack, SJ}, title = {HLAtools, Searching Shared HLA Amino Acid Residue Prevalence, and the Global Frequency Browsers: New Computational Resources for Working With HLA Data and Visualizing Global Patterns of HLA Variation.}, journal = {International journal of immunogenetics}, volume = {52}, number = {6}, pages = {358-370}, pmid = {40947766}, issn = {1744-313X}, support = {U01AI069197//National Institute of Allergy and Infectious Diseases (NIAID)/ ; U01 AI069197/AI/NIAID NIH HHS/United States ; R25 HL125451/HL/NHLBI NIH HHS/United States ; R01 AI128775/AI/NIAID NIH HHS/United States ; R25HL125451/HL/NHLBI NIH HHS/United States ; R01AI128775//National Institute of Allergy and Infectious Diseases (NIAID)/ ; }, mesh = {Humans ; *HLA Antigens/genetics ; Alleles ; Gene Frequency ; *Software ; Haplotypes ; *Computational Biology/methods ; *Amino Acids/genetics ; }, abstract = {The highly polymorphic HLA genes inform susceptibility and resistance to infectious and autoimmune diseases and cancers and are key for successful solid-organ and stem-cell transplantation therapies. Over 41,000 HLA alleles are known and are unevenly distributed across the human population. Here, we describe HLAtools, Searching Shared HLA Amino-Acid Residue Prevalence (SSHAARP) and the Global Frequency Browser (GFB), new informatic tools developed to facilitate working with HLA data and visualizing the global distribution of HLA variants in human populations. HLAtools is an R package that consumes static resources for HLA alleles and sequences and makes these data locally computable alongside data-query, data-customization and data-analysis functions. The package further includes new reference datasets that dissect and catalogue HLA regions and HLA gene structures and provide insight into the organization of HLA pseudogenes and gene fragments. SSHAARP is an R package that describes the frequency distributions of individual HLA haplotypes, alleles and amino-acid motifs as global heatmaps. Allele frequency maps for more than 800 HLA alleles can be browsed using the GFB web and mobile applications. HLAtools and SSHAARP are available from the Comprehensive R Archive Network, and the GFB apps are available on GitHub.}, }
@article {pmid40949174, year = {2025}, author = {Lu, Y and Xu, H and Sun, Y and Ihejirika, SA and Chiang, CW and Darst, BF and Song, S and Shen, Y and Ye, K}, title = {Gene-Diet Interaction Analysis in UK Biobank Identified Genetic Loci That Modify the Association Between Fish Oil Supplementation and the Incidence of Dementia.}, journal = {Current developments in nutrition}, volume = {9}, number = {9}, pages = {107524}, pmid = {40949174}, issn = {2475-2991}, abstract = {BACKGROUND: Dementia is a common disease influenced by both genetic and environmental factors. APOE ε4 is well-known to increase risk of dementia, and it has been shown to attenuate the protective association of fish oil supplements (FOS) and the incidence of dementia.<br><br>OBJECTIVES: To identify additional genetic factors with modifying effects, we performed a genome-wide scan.<br><br>METHODS: We performed genome-wide association studies (GWAS) of incident all-cause dementia, Alzheimer's disease, and vascular dementia in 357,631 participants from UK Biobank and the FOS subgroups. Single-nucleotide polymorphisms (SNPs) suggestively associated with dementia (P < 1 &#xd7; 10[-5]) were then evaluated for their interactions with fish oil status in Cox regression models. Furthermore, we conducted gene set enrichment analysis to identify the relevant cell types for these interaction signals.<br><br>RESULTS: Time-to-event GWAS identified 6, 5, and 2 genome-wide significant loci (P < 5 &#xd7; 10[-8]) for the incidence of all-cause dementia, Alzheimer's disease, and vascular dementia, respectively. Most of them overlapped with previously known GWAS loci for Alzheimer's disease and related dementia. A total of 178 suggestive GWAS loci (P < 1 &#xd7; 10[-5]) were passed onto interaction analysis, and 43 of them were found to significantly modify the association between FOS and dementia incidence (P < 2.8 &#xd7; 10[-4] with Bonferroni correction). One locus overlapped with a known Alzheimer's disease GWAS locus (EED/PICALM) and 2 with GWAS loci for circulating &#x3c9;-3 fatty acids (SRSF4 and PSMG1). Candidate interacting genes exhibited cell-type-specific expression in the nervous system.<br><br>CONCLUSIONS: In total, 43 genetic loci modify the association between FOS and dementia. These findings indicate a need for genome-informed personalized nutrition of FOS for the purpose of dementia prevention.}, }
@article {pmid40949756, year = {2025}, author = {Visani, GM and Pun, MN and Minervina, AA and Bradley, P and Thomas, P and Nourmohammad, A}, title = {T-cell receptor specificity landscape revealed through de novo peptide design.}, journal = {ArXiv}, volume = {}, number = {}, pages = {}, pmid = {40949756}, issn = {2331-8422}, support = {R01 AI136514/AI/NIAID NIH HHS/United States ; R35 GM141457/GM/NIGMS NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; }, abstract = {T-cells play a key role in adaptive immunity by mounting specific responses against diverse pathogens. An effective binding between T-cell receptors (TCRs) and pathogen-derived peptides presented on Major Histocompatibility Complexes (MHCs) mediate an immune response. However, predicting these interactions remains challenging due to limited functional data on T-cell reactivities. Here, we introduce a computational approach to predict TCR interactions with peptides presented on MHC class I alleles, and to design novel immunogenic peptides for specified TCR-MHC complexes. Our method leverages HERMES, a structure-based, physics-guided machine learning model trained on the protein universe to predict amino acid preferences based on local structural environments. Despite no direct training on TCR-pMHC data, the implicit physical reasoning in HERMES enables us to make accurate predictions of both TCR-pMHC binding affinities and T-cell activities across diverse viral epitopes and cancer neoantigens, achieving up to 0.72 correlation with experimental data. Leveraging our TCR recognition model, we develop a computational protocol for de novo design of immunogenic peptides. Through experimental validation in three TCR-MHC systems targeting viral and cancer peptides, we demonstrate that our designs-with up to five substitutions from the native sequence-activate T-cells at success rates of up to 50%. Lastly, we use our generative framework to quantify the diversity of the peptide recognition landscape for various TCR-MHC complexes, offering key insights into T-cell specificity in both humans and mice. Our approach provides a platform for immunogenic peptide and neoantigen design, as well as for evaluating TCR specificity, offering a computational framework to inform design of engineered T-cell therapies and vaccines.}, }
@article {pmid40950014, year = {2025}, author = {Kikawa, C and Huddleston, J and Loes, AN and Turner, SA and Lee, J and Barr, IG and Cowling, BJ and Englund, JA and Greninger, AL and Harvey, R and Hasegawa, H and Ho, F and Lacombe, K and Leung, NHL and Lewis, NS and Peck, H and Watanabe, S and Smith, DJ and Bedford, T and Bloom, JD}, title = {Near real-time data on the human neutralizing antibody landscape to influenza virus to inform vaccine-strain selection in September 2025.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950014}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 AI165818/AI/NIAID NIH HHS/United States ; 75N93021C00015/AI/NIAID NIH HHS/United States ; 75N93021C00014/AI/NIAID NIH HHS/United States ; S10 OD020069/OD/NIH HHS/United States ; F30 AI186284/AI/NIAID NIH HHS/United States ; R01 AI165821/AI/NIAID NIH HHS/United States ; }, abstract = {The hemagglutinin of human influenza virus evolves rapidly to erode neutralizing antibody immunity. Twice per year, new vaccine strains are selected with the goal of providing maximum protection against the viruses that will be circulating when the vaccine is administered ~8-12 months in the future. To help inform this selection, here we quantify how the antibodies in recently collected human sera neutralize viruses with hemagglutinins from contemporary influenza strains. Specifically, we use a high-throughput sequencing-based neutralization assay to measure how 188 human sera collected from Oct 2024 to April 2025 neutralize 140 viruses representative of the H3N2 and H1N1 strains circulating in humans as of the summer of 2025. This data set, which encompasses 26,148 neutralization titer measurements, provides a detailed portrait of the current human neutralizing antibody landscape to influenza A virus. The full data set and accompanying visualizations are available for use in vaccine development and viral forecasting.}, }
@article {pmid40950047, year = {2025}, author = {Eldred, KC and Wooten, M and Janssens, DH and Hahn, J and Neph, SJ and Edgerton, SJ and Wyatt-Draher, G and Sherman, SM and Ranchalis, JE and Stergachis, AB and Reh, TA and Henikoff, S}, title = {CUT&amp;TIME captures the history of open chromatin in developing neurons.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950047}, issn = {2692-8205}, support = {DP5 OD029630/OD/NIH HHS/United States ; K99 GM152821/GM/NIGMS NIH HHS/United States ; }, abstract = {Chromatin structure plays a central role in defining cell identity by regulating gene expression. During development, shifts in chromatin structure facilitate changes in gene expression needed to specify distinct cell types. To understand how changes in chromatin structure influence the developmental trajectory of neural progenitor cells, we developed CUT&amp;TIME, a technique that uses a hyperactive 6-methyl adenosine (6mA) methyltransferase pulsed in living cells to map historical chromatin accessibility genome-wide in single cells. We show that CUT&amp;TIME produces a record of the chromatin landscape during neurogenesis in the developing retina, specifically as neural progenitors produce the major projection neuron type, retinal ganglion cells (RGCs). We further show that this method is compatible with single cell profiling technologies, which allows us to visualize and capture the diversity of chromatin states that produce RGCs. Additionally, we identify changes in promoter accessibility associated with the transition from progenitor to RGC. Together, these data demonstrate that CUT&amp;TIME captures a historical record of chromatin structure, which can be used to identify early changes in accessibility associated with cell-fate commitment.}, }
@article {pmid40950199, year = {2025}, author = {Chang, CH and de la Cruz, AF and Natividad, IM and Noyola, A and Malik, HS}, title = {Rapid protamine evolution suppresses meiotic drive in Drosophila.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40950199}, issn = {2692-8205}, abstract = {Many animal species replace histones with protamines during spermatogenesis. Despite their importance for sperm function, protamines rapidly evolve in many species; the biological causes behind their rapid evolution remain unknown. Here, using in vivo gene replacement, we investigated the causes and consequences underlying the rapid evolution of protamine Mst77F, which is essential for male fertility in D. melanogaster. Mst77F ortholog replacements led to defects in DNA compaction of X-chromosome-bearing sperm compared to Y-chromosome-bearing sperm during spermatogenesis, resulting in fewer X-bearing mature sperm and male-biased progeny. Unlike D. melanogaster, Mst77F is not essential for male fertility in D. yakuba but is still required to suppress sex-ratio distortion. Our results suggest that relentless pressure to suppress sex chromosomal meiotic drive drives the rapid evolution of protamines.}, }
@article {pmid40950478, year = {2025}, author = {Xu, S and Hudson, A and Janes, HE and Tomaras, GD and Ackerman, ME}, title = {Candidate Correlates of Protection in the HVTN505 HIV-1 Vaccine Efficacy Trial Identified by Positive-Unlabeled Learning.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40950478}, support = {P01 AI162242/AI/NIAID NIH HHS/United States ; R56 AI165448/AI/NIAID NIH HHS/United States ; UM1 AI068618/AI/NIAID NIH HHS/United States ; }, abstract = {With a goal of unveiling mechanisms by which vaccines can provide protection against HIV-1 acquisition, several studies have explored correlates of risk of HIV-1 acquisition in HVTN 505, which was a phase IIb trial conducted to assess the safety and efficacy of a DNA plasmid and recombinant adenovirus serotype 5-vectored HIV vaccine regimen among individuals in the United States who were vulnerable to acquiring HIV. While this trial failed to meet its predetermined efficacy criteria, both immunological and virological correlates of reduced risk of acquisition have been reported, suggesting that at least some vaccine recipients were protected from some viruses. In this work, we describe application of a novel Positive-Unlabeled machine learning-based approach to infer protection status among vaccine recipients that did not acquire HIV, resulting in improved power to detect potential correlates of immunity. Having established the analytical robustness of protection status predictions using cross-validation and permutation testing strategies, we report increased confidence in previously identified correlates of risk, such as vaccine-elicited anti-HIV-1 Env glycoprotein IgG3 antibodies and antibody-dependent phagocytosis, and the new observation of an inverse correlation between inferred vaccine-mediated protection and virus-specific IgA responses. Though its biological validity is not established, this inference approach offers a new means to use case-control datasets to identify candidate markers of effective immune responses in the context of low vaccine efficacy.}, }
@article {pmid40950500, year = {2025}, author = {Wang, Z and Taylor, KD and Rotter, JI and Rich, SS and Zheng, Y and Hou, L and Guo, X and Bressler, J and Raffield, LM and Liu, Y and Kaplan, R and Lloyd-Jones, DM and Morrison, AC and Fornage, M and Sofer, T}, title = {Estimating population structure using epigenome-wide methylation data.}, journal = {medRxiv : the preprint server for health sciences}, volume = {}, number = {}, pages = {}, pmid = {40950500}, support = {R01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL161012/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; }, abstract = {INTRODUCTION: In epigenome-wide association analysis (EWAS), unaddressed population stratification often leads to inflation. We aimed to compute methylation population scores (MPSs) that predict genetic principal components (GPCs) using a feature selection and regression approach.<br><br>METHODS: We used multi-ethnic methylation data (Illumina 450K/EPIC array) from unrelated MESA (n=929), CARDIA (n=1123), JHS (n=1365), ARIC (n=2338), and HCHS/SOL (n=1475) individuals, randomly assigning 85% of participants from each cohort to a training dataset and the remaining 15% to a test dataset. First, we estimated the associations of GPCs with each available CpG methylation site using linear regression within each cohort, adjusting for age, sex, smoking status, race/ethnic background (as a proxy for background information associated with lifestyle and other environmental exposures that may impact methylation), alcohol use status, body mass index, and cell type proportions. We meta-analyzed the associations across cohorts and selected CpG sites with association FDR-adjusted q-value <0.05. We next aggregated individuallevel data across the cohort-specific training datasets, and applied two-stage weighted least squares Lasso regression, with the GPCs as the outcomes and the selected CpG sites as penalized predictors, adjusting for the aforementioned covariates. The developed MPSs are the weighted sum of selected CpG sites from the Lasso. To evaluate the developed MPSs, we constructed them in the test dataset, and compared them with GPCs, and with MPSs constructed based on a previously-published paper. Comparison was based on correlation analysis and data visualization. We demonstrate the use of the MPSs in EWAS.<br><br>RESULTS: In the test dataset, the MPSs were highly correlated with GPCs, with correlation decreasing, though not monotonically, for later components. Specifically, MPS1 and GPC1 had R2= 0.99, while MPS7 and GPC7 had R2=0.27 (the lowest observed correlation). In data visualization, MPSs had similar patterns as GPCs in differentiating self-reported White, Black, and Hispanic/Latino groups, while outperforming MPC constructed using alternative published methods. MPSs showed comparable performance to GPCs in reducing some of the inflation in EWAS.<br><br>CONCLUSIONS: Methylation-based population scores provide a reliable estimate of population structure in the data and can complement GPCs when genetic data are absent. Unlike previous methods based on unsupervised methylation PCA, MPSs uses supervised learning with covariate adjustment to capture genetic structure across diverse populations. The weights for each GPCs derived in our study can be applied to generate MPSs in other studies.}, }
@article {pmid40951278, year = {2025}, author = {Peoples, AR and Obón-Santacana, M and Kim, AE and Kawaguchi, ES and Fu, Y and Qu, C and Moratalla-Navarro, F and Morrison, J and Lin, Y and Arndt, V and Berndt, SI and Bien, SA and Bishop, DT and Bouras, E and Brenner, H and Buchanan, DD and Campbell, PT and Chan, AT and Chang-Claude, J and Conti, DV and Corley, DA and Devall, MA and Dimou, N and Drew, DA and Gruber, SB and Gunter, MJ and Harlid, S and Harrison, TA and Hoffmeister, M and Hsu, L and Huyghe, JR and Keku, TO and Kundaje, A and Lewinger, JP and Li, L and Lynch, BM and Marchand, LL and Martín, V and Murphy, N and Newton, CC and Ogino, S and Hardikar, S and Ose, J and Pai, RK and Palmer, JR and Papadimitriou, N and Pardamean, B and Pellatt, AJ and Pinchev, M and Platz, EA and Potter, JD and Rennert, G and Ruiz-Narvaez, EA and Sakoda, LC and Schoen, RE and Shcherbina, A and Stern, MC and Su, YR and Thomas, CE and Tian, Y and Tsilidis, KK and Um, CY and van Duijnhoven, FJB and van Guelpen, B and Visvanathan, K and Wang, J and White, E and Wolk, A and Woods, MO and Wu, AH and Ulrich, CM and Peters, U and Gauderman, WJ and Moreno, V}, title = {Genetic risk factors modulate the association between physical activity and colorectal cancer.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40951278}, issn = {2693-5015}, support = {75N92021D00005/WH/WHI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; U01 CA164930/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA201407/CA/NCI NIH HHS/United States ; UM1 CA167552/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; P01 CA196569/CA/NCI NIH HHS/United States ; HHSN268201700006C/HL/NHLBI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA059045/CA/NCI NIH HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; R01 CA197350/CA/NCI NIH HHS/United States ; R01 CA076366/CA/NCI NIH HHS/United States ; R35 CA197735/CA/NCI NIH HHS/United States ; R01 CA072520/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 CA273198/CA/NCI NIH HHS/United States ; K05 CA154337/CA/NCI NIH HHS/United States ; R01 AG083580/AG/NIA NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; R01 CA151993/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; R01 CA048998/CA/NCI NIH HHS/United States ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; R21 CA191312/CA/NCI NIH HHS/United States ; R01 CA244588/CA/NCI NIH HHS/United States ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; R01 CA137178/CA/NCI NIH HHS/United States ; U01 CA074794/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; R01 CA063464/CA/NCI NIH HHS/United States ; P01 CA033619/CA/NCI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA060987/CA/NCI NIH HHS/United States ; T32 ES013678/ES/NIEHS NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; U01 CA084968/CA/NCI NIH HHS/United States ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; }, abstract = {BACKGROUND: Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-PA interaction analysis.<br><br>METHODS: Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (&#x2265; 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity.<br><br>RESULTS: PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81-0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6&#xd7;10[- 8]). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75-0.85), but no significant PA-CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5&#xd7;10[- 8]). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72-0.82).<br><br>CONCLUSIONS: In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.}, }
@article {pmid40951524, year = {2025}, author = {Koedijk, JB and Barneh, F and Meesters-Ensing, JI and van Tuil, M and Sonneveld, E and Lambo, S and Perzolli, A and Schweighart, EK and Ferrao Blanco, MN and van der Meulen, M and Deli, A and Haasjes, E and Bang Christensen, K and de Groot-Kruseman, HA and Meshinchi, S and Hasle, H and Belderbos, ME and Luesink, M and Goemans, BF and Nierkens, S and Hehir-Kwa, J and Zwaan, CM and Heidenreich, O}, title = {Bone marrow lymphocyte dynamics during chemotherapy in pediatric acute myeloid leukemia.}, journal = {HemaSphere}, volume = {9}, number = {9}, pages = {e70212}, pmid = {40951524}, issn = {2572-9241}, }
@article {pmid40952729, year = {2025}, author = {Rossouw, JE and Aragaki, AK and Manson, JE and Szmuilowicz, ED and Harrington, LB and Johnson, KC and Allison, M and Haring, B and Saquib, N and Shadyab, AH and Rexrode, KM and Liu, L and Mouton, CP and LaCroix, AZ}, title = {Menopausal Hormone Therapy and Cardiovascular Diseases in Women With Vasomotor Symptoms: A Secondary Analysis of the Women's Health Initiative Randomized Clinical Trials.}, journal = {JAMA internal medicine}, volume = {185}, number = {11}, pages = {1330-1339}, pmid = {40952729}, issn = {2168-6114}, mesh = {Aged ; Female ; Humans ; Middle Aged ; *Cardiovascular Diseases/epidemiology/chemically induced ; *Estrogen Replacement Therapy/methods/adverse effects ; *Estrogens, Conjugated (USP)/therapeutic use/administration &amp; dosage ; *Hot Flashes/drug therapy ; *Medroxyprogesterone Acetate/therapeutic use/administration &amp; dosage ; Postmenopause ; Randomized Controlled Trials as Topic ; Women's Health ; }, abstract = {IMPORTANCE: Identification of appropriate patients for treatment of vasomotor symptoms (VMS) with menopausal hormone therapy (HT) is challenging.<br><br>OBJECTIVE: To assess risk of cardiovascular disease (CVD) due to HT in women with VMS.<br><br>In this secondary analysis of 2 randomized clinical trials of HT, postmenopausal women aged 50 to 79 years from 40 US clinical centers were included. Data were collected from November 1993 to September 2012, and data were analyzed from December 2024 to May 2025.<br><br>INTERVENTIONS: Conjugated equine estrogens (CEE), 0.625 mg per day, or CEE with medroxyprogesterone acetate (MPA), 2.5 mg per day, vs placebo.<br><br>MAIN OUTCOMES AND MEASURES: Atherosclerotic CVD (ASCVD; defined as composite of nonfatal myocardial infarction, hospitalization for angina, coronary revascularization, ischemic stroke, peripheral arterial disease, carotid artery disease, or CVD death).<br><br>RESULTS: Of 27&#x202f;347 included postmenopausal women, the mean (SD) age was 63.4 (7.2) years; a total of 10&#x202f;739 (39.3%) had a hysterectomy, and 16&#x202f;608 (60.7%) had an intact uterus. The median (IQR) follow-up was 7.2 (6.4-8.1) years and 5.6 (4.8-6.5) years for those in the CEE alone trial and the CEE plus MPA trial, respectively. In the CEE alone trial, moderate or severe VMS were present at baseline in 905 (27.6%), 705 (14.7%), and 220 (8.7%) women aged 50 to 59 years, 60 to 69 years, and 70 to 79 years, respectively; in the CEE plus MPA trial, moderate or severe VMS was present in 1225 (22.4%), 649 (8.7%), and 172 (4.8%), respectively. Among women with moderate or severe VMS at enrollment, 3382 (96.7%) recalled having symptoms near menopause onset. CEE alone reduced VMS by 41% across all age groups (overall relative risk [RR], 0.59; 95% CI, 0.53-0.66). However, in the CEE plus MPA trial, VMS reduction was attenuated with age (age 50-59 years: RR, 0.41; 95% CI, 0.35-0.48; age 60-69 years: RR, 0.72; 95% CI, 0.61-0.85; age 70-79 years: RR, 1.20; 95% CI, 0.91-1.59; interaction P for trend&#x2009;<&#x2009;.001). Both CEE alone and CEE plus MPA appeared to have neutral effects on ASCVD in women with moderate or severe VMS aged 50 to 59 years (CEE alone: hazard ratio [HR], 0.85; 95% CI, 0.53-1.35; CEE plus MPA: HR, 0.84; 95% CI, 0.44-1.57). While the estimated risk was higher for CEE alone in women with VMS aged 60 to 69 years, there was no clear signal of harm (CEE alone: HR, 1.31; 95% CI, 0.90-1.90; CEE plus MPA: HR, 0.84; 95% CI, 0.51-1.39). However, women with VMS 70 years and older had increased risks of ASCVD (CEE alone: HR, 1.95; 95% CI, 1.06-3.59; 217 excess events per 10&#x202f;000 person-years; interaction P for trend&#x2009;=&#x2009;.03; CEE plus MPA: HR, 3.22; 95% CI, 1.36-7.63; 382 excess events per 10&#x202f;000 person-years; interaction P for trend&#x2009;=&#x2009;.02).<br><br>CONCLUSIONS AND RELEVANCE: In this secondary analysis of 2 randomized clinical trials, among younger postmenopausal women aged 50 to 59 years, both CEE alone and CEE plus MPA reduced VMS without significantly affecting ASCVD risk. In women with VMS 70 years and older, risks for ASCVD were increased in both trials. The findings support guideline recommendations for treatment of VMS with HT in women aged 50 to 59 years, caution if initiating HT in women aged 60 to 69 years, and avoidance of HT in women 70 years and older.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00000611.}, }
@article {pmid40953734, year = {2026}, author = {Salit, RB and Fan, X and Gooley, TA and Halpern, AB and Ratsamee, N and Marshall, A and Scott, BL and Deeg, HJ}, title = {Pre-Hematopoietic Cell Transplantation Ruxolitinib in Transplantation-Eligible Patients with Myelofibrosis: Long-Term Outcomes of a Phase II Prospective Study.}, journal = {Transplantation and cellular therapy}, volume = {32}, number = {1}, pages = {80.e1-80.e15}, doi = {10.1016/j.jtct.2025.09.020}, pmid = {40953734}, issn = {2666-6367}, mesh = {Humans ; Nitriles ; Middle Aged ; *Primary Myelofibrosis/therapy/drug therapy/mortality ; Male ; Female ; Pyrimidines/therapeutic use ; *Hematopoietic Stem Cell Transplantation/methods ; Adult ; Prospective Studies ; *Pyrazoles/therapeutic use ; Aged ; Transplantation Conditioning/methods ; Treatment Outcome ; }, abstract = {Ruxolitinib (Rux), the first FDA-approved JAK inhibitor for the treatment of myelofibrosis (MF), was initially studied in patients who were ineligible for hematopoietic cell transplantation (HCT). However, the resultant decrease in splenomegaly and improvement in symptoms allowed some of the study patients to become HCT-eligible. We aimed to determine whether giving Rux to HCT-eligible MF patients would yield favorable HCT outcomes in relation to a historical cohort at our center. We conducted this single-arm Phase II prospective single-center study of Rux followed by HCT in adult patients with primary and secondary MF between 2014 and 2020. Patients were not required to have symptoms or splenomegaly. Patients took Rux for at least 8 weeks (no maximum) prior to the start of conditioning and tapered off by day -4 of HCT conditioning. A total of 101 patients were enrolled in the study (median age, 57 years; range, 34 to 71 years), of whom 61 (60%) proceeded to HCT (59% primary MF, 70% DIPSS [dynamic international prognostic scoring system] intermediate-2 or high-risk) after a median of 7 months (range, 2 to 89 months) on Rux. Patients engrafted at a median of 20 days; there was 1 primary graft failure. Nonrelapse mortality (NRM) was 13% at 1 year, compared to 26% in our historical cohort. With a median follow-up of 5.6 years among survivors, overall survival was 79% (95% confidence interval [CI], 69% to 90%) at 2 years, compared to 67% in our historical cohort, and 5-year survival was 74% (95% CI, 64% to 86%). The hazard ratio of death for those who had a Rux response relative to those who did not was 0.57 (95% CI, 0.20 to 1.61; P = .29). In this prospective Phase II study, patients receiving pre-HCT Rux had encouraging NRM and survival rates relative to historical patients at our center who proceeded to HCT without prior Rux.}, }
@article {pmid40954009, year = {2025}, author = {Jindal, T and Jiang, CY and Alhalabi, O and Nguyen, CB and Oh, E and Tsung, I and Bakaloudi, DR and Talukder, R and Davidsohn, M and Freeman, D and Epstein, IY and Ding, CC and Nizam, A and Glover, MJ and Khaki, AR and Taylor, AK and Lemke, E and Jang, A and Evans, ST and Shin, D and Pywell, C and Basu, A and Bilen, MA and Zakharia, Y and Barata, P and Milowsky, MI and Brown, J and Kilari, D and Emamekhoo, H and Hoimes, CJ and Shah, S and Davis, NB and Gupta, S and Grivas, P and Bellmunt, J and Alva, A and Campbell, MT and Koshkin, VS}, title = {Outcomes with Enfortumab Vedotin in Patients with Histologic Subtypes of Advanced Urothelial Carcinoma: Analysis of the UNITE Study.}, journal = {European urology}, volume = {}, number = {}, pages = {}, doi = {10.1016/j.eururo.2025.09.003}, pmid = {40954009}, issn = {1873-7560}, }
@article {pmid40956289, year = {2025}, author = {Lima, SM and Minlikeeva, AN and Johnson, CE and Guertin, KA and Bandera, EV and Zheng, W and Bethea, TN and Petrick, JL and Joslin, CE and Myers, ER and Harris, HR and Peres, LC and Setiawan, VW and Wu, AH and Rosenberg, L and Schildkraut, JM and Ochs-Balcom, HM}, title = {Regular Physical Inactivity and Ovarian Cancer Risk in the Ovarian Cancer in Women of African Ancestry Consortium.}, journal = {Cancer epidemiology, biomarkers &amp; prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology}, volume = {34}, number = {12}, pages = {2302-2305}, pmid = {40956289}, issn = {1538-7755}, support = {K01 CA212056/CA/NCI NIH HHS/United States ; R01 CA058598/CA/NCI NIH HHS/United States ; R01 CA058420/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; HHSN268201600004C/HL/NHLBI NIH HHS/United States ; R01 CA076016/CA/NCI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; R01 CA207260/CA/NCI NIH HHS/United States ; U01 CA202979/CA/NCI NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; UM1 CA173642/CA/NCI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; UM1 CA164974/CA/NCI NIH HHS/United States ; HHSN268201600003C/HL/NHLBI NIH HHS/United States ; P01 CA017054/CA/NCI NIH HHS/United States ; R01 CA142081/CA/NCI NIH HHS/United States ; UM1-CA164974//National Institutes of Health (NIH)/ ; U01-CA164974//National Institutes of Health (NIH)/ ; R01-CA058420//National Institutes of Health (NIH)/ ; R01-CA61093//National Cancer Institute (NCI)/ ; P01-CA17054//National Cancer Institute (NCI)/ ; R01-CA058598//National Cancer Institute (NCI)/ ; P30-CA014089//National Cancer Institute (NCI)/ ; U01 CA202979/CA/NCI NIH HHS/United States ; UM1-CA173642-05//National Institutes of Health (NIH)/ ; 2II0200//California Cancer Research Program/ ; R01-CA076016//National Cancer Institute (NCI)/ ; R01-CA142081//National Cancer Institute (NCI)/ ; HHSN268201600018C/HL/NHLBI NIH HHS/United States ; HHSN268201600001C/HL/NHLBI NIH HHS/United States ; HHSN268201600002C/HL/NHLBI NIH HHS/United States ; HHSN268201600003C and HHSN268201600004C//U.S. Department of Health and Human Services (HHS)/ ; NIH/NHLBI-CSB-WH-2016-01-CM//National Heart, Lung, and Blood Institute (NHLBI)/ ; R01-CA207260//National Institutes of Health (NIH)/ ; K01-CA212056//National Institutes of Health (NIH)/ ; }, mesh = {Adult ; Aged ; Female ; Humans ; Middle Aged ; *Black or African American/statistics &amp; numerical data ; Black People/statistics &amp; numerical data ; Carcinoma, Ovarian Epithelial ; Case-Control Studies ; Cohort Studies ; *Exercise ; *Ovarian Neoplasms/epidemiology/ethnology/etiology ; Risk Factors ; *Sedentary Behavior ; White/statistics &amp; numerical data ; }, abstract = {BACKGROUND: Regular physical inactivity may increase ovarian cancer risk, but few studies have investigated whether this association is similar among Black and White women.<br><br>METHODS: In a pooled nested case-control study within the Ovarian Cancer in Women of African Ancestry consortium, logistic regression models evaluated regular recreational physical inactivity with risk of epithelial ovarian cancer among Black (223 cases; 1,472 controls) and White women (985 cases; 6,212 controls) enrolled in four cohort studies. Models were further stratified by histologic type.<br><br>RESULTS: Regular physical inactivity was not associated with the risk of overall ovarian cancer among Black [OR = 1.16; 95% confidence interval (CI), 0.83-1.61] or White women (OR = 1.03; 95% CI, 0.87-1.23). We did not detect associations according to histologic type.<br><br>CONCLUSIONS: Physical inactivity was not associated with ovarian cancer among Black or White women in a consortium of cohort studies.<br><br>IMPACT: These results are counter to case-control-based studies and emphasize the complexity of investigating physical activity prospectively.}, }
@article {pmid40956611, year = {2025}, author = {Bose, A and Bankhead, A and Coleman, I and Persse, T and Han, W and Galipeau, P and Hanratty, B and Chu, T and Lucas, J and Li, D and Bilkis, R and Itagi, P and Hassan, S and Beightol, M and Ko, M and Dumpit, R and Haffner, M and Pritchard, C and Ha, G and Nelson, PS}, title = {Multiomic assessments of LNCaP and derived cell strains reveal determinants of prostate cancer pathobiology.}, journal = {The Journal of clinical investigation}, volume = {135}, number = {22}, pages = {}, pmid = {40956611}, issn = {1558-8238}, support = {R21 CA277368/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; R50 CA274336/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; DP2 CA280624/CA/NCI NIH HHS/United States ; P01 CA163227/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R01 CA280056/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/pathology/metabolism ; Receptors, Androgen/genetics/metabolism ; Cell Line, Tumor ; *Genomic Instability ; *Transcriptome ; Gene Expression Regulation, Neoplastic ; *Neoplasm Proteins/genetics/metabolism ; }, abstract = {A cornerstone of research to improve cancer outcomes involves studies of model systems to identify causal drivers of oncogenesis, understand mechanisms leading to metastases, and develop new therapeutics. Although most cancer types are represented by large cell line panels that reflect diverse neoplastic genotypes and phenotypes found in patients, prostate cancer is notable for a very limited repertoire of models that recapitulate the pathobiology of human disease. Of these, the lymph node carcinoma of the prostate (LNCaP) cell line has served as the major resource for basic and translational studies. Here, we delineated the molecular composition of LNCaP and multiple substrains through analyses of whole-genome sequences, transcriptomes, chromatin structure, androgen receptor (AR) cistromes, and functional studies. Our results determined that LNCaP exhibits substantial subclonal diversity, ongoing genomic instability, and phenotype plasticity. Several oncogenic features were consistently present across strains, but others were unexpectedly variable, such as ETV1 expression, Y chromosome loss, a reliance on WNT and glucocorticoid receptor activity, and distinct AR alterations maintaining AR pathway activation. These results document the inherent molecular heterogeneity and ongoing genomic instability that drive diverse prostate cancer phenotypes and provide a foundation for the accurate interpretation and reproduction of research findings.}, }
@article {pmid40956886, year = {2025}, author = {Sefik, E and Philbrick, W and Zhang, F and Agrawal, K and Van Lee, B and Sam, J and Karatepe, K and Zheng, Y and Liang, K and Peng, S and Mirza, H and Rangavajhula, A and Simon, P and Arun, N and Babu, P and Eynon, E and Chiorazzi, M and Shan, L and Halene, S and Luo, HR and Rongvaux, A and Kluger, Y and Flavell, RA}, title = {Humanization of CD47 enables development of functional human neutrophils via postirradiation remodeling of the bone marrow.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {38}, pages = {e2426546122}, pmid = {40956886}, issn = {1091-6490}, support = {T32 AI007019/AI/NIAID NIH HHS/United States ; AWD0002623//F. Hoffmann-La Roche Ltd./ ; na//Celiac Disease Foundation/ ; DRG-2316-18//Damon Runyon Cancer Research Foundation (DRCRF)/ ; P30 DK045735/DK/NIDDK NIH HHS/United States ; }, mesh = {Animals ; *Neutrophils/immunology/cytology/metabolism/radiation effects ; Humans ; Mice ; *CD47 Antigen/genetics/metabolism/immunology ; *Bone Marrow/radiation effects/metabolism/immunology ; Mice, Inbred C57BL ; Myelopoiesis ; Mice, Transgenic ; }, abstract = {Murine and human immune systems differ significantly, particularly within the myeloid lineage. Humanized mice, generated by transplanting human hematopoietic stem, progenitor cells into genetically modified mice, are invaluable to study human immune development and function in vivo. However, a major limitation of current models is suboptimal myelopoiesis, particularly lack of functional human neutrophils, hampering the modeling of human immune responses and chronic diseases. Here, we describe a humanized mouse model, named MaGIC for genes replaced, in the C57Bl/6 N strain, which improves human myelopoiesis and enables development of functional human neutrophils. In MaGIC mice, human cytokines M-CSF/CSF1(M), GM-CSF/CSF2(G) and IL-6(I) are knocked-in replacing mouse genes and murine IL2rg and Rag1(a) are deleted. Human THPO in these mice supports human hematopoiesis. More importantly, insertion of human CD47 (C) under the control of endogenous mouse CD47 promoter enables xenotransplantation and human neutrophil development. MaGIC mice support all human neutrophil subsets found in human bone marrow and blood, a major improvement. This is achieved by creating a niche postirradiation for human granulocyte-macrophage progenitors via reduced murine CD47 and physiological levels of human CD47. These mice also have mature human monocytes, tissue macrophages, alveolar macrophages, dendritic cells, and NK cells, enabled by humanized M-CSF and GM-CSF. Human neutrophils in MaGIC mice are fully functional in chemotaxis, phagocytosis, reactive oxygen species production, and neutrophil extracellular trap formation in response to inflammation. MaGIC mice address critical gaps in current models and enable incisive translational research on human neutrophils, advancing studies in infectious, autoimmune, and inflammatory diseases.}, }
@article {pmid40959943, year = {2025}, author = {Chao, HX and Ma, T and Hegerova, L and Nester, T and Sen, N and Er, L and Harris, S and Lockwood, T and Buchan, JG and Lannert, KW and Gasper, J and Goffena, J and Zalusky, MPG and Storz, SHR and Montemayor-Garcia, C and Pagano, MB and Johnsen, JM and Panch, SR and Miller, DE}, title = {Long-read DNA sequencing resolves a rare case of alloimmune hemolysis mimicking autoimmune hemolysis.}, journal = {Transfusion}, volume = {65}, number = {11}, pages = {2192-2198}, doi = {10.1111/trf.18403}, pmid = {40959943}, issn = {1537-2995}, support = {DP5 OD033357/OD/NIH HHS/United States ; DP5OD033357/NH/NIH HHS/United States ; }, mesh = {Humans ; Female ; *Anemia, Hemolytic, Autoimmune/genetics/diagnosis/blood/immunology ; Middle Aged ; *Hemolysis/immunology/genetics ; *Isoantibodies/blood/immunology ; *Sequence Analysis, DNA/methods ; *Transfusion Reaction/genetics ; *Kell Blood-Group System/genetics/immunology ; }, abstract = {BACKGROUND: Immune hemolytic anemia poses a significant challenge in transfusion medicine, as identification of underlying alloantibodies can be masked by warm and/or cold autoantibodies. This increases the risk of transfusing incompatible blood, which can precipitate or exacerbate hemolysis. Identifying alloantibodies in the presence of autoantibodies remains difficult with standard serologic and genotypic methods, often delaying accurate diagnosis and appropriate transfusion strategies.<br><br>CASE REPORT: We describe a 63-year-old woman with autoimmune hemolytic anemia who suffered near-fatal hemolysis following transfusion. Despite extensive serologic and genotypic testing, the cause of her hemolytic transfusion reactions remained elusive. Given her clinical course and transfusion history, we hypothesized that her acute hemolytic transfusion reactions could be due to immune sensitization to a high-incidence RBC antigen. Research whole-genome long-read sequencing (LRS) revealed homozygosity for a rare KEL*02N.16 allele, consistent with a rare Ko phenotype, which was validated by Sanger sequencing. Retrospective serologic testing with Ko RBCs further confirmed alloimmunization within the Kell system.<br><br>CONCLUSION: This case highlights the limitations of conventional serologic and genotypic methods in detecting rare blood group phenotypes, and emphasizes the diagnostic power of long-read sequencing in transfusion medicine. Early molecular testing in complex hemolytic cases can facilitate targeted transfusion strategies, reduce the risk of severe hemolysis, and improve patient outcomes. As sequencing technologies become more accessible, they have the potential to revolutionize blood group typing and alloimmunization risk assessment in clinical practice.}, }
@article {pmid40960399, year = {2025}, author = {Lotter, W and Hippe, DS and Oshiro, T and Lowry, KP and Milch, HS and Miglioretti, DL and Elmore, JG and Lee, CI and Hsu, W}, title = {Influence of Mammography Acquisition Parameters on AI and Radiologist Interpretive Performance.}, journal = {Radiology. Artificial intelligence}, volume = {7}, number = {6}, pages = {e240861}, pmid = {40960399}, issn = {2638-6100}, support = {R37 CA240403/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Mammography/methods ; Female ; Retrospective Studies ; *Breast Neoplasms/diagnostic imaging ; Middle Aged ; *Artificial Intelligence ; *Radiologists ; Sensitivity and Specificity ; Breast/diagnostic imaging ; Aged ; *Radiographic Image Interpretation, Computer-Assisted/methods ; Adult ; Clinical Competence ; }, abstract = {Purpose To evaluate the impact of screening mammography acquisition parameters on the interpretive performance of artificial intelligence (AI) and radiologists. Materials and Methods The associations between seven mammogram acquisition parameters-mammography machine version, kilovoltage peak, x-ray exposure delivered, relative x-ray exposure, paddle size, compression force, and breast thickness-and AI and radiologist performance in interpreting two-dimensional screening mammograms acquired by a diverse health system between December 2010 and 2019 were retrospectively evaluated. The top 11 AI models and the ensemble model from the Digital Mammography Dialogue on Reverse Engineering Assessment and Methods (DREAM) Challenge were assessed. The associations between each acquisition parameter and the sensitivity and specificity of the AI models and the radiologists' interpretations were separately evaluated using generalized estimating equations-based models at the examination level, adjusted for several clinical factors. Results The dataset included 28 278 screening two-dimensional mammograms from 22 626 women (mean age ± SD, 58.5 years ± 11.5; 4913 women had multiple mammograms). Of these, 324 examinations resulted in a breast cancer diagnosis within 1 year. The acquisition parameters were significantly associated with the performance of both AI and radiologists, with absolute effect sizes reaching 10% for sensitivity and 5% for specificity; however, the associations differed between AI and radiologists for several parameters. Increased exposure delivered reduced the specificity for the ensemble AI (-4.5% per 1 SD increase; P < .001) but not radiologists (P = .44). Increased compression force reduced the specificity for radiologists (-1.3% per 1 SD increase; P < .001) but not for AI (P = .60). Conclusion Screening mammography acquisition parameters impacted the performance of both AI and radiologists, with some parameters impacting performance differently. Keywords: AI Robustness, Mammography, Medical Physics Supplemental material is available for this article. © RSNA, 2025 See also commentary by Lee and Bae in this issue.}, }
@article {pmid40961411, year = {2025}, author = {Siddiqui, NS and Bouchi, Y and Shah, SJH and Alqarni, S and Sood, S and Lee, Y and Park, J and Kang, J}, title = {Clinician's Artificial Intelligence Checklist and Evaluation Questionnaire: Tools for Oncologists to Assess Artificial Intelligence and Machine Learning Models.}, journal = {JCO clinical cancer informatics}, volume = {9}, number = {}, pages = {e2500067}, doi = {10.1200/CCI-25-00067}, pmid = {40961411}, issn = {2473-4276}, mesh = {Humans ; *Artificial Intelligence/standards ; *Machine Learning ; Surveys and Questionnaires ; *Checklist ; *Oncologists ; *Medical Oncology/methods/standards ; *Neoplasms/diagnosis/therapy ; }, abstract = {Advancements in oncology are accelerating in the fields of artificial intelligence (AI) and machine learning. The complexity and multidisciplinary nature of oncology necessitate a cautious approach to evaluating AI models. The surge in development of AI tools highlights a need for organized evaluation methods. Currently, widely accepted guidelines are aimed at developers and do not provide necessary technical background for clinicians. Additionally, published guides introducing clinicians to AI in medicine often lack user-friendly evaluation tools or lack specificity to oncology. This paper provides background on model development and proposes a yes/no checklist and questionnaire designed to help oncologists effectively assess AI models. The yes/no checklist is intended to be used as a more efficient scan of whether the model conforms to published best standards. The open-ended questionnaire is intended for a more in-depth survey. The checklist and the questionnaire were developed by clinical and AI researchers. Initial discussions identified broad domains, gradually narrowing to model development points relevant to clinical practice. The development process included two literature searches to align with current best practices. Insights from 24 articles were integrated to refine the questionnaire and the checklist. The developed tools are intended for use by clinicians in the field of oncology looking to evaluate AI models. Cases of four AI applications in oncology are analyzed, demonstrating utility in real-world scenarios and enhancing case-based learning for clinicians. These tools highlight the interdisciplinary nature of effective AI integration in oncology.}, }
@article {pmid40963258, year = {2026}, author = {Santiago-Torres, M and Mull, KE and Shi, D and Alexander, AC and Nollen, NL and Sullivan, BM and Zvolensky, MJ and Bricker, JB}, title = {Intersectionality in cigarette smoking cessation: A latent class analysis to predict 12-month cessation in a randomized controlled trial.}, journal = {Addiction (Abingdon, England)}, volume = {121}, number = {1}, pages = {173-185}, doi = {10.1111/add.70185}, pmid = {40963258}, issn = {1360-0443}, support = {R01 CA192849/CA/NCI NIH HHS/United States ; R01CA192849/CA/NCI NIH HHS/United States ; R01CA192849/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Smoking Cessation/methods/statistics &amp; numerical data ; Male ; Female ; Adult ; Middle Aged ; *Cigarette Smoking/therapy/epidemiology ; Latent Class Analysis ; United States ; *Mobile Applications ; Sexual and Gender Minorities/statistics &amp; numerical data ; Marital Status ; Depression ; }, abstract = {BACKGROUND AND AIMS: Currently, smoking cessation intervention research on marginalized populations focuses on a single attribute (e.g. race). However, these attributes intersect and research on this intersectionality has been rare. This study applied latent class analysis (LCA) to examine how multiple theory-driven baseline factors interact and predict 12-month 30-day point prevalence abstinence from cigarette smoking in 2415 adult participants in a digital smoking cessation intervention.<br><br>DESIGN: Theory-based analysis of a randomized trial with 12-month smoking cessation follow-up.<br><br>SETTING: United States (US).<br><br>PARTICIPANTS: A total of 2415 adults who smoke that were recruited from all 50&#x2009;US states and enrolled in the trial between May 2017 and September 2018.<br><br>INTERVENTION AND COMPARATOR: In the parent RCT, participants were randomized to receive iCanQuit, an Acceptance and Commitment Therapy-based smartphone smoking cessation app (n&#x2009;=&#x2009;1214) or QuitGuide, a US Clinical Practice Guidelines-based smoking cessation app (n&#x2009;=&#x2009;1201) for 12&#x2009;months.<br><br>MEASUREMENTS: Guided by Sheffer et al.,six theory-based factors were examined, including social identities: gender, race and ethnicity, marital status, sexual and gender minority (SGM) identity and socio-economic status (SES; education, income, employment); and lived experiences: positive screen for experiencing depression symptoms. Social identity and lived experiences data were collected via baseline questionnaires. The primary smoking cessation outcome was self-reported complete-case 30-day point prevalence abstinence at 12&#x2009;months. SAS PROC LCA was used to identify classes based on the six selected factors and to predict 12-month smoking cessation.<br><br>FINDINGS: A 4-class model showed the best goodness-of-fit statistics and interpretability. Participants in class 1 (n&#x2009;=&#x2009;352, 14.6%) were more likely to be women, individuals of Black race and those with single marital status. Participants in class 2 (n&#x2009;=&#x2009;322, 13.3%) were more likely to be men, SGM individuals and socioeconomically advantaged, as indicated by higher education, higher income or employment. Participants in class 3 (n&#x2009;=&#x2009;368, 15.2%) were socioeconomically disadvantaged and screened positive for experiencing depression symptoms at baseline (CES-D &#x2265; 16). Finally, participants in class 4 (n&#x2009;=&#x2009;1373, 56.9%) were more likely to be women, individuals of White race and married. Class 2 had the highest smoking cessation rate (32.8%) at 12&#x2009;months, followed by class 1 (27.3%), class 4 (24.2%) and class 3 (15.4%). Compared with class 2, class 3 had 63% lower odds of quitting smoking (odds ratio&#x2009;=&#xa0;0.37; 95% confidence interval = 0.20-0.71, P&#xa0;=&#x2009;0.016).<br><br>CONCLUSIONS: People with both socioeconomic disadvantage and symptoms of depression appear to have a harder time quitting smoking than other people who try to quit.}, }
@article {pmid40963735, year = {2023}, author = {Shao, Y and Todd, K and Shutes-David, A and Millard, SP and Brown, K and Thomas, A and Chen, K and Wilson, K and Zeng, QT and Tsuang, DW}, title = {Identifying Probable Dementia in Undiagnosed Black and White Americans Using Machine Learning in Veterans Health Administration Electronic Health Records.}, journal = {Big data and cognitive computing}, volume = {7}, number = {4}, pages = {}, pmid = {40963735}, issn = {2504-2289}, support = {R56 AG059739/AG/NIA NIH HHS/United States ; }, abstract = {The application of natural language processing and machine learning (ML) in electronic health records (EHRs) may help reduce dementia underdiagnosis, but models that are not designed to reflect minority populations may instead perpetuate underdiagnosis. To improve the identification of undiagnosed dementia, particularly in Black Americans (BAs), we developed support vector machine (SVM) ML models to assign dementia risk scores based on features identified in unstructured EHR data (via latent Dirichlet allocation and stable topic extraction in n = 1 M notes) and structured EHR data. We hypothesized that separate models would show differentiation between racial groups, so the models were fit separately for BAs (n = 5 K with dementia ICD codes, n = 5 K without) and White Americans (WAs; n = 5 K with codes, n = 5 K without). To validate our method, scores were generated for separate samples of BAs (n = 10 K) and WAs (n = 10 K) without dementia codes, and the EHRs of 1.2 K of these patients were reviewed by dementia experts. All subjects were age 65+ and drawn from the VA, which meant that the samples were disproportionately male. A strong positive relationship was observed between SVM-generated risk scores and undiagnosed dementia. BAs were more likely than WAs to have undiagnosed dementia per chart review, both overall (15.3% vs. 9.5%) and among Veterans with >90th percentile cutoff scores (25.6% vs. 15.3%). With chart reviews as the reference standard and varied cutoff scores, the BA model performed slightly better than the WA model (AUC = 0.86 with negative predictive value [NPV] = 0.98, positive predictive value [PPV] = 0.26, sensitivity = 0.61, specificity = 0.92 and accuracy = 0.91 at >90th percentile cutoff vs. AUC = 0.77 with NPV = 0.98, PPV = 0.15, sensitivity = 0.43, specificity = 0.91 and accuracy = 0.89 at >90th). Our findings suggest that race-specific ML models can help identify BAs who may have undiagnosed dementia. Future studies should examine model generalizability in settings with more females and test whether incorporating these models into clinical settings increases the referral of undiagnosed BAs to specialists.}, }
@article {pmid40964006, year = {2025}, author = {Moosavi, D and Lim, U and Hullar, M and Rettenmeier, C and Kwee, S and Monroe, K and Ernst, T and Randolph, T and Wilkens, L and Marchand, LL and Lampe, J and Park, SY}, title = {Association Between Plant-Based Diet Quality and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) in the Multiethnic Cohort Study.}, journal = {Research square}, volume = {}, number = {}, pages = {}, pmid = {40964006}, issn = {2693-5015}, support = {P01 CA168530/CA/NCI NIH HHS/United States ; R01 MD018265/MD/NIMHD NIH HHS/United States ; U01 CA164973/CA/NCI NIH HHS/United States ; }, abstract = {BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly non-alcoholic fatty liver disease (NAFLD), is a growing public health concern with limited effective treatments. Diet quality may influence MASLD risk, yet the role of plant-based diet quality across diverse populations remains unclear.<br><br>OBJECTIVE: To evaluate the associations of plant-based dietary patterns with liver fat content or MASLD prevalence in multiethnic older adults.<br><br>METHODS: We analyzed cross-sectional data on 1,598 participants in the Adiposity Phenotype Study (APS), nested within the Multiethnic Cohort Study. Scores for three established plant-based diet indices were computed from food frequency questionnaire responses: overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI). Liver fat was measured using MRI, and MASLD was defined, among participants reporting zero to low alcohol intakes. Multivariable linear models of liver fat and logistic models of MASLD were used to estimate their associations with the plant-based diet indices, adjusting for demographic, lifestyle, and anthropometric covariates.<br><br>RESULTS: Higher hPDI scores were associated with lower liver fat content (adjusted mean for 4th (5.39) vs. 1st quartile (6.52) and reduced likelihood of MASLD (OR for 4th vs. 1st quartile = 0.58 (95% CI: 0.41-0.81). When stratified across five racial and ethnic groups, stronger inverse associations were observed among Latino and White participants (p-heterogeneity = 0.001) than among African American, Japanese American, or Native Hawaiian participants. No consistent associations were observed for PDI or uPDI. Among hPDI components, higher nut and lower animal fat intakes were associated with lower liver fat and MASLD.<br><br>CONCLUSIONS: Greater adherence to a healthful plant-based diet is associated with lower liver fat and MASLD prevalence, with some racial and ethnic variation. These findings underscore the importance of plant-food quality and may inform dietary strategies for MASLD prevention in heterogeneous populations.}, }
@article {pmid40964310, year = {2025}, author = {Ramsey, EL and Dobersch, S and Freie, B and Hong, NH and Wu, X and Kugel, S and Eisenman, RN and Carroll, PA}, title = {MondoA mediates transcriptional coordination between the MYC network and the integrated stress response in pancreatic ductal adenocarcinoma.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964310}, issn = {2692-8205}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R35 CA231989/CA/NCI NIH HHS/United States ; R37 CA241472/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; }, abstract = {MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m[6]A) of mRNA. MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Re-establishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Lastly, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.}, }
@article {pmid40964312, year = {2025}, author = {Bansal, AM and Horowitz, LF and Yeung, M and Gujral, TS and Folch, A}, title = {BIOPRINTING OF MICRODISSECTED TUMOR "CUBOIDS" IN HYDROGELS.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964312}, issn = {2692-8205}, support = {R01 CA181445/CA/NCI NIH HHS/United States ; R21 CA251952/CA/NCI NIH HHS/United States ; }, abstract = {Microscale tumor models made from microdissected tumors that retain much of the original human tumor microenvironment (TME) are emerging as an alternative to preclinical animal models. We have introduced a drug testing approach that utilizes regularly-cut, cuboidal-shaped microdissected tissues, or "cuboids," as a way to maximize creation of microtissues from scarce biopsy materials. However, microtissues (e.g., cuboids, organoids, spheroids, etc.) can be difficult to place in precise locations, especially in applications that require their culture in hydrogels. Here, using cuboids from mouse tumor models, we demonstrate a simple bioprinting strategy for precise placement and immobilization of cuboids in hydrogel. We use a commercial bioprinter to bioprint -containing hydrogel into arrays of small hydrogel dots containing cuboids, or "cuboid dots," either onto a Transwell insert or into traps on a microplate. The hydrogel serves to immobilize the cuboids in place and provides a matrix to support cuboid viability. We demonstrate proof-of-concept applications for cancer drug testing and for protein profiling analysis. This approach will enable interface of cuboids with other devices, such as on top of a sensor or in a microfluidic platform. Furthermore, this automated process of dispensing and localizing cuboids (or other microtissue formats such as spheroids or organoids) could further their application to drug discovery and personalized medicine.}, }
@article {pmid40964329, year = {2025}, author = {Semenova, G and Frank, S and Dumpit, R and Han, W and Coleman, I and Gulati, R and Morrissey, C and Haffner, MC and Nelson, PS and Lee, JK}, title = {Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964329}, issn = {2692-8205}, support = {R50 CA221836/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; R50 CA274336/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; }, abstract = {Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive subtype of prostate cancer (PC) without curative treatments. Antibody-drug conjugates (ADCs) emerged as promising cancer therapeutics that selectively deliver cytotoxic agents (payloads) to the tumors. Although ADCs have been successfully applied in the treatment of hematological and solid tumors, ADC monotherapy has not demonstrated durable responses in mCRPC and the mechanisms of PC resistance to ADCs have not been thoroughly investigated. Our study aimed to improve ADC efficacy using a new integrated approach for custom ADC design and multiplexing. To nominate rational combinations of ADC targets and ADC payloads, we (1) examined protein co-expression of three clinically relevant surface antigens-B7 homolog 3 (B7-H3), prostate specific membrane antigen (PSMA), and six-transmembrane epithelial antigen of prostate-1 (STEAP1)-in a series of human mCRPC samples and (2) screened established ADC payloads and their combinations in mCRPC cell lines with different phenotypes. We identified synergistic interactions between DNA-damaging payloads and Bcl-xL inhibitor A-1331852 as well as their coordinated induction of the intrinsic apoptosis pathway. The functional relevance of isolated p53 loss and impaired PC responses to three genotoxic ADCs (B7-H3-seco-DUBA, PSMA-SG3249, and STEAP1-DXd) and their combinations with A-1331852 was established using genetic knockout models. Lastly, we found enhanced in vivo antitumor activity in mCRPC by combining the clinically relevant agents B7-H3-seco-DUBA (vobramitamab duocarmazine) and A-1331852. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with Bcl-xL inhibitors for mCRPC.}, }
@article {pmid40964353, year = {2025}, author = {Gieselmann, L and DeLaitsch, AT and Rohde, M and Radford, C and Worczinski, J and Momot, A and Ahmadov, E and Burger, JA and Havenar-Daughton, C and Deshpande, S and Giovannoni, F and Corti, D and Kreer, C and Ercanoglu, MS and Schommers, P and Georgiev, IS and West, AP and Knüfer, J and Stumpf, R and Kroidl, A and Geldmacher, C and Maganga, L and William, W and Ntinginya, NE and Hoelscher, M and Yang, Z and Wei, Q and Renfrow, M and Green, TJ and Novak, J and van Gils, MJ and Gristick, HB and Gruell, H and Bloom, JD and Seaman, MS and Bjorkman, PJ and Klein, F}, title = {Identification of a broad and potent V3 glycan site bNAb targeting an N332gp120 glycan-independent epitope.}, journal = {bioRxiv : the preprint server for biology}, volume = {}, number = {}, pages = {}, pmid = {40964353}, issn = {2692-8205}, support = {INV-036842/GATES/Gates Foundation/United States ; R01 AI162236/AI/NIAID NIH HHS/United States ; U54 AI170856/AI/NIAID NIH HHS/United States ; INV-002143/GATES/Gates Foundation/United States ; U01 AI169385/AI/NIAID NIH HHS/United States ; P01 AI100148/AI/NIAID NIH HHS/United States ; R01 AI140891/AI/NIAID NIH HHS/United States ; }, abstract = {Broadly neutralizing antibodies (bNAbs) against HIV-1 can suppress viremia in vivo and inform vaccine development. Here, we characterized 007, a V3 glycan site bNAb exhibiting high levels of antiviral activity against multiclade pseudovirus panels[1-3] (GeoMean IC50 = 0.012 μg/mL, breadth = 69%, 217 virus strains) by targeting a N332gp120 glycan-independent V3 epitope, a site of Env vulnerability to which only weakly neutralizing antibodies had previously been identified. Functional analyses demonstrated distinct binding and neutralization profiles compared to classical V3 glycan site bNAbs. A 007 Fab-Env cryo-EM structure revealed contacts with the V3 [324]GD/NIR[327] motif and interactions with N156gp120 and N301gp120 glycans. In contrast to classical V3 bNAbs, 007 binding to Env does not depend on the N332gp120 glycan, rendering it resistant to common escape mutations. Structures of 007 IgG-Env trimer complexes showed two Env trimers crosslinked by three bivalent IgGs, and bivalent 007 IgG was up to ~300-fold more potent than monovalent 007 IgG heterodimer, suggesting a role for avidity in potent neutralization. Finally, in HIV-1ADA-infected humanized mice, 007 caused transient decline of viremia and overcame classical V3 escape mutations, highlighting 007's potential for HIV-1 prevention, therapy, functional cure, and vaccine design.}, }
@article {pmid40966416, year = {2026}, author = {Ferreira, AC and Dutta, D and Rowan, CM and Renbarger, J and Cooke, KR and Carpenter, PA and Krance, R and Duncan, C and Cruz, CRY and Jacobsohn, D and Bollard, CM and Hill, E and Paczesny, S}, title = {Risk biomarkers of chronic GVHD in children aged 10 years or younger and children/adults older than 10 years.}, journal = {Blood advances}, volume = {10}, number = {1}, pages = {168-180}, pmid = {40966416}, issn = {2473-9537}, support = {P30 CA138313/CA/NCI NIH HHS/United States ; R01 CA168814/CA/NCI NIH HHS/United States ; R01 CA264921/CA/NCI NIH HHS/United States ; R01 HD074587/HD/NICHD NIH HHS/United States ; }, mesh = {Humans ; Child ; *Graft vs Host Disease/etiology/blood/diagnosis ; *Biomarkers/blood ; Male ; Female ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Adolescent ; Child, Preschool ; Chronic Disease ; Risk Factors ; Adult ; Infant ; Interleukin-1 Receptor-Like 1 Protein/blood ; Prospective Studies ; Young Adult ; Age Factors ; Transplantation, Homologous ; }, abstract = {Assessment of risk biomarkers of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) in pediatric patients is lacking. We conducted a prospective study of 318 patients (129 children aged ≤10 years and 189 children/adults aged >10 years). Six plasma biomarkers (C-X-C motif chemokine ligand 9 [CXCL9], interleukin-1 receptor-like 1 [IL1RL1], regenerating islet-derived 3-α [REG3α], matrix metallopeptidase-3 [MMP3], dickkopf-WNT signaling pathway inhibitor-3 [DKK3], and sCD163) were assessed at day 100 after HCT. We performed day-100 landmark analyses for cGVHD, stratifying at age ≤10 years vs >10 years and dichotomizing markers using the Youden index. IL1RL1 associated with future cGVHD in both age groups, as did DKK3. CXCL9, REG3α, and MMP3 are associated with cGVHD in patients aged >10 years. This 5-marker panel has an area under the curve (AUC) of 0.71 in children aged ≤10 years and 0.72 in children/adults aged >10 years for cGVHD risk, and an AUC of 0.86 in children aged ≤10 years and 0.80 in children/adults aged >10 years for moderate/severe cGVHD risk. A 5-biomarker panel (IL1RL1, REG3α, MMP3, DKK3, and sCD163) was associated with transplant-related mortality (TRM) in both age groups. Biomarkers measured 3 months post-HCT predict susceptibility and/or are prognostic for cGVHD and TRM in both children aged ≤10 years and children/adults aged >10 years, allowing for additional risk stratification.}, }
@article {pmid40966421, year = {2025}, author = {Ramsower, CA and Wright, G and Li, H and Cerhan, JR and Maurer, MJ and Mwangi, R and Rosenthal, AC and Novak, AJ and Link, BK and Witzig, TE and Habermann, TM and Kridel, R and LeBlanc, ML and Shadman, M and Smith, SM and Friedberg, JW and Scott, DW and Steidl, C and Staudt, LM and Rimsza, LM}, title = {Development and validation of a gene expression signature to predict early events in patients with follicular lymphoma.}, journal = {Blood advances}, volume = {9}, number = {24}, pages = {6443-6454}, pmid = {40966421}, issn = {2473-9537}, mesh = {Humans ; *Lymphoma, Follicular/genetics/diagnosis/mortality/therapy ; *Gene Expression Profiling/methods ; Male ; Female ; *Transcriptome ; Middle Aged ; *Gene Expression Regulation, Neoplastic ; Biomarkers, Tumor/genetics ; Prognosis ; Aged ; Retrospective Studies ; }, abstract = {Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.}, }
@article {pmid40966481, year = {2025}, author = {Lee, SJ and Logan, B and Horowitz, MM and Dehn, JG and Pidala, J and Grunwald, MR and Westervelt, P and Farhadfar, N and Hogan, WJ and Bashey, A and Hayes-Lattin, B and Hill, L and Brunstein, C and Arai, S and Srour, SA and Symons, H and Uberti, J and Vasu, S and Pusic, I and Juckett, M and Leifer, E and He, N and Devine, S and Shaw, BE and Ciurea, SO}, title = {Primary Results From Blood and Marrow Transplant Clinical Trials Network 1702: Clinical Transplant-Related Long-Term Outcomes of Alternative Donor Allogeneic Transplantation.}, journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology}, volume = {43}, number = {31}, pages = {3369-3380}, pmid = {40966481}, issn = {1527-7755}, support = {U10 HL069294/HL/NHLBI NIH HHS/United States ; UG1 HL138645/HL/NHLBI NIH HHS/United States ; UG1 HL108945/HL/NHLBI NIH HHS/United States ; UG1 HL108987/HL/NHLBI NIH HHS/United States ; UG1 HL069246/HL/NHLBI NIH HHS/United States ; UG1 HL109137/HL/NHLBI NIH HHS/United States ; P30 CA016058/CA/NCI NIH HHS/United States ; U24 CA076518/CA/NCI NIH HHS/United States ; U24 HL138660/HL/NHLBI NIH HHS/United States ; }, mesh = {Adolescent ; Adult ; Aged ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; *Bone Marrow Transplantation ; Graft vs Host Disease/etiology ; *Hematopoietic Stem Cell Transplantation/methods/adverse effects/mortality ; Transplantation, Homologous ; Treatment Outcome ; *Unrelated Donors ; }, abstract = {PURPOSE: The likelihood of finding a human leukocyte antigen (HLA)-matched unrelated donor (MUD) for hematopoietic cell transplantation can be predicted using a donor search prognosis score. Patients without a MUD may use alternative donors (haploidentical related, mismatched unrelated, or umbilical cord blood).<br><br>METHODS: This multicenter biological assignment trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1702). Eligibility criteria were broad to mirror clinical practice. The primary end point was 2-year survival from evaluability and compared between those Very Likely (>90%) and Very Unlikely (<10%) to find a MUD. All other patients, Less Likely to find a MUD, were enrolled in an observational arm. Transplant outcomes were compared for all three groups.<br><br>RESULTS: A total of 1,751 evaluable patients at 47 centers were Very Likely (54.7%), Less Likely (29.5%), and Very Unlikely (15.8%) to identify a MUD. Survival did not differ in univariate (hazard ratio [HR], 1.00 [95% CI, 0.82 to 1.21]; P = .98) or multivariate (HR, 1.07 [95% CI, 0.86 to 1.33]; P = .56) analyses between the Very Unlikely and Very Likely groups, measured through 2 years from the beginning of a search for a MUD or alternative donor. Of the transplanted patients (n = 1,179), MUD was used for 94% of the Very Likely, 38% of Less Likely, and 9% of Very Unlikely patients. Multivariate analyses showed no differences in relapse, treatment-related mortality, disease-free survival, and acute and chronic graft-versus-host diseases for the three search prognosis groups after transplantation.<br><br>CONCLUSION: Using a donor search prognosis strategy to prioritize an alternative donor for patients Very Unlikely to find a MUD resulted in survival and transplant outcomes that were not statistically different compared with those Very Likely to find a MUD.}, }
@article {pmid40966492, year = {2025}, author = {Desai, M and Sharma, SV and Fokom Domgue, J and Chido-Amajuoyi, O and Yu, R and Chan, W and Darkoh, C and Shete, S}, title = {Healthcare professionals' awareness of and barriers to shared-clinical-decision-making for HPV vaccination among adults 27-45 years.}, journal = {Human vaccines &amp; immunotherapeutics}, volume = {21}, number = {1}, pages = {2560061}, pmid = {40966492}, issn = {2164-554X}, support = {P30 CA016672/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Papillomavirus Vaccines/administration &amp; dosage ; Adult ; Cross-Sectional Studies ; Female ; Middle Aged ; *Health Personnel/psychology/statistics &amp; numerical data ; Male ; *Papillomavirus Infections/prevention &amp; control ; Texas ; *Vaccination/psychology/statistics &amp; numerical data ; *Health Knowledge, Attitudes, Practice ; Surveys and Questionnaires ; *Decision Making, Shared ; *Clinical Decision-Making ; }, abstract = {The Advisory Committee on Immunization Practices recommends human papillomavirus (HPV) vaccination for inadequately vaccinated adults aged 27-45 based on shared clinical decision-making (SCDM). However, little is known about awareness and barriers to SCDM among US healthcare providers (HCPs), especially in Texas, where HPV vaccination rates are below the national average. Between January and April 2021, we conducted a population-based cross-sectional survey (12% response rate) of HCPs licensed in Texas to assess the prevalence and factors associated with awareness of the SCDM recommendation. HCPs were asked if they were aware and if they foresaw any barriers in implementing SCDM for HPV vaccine recommendation. Among the 1,279 respondents, 54.26% were aware of this recommendation. HCPs practicing as gynecologists/obstetricians (adjusted odds ratio [aOR]: 6.12; 95%CI: 2.60-14.40, p < .001), those working in Federally Qualified Health Centers (aOR: 2.13, 95%CI: 1.24-3.65, p = .006) or group practices (aOR: 1.68, 95%CI: 1.22-2.30, p = .001), those seeing ≤ 100 patients/week (aOR: 1.70, 95%CI: 1.15-2.51, p = .008), those who had received formal training on HPV vaccination promotion and counseling within the past two years (aOR: 3.42, 95%CI: 2.29-5.10, p = < 0.001), between two and five years ago (aOR: 2.35, 95%CI: 1.67-3.30, p = < 0.001), and more than five years ago (aOR: 1.70, 95%CI: 1.16-2.50, p = .006) had significantly higher odds of awareness of SCDM recommendation. HCPs practicing as nurse practitioners/advanced nurse practitioners (aOR: 0.56; 95%CI: 0.38-0.82, p = .003), physician assistants (aOR: 0.62; 95%CI: 0.41-0.94, p = .023), aged 55 years or older (aOR: 0.57; 95%CI: 0.32-0.99, p = .046), Asian (aOR: 0.59, 95%CI: 0.43-0.81, p = .001) and non-Hispanic Black (aOR: 0.62, 95%CI: 0.40-0.97, p = .037) had significantly lower odds of awareness of SCDM recommendation. Overall, 44.96% of HCPs anticipated no barriers and planned to engage in SCDM, while 18.32% cited time commitment as an anticipated barrier. Internists cited time commitment (39.13%) as an anticipated barrier more frequently than other specialties, while physician assistants were more frequently unclear about how to implement SCDM (12.36%). We found limited awareness of the SCDM recommendation guideline for HPV vaccination among Texas HCPs. Therefore, training HCPs to use decision aids to actively engage patients in the SCDM process could improve HPV vaccination rates among unvaccinated adults aged 27-45.}, }
@article {pmid40966708, year = {2025}, author = {Bagshaw, P and Potter, JD and Bagshaw, S}, title = {The problem with ten-year private healthcare contracts.}, journal = {The New Zealand medical journal}, volume = {138}, number = {1622}, pages = {119-120}, doi = {10.26635/6965.7171}, pmid = {40966708}, issn = {1175-8716}, }
@article {pmid40968289, year = {2025}, author = {Kim, E and Helfrich, C and Yoon, H and Chue, B and Ho, E and Aramaki, T and Duggan, C}, title = {Effects of a clinic-referred telemedical intervention to improve exercise uptake during chemotherapy.}, journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer}, volume = {33}, number = {10}, pages = {861}, pmid = {40968289}, issn = {1433-7339}, mesh = {Humans ; Female ; Middle Aged ; Male ; Quality of Life ; *Neoplasms/drug therapy/rehabilitation/pathology ; *Exercise Therapy/methods ; Telemedicine ; Aged ; *Antineoplastic Agents/therapeutic use ; *Exercise ; Adult ; }, abstract = {PURPOSE: We successfully implemented the American College of Sports Medicine's (ACSM's) Exercise is Medicine® (EIM) initiative in a community oncology clinic. This study evaluated the impact of the evidence-based exercise intervention, adhering to ACSM guidelines on patient outcomes.<br><br>METHODS: Using a quasi-experimental research design, An experienced ACSM-certified cancer exercise trainer delivered a 12-week biweekly, online group exercise intervention to 19 patients undergoing chemotherapy. Fifteen (78.8%) completed pre/post-self-report surveys on the program's acceptability and impact, change in physical activity vital signs (PAVS), and health-related quality of life (HRQOL). We also assessed exercise uptake and PAVS at each clinic visit. Data were analyzed using t-tests and content analysis.<br><br>RESULTS: On average, participants were 60&#xa0;years, female (94%), non-Latino/White (60%), had stage IV cancer (92.3%), And had been receiving chemotherapy for An average of 10&#xa0;months. The intervention was acceptable (86.4% enrollment) and had excellent retention (89.5%), with moderate adherence (68%). No adverse events were reported. Reasons for lack of adherence were medical reasons and treatment side effects. Compared to baseline, participants reported non-statistically significant increased aerobic exercise and improvements in HRQOL post-intervention. Participants rated the intervention as satisfactory, acceptable, and suitable (all&#x2009;>&#x2009;4 out of 5 on a Likert scale). In open-text comments, six (40%) of the participants appreciated being asked about PAVS at the clinic, while three (20%) did not.<br><br>CONCLUSIONS: Patients undergoing chemotherapy, the majority of whom had stage IV cancer, could safely participate in an online group exercise program. Larger studies among different patient populations are needed.}, }
@article {pmid40968359, year = {2025}, author = {Li, Z and M Patel, Z and Song, D and Yasa, SN and Cannoodt, R and Yan, G and Li, JJ and Pinello, L}, title = {Systematic benchmarking of computational methods to identify spatially variable genes.}, journal = {Genome biology}, volume = {26}, number = {1}, pages = {285}, pmid = {40968359}, issn = {1474-760X}, support = {R35 HG010717/HG/NHGRI NIH HHS/United States ; 1R35HG010717-01//National Human Genome Research Institute (NHGRI)/ ; }, mesh = {*Benchmarking ; *Computational Biology/methods ; Algorithms ; *Gene Expression Profiling/methods ; Humans ; Transcriptome ; }, abstract = {BACKGROUND: Spatially resolved transcriptomics offers unprecedented insight by enabling the profiling of gene expression within the intact spatial context of cells, effectively adding a new and essential dimension to data interpretation. To efficiently detect spatial structure of interest, an essential step in analyzing such data involves identifying spatially variable genes (SVGs). Despite researchers having developed several computational methods to accomplish this task, the lack of a comprehensive benchmark evaluating their performance remains a considerable gap in the field.<br><br>RESULTS: Here, we systematically evaluate 14 methods using 96 spatial datasets and 6 metrics. We compare the methods regarding gene ranking and classification based on real spatial variation, statistical calibration, and computation scalability and investigate the impact of identified SVGs on downstream applications such as spatial domain detection. Finally, we explore the applicability of the methods to spatial ATAC-seq data to examine their effectiveness in identifying spatially variable peaks (SVPs). Overall, SPARK-X outperforms other benchmarked methods and Moran's I achieves a competitive performance, representing a strong baseline for future method development. Moreover, our results reveal that most methods are poorly calibrated, and more specialized algorithms are needed to identify spatially variable peaks.<br><br>CONCLUSIONS: Our benchmarking provides a detailed comparison of SVG detection methods and serves as a reference for both users and method developers.}, }
@article {pmid40970704, year = {2025}, author = {Lewis, KN and Zepeda-Rivera, MA and Baryiames, AA and Jones, DS and LaCourse, KD and Bullman, S and Johnston, CD}, title = {Complete genome sequence for Slackia exigua strain SB208, isolated from a human colonic adenocarcinoma.}, journal = {Microbiology resource announcements}, volume = {14}, number = {10}, pages = {e0044525}, pmid = {40970704}, issn = {2576-098X}, support = {R01 DE027850/DE/NIDCR NIH HHS/United States ; R01 CA290034/CA/NCI NIH HHS/United States ; R01 CA288827, R01 CA290034, R00 CA229984-03/CA/NCI NIH HHS/United States ; R01 CA288827/CA/NCI NIH HHS/United States ; R00 CA229984/CA/NCI NIH HHS/United States ; }, abstract = {We report the complete genome sequence of Slackia exigua SB208, isolated from the resected tumor tissue of a treatment-naïve patient with colorectal cancer. This genome is composed of a single chromosome that is approximately 2 Mb in length with an overall guanine-cytosine (GC) content of 62.5%.}, }
@article {pmid40971295, year = {2025}, author = {Ishida, T and Mercoli, J and Heck, AM and Phelps, I and Varnum-Finney, B and Dozono, S and Nourigat-McKay, C and Kraskouskas, K and Wellington, R and Waltner, O and Jackson, DL and Delaney, C and Rafii, S and Bernstein, ID and Aldinger, KA and ,  and Trapnell, C and Zhao, HG and Hadland, B}, title = {Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.}, journal = {Cell reports}, volume = {44}, number = {10}, pages = {116289}, pmid = {40971295}, issn = {2211-1247}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 HL168110/HL/NHLBI NIH HHS/United States ; U24 DK126127/DK/NIDDK NIH HHS/United States ; K08 HL140143/HL/NHLBI NIH HHS/United States ; R24 HD000836/HD/NICHD NIH HHS/United States ; R01 HL179317/HL/NHLBI NIH HHS/United States ; RC2 DK114777/DK/NIDDK NIH HHS/United States ; }, mesh = {*Hematopoietic Stem Cells/cytology/metabolism ; Animals ; *Liver/cytology/embryology ; *Single-Cell Analysis/methods ; *Cell Differentiation ; Mice ; *Fetus/cytology ; Mice, Inbred C57BL ; Hematopoiesis ; Stem Cell Niche ; }, abstract = {Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.}, }
@article {pmid40971674, year = {2025}, author = {Dinan, MA and Stratton, KL and Leisenring, WM and Yasui, Y and Chow, EJ and Tonorezos, ES and Moskowitz, CS and Yeh, JM and Noyd, D and Armstrong, GT and Oeffinger, KC}, title = {Treatment exposure-based risk-stratification for care of survivors of childhood cancer: a report from the childhood cancer survivor study.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {12}, pages = {2580-2590}, pmid = {40971674}, issn = {1460-2105}, support = {//American Lebanese-Syrian Associated Charities/ ; P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA021765/CA/NCI NIH HHS/United States ; //St Jude Children's Research Hospital/ ; R01 CA134722/CA/NCI NIH HHS/United States ; CA21765//Cancer Center Support/ ; U24 CA055727/CA/NCI NIH HHS/United States ; U24CA55727/CA/NCI NIH HHS/United States ; //C. Roberts, Principal Investigator/ ; R01CA134722-S1/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Cancer Survivors/statistics &amp; numerical data ; Male ; *Neoplasms/therapy/mortality/epidemiology ; Adult ; Child ; Adolescent ; Risk Assessment ; Young Adult ; Proportional Hazards Models ; Child, Preschool ; United Kingdom/epidemiology ; Chronic Disease/epidemiology ; Infant ; }, abstract = {BACKGROUND: Treatment exposure-based risk-stratification of long-term cancer survivors may help inform health care in survivorship clinics. We used the large, diverse population of the Childhood Cancer Survivor Study to test a modified, exposure-based strata previously developed within United Kingdom to classify survivors with respect to risk of late morbidity and health-related mortality.<br><br>METHODS: Five-year survivors of childhood cancer were categorized into low-, medium-, and high-risk groups based on treatment exposures and diagnosis. Primary endpoints included cumulative health-related (ie, nonrecurrence, nonexternal) late mortality and cumulative incidence of severe or fatal (CTCAE grade 3-5) chronic health conditions conditional on reaching age 20 without the outcome. Siblings were a comparison group for chronic health conditions. Cox proportional hazards models were adjusted for sex, race, ethnicity, and age at diagnosis.<br><br>RESULTS: Among 15,346 survivors diagnosed 1970-1999, the risk of developing a severe chronic condition by age 35 was 11.9% (95% confidence interval [CI] = 9.9% to 14.3%), 15.1% (13.7% to 16.6%), and 25.4% (24.3% to 26.5%) for low-, medium-, and high-risk survivors, respectively, and 6.9% (6.1% to 7.9%) for siblings. Multivariable analysis confirmed higher likelihood of developing a chronic condition in high (hazard ratio [HR] = 2.9, 2.5 to 3.4) and medium (HR = 1.5, 1.3 to 1.8) versus the low-risk group. Health-related mortality was similarly increased among high (HR = 5.1, 3.8 to 7.0) and medium (HR = 2.5, 1.8 to 3.4) risk groups, as well as Black versus Non-Hispanic White survivors (HR = 1.7, 1.3 to 2.1).<br><br>CONCLUSIONS: Exposure-based risk categorizations can provide generalized risk stratification regarding future chronic health conditions and early mortality and may be useful in guiding management of childhood cancer survivors.}, }
@article {pmid40971752, year = {2025}, author = {Raychaudhuri, R and Garraway, IP and Maxwell, KN and Rettig, M and Desai, H and Schoen, MW and Schweizer, MT and Beltran, H and Nelson, PS and Montgomery, B}, title = {Prognostic Significance of RB1 Alterations on Outcomes in Metastatic Prostate Cancer.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500341}, pmid = {40971752}, issn = {2473-4284}, support = {P50 CA097186/CA/NCI NIH HHS/United States ; R37 CA241486/CA/NCI NIH HHS/United States ; T32 CA009515/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; Aged ; *Retinoblastoma Binding Proteins/genetics ; Prognosis ; Retrospective Studies ; Middle Aged ; *Prostatic Neoplasms, Castration-Resistant/genetics/mortality/pathology ; *Ubiquitin-Protein Ligases/genetics ; Neoplasm Metastasis ; *Prostatic Neoplasms/genetics/mortality/pathology ; }, abstract = {PURPOSE: Emerging evidence suggests that RB1 inactivation may be a strong predictor of poor survival for men with prostate cancer (PC); however, large-scale validation is lacking.<br><br>METHODS: We analyzed whether RB1 alterations are associated with inferior survival in advanced PC and evaluated the impact of co-occurring genomic alterations on outcomes using retrospective data from the Veteran's Health Administration and Veterans Affairs Multi-Omics Analysis Platform for Prostate Cancer from 2016 to 2023.<br><br>RESULTS: The primary outcome was overall survival (OS) from onset of metastatic castration-resistant prostate cancer (mCRPC), as well as OS from initiation of life-prolonging therapy other than androgen deprivation therapy, and time to development of mCRPC. Eighty-seven (3.5%) of the 2,512 included patients had an RB1 alteration detected. The median age at diagnosis in the RB1-altered group was 71 (IQR, 65-76) years, and 68 (IQR, 62-73) years in the RB1 wild-type group. The median overall survival from diagnosis of mCRPC was 1.31 years (95% CI, 0.89 to 1.84) in those with an RB1 alteration compared with 2.99 years (95% CI, 2.79 to 3.23). RB1 alteration alone conferred similar poor prognosis when compared with patients who had combined PTEN and TP53 alterations. A dose effect was seen with increasing numbers of tumor suppressor genes (TSGs-RB1, TP53, and PTEN) conferring poorer outcomes. The median survival of patients from diagnosis of mCRPC with zero, one, two, and three TSGs was 3.74, 2.61, 1.61, and 0.87 years, respectively. BRCA2 alterations were not associated with significantly worse outcomes unless accompanied by RB1 alteration.<br><br>CONCLUSION: In this large, real-world cohort of men with mCRPC, RB1 alterations emerged as a strong indicator of poor prognosis and can be used to stratify studies alone or in conjunction with other TSG alterations.}, }
@article {pmid40971753, year = {2025}, author = {Loeb, S and Keith, SW and Gross, L and Hartman, RL and Beer, TM and Brierley, KL and Cheng, HH and Couvillon, A and Dicker, AP and Friedman, S and Gomella, LG and Karsh, L and Kelly, WK and Lallas, CD and Leader, AE and Mann, MJ and Mark, JR and Mille, P and Paller, CJ and Rana, HQ and Sokolova, AO and Trabulsi, EJ and Whang, YE and Giri, VN}, title = {Patient-Reported Outcomes From Males Regarding Germline Testing for Prostate Cancer: Results From the PROGRESS Registry.}, journal = {JCO precision oncology}, volume = {9}, number = {}, pages = {e2500571}, pmid = {40971753}, issn = {2473-4284}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; P30 CA056036/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Male ; *Prostatic Neoplasms/genetics/diagnosis ; Middle Aged ; Registries ; *Genetic Testing ; *Patient Reported Outcome Measures ; Aged ; Germ-Line Mutation ; Adult ; }, abstract = {PURPOSE: Prostate cancer (PCA) germline testing (GT) informs precision therapy, cancer screening, and hereditary cancer risk for patients and families. To support patient-centered PCA GT, studying patient-reported outcomes (PROs) is essential.<br><br>METHODS: PROGRESS was a national patient-driven registry (January 2021-April 2022) for English-speaking males older than 18 years with previous/current PCA GT and Internet access. Surveys collected demographics, PCA history, family cancer history, mode of genetics care delivery, satisfaction with genetic counseling, decisional conflict, cancer genetics knowledge, and attitudes toward GT. Multiple linear regression modeling was used to estimate and draw inferences (&#x3b1; = .05) on strength of relationships between participant characteristics and PROs.<br><br>RESULTS: Analyses focused on 414 participants: White (88%), Black (3%), Asian (6%), and mixed/other (3%). Most participants were non-Hispanic (95.2%) and 46.9% had PCA. Genetic results were positive (pathogenic/likely pathogenic variants; mutations) in 27.9%. The three most common modes of genetics care were meeting with genetics professional (in-person or remotely; 30.9%), discussing with doctor (21.1%), and using website (20.8%). In covariate-adjusted models, satisfaction scores were highest with pretest counseling by phone (&#x3b2; = 1.31; 95% CI, 0.26 to 2.36) or discussion with doctor (&#x3b2; = 1.25; 95% CI, 0.38 to 2.12). Lower decisional conflict scores were reported for pretest counseling by phone (&#x3b2; = -3.76; 95% CI, -7.28 to -0.24). Males with mutations reported higher GT benefit scores (&#x3b2; = .30; 95% CI, 0.02 to 0.59) and importance of GT (&#x3b2; = .34; 95% CI, 0.08 to 0.61). Asian Americans reported lower GT satisfaction (&#x3b2; = -2.91; 95% CI, -4.34 to -1.48) and higher decisional conflict (&#x3b2; = 8.93; 95% CI, 4.36 to 13.51).<br><br>CONCLUSION: PROGRESS Registry informs the first comprehensive report of PROs among males undergoing PCA GT, providing insights into opportunities to improve patient experience and leverage the benefit of GT.}, }
@article {pmid40971983, year = {2025}, author = {Carone, M and Wolock, CJ and Olivas-Martinez, A and Rotnitzky, A and Gilbert, PB}, title = {Immune Correlates and Vaccine Immunobridging: Statistical Innovations, Challenges, and Opportunities.}, journal = {The Journal of infectious diseases}, volume = {232}, number = {5}, pages = {1024-1028}, pmid = {40971983}, issn = {1537-6613}, support = {R37 AI029168/AI/NIAID NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; /NH/NIH HHS/United States ; R01 HL137808/HL/NHLBI NIH HHS/United States ; /NH/NIH HHS/United States ; }, mesh = {Humans ; Biomarkers ; *Immunogenicity, Vaccine ; Randomized Controlled Trials as Topic ; *Vaccine Efficacy ; *Vaccines/immunology ; }, abstract = {In immunobridging, an investigational vaccine is approved based on a randomized trial of this vaccine versus an approved vaccine with an immunogenicity primary endpoint. Justification for immunobridging requires demonstration that meeting trial success criteria implies the investigational vaccine provides worthwhile protection against a relevant endpoint for a context of use. We consider recent statistical approaches whose integration supports immunobridging: (1) variable importance prediction analysis characterizing immune markers as correlates of risk; (2) controlled risk causal analysis evaluating markers as correlates of protection; and (3) transportability analysis combining data from efficacy and immunobridging trials for estimating investigational versus approved relative-vaccine efficacy.}, }
@article {pmid40972035, year = {2025}, author = {Watling, CZ and Petrick, JL and Graubard, BI and Zhang, X and Barnett, MJ and Buring, JE and Chen, Y and Eliassen, AH and Gaziano, JM and Hofmann, JN and Huang, WY and Kang, JH and Koshiol, J and Loftfield, E and Lee, IM and Moore, SC and Mucci, LA and Neuhouser, ML and Newton, CC and Palmer, JR and Purdue, MP and Rosenberg, L and Sesso, HD and Shrubsole, M and Tinker, L and Triplette, M and Um, CY and Visvanathan, K and Watts, EL and Wactawski-Wende, J and Willett, W and Wu, F and Zheng, W and Campbell, PT and Barupal, D and McGlynn, KA}, title = {Pre-diagnostic circulating bile acid concentrations and liver cancer risk: a nested case-control analysis of 12 cohorts.}, journal = {JNCI cancer spectrum}, volume = {9}, number = {5}, pages = {}, pmid = {40972035}, issn = {2515-5091}, support = {CA34944, CA40360, CA097193, HL26490 and HL34595//PHS HHS/United States ; 75N92021D00002/HL/NHLBI NIH HHS/United States ; U01 CA167462/CA/NCI NIH HHS/United States ; U01 CA164974/CA/NCI NIH HHS/United States ; //Intramural Research Program of the Division of Cancer Epidemiology and Genetics, and contracts from the Division of Cancer Prevention, NCI, NIH, DHHS/ ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U24ES035386/GF/NIH HHS/United States ; UM1 CA182913/CA/NCI NIH HHS/United States ; R01 HL026490/HL/NHLBI NIH HHS/United States ; R01 HL080467/HL/NHLBI NIH HHS/United States ; #187861//Canadian Institutes of Health Research Fellowship/ ; RC1 HL099355/HL/NHLBI NIH HHS/United States ; U01CA63673, UM1CA167462, and U01CA167462//CARET/ ; 75N92021D00005/WH/WHI NIH HHS/United States ; U01 CA063673/CA/NCI NIH HHS/United States ; R01 HL043851/HL/NHLBI NIH HHS/United States ; U01 167552/BC/NCI NIH HHS/United States ; P30 DK058404/DK/NIDDK NIH HHS/United States ; R01 HL034595/HL/NHLBI NIH HHS/United States ; U24 ES035386/ES/NIEHS NIH HHS/United States ; //National Institutes of Health Intramural Program/ ; 75N92021D00003/WH/WHI NIH HHS/United States ; UM1 CA186107/CA/NCI NIH HHS/United States ; R01 CA047988/CA/NCI NIH HHS/United States ; CA047988, CA182913, HL043851, HL080467 and HL099355//WHS/ ; R01 CA040360/CA/NCI NIH HHS/United States ; U01 CA182913/CA/NCI NIH HHS/United States ; U01CA164974/GF/NIH HHS/United States ; U01 CA202979/CA/NCI NIH HHS/United States ; UM1 CA167462/CA/NCI NIH HHS/United States ; R01 CA097193/CA/NCI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; R01 CA034944/CA/NCI NIH HHS/United States ; 75N92021D00001, 75N92021D00002, 75N92021D00003, 75N92021D00004, 75N92021D00005//National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts/ ; }, mesh = {Humans ; Case-Control Studies ; *Bile Acids and Salts/blood ; Male ; *Liver Neoplasms/blood/epidemiology/etiology ; Middle Aged ; Female ; Prospective Studies ; Aged ; Odds Ratio ; Logistic Models ; Risk Factors ; Adult ; United States/epidemiology ; Cholangiocarcinoma/blood/epidemiology ; *Carcinoma, Hepatocellular/blood/epidemiology ; }, abstract = {BACKGROUND: Bile acids are produced in the liver and are important for lipid digestion. Higher-circulating bile acid levels, however, have been linked to metabolic disorders, inflammation, and gut microbiota dysbiosis, which have been implicated in liver carcinogenesis. To date, few epidemiological studies have explored the association between circulating bile acids and liver cancer risk.<br><br>METHODS: We conducted a nested case-control study among 12 prospective cohort studies located in the United States. Fifteen prediagnostic circulating bile acids were measured from blood samples among 872 individuals who developed liver cancer and 872 matched control participants. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted conditional logistic regression analysis of circulating bile acid levels and liver cancer risk.<br><br>RESULTS: Primary conjugated bile acid concentrations were positively associated with higher risk of liver cancer (OR per doubling in concentrations [log2] and 95% CI of glycocholic acid: 1.32, 1.24 to 1.40; glycochenodeoxycholic acid: 1.33, 1.24 to 1.43; taurocholic acid: 1.28, 1.22 to 1.35; and taurchenodeoxycholic acid: 1.32, 1.24 to 1.39). Secondary conjugated bile acids were also positively associated with liver cancer risk (doubling of concentrations OR ranged from 1.11 to 1.22). Unconjugated bile acid concentrations were generally not associated with liver cancer risk, except lithocholic acid (OR per doubling: 1.27, 1.16 to 1.39). When analyses were separated into the 2 main subtypes of liver cancer, hepatocellular carcinoma (HCC; 438 cases/438 controls) and intrahepatic cholangiocarcinoma (ICC; 111 cases/111 controls), significant heterogeneity was observed for primary conjugated bile acid concentrations (all P&#x2009;<&#x2009;.001) that showed positive significant associations with HCC but not ICC.<br><br>CONCLUSIONS: These results suggest that bile acids may be important markers of HCC risk and contribute to hepatocarcinogenesis; however, further research using serial measurements is needed.}, }
@article {pmid40972578, year = {2025}, author = {Wang, N and Ockerman, FP and Zhou, LY and Grove, ML and Alkis, T and Barnard, J and Bowler, RP and Clish, CB and Chung, S and Drzymalla, E and Evans, AM and Franceschini, N and Gerszten, RE and Gillman, MG and Hutton, SR and Kelly, RS and Kooperberg, C and Larson, MG and Lasky-Su, J and Meyers, DA and Woodruff, PG and Reiner, AP and Rich, SS and Rotter, JI and Silverman, EK and Vasan, RS and Weiss, ST and Wong, KE and Wood, AC and Wu, L and ,  and Yarden, R and Blackwell, TW and Smith, AV and Chen, H and Raffield, LM and Yu, B}, title = {Genetic architecture and analysis practices of circulating metabolites in the NHLBI Trans-Omics for Precision Medicine Program.}, journal = {American journal of human genetics}, volume = {112}, number = {11}, pages = {2720-2738}, pmid = {40972578}, issn = {1537-6605}, support = {R01 HL120393/HL/NHLBI NIH HHS/United States ; R01 HL163972/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; R01 HL168683/HL/NHLBI NIH HHS/United States ; R01 MD012765/MD/NIMHD NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; K01 HL146980/HL/NHLBI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; R01 DK117445/DK/NIDDK NIH HHS/United States ; T32 GM135123/GM/NIGMS NIH HHS/United States ; U54 HG013243/HG/NHGRI NIH HHS/United States ; }, mesh = {Humans ; *Precision Medicine/methods ; Genome-Wide Association Study ; Female ; National Heart, Lung, and Blood Institute (U.S.) ; Male ; *Metabolomics/methods ; United States ; *Metabolome/genetics ; Polymorphism, Single Nucleotide/genetics ; }, abstract = {Circulating metabolite levels partly reflect the state of human health and diseases and can be impacted by genetic determinants. Hundreds of loci associated with circulating metabolites have been identified; however, most findings focus on predominantly European ancestry or single-study analyses. Leveraging the rich metabolomics resources generated by the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) Program, we harmonized and accessibly cataloged 1,729 circulating metabolites among 25,058 ancestrally diverse samples. From our comparison of multiple methods, we provided a set of reasonable strategies for outlier and imputation handling to process metabolite data and show that inverse normalization by study and half-minimum imputation provide mostly similar results for pooled or meta-analysis. Following the practical analysis framework, we further performed a genome-wide association analysis on 1,135 selected metabolites using whole-genome sequencing data from 16,359 individuals passing the quality-control filters and discovered 1,775 independent loci associated with 667 metabolites. Among 160 unreported locus-metabolite pairs, we identified associations with loci locating within previously implicated metabolite-associated genes, as well as associations with loci locating in genes such as GAB3 and VSIG4 (located on the X chromosome) that may play a role in metabolic regulation. In the sex-stratified analysis, we revealed 85 independent locus-metabolite pairs with evidence of sexual dimorphism, which were located in well-known metabolic genes such as FADS2, D2HGDH, SUGP1, and UGT2B17, strongly supporting the importance of exploring sex difference in the human metabolome. Taken together, our study depicted the genetic contribution to circulating metabolite levels, providing additional insight into the understanding of human health.}, }
@article {pmid40972587, year = {2025}, author = {Wellington, R and Cheng, X and Dutta, S and Campbell, CA and Trapnell, C and Espin-Palazon, R and Hadland, B and Doulatov, S}, title = {Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells.}, journal = {Stem cell reports}, volume = {20}, number = {10}, pages = {102641}, pmid = {40972587}, issn = {2213-6711}, support = {RC2 DK127989/DK/NIDDK NIH HHS/United States ; R01 HL169156/HL/NHLBI NIH HHS/United States ; R01 DK131162/DK/NIDDK NIH HHS/United States ; DP2 HL147126/HL/NHLBI NIH HHS/United States ; R01 HL168110/HL/NHLBI NIH HHS/United States ; R01 HL151651/HL/NHLBI NIH HHS/United States ; R01 HL179317/HL/NHLBI NIH HHS/United States ; }, mesh = {*Induced Pluripotent Stem Cells/cytology/metabolism ; Animals ; Humans ; Zebrafish ; Cell Differentiation/genetics ; *Hematopoiesis/genetics ; *Hematopoietic Stem Cells/cytology/metabolism ; Signal Transduction ; *Endothelial Cells/cytology/metabolism ; Fibroblast Growth Factors/metabolism ; Gene Expression Regulation, Developmental ; }, abstract = {Hematopoietic stem cells (HSCs) arise in embryogenesis from a specialized hemogenic endothelium (HE) via endothelial-to-hematopoietic transition (EHT). While induced pluripotent stem cells (iPSCs) give rise to HE with robust hemogenic potential, bona fide HSC generation from iPSCs remains challenging. We map single-cell dynamics of EHT from iPSCs and integrate it with human embryo datasets to identify ligand-receptor interactions that drive transcriptional divergence between iPSC-derived and embryonic cell states. The expression of endothelial genes predicted to be regulated by FGF signaling was incompletely repressed during iPSC-derived EHT. FGF activity declined at the onset of EHT to enable normal hematopoiesis in the zebrafish, and chemical inhibition of FGF signaling during EHT enhanced HSC and progenitor generation in the zebrafish and from iPSCs. In summary, we generate a single-cell map of iPSC-derived EHT, identify ligand-receptor interactions that can improve iPSC differentiation, and uncover elevated FGF signaling as a barrier to hematopoiesis.}, }
@article {pmid40972633, year = {2026}, author = {Agnandji, ST and Bok, J and Alabi, A and Kabwende, AL and Mbouna, A and Bie, J and Moukiti, E and Lalremruata, A and Esen, M and Kreidenweiss, A and Kc, N and Sim, BKL and Richie, TL and Preston Church, LW and McCall, MBB and Hoffman, SL and Kremsner, PG and Mordmüller, B}, title = {Safety, tolerability, and protective efficacy of a radiation-attenuated, whole sporozoite malaria vaccine in children in Gabon: a randomised, double-blind, placebo-controlled, phase 2 trial.}, journal = {The Lancet. Infectious diseases}, volume = {26}, number = {1}, pages = {79-90}, doi = {10.1016/S1473-3099(25)00434-7}, pmid = {40972633}, issn = {1474-4457}, mesh = {Humans ; *Malaria Vaccines/adverse effects/immunology/administration &amp; dosage ; Double-Blind Method ; Gabon/epidemiology ; *Malaria, Falciparum/prevention &amp; control ; Child, Preschool ; Male ; Female ; Child ; *Plasmodium falciparum/immunology/radiation effects ; Infant ; *Sporozoites/immunology/radiation effects ; Vaccines, Attenuated/immunology/adverse effects/administration &amp; dosage ; *Vaccine Efficacy ; Antimalarials/therapeutic use ; Parasitemia/prevention &amp; control ; }, abstract = {BACKGROUND: Highly effective malaria vaccines are crucial to further reduce the burden of malaria. The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) Vaccine protects adults; however, there are insufficient efficacy data in child populations. We aimed to assess the safety and efficacy of the PfSPZ Vaccine in children aged 1-12 years in Gabon.<br><br>METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was conducted at the Centre de Recherches M&#xe9;dicales de Lambar&#xe9;n&#xe9;, Lambar&#xe9;n&#xe9;, Gabon. Healthy children were stratified by age (1-2, 3-6, and 7-12 years) and allocated 2:1 by block randomisation to receive 9&#xb7;0&#x2009;&#xd7;&#x2009;10[5] PfSPZ Vaccine or placebo (normal saline), administered by direct venous inoculation on days 1, 8, and 29. Artemether-lumefantrine was given before the third vaccination to clear latent parasitaemia. The co-primary endpoints were safety, evaluated in the intention-to-treat population by severe adverse events within 7 days (solicited) and 28 days (unsolicited) of vaccination and by serious adverse events; and vaccine efficacy, measured as time to first P falciparum-positive thick blood smear (TBS), 2-26 weeks after immunisation in those who received three vaccinations (ie, the modified intention-to-treat population). The trial was registered at ClinicalTrials.gov, NCT03521973, and is complete.<br><br>FINDINGS: Between June 21, 2018, and April 30, 2019, 345 children were assessed for eligibility, of whom 200 were enrolled to the study: 134 were allocated to receive PfSPZ Vaccine and 66 to receive placebo. 192 participants received three vaccinations and comprised the modified intention-to-treat population. Systemic adverse events were reported by 33 (25%) of 134 participants in the vaccine group (47 events) and 15 (23%) of 66 participants in the placebo group (25 events); subjective fever was the most reported event in both groups. Three grade 3 systemic adverse events were reported (two cases of elevated body temperature and one case of subjective fever), all in the placebo group. 32 serious adverse events were reported across 22 study participants, 13 (10%) of 134 in the vaccine group and nine (14%) of 66 in the placebo group, all of which were considered unrelated to the intervention. There were no treatment-related deaths. 25 (19%) of 129 vaccine recipients and 14 (23%) of 63 placebo recipients became TBS-positive for P falciparum at 2-26 weeks after vaccination. The age-stratum-adjusted vaccine efficacy (1&#x2009;-&#x2009;hazard ratio) was 9% (95% CI -75 to 53; p=0&#xb7;78).<br><br>INTERPRETATION: PfSPZ Vaccine is well tolerated and safe, but it did not prevent P falciparum infection in children in Gabon. Whether presumptive treatment during immunisation or more potent PfSPZ vaccines can establish vaccine efficacy is currently under investigation.<br><br>FUNDING: German Center for Infection Research, European and Developing Countries Clinical Trials Partnership, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.}, }
@article {pmid40972808, year = {2025}, author = {Bhat, P and Van Amburg, JC and Potts, CR and Gracie, TJ and Cartailler, JA and Parker, AC and Savona, MR and Lu, R and Lee, SC and Welner, RS and Bick, AG and Ferrell, PB}, title = {A 30-gene classifier distinguishes low-risk MDS HSPCs from healthy HSPCs.}, journal = {Experimental hematology}, volume = {152}, number = {}, pages = {105252}, pmid = {40972808}, issn = {1873-2399}, support = {T32 GM145734/GM/NIGMS NIH HHS/United States ; R38 HL167237/HL/NHLBI NIH HHS/United States ; R01 CA259480/CA/NCI NIH HHS/United States ; R56 DK138826/DK/NIDDK NIH HHS/United States ; I01 BX005991/BX/BLRD VA/United States ; }, mesh = {Humans ; *Myelodysplastic Syndromes/genetics/pathology/metabolism ; *Hematopoietic Stem Cells/metabolism/pathology ; *Transcriptome ; Male ; Cell Differentiation ; Female ; Aged ; Gene Expression Profiling ; }, abstract = {Myelodysplastic syndromes (MDS) are a group of malignant clonal disorders that are characterized by functional impairment of hematopoiesis, morphologic dysplasia, and genetic heterogeneity. While less likely to transform to acute leukemia, lower-risk MDS (LR-MDS) include patients with IPSS-M moderate low risk, low risk, and very low risk patients and have a limited median survival of 3 to 10 years. Further, there is growing interest in discovering translational targets of LR-MDS pathophysiology. Clonal populations within the hematopoietic stem and progenitor (HSPC) to myeloid differentiation spectrum are widely considered to be a major contributor to MDS pathophysiology. A granular assessment of cell-type and lineage-specific states that contribute to LR-MDS pathophysiology remains to be elucidated. Here, we leverage single-cell transcriptomics to characterize cell states across the HSPC-myeloid differentiation landscape in LR-MDS. We develop a 30-gene score to classify LR-MDS HSPCs and identify novel molecular features of LR-MDS. The genes in our score suggest dysfunction in vesicular trafficking, which we further resolve across the myeloid differentiation axis. The gene products of vesicular trafficking-related pathways may be suitable translational targets for LR-MDS.}, }
@article {pmid40973225, year = {2025}, author = {Ch'en, PY and Zhang, Y and Hippe, DS and Akaike, T and Miller, NJ and Church, C and Lachance, K and Finberg, A and Gooley, T and Hall, E and Bhatia, S and Nghiem, P}, title = {Real-world outcomes of patients receiving salvage therapies for immune checkpoint inhibitor-resistant Merkel cell carcinoma: a rationale for future clinical trials.}, journal = {Journal for immunotherapy of cancer}, volume = {13}, number = {9}, pages = {}, pmid = {40973225}, issn = {2051-1426}, support = {P01 CA225517/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Salvage Therapy/methods ; *Immune Checkpoint Inhibitors/therapeutic use/pharmacology ; *Carcinoma, Merkel Cell/drug therapy/mortality/pathology ; Male ; Female ; Aged ; Middle Aged ; *Drug Resistance, Neoplasm ; Aged, 80 and over ; *Skin Neoplasms/drug therapy/mortality ; Treatment Outcome ; Prospective Studies ; }, abstract = {BACKGROUND: Merkel cell carcinoma is an aggressive skin cancer that progresses to advanced/metastatic disease in~40% of patients. First-line immune checkpoint inhibitors (ICI) that block the programmed cell death protein-1/programmed death-ligand 1 axis provide 3-year progression-free responses in only~40% of patients. The relative efficacy of salvage therapies in this setting is unclear.<br><br>METHODS: In a prospectively enrolled single-center cohort, 106 patients had disease progression during or shortly after ICI and received at least one local or systemic salvage therapy. Baseline disease characteristics, treatments, and outcomes data were collected. Patients were stratified by primary resistance (no response to initial ICI) or acquired resistance (loss of ICI response after initial benefit). Primary outcomes were progression-free survival (PFS) and disease-specific survival (DSS). Associations between salvage therapies and outcomes were evaluated using Cox models with time-varying covariates for treatments and adjustments for disease burden and ICI resistance type.<br><br>RESULTS: In this cohort, 44 patients (42%) met criteria for primary resistance and 31 (29%) had acquired resistance. Median PFS from salvage initiation was more than double for patients with acquired versus primary resistance (9.5 vs 4.7 months; p=0.006). Median DSS was not reached for acquired resistance and 14.3 months for primary resistance (p=0.006). A minority of patients (n=14) survived &#x2265;3 years after salvage initiation, typically following customized, multimodal salvage strategies. Among salvage regimens (ICI alone, ICI+radiation therapy (RT), chemotherapy, chemotherapy+ICI), only ICI+RT had a statistically significant association with improved DSS relative to ICI alone (after adjustment, including disease burden and ICI resistance type: adjusted HR 0.35, 95%&#x2009;CI 0.14 to 0.91).<br><br>CONCLUSIONS: Patients with acquired resistance receiving salvage therapy have improved survival compared with those with primary resistance. While the addition of radiation to ICI was clearly associated with improved DSS, there continues to be a major need for new approaches to address ICI-resistant disease. Nevertheless, a durable benefit in select patients is possible via sequential, individualized, multidisciplinary treatments. We anticipate these data will be relevant for the design of clinical trials for this challenging ICI-resistant setting.}, }
@article {pmid40974095, year = {2025}, author = {Kistler, K and Bedford, T}, title = {Seasonal Influenza Viruses Show Distinct Adaptive Dynamics During Growth in Chicken Eggs.}, journal = {Molecular biology and evolution}, volume = {42}, number = {10}, pages = {}, pmid = {40974095}, issn = {1537-1719}, mesh = {Animals ; Chickens ; Hemagglutinin Glycoproteins, Influenza Virus/genetics ; *Influenza A Virus, H3N2 Subtype/genetics/growth &amp; development ; Mutation ; Humans ; Influenza A Virus, H1N1 Subtype/genetics/growth &amp; development ; Evolution, Molecular ; Chick Embryo ; Epistasis, Genetic ; *Influenza B virus/genetics/growth &amp; development ; Adaptation, Physiological/genetics ; }, abstract = {Human influenza viruses are grown in chicken eggs for vaccine production. Sequences of these egg-passaged viruses give us the opportunity to examine the evolution that occurs when these human viruses are subjected to the selective pressure of growing in chicken eggs, which (among other things) express different sialic acid receptors. The repetition of this evolutionary experiment in hundreds of strains over the past several decades allows us to identify mutations that adapt the virus to eggs and epistatic constraints that influence them. We analyze influenza A/H3N2, A/H1N1pdm, B/Vic, and B/Yam sequences that were passaged in eggs and find that almost all of the adaptive mutations are located around the receptor-binding pocket of hemagglutinin (HA). We observe epistatic interactions both between adaptive mutations and between these mutations and the continually evolving human influenza HA background sequence. Our results show that this background dependence is greatest for influenza A/H3N2, and then A/H1N1pdm, with B/Vic and B/Yam showing little-to-no background dependence. We find that the total number of adaptive mutations and the length of adaptive walk also follow the same pattern between the influenza subtypes, suggesting that background dependence, number of adaptive mutations, and extent of additive versus epistatic interactions may all be related features of the fitness landscape.}, }
@article {pmid40974097, year = {2025}, author = {Deslandes, B and Wu, X and Lee, MA and Goudswaard, LJ and Jones, GW and Gsur, A and Lindblom, A and Ogino, S and Vymetalkova, V and Wolk, A and Wu, AH and Huyghe, JR and Peters, U and Phipps, AI and Thomas, CE and Pai, RK and Grant, RC and Buchanan, DD and Yarmolinsky, J and Gunter, MJ and Zheng, J and Hazelwood, E and Vincent, EE}, title = {Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development.}, journal = {Journal of leukocyte biology}, volume = {117}, number = {10}, pages = {}, pmid = {40974097}, issn = {1938-3673}, support = {AZV NU22J-03-00033//Ministry of Health of the Czech Republic/ ; U01 CA167551/NH/NIH HHS/United States ; C18281/A29019//Cancer Research UK 25/ ; C18281/A29019//CRUK Integrative Cancer Epidemiology Programme/ ; U19 CA148107/GF/NIH HHS/United States ; C18281/A30905//Cancer Research UK Population Research Committee/ ; HHSN268201200008C/HL/NHLBI NIH HHS/United States ; R01 CA081488/CA/NCI NIH HHS/United States ; HHSN268201200008I/GF/NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; 218495/Z/19/Z/WT_/Wellcome Trust/United Kingdom ; U01 CA122839/NH/NIH HHS/United States ; MC_UU_00032/03/MRC_/Medical Research Council/United Kingdom ; U19 CA148107/CA/NCI NIH HHS/United States ; R01 CA81488/GF/NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; R01 CA143247/NH/NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; //University of Bristol/ ; LX22NPO5102//National Institute for Cancer Research/ ; HHSN268201200008I/HL/NHLBI NIH HHS/United States ; 001/WHO_/World Health Organization/International ; }, mesh = {Humans ; *Colorectal Neoplasms/genetics/immunology/pathology ; *CD4-Positive T-Lymphocytes/metabolism/immunology ; *Mendelian Randomization Analysis ; *Transcriptome ; Male ; Female ; *Gene Expression Regulation, Neoplastic ; Lymphocyte Activation/genetics ; Genetic Predisposition to Disease ; }, abstract = {Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells-a highly dynamic lymphocyte subtype-undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified 6 genes-FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258-with strong evidence for a causal role in CRC development (FDR-P < 0.05; colocalisation H4 > 0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.}, }
@article {pmid40974099, year = {2025}, author = {Dreyzin, A and Ware, M and Stumbras, K and Kairalla, J and Hibbitts, E and Mossman, B and Balsamo, L and Rodwin, R and Ness, KK and Conley, CC and Raetz, E and Devidas, M and Sung, L and Loh, M and Hunger, SP and Schore, RJ and Angiolillo, A and Kadan-Lottick, N}, title = {Caregivers' Perspectives on Changes in Family Life During B-ALL Therapy: A Qualitative Study From the Children's Oncology Group.}, journal = {Pediatric blood &amp; cancer}, volume = {72}, number = {12}, pages = {e32057}, pmid = {40974099}, issn = {1545-5017}, support = {T32 CA261787/CA/NCI NIH HHS/United States ; UG1CA189955//NCTN Statistics and Data Center/ ; //Children's Oncology Group/ ; //NCORP Grant for Cancer Control Studies/ ; U10CA180886-06S1/NH/NIH HHS/United States ; U10CA98543/NH/NIH HHS/United States ; U10 CA098543/CA/NCI NIH HHS/United States ; U10CA095861/CA/NCI NIH HHS/United States ; U10 CA098413/CA/NCI NIH HHS/United States ; U10CA180886/NH/NIH HHS/United States ; U10 CA095861/CA/NCI NIH HHS/United States ; UG1 CA189955/CA/NCI NIH HHS/United States ; U10CA98413/NH/NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; T32CA261787//St. Baldrick's Foundation/ ; U10 CA180886/CA/NCI NIH HHS/United States ; U10CA180899//NCTN Network Group Operations Center/ ; }, mesh = {Humans ; Male ; Female ; *Caregivers/psychology ; Child ; Child, Preschool ; *Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy/psychology ; Qualitative Research ; Adolescent ; Adult ; Prospective Studies ; Follow-Up Studies ; Middle Aged ; *Family/psychology ; }, abstract = {BACKGROUND: Treatment of pediatric B-acute lymphoblastic leukemia (B-ALL) impacts both patients and their caregivers. An understanding of family functioning during therapy can inform family-centered care. We aimed to prospectively identify negative and positive changes in family life as perceived by caregivers throughout ALL therapy.<br><br>METHODS: Caregivers of children aged &#x2265;4&#xa0;years with average-risk B-ALL enrolled on the Children's Oncology Group trial AALL0932 who consented to an ancillary study were asked: "How has family life changed since your child's diagnosis of leukemia for the better or for the worse?" Written free responses were collected at approximately 2, 8, 17, 26 (end of therapy for females), and 38 (end of therapy for males) months post-diagnosis. Inductive content analysis was used to create codes, subcategories, and categories. Descriptive statistics were used to characterize the sample and frequencies of reported codes.<br><br>RESULTS: Overall, 994 responses were collected from caregivers of 468 children across all timepoints. Twenty-seven individual codes were identified, categorized by negative changes (reported by 89% of caregivers) and positive changes (reported by 58% of caregivers). Subcategories of negative changes, including changes in daily routines, work and finance, patient health and care needs, effects on other family members, and emotional changes, were identified across all timepoints, but were most prevalent early in therapy. Importantly, positive changes were also identified, including family support, community support, and changes in outlook.<br><br>CONCLUSION: This study identifies negative and positive family changes perceived by caregivers of children undergoing B-ALL therapy that can inform future interventions to better support families.}, }
@article {pmid40975064, year = {2025}, author = {Nishida-Aoki, N and Zhu, S and Chan, M and Kang, Y and Fujita, M and Jiang, X and McCabe, M and Vaz, JM and Davidson, NE and Ghajar, CM and Hansen, K and Welm, AL and Pillarisetty, VG and Gujral, TS}, title = {Drug screening in 3D microtumors reveals DDR1/2-MAPK12-GLI1 as a vulnerability in cancer-associated fibroblasts.}, journal = {Cell reports. Medicine}, volume = {6}, number = {10}, pages = {102357}, pmid = {40975064}, issn = {2666-3791}, support = {P30 CA015704/CA/NCI NIH HHS/United States ; R01 CA272677/CA/NCI NIH HHS/United States ; R01 CA273081/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; *Cancer-Associated Fibroblasts/metabolism/drug effects/pathology ; *Discoidin Domain Receptor 1/metabolism ; *Zinc Finger Protein GLI1/metabolism ; Animals ; Cell Line, Tumor ; *Discoidin Domain Receptor 2/metabolism ; Mice ; Signal Transduction/drug effects ; Extracellular Matrix/metabolism/drug effects ; Drug Screening Assays, Antitumor ; Cell Proliferation/drug effects ; Tumor Microenvironment/drug effects ; Antineoplastic Agents/pharmacology ; *Neoplasms/pathology/drug therapy/metabolism ; }, abstract = {Interactions between cancer cells and surrounding stromal cells are critical for tumor biology and treatment response. We compare drug screening results from conventional 2D cancer cell lines with 3D tumor tissues and find that, on average, three times more drugs are effective in 3D microtumors. We confirm the effectiveness of doramapimod, a compound that reduces microtumor viability and suppresses tumor growth in mouse models but has no effect on cancer cell growth in monolayers. Mechanistically, doramapimod targets DDR1/2 and MAPK12 kinases in cancer-associated fibroblasts (CAFs), decreasing extracellular matrix (ECM) production and enhancing interferon signaling. These kinases regulate ECM through GLI1 activity in CAFs, independently of canonical hedgehog signaling. Inhibiting the DDR1/2-MAPK12-GLI axis enhances the effectiveness of chemotherapy and immunotherapy in patient tumor slices and preclinical models. These findings highlight the importance of DDR1/2-MAPK12-GLI axis in CAF function and demonstrate the utility of 3D tissue models in identifying microenvironment-specific therapeutic targets.}, }
@article {pmid40975076, year = {2025}, author = {Stover, J and Sonneveldt, E and Tam, Y and Horton, KC and Phillips, AN and Smith, J and Martin-Hughes, R and Ten Brink, D and Citron, DT and Kim, HY and Akullian, A and Mudimu, E and Pickles, M and Bershteyn, A and Williamson, J and Meyer-Rath, G and Jamieson, L and Sully, EA and White, JN and Heaton, A and Clark, RA and Tong, H and Richards, AS and McQuaid, CF and Houben, RMGJ and White, RG and Dimitrov, D and Kaftan, D}, title = {Effects of reductions in US foreign assistance on HIV, tuberculosis, family planning, and maternal and child health: a modelling study.}, journal = {The Lancet. Global health}, volume = {13}, number = {10}, pages = {e1669-e1680}, pmid = {40975076}, issn = {2214-109X}, support = {INV-019496/GATES/Gates Foundation/United States ; R01 AI174932/AI/NIAID NIH HHS/United States ; INV-040455/GATES/Gates Foundation/United States ; R01 MH130238/MH/NIMH NIH HHS/United States ; INV-035506/GATES/Gates Foundation/United States ; R01 MH124478/MH/NIMH NIH HHS/United States ; R01 HL169021/HL/NHLBI NIH HHS/United States ; INV-001754/GATES/Gates Foundation/United States ; U01 AI068617/AI/NIAID NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; R01 AI179417/AI/NIAID NIH HHS/United States ; UM1 AI068617/AI/NIAID NIH HHS/United States ; R01 AI147321/AI/NIAID NIH HHS/United States ; UM1 AI068613/AI/NIAID NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; }, mesh = {Humans ; *Tuberculosis/economics/prevention &amp; control/epidemiology ; *HIV Infections/economics/prevention &amp; control/epidemiology ; United States ; *Family Planning Services/economics ; Female ; *Child Health/economics ; Child ; Models, Theoretical ; Pregnancy ; *International Cooperation ; Global Health ; Developing Countries ; *Maternal Health/economics ; }, abstract = {BACKGROUND: The USA has traditionally been the largest donor to health programmes in low-income and middle-income countries (LMICs). In January 2025, almost all such funding was stopped and prospects for its resumption are uncertain. The suddenness of the funding cuts makes it difficult for national health programmes in LMICs to adapt. We aimed to estimate the impact of these cuts on deaths and other outcomes (new infections, number of family planning users, and unplanned pregnancies) for four health areas that have been a focus of a substantial amount of US foreign assistance: HIV, tuberculosis, family planning, and maternal and child health.<br><br>METHODS: We applied established mathematical models to the countries receiving US foreign assistance in each domain to estimate health impacts over the period 2025 to 2030. We used six models of HIV, three different approaches to estimate family planning impact, and one model each for tuberculosis and maternal and child health, applying these models to as many as 80 countries. We compared model projections assuming constant funding (status quo) with projections assuming complete elimination of US funding in each country. Some models also considered partial cuts or restoration of funding over time.<br><br>FINDINGS: A complete cessation of US funding without replacement by other sources would lead to drastic increases in deaths from 2025 to 2030: 4&#xb7;1 million (range 1&#xb7;6-6&#xb7;6) additional AIDS-related deaths across 55 countries, 606&#x2008;900 (95% uncertainty interval [UI] 466&#x2008;000-768&#x2008;800) additional tuberculosis deaths across 79 countries, 40-55 million additional unplanned pregnancies and 12-16 million unsafe abortions across 51 countries, and 2&#xb7;5 million (1&#xb7;3-4&#xb7;5) additional child deaths from causes other than HIV and tuberculosis across 24 countries. Restoration of funding for HIV treatment but not prevention would avoid most of the increase in deaths but still result in nearly 1 million more new HIV infections from 2025 to 2030.<br><br>INTERPRETATION: Substantial progress has been made in improving global health in the past few decades. This progress has strengthened hope in reaching global development goals. However, the recent funding cuts threaten to change these trajectories and could lead to sharp increases in avoidable mortality for the poorest countries. Even a partial restoration of US funding would combat the most severe effects and provide time for countries that have received substantial US foreign assistance to adjust to the new funding landscape.<br><br>FUNDING: Economic and Social Research Council; Engineering and Physical Sciences Research Council; European and Developing Countries Clinical Trials Partnership; Gates Foundation; Global Fund to Fight AIDS, Tuberculosis, and Malaria; Open Philanthropy; UK Foreign, Commonwealth &amp; Development Office; UK Medical Research Council; UN Population Fund; UNAIDS; US National Institute of Allergy and Infectious Diseases; University of Edinburgh; US National Institutes of Health; US President's Emergency Plan for AIDS Relief; Wellcome Trust; World Bank; WHO.}, }
@article {pmid40975077, year = {2025}, author = {Mo, T and Joffe, M and Cubasch, H and Galukande, M and Parham, G and Pinder, L and Zietsman, A and Anderson, BO and Naamala, A and Kaggwa, A and Nakazibwe, T and Nteziryayo, A and Pontac, J and Offiah, SA and Angelica, A and Oyamienlen, CS and Ezeigbo, E and Iwuoha, K and Chen, WC and Walubita, E and Lusaka, M and Nyangasi, M and Mohammed, S and Narh, CT and Boucheron, P and Foerster, M and Schüz, J and Dos-Santos-Silva, I and McCormack, V}, title = {Breast cancer overall survival, annual risks of death, and survival gap apportionment in sub-Saharan Africa (ABC-DO): 7-year follow-up of a prospective cohort study.}, journal = {The Lancet. Global health}, volume = {13}, number = {10}, pages = {e1681-e1690}, pmid = {40975077}, issn = {2214-109X}, support = {001/WHO_/World Health Organization/International ; R01 CA192627/CA/NCI NIH HHS/United States ; R01 CA244559/CA/NCI NIH HHS/United States ; R01 CA250012/CA/NCI NIH HHS/United States ; }, mesh = {Humans ; Female ; *Breast Neoplasms/mortality ; Africa South of the Sahara/epidemiology ; Prospective Studies ; Middle Aged ; Adult ; Follow-Up Studies ; Aged ; Young Adult ; }, abstract = {BACKGROUND: There are few estimates of breast cancer survival and its determinants at 5 years and beyond in sub-Saharan Africa. We aimed to estimate survival up to 7 years, estimate annual mortality risk, and apportion survival gaps.<br><br>METHODS: The African Breast Cancer-Disparities in Outcomes (ABC-DO) prospective cohort study was done at eight hospitals across five sub-Saharan African countries (Namibia, Nigeria, South Africa, Uganda, and Zambia). We prospectively recruited women (aged &#x2265;18 years) who attended hospital with suspected breast cancer. Vital status was updated telephonically once every 3 months for 7 years. We collected detailed sociodemographic, clinical, and treatment data. The primary outcome was overall survival. We estimated age-standardised net survival, conditional survival, and predicted survival gains if there were favourable shifts in the distribution of prognostic factors aligned with the WHO Global Breast Cancer Initiative (GBCI).<br><br>FINDINGS: Between Sept 8, 2014, and Dec 31, 2017, 2313 women were recruited and followed up to Jan 1, 2022, and for a further year in South Africa. We excluded 87 women without breast cancer, 14 women from small racial groups (eight White and six Asian women in South Africa), 57 women with previous treatment or possible recurrences, and two women without follow-up data. The remaining 2153 (93%) women were categorised by country and race, as follows: three groups in Namibia (60 White women, 50 mixed race women, and 367 Black women), two in South Africa (37 mixed race women and 638 Black women), and one group of Black women in each of Uganda (419 women), Zambia (198 women), and Nigeria (384 women). During follow-up to at most 7 years, 1323 (61%) of 2153 women died, 672 (31%) were alive at administrative censoring, and 158 (7%) were lost to follow-up, giving crude survival at 3 years, 5 years, and 7 years of 51%, 40%, and 33%, respectively. Large between-country variations in 5-year age-standardised net survival were observed: 35-42% in Zambia and Nigeria; 52-58% in Black women in Uganda, South Africa, and Namibia; and over 83% in non-Black Namibian women. The annual probability of death (1-year conditional net survival, censored before the COVID-19 pandemic) declined generally from 2-3 years after diagnosis, but remained at 8-21% for Black women in Namibia, Uganda, and Nigeria during the fifth year after diagnosis. Reaching the GBCI 60% stage I or II target and accessing treatment would lead to an approximate reduction in deaths by a third among Black women in Namibia, Nigeria, South Africa, Uganda, and Zambia.<br><br>INTERPRETATION: Survival after breast cancer is poor in several sub-Saharan African countries, with a substantial risk of death even among women who have survived beyond 3 years after diagnosis. Understanding and preventing deaths among longer-term breast cancer survivors requires further research.<br><br>FUNDING: National Cancer Institute, Susan G Komen, and International Agency for Research on Cancer.<br><br>TRANSLATIONS: For the Yoruba, Hausa, Igbo, Luganda and French translations of the abstract see Supplementary Materials section.}, }
@article {pmid40977057, year = {2025}, author = {Ebrahimi, E and Naudin, S and Dimou, N and Mayén, AL and Wang, M and Abnet, CC and Åkesson, A and Barnett, MJ and Bellocco, R and Berrington de Gonzalez, A and Bonn, SE and Chen, C and Christiani, DC and Crane, TE and Eliassen, AH and Freudenheim, JL and Gao, YT and Garcia-Closas, M and Gierach, G and Giovannucci, EL and Gram, IT and Håkansson, N and Hirabayashi, M and Hou, T and Huang, BZ and Huerta, JM and Jayasekara, H and Koh, WP and Lacey, JV and Lagerros, YT and Loftfield, E and MacInnis, RJ and Mannisto, S and Martinez, ME and McCullough, ML and Milne, RL and Moore, SC and Mucci, LA and Neuhouser, ML and Platz, EA and Poynter, JN and Prizment, AE and Rees, S and Robien, K and Rohan, TE and Sawada, N and Setiawan, VW and Shams-White, MM and Shu, XO and Sinha, R and Stampfer, MJ and Stolzenberg-Solomon, RZ and Thomson, CA and Um, CY and van den Brandt, PA and Visvanathan, K and Wang, R and Wang, SS and White, E and White, KK and Willet, WC and Wolk, A and Yano, Y and Yaun, SS and Yuan, JM and Zheng, W and Riboli, E and Smith-Warner, SA and Brennan, P and Ferrari, P}, title = {Alcohol consumption and upper aerodigestive tract squamous cell carcinoma: evidence from 28 prospective cohorts.}, journal = {Journal of the National Cancer Institute}, volume = {117}, number = {12}, pages = {2598-2611}, pmid = {40977057}, issn = {1460-2105}, support = {/CP/NCI NIH HHS/United States ; //Medical Research Council of Canada/ ; //Canadian National Breast Screening Study/ ; U01-CA-086308/BC/NCI NIH HHS/United States ; //Swedish Cancer Foundation/ ; //Alberta Heritage Fund for Cancer Research/ ; //NIH/ ; //Department of National Health and Welfare/ ; UM1-CA167462/GF/NIH HHS/United States ; //Ministry of Health and Social Services of Qu&#xe9;bec/ ; /CA/NCI NIH HHS/United States ; NU58DP007114//Maryland Cigarette Restitution Fund/ ; U01-CA063673/GF/NIH HHS/United States ; //Maryland Cancer Registry, Center for Cancer Prevention and Control/ ; 2017-00644//Swedish Research Council/ ; //Campaign Against Cancer and Heart Disease/ ; 2021-00160//Swedish Research Council/ ; GR-IARC-2015-05-05-01/GF/NIH HHS/United States ; AAA R01/GF/NIH HHS/United States ; U01-AG-18033/AG/NIA NIH HHS/United States ; R01 AA024770/AA/NIAAA NIH HHS/United States ; //Maryland Department of Health/ ; //Swedish Infrastructure for Medical Population-based Life-course and Environmental Research/ ; /NH/NIH HHS/United States ; /HH/HHS/United States ; //Nova Scotia Department of Health/ ; U01-CA167462/GF/NIH HHS/United States ; //Beta-Carotene and Retinol Efficacy Trial/ ; 001/WHO_/World Health Organization/International ; //The Alpha-Tocopherol Beta-Carotene Cancer Prevention/ ; //Canadian Cancer Society/ ; //Ontario Ministry of Health/ ; //The Breast Cancer Detection Demonstration/ ; R01AA024770/GF/NIH HHS/United States ; /CC/CDC HHS/United States ; //Manitoba Health Services Commission/ ; }, mesh = {Humans ; *Alcohol Drinking/adverse effects/epidemiology ; Female ; Male ; Middle Aged ; Prospective Studies ; *Carcinoma, Squamous Cell/epidemiology/etiology ; Aged ; Risk Factors ; *Head and Neck Neoplasms/epidemiology/etiology ; Adult ; Proportional Hazards Models ; Smoking/adverse effects/epidemiology ; Squamous Cell Carcinoma of Head and Neck/epidemiology ; }, abstract = {BACKGROUND: This study aimed to investigate the association between alcohol consumption and squamous cell cancers of the upper aerodigestive tract (UADT), using data from 28 cohorts within the Pooling Project of Prospective Studies of Diet and Cancer (DCPP).<br><br>METHODS: Individual-level data from 2&#xa0;365&#xa0;437 participants were pooled. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models to quantify the association between alcohol consumption (g/day) and UADT cancer risk, adjusting for potential confounders. Analyses were conducted by sex, smoking status, geographic region, and alcoholic beverages.<br><br>RESULTS: Over a median follow-up of 15.5&#x2009;years, 6903 UADT cancer cases were identified. Alcohol consumption was positively associated with UADT cancer risk overall. Even at intakes as low as 5-<15&#x2009;g/day, the HR estimate was 1.12 (95% CI = 1.03 to 1.21) compared with the reference group (0.1-<5&#x2009;g/day). The HR10&#xa0;g/day (95% CI) was 1.16 (1.14 to 1.18) for women and 1.12 (1.11 to 1.13) for men (Pheterogeneity < .0001). HR10&#xa0;g/day estimates were 1.14 (1.13 to 1.15) in current, 1.10 (1.09 to 1.12) in former, and 1.15 (1.12 to 1.18) in never smokers. Consistent UADT HR10&#xa0;g/day estimates were observed across all beverage types. HR10&#xa0;g/day estimates varied across geographic regions, with HR10&#xa0;g/day (95% CI) equal to 1.15 (1.14 to 1.17) in Europe-Australia, 1.13 (1.11 to 1.15) in Asia, and 1.11 (1.09 to 1.12) in North America (Pheterogeneity < .0001).<br><br>CONCLUSION: Alcohol consumption was associated with UADT cancer risk, irrespective of smoking status or beverage type. However, due to differential baseline risks, alcohol is expected to impact the UADT cancer burden more in smokers than never smokers. These findings support public health strategies to reduce alcohol consumption.}, }
@article {pmid40978103, year = {2025}, author = {Bukavina, L and Isali, I and Parekh, S and Psutka, S and Uzzo, N and Leonard, S and Calaway, A and Patel, S and Grivas, P and Jia, A and Correa, A and Brown, JR and Kutikov, A and Ponsky, L and Uzzo, R and Sindhani, M and Catto, J and Wu, CW and Abbosh, PH}, title = {Genetic susceptibility and environmental risk factors in bladder cancer: Evidence from the UK biobank.}, journal = {Bladder cancer (Amsterdam, Netherlands)}, volume = {11}, number = {3}, pages = {23523735251370863}, pmid = {40978103}, issn = {2352-3735}, abstract = {PURPOSE: This study aims to identify specific genotypes within the UK Biobank (UKB) cohort contributing to a genetic predisposition for bladder cancer (UBC). It highlighted the impact of environmental exposures and the broader role of certain genes in UBC development, offering a comprehensive understanding of the genetic basis for UBC susceptibility.<br><br>EXPERIMENTAL DESIGN: Leveraging the rich data from the UKB- a longitudinal study involving participants across the UK-the primary outcome was the presence of UBC, determined using ICD-10 and ICD-9 codes. The study employed rigorous Genome-Wide Association Study (GWAS) protocols, Phenome-Wide Association (PheWAS) frameworks, and gene-level pleiotropy analyses. Quality control measures were applied, such as single-nucleotide polymorphisms (SNP) missingness and minor allele frequency thresholds. Polygenic Risk Score (PRS) evaluations were also conducted based on the Mavaddat score using UKB's high-density genome-wide SNP dataset.<br><br>RESULTS: Our GWAS identified significant associations between UBC risk and genetic variants, notably in the PSCA and TERT genes. The UGT1A polymorphism was found to be protective against UBC, particularly in heavy smokers. The PheWAS framework linked UBC-predisposition polymorphisms to other conditions, such as prostate cancer.<br><br>CONCLUSIONS: Our GWAS identified significant associations between UBC risk and genetic variants across loci, including PSCA, TERT, TACC3 and TMEM129. The protective effect of the UGT1A variant against UBC, especially concerning tobacco exposure, suggests the potential for genetic-based preventive strategies in UBC management.Patient summary In our study of a large group from the United Kingdom (UK), we explored genetic factors that might increase the likelihood of developing UBC. We discovered that certain genetic changes offer protection against UBC, particularly in individuals exposed to tobacco smoke. Understanding these genetic factors could improve strategies for preventing and treating UBC.}, }
@article {pmid40978447, year = {2025}, author = {Shukla, S and Stingaciu, LR and Stanley, C and Agarwal, P and Cuneo, M and Stadler, AM and Myles, D}, title = {Dynamical Signatures of Thermotoga maritima Maltose-Binding Proteins Affected by Ligand Binding.}, journal = {ACS omega}, volume = {10}, number = {36}, pages = {41446-41456}, pmid = {40978447}, issn = {2470-1343}, abstract = {Functional segregation among protein isoforms depends on the interplay of their overall structures and the molecular dynamics of these structures. Thermotoga maritima maltose-binding protein (tmMBP) isoforms show size-dependent differential binding of maltose and malto-oligomers while maintaining remarkable fold conservation. This differential behavior needs detailed characterization in native-like aqueous conditions to understand the effects of protein dynamics on ligand binding and recognition. Small-angle neutron scattering (SANS), neutron spin echo (NSE) spectroscopy, and dynamic light scattering (DLS) were used in conjunction with previously published computational molecular dynamics (MD) simulations to understand the dynamic behavior of tmMBPs experimentally. SANS provided information on the overall structure of the molecules, while NSE was used to determine the dynamics in the nanosecond time scale. Both tmMBP2 and tmMBP3 have a bidomain architecture linked with a flexible hinge, with the binding pocket sitting in the cleft between the two domains. tmMBP2 and tmMBP3 showed different solution dynamics, with the translational and rotational components dominating the dynamics of both systems, resulting in a clear differentiation of their diffusion pattern. A faster dynamics component was also observed and was attributed to segmental dynamics. Differences observed between the ligand-free (apo) and ligand-bound (holo) states of the two proteins are attributed to conformational entropy. Our results highlight the intricacies of how structure and dynamics can together shape binding to a repertoire of substrates in structurally similar proteins.}, }
@article {pmid40979096, year = {2025}, author = {Muhammad, M and Castro-Reyes, P and Chakoian, M and Duron, Y and Gay, S and Grant, H and Hempstead, B and Hoffman, L and Mapes, D}, title = {Community/patient group champion team retrospective look at engage for equity PLUS: Results from a post-intervention champion team focus group.}, journal = {Journal of clinical and translational science}, volume = {9}, number = {1}, pages = {e179}, pmid = {40979096}, issn = {2059-8661}, abstract = {Community/patient voice has long been stifled in favor of the priorities of powerful health organizations that set the agenda for institutional practices and policies shaping health equity research. Academic Health Centers (AHC) and Clinical Translational Science Centers (CTSC) promote missions that are often unaligned with the realities of community and patient experiences when interacting with researchers and representatives from these institutions. Implementation science has increasingly adopted collaborative and participatory approaches to the design and implementation of health interventions co-created with community/patient group members as equal participants within community-academic partnerships. Community-based participatory research/community-engaged research are widely recognized as approaches to health intervention research that offers the potential for community-patient voice to be heard when the principles of authentic participatory research are adhered to throughout all aspects of the project. For AHC's and CTSC's to be fully engaged, the populations they serve must have access to institutional leadership and influence over decision-making about the organizational resources allocated to community/patient groups beyond efforts to cultivate a positive public image. The E2 community/patient champion team focus groups provide unique perspectives on how equitable institutional transformation can be accomplished in a retrospective assessment of the E2 PLUS Intervention.}, }
@article {pmid40980587, year = {2025}, author = {Deo, R and Choudhary, MC and Glover, OT and Ignacio, RB and Boucau, J and Chew, KW and Moser, C and Currier, JS and Eron, JJ and Javan, AC and Giganti, MJ and Aga, E and Gibbs, M and Cohen, T and Streicher, K and Soboleva, K and Fletcher, CV and Daar, ES and Greninger, AL and Coombs, RW and Fischer, W and Hughes, MD and Smith, D and Wohl, DA and Barczak, AK and Li, JZ}, title = {Rapid Elimination of Culturable SARS-CoV-2 With Intramuscular or Intravenous Administration of Antiviral Monoclonal Antibody Therapy.}, journal = {Open forum infectious diseases}, volume = {12}, number = {9}, pages = {ofaf542}, pmid = {40980587}, issn = {2328-8957}, support = {UM1 AI069424/AI/NIAID NIH HHS/United States ; UM1 AI068634/AI/NIAID NIH HHS/United States ; UM1 AI068616/AI/NIAID NIH HHS/United States ; UM1 AI106701/AI/NIAID NIH HHS/United States ; UM1 AI068636/AI/NIAID NIH HHS/United States ; }, abstract = {We evaluated intramuscular (IM) versus intravenous (IV) administration of tixagevimab/cilgavimab in early COVID-19. Both routes achieved rapid elimination of culturable virus and minimal emergence of resistance. These results support IM delivery as a viable alternative to IV, with important implications for scalable deployment in future viral pandemics.}, }
@article {pmid40982561, year = {2025}, author = {Chen, C and Lovendahl, KN and Overbaugh, JM and Lee, KK}, title = {Interprotomer crosstalk in mosaic viral glycoprotein trimers provides insight into polyvalent immunogen co-assembly.}, journal = {PLoS pathogens}, volume = {21}, number = {9}, pages = {e1013143}, pmid = {40982561}, issn = {1553-7374}, support = {S10 OD030237/OD/NIH HHS/United States ; }, mesh = {*Spike Glycoprotein, Coronavirus/immunology/chemistry/metabolism/genetics ; *SARS-CoV-2/immunology/genetics ; Humans ; Protein Multimerization ; *COVID-19/immunology/virology/prevention &amp; control ; *COVID-19 Vaccines/immunology ; Glycosylation ; Antigens, Viral/immunology ; }, abstract = {SARS-CoV-2 variants have demonstrated the ability to evade immune responses, leading to waves of infection throughout the pandemic. In response, bivalent mRNA vaccines, encoding the original Wuhan-Hu-1 and emerging variants, were developed to display both spike antigens. To date, it has not been determined whether co-transfection and co-translation of different SARS-CoV-2 variants results in co-assembly of mosaic heterotrimer antigens and how this may affect trimer stability, dynamics, and antigenicity. Understanding whether such mosaic heterotrimers can form and their implications for antigen structure can provide important information to guide future polyvalent vaccine design where multiple variants of an antigen are co-formulated. To investigate this, we purified mosaic spike assemblies of both genetically close (Omicron BA.2 and XBB) and distant (Omicron BA.2 and Wuhan-Hu-1 G614) strains. We found that the stability and integrity of mosaic spike trimers were maintained without misfolding or aggregation. Glycosylation profiles likewise were preserved relative to the homotrimer counterparts. Hydrogen/deuterium-exchange mass spectrometry and biolayer-interferometry were used to investigate the mosaic spike dynamics and any impact on epitope presentation and receptor binding. The Omicron-XBB heterotrimer, sharing a common fusion subunit sequence, retained protomer-specific dynamics similar to the corresponding homotrimers in antigenically important regions. The Omicron-G614 heterotrimer, co-assembling from protomers of divergent fusion subunit sequences, likewise showed overall similar dynamics and conformations in the receptor-binding subunit compared to the homotrimers. However, the incorporation of the Wuhan-Hu-1 G614 protomer led to a stabilizing effect on the relatively unstable Omicron fusion subunit in the heterotrimer. These findings reveal structural dynamic crosstalk in mosaic trimers, suggesting a potential for enhanced immunogen display and important considerations to be aware of in the use of polyvalent nucleic acid vaccines.}, }
@article {pmid40982684, year = {2025}, author = {Alencar, GF and Mohamed, AO and Burnett, MG and Jean, SS and Nelson, AR and Su, Y and Voillet, V and Bates, BM and Rodgers Suarez, M and Ruskin, SL and Trieu, L and Lam, JL and Bekiranov, S and Gottardo, R and Greenberg, PD and Anderson, KG}, title = {Triple checkpoint blockade of PD-1, Tim-3, and Lag-3 enhances adoptive T cell immunotherapy in a mouse model of ovarian cancer.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {39}, pages = {e2419888122}, pmid = {40982684}, issn = {1091-6490}, support = {K22 CA266737/CA/NCI NIH HHS/United States ; 5T32AI007496-29//HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; no number//Lonza Houston (Lonza Houston, Inc.)/ ; no number//Parker Institute for Cancer Immunotherapy (PICI)/ ; P30 CA044579/CA/NCI NIH HHS/United States ; R01 CA033084/CA/NCI NIH HHS/United States ; T32 CA009657/CA/NCI NIH HHS/United States ; P01 CA018029/CA/NCI NIH HHS/United States ; T32 AI007496/AI/NIAID NIH HHS/United States ; R37 CA033084/CA/NCI NIH HHS/United States ; Ann and Sol Schreiber Mentored Investigator Training Grant//Ovarian Cancer Research Alliance (OCRA)/ ; no number//Celgene Corporation | Juno Therapeutics/ ; CA009657-26A1 CA266737 P30CA044579 CA018029 CA033084//HHS | NIH | National Cancer Institute (NCI)/ ; }, mesh = {Animals ; Female ; *Ovarian Neoplasms/therapy/immunology/pathology/genetics ; Mice ; *Programmed Cell Death 1 Receptor/antagonists &amp; inhibitors/immunology ; *Immunotherapy, Adoptive/methods ; *Hepatitis A Virus Cellular Receptor 2/antagonists &amp; inhibitors/immunology/metabolism ; Mesothelin ; Lymphocyte Activation Gene 3 Protein ; *Immune Checkpoint Inhibitors/pharmacology ; *T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; Disease Models, Animal ; *Antigens, CD/immunology/metabolism/genetics ; Cell Line, Tumor ; Humans ; }, abstract = {The five-year survival rate for ovarian cancer patients remains below 50%, underscoring the need for innovative therapies. One promising approach involves engineering T cells to specifically target proteins uniquely overexpressed in tumors, thereby controlling tumor growth without toxicity to healthy tissues. Mesothelin (MSLN) contributes to the malignant and invasive phenotype in ovarian cancer and has limited expression in healthy cells, making it a candidate immunotherapy target. Our previous results in a mouse model of ovarian cancer demonstrated that T cells engineered to express a T cell receptor (TCR) targeting MSLN (TCRMSLN) mediated therapeutic activity, delaying tumor growth and prolonging mouse survival. However, inhibitory ligands expressed in the tumor microenvironment (TME) interacted with inhibitory receptors on activated T cells, suppressing antitumor function. We hypothesized combining engineered T cells with checkpoint blockade would enhance T cell function and improve therapeutic efficacy, but administration of monospecific antibodies targeting individual inhibitory pathways had no significant impact on T cell efficacy. By contrast, the combination of PD-1, Tim-3, and Lag-3 blockade with engineered T cells significantly improved T cell function and overall animal survival relative to treatment with antibody alone or TCRMSLN with singlet or doublet antibody combinations. Single-cell RNA sequencing revealed TCRMSLN T cells treated with the triplet antibody combination increased expression of genes involved in interferon responses and metabolic function, and reduced expression of genes associated with exhaustion. These results suggest that strategies to disrupt multiple inhibitory pathways simultaneously may be necessary for improved adoptive T cell therapy efficacy in patients.}, }
@article {pmid40983593, year = {2026}, author = {Fitchett, G and Campbell, D and Chang, C and Hester, C and King, S and Peery, B and Saks, NT}, title = {Developing and implementing spiritual screening in healthcare: six successful models.}, journal = {Journal of health care chaplaincy}, volume = {32}, number = {1}, pages = {61-82}, doi = {10.1080/08854726.2025.2563472}, pmid = {40983593}, issn = {1528-6916}, mesh = {Humans ; *Spirituality ; *Mass Screening ; *Pastoral Care ; *Chaplaincy Service, Hospital/organization &amp; administration ; Program Development ; }, abstract = {Healthcare chaplains recognize the importance of informed referrals for spiritual care; they are essential for spiritual care in outpatient settings. Research about the prevalence and harmful effects of religious/spiritual distress underscores the importance of effective methods for identifying patients who would benefit from spiritual care. Spiritual screening is a valuable way to help healthcare colleagues identify patients who would benefit from further assessment and spiritual care. To help spiritual care programs implement spiritual screening, in this article chaplains from six organizations with successful spiritual screening describe the development and implementation of their programs. The settings for these screening programs include hospital inpatients, oncology outpatient centers, palliative care, and population health. The descriptions include the screening questions used, how they are administered, and what it took to get them implemented. Common and unique features of these six approaches to spiritual screening are discussed along with areas for future research.}, }
@article {pmid40985256, year = {2025}, author = {Jeon, JJ and Kim, YH and Son, H and Lee, JY and Ha, MC and Jung, SW and Lee, S}, title = {Incidence of cutaneous malignancy following the concomitant use of ciclosporin and narrowband ultraviolet B phototherapy in patients with vitiligo.}, journal = {Clinical and experimental dermatology}, volume = {51}, number = {1}, pages = {103-106}, doi = {10.1093/ced/llaf428}, pmid = {40985256}, issn = {1365-2230}, support = {//Korea Health Technology Research/ ; //Korea Health Industry Development Institute/ ; HI23C1506//Ministry of Health and Welfare/ ; }, mesh = {Humans ; *Vitiligo/therapy/drug therapy ; *Ultraviolet Therapy/adverse effects/methods ; Male ; Female ; *Cyclosporine/adverse effects/therapeutic use ; Adult ; *Skin Neoplasms/epidemiology/etiology ; Incidence ; Middle Aged ; Republic of Korea/epidemiology ; Young Adult ; Adolescent ; Aged ; *Dermatologic Agents/adverse effects ; Child ; Combined Modality Therapy ; *Immunosuppressive Agents/adverse effects ; Cohort Studies ; }, abstract = {This nationwide population-based cohort study investigates the incidence of cutaneous malignancies associated with the concomitant treatment of ciclosporin and narrowband ultraviolet B (NBUVB) phototherapy in patients with vitiligo, using the Korean National Health Insurance Service database. Concomitant ciclosporin and NBUVB phototherapy may not significantly increase the incidence of cutaneous malignancies. Given the chronic autoimmune nature of vitiligo and its economic impact, these findings provide novel insights into the potential safety of these combination regimens.}, }
@article {pmid40985344, year = {2025}, author = {Hausmann, O and Schobert, PP and Ose, J and Himbert, C and Pletneva, M and Jedrzkiewicz, J and Nguyen, A and Lin, T and Warby, CA and Hardikar, S and Peoples, AR and Strehli, I and Huang, LC and Cohan, JN and Pickron, B and Scaife, C and Li, CI and Grady, WM and Shibata, D and Toriola, AT and Schneider, M and Figueiredo, JC and Siegel, EM and Gigic, B and Herzig, S and Ilozumba, MN and Ulrich, CM}, title = {Associations of Biomarkers of Systemic Inflammation, Angiogenesis, and Cell-to-Cell Adhesion With Tumor Budding Among Early-Onset and Later-Onset Colorectal Cancer Patients.}, journal = {Cancer medicine}, volume = {14}, number = {18}, pages = {e71267}, pmid = {40985344}, issn = {2045-7634}, support = {R01CA254108/NH/NIH HHS/United States ; R01 AG083580/AG/NIA NIH HHS/United States ; R01CA189184/NH/NIH HHS/United States ; //Stiftung LebensBlicke/ ; U01CA206110/NH/NIH HHS/United States ; R03CA270473/NH/NIH HHS/United States ; P30CA042014/CA/NCI NIH HHS/United States ; K07222060/NH/NIH HHS/United States ; R01CA207371/NH/NIH HHS/United States ; }, mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; Age of Onset ; Angiogenesis ; *Biomarkers, Tumor/blood ; Cell Adhesion ; *Colorectal Neoplasms/pathology/blood ; *Inflammation/blood ; Intercellular Adhesion Molecule-1/blood ; Neoplasm Staging ; *Neovascularization, Pathologic/blood/pathology ; Prognosis ; }, abstract = {BACKGROUND: High tumor budding and elevated systemic inflammation are adverse prognostic indicators in colorectal cancer. Its underlying mechanisms remain poorly understood. It is unclear whether systemic inflammation, angiogenesis, and cell-to-cell adhesion influence tumor budding.<br><br>METHODS: We investigated n&#x2009;=&#x2009;132 stage I-III colorectal cancer patients recruited at Huntsman Cancer Institute enrolled in the ColoCare Study. Tumor budding was evaluated using an evidence-based scoring system, and patient sera were analyzed for nine circulating biomarkers using the Meso Scale Discovery platform. We examined associations between biomarkers and tumor budding using multivariable linear regression models adjusted for age, sex, neoadjuvant treatment, stage, and non-steroidal anti-inflammatory drug use.<br><br>RESULTS: The study population was predominantly non-Hispanic White (95%), with a mean age of 61&#x2009;years; 56% were male. Most tumors were stage III (47%), located in the colon (64%), and exhibited low-grade tumor budding (58%). Soluble intercellular adhesion molecule 1 was inversely associated with tumor budding overall (M1: &#x3b2;&#x2009;=&#x2009;-0.57, p&#x2009;=&#x2009;0.03), among females (M1: &#x3b2;&#x2009;=&#x2009;-0.81, p-value&#x2009;=&#x2009;0.03) and later-onset (&#x2265;&#x2009;50&#x2009;years) colorectal cancer (M1: &#x3b2;&#x2009;=&#x2009;-0.71, p-value&#x2009;=&#x2009;0.008). C-reactive protein was positively associated with tumor budding in males (M1: &#x3b2;&#x2009;=&#x2009;0.23, p&#x2009;=&#x2009;0.001), while interleukin-8 (M1: &#x3b2;&#x2009;=&#x2009;0.96, p-value&#x2009;=&#x2009;0.01) and soluble vascular adhesion molecule 1 (M2: &#x3b2;&#x2009;=&#x2009;1.48, p-value&#x2009;=&#x2009;0.04) were positively associated with tumor budding in early-onset patients. However, these associations did not remain statistically significant after correction for multiple testing.<br><br>CONCLUSION: Overall, our findings do not provide evidence of a significant association between biomarkers of systemic inflammation, angiogenesis, and cell-to-cell adhesion with tumor budding count. We observed patterns for some biomarkers, yet none remained statistically significant after correction for multiple testing. These findings provide preliminary insights for future studies.<br><br>TRIAL REGISTRATION: ClinicalTrials.gov: NCT02328677.}, }
@article {pmid40986340, year = {2025}, author = {Su, Y and Thelen, A and Wirth, LV and Jenkins, CM and Mak, SR and Chen, DG and Gottardo, R and Greenberg, PD}, title = {A TGF-βR/IL-2R immunomodulatory fusion protein transforms immunosuppression into T cell activation to enhance adoptive T cell therapy.}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, volume = {122}, number = {39}, pages = {e2516951122}, pmid = {40986340}, issn = {1091-6490}, support = {CA18029/GF/NIH HHS/United States ; CA225517/GF/NIH HHS/United States ; DRQ-13-22//Damon Runyon Cancer Research Foundation (DRCRF)/ ; Hartwell Innovation Award//Hartwell Foundation (HARTWELL)/ ; CA015704/GF/NIH HHS/United States ; }, mesh = {Humans ; *Immunotherapy, Adoptive/methods ; *Lymphocyte Activation/immunology ; *Receptors, Transforming Growth Factor beta/genetics/immunology/metabolism ; *Recombinant Fusion Proteins/genetics/immunology ; Interleukin-2/metabolism ; Signal Transduction ; STAT5 Transcription Factor/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Tumor Microenvironment/immunology ; *Receptors, Interleukin-2/genetics/immunology/metabolism ; Phosphorylation ; Transforming Growth Factor beta ; Immunosuppression Therapy ; T-Lymphocytes/immunology ; }, abstract = {Adoptive T cell therapies have shown limited efficacy against solid tumors due in part to immunosuppressive cues such as from TGF-β and insufficient survival/proliferative signals within the tumor microenvironment (TME). We engineered chimeric immunomodulatory fusion proteins (IFPs) that convert immunosuppressive TGF-β signals into proliferative/survival Interleukin 2 (IL-2) signals in T cells. Chimeric TGF-βR/IL-2R IFPs were constructed by fusing extracellular domains of the TGF-β receptor chains with intracellular domains of IL-2Rβ and IL-2Rγ to enable TGF-β binding to trigger STAT5 phosphorylation and activate the downstream IL-2 pathway. In human primary CD8[+] T cells, select IFP designs robustly induced p-STAT5 upon exposure to TGF-β1, and simultaneously reduced canonical SMAD2/3 signaling. IFP-expressing T cells proliferated and displayed enhanced viability in response to TGF-β1, effectively leveraging TGF-β-rich conditions to outcompete nontransduced cells. Transcriptomic analyses revealed that IFP signaling promoted T cell activation and allowed maintenance of stemness during culture with TGF-β. Functionally, coexpressing IFPs with a mesothelin-specific T cell receptor improved tumor killing and promoted T cell expansion in the presence of TGF-β1, highlighting both neutralization of TGF-β-mediated suppression and enhanced proliferation. TGF-βR/IL-2R IFPs appear promising for reprogramming the signals T cells receive in the TME and improving efficacy of adoptive T cell therapy in solid tumors.}, }
@article {pmid40986647, year = {2025}, author = {Ribi, K and Cole, BF and Fleming, GF and Walley, BA and Francis, PA and Abdi, E and Burstein, HJ and Cheng, KL and Chia, SKL and Dakhil, SR and Davidson, NE and Della-Fiorentina, SA and Frith, AE and Levine, E and Lupichuk, S and Pritchard, K and Salim, M and Stearns, V and Stewart, J and Valero, V and van der Westhuizen, A and Pagani, O and Loi, S and Colleoni, M and Gelber, RD and Goldhirsch, A and Coates, AS and Regan, MM and Bernhard, J}, title = {Prognostic value of patient-reported depression in women with hormone-responsive early breast cancer in TEXT and SOFT.}, journal = {Cancer}, volume = {131}, number = {19}, pages = {e70094}, doi = {10.1002/cncr.70094}, pmid = {40986647}, issn = {1097-0142}, support = {//Pfizer/ ; /CA/NCI NIH HHS/United States ; //European Thoracic Oncology Program and International Breast Cancer Study Group Partners Foundation/ ; }, mesh = {Adult ; Female ; Humans ; Middle Aged ; Androstadienes/administration &amp; dosage/therapeutic use ; Antidepressive Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; *Breast Neoplasms/drug therapy/psychology/mortality/complications ; *Depression/drug therapy ; Disease-Free Survival ; Premenopause ; Prognosis ; Tamoxifen/therapeutic use/administration &amp; dosage ; }, abstract = {BACKGROUND: Depression has been identified as an adverse mental health outcome in women with breast cancer (BC). Depression was investigated as a risk factor for poor survival in premenopausal women with hormone-responsive early BC treated in the TEXT (Tamoxifen and Exemestane Trial) and SOFT (Suppression of Ovarian Function Trial) trials.<br><br>METHODS: The data used were from a subset of patients who participated in TEXT or SOFT and completed the Center of Epidemiologic Studies-Depression scale. Associations between baseline depression-score categories and baseline characteristics were assessed using the Cochran-Mantel-Haenszel test controlling for antidepressant use. Multivariable proportional hazards regression models were used to test the association between baseline depression and disease-free survival (DFS) and overall survival (OS). Regression models were adjusted for factors known to be associated with outcomes, baseline antidepressant use, and early treatment cessation.<br><br>RESULTS: Forty percent (2287 of 5738) of the women enrolled in the SOFT and TEXT trials were included in this analysis (SOFT, n&#xa0;=&#xa0;1259; TEXT, n&#xa0;=&#xa0;1028). Twenty-seven percent of women reported mild-to-moderate or severe depression at baseline. Race (p&#xa0;=&#xa0;.001), body mass index (p&#xa0;=&#xa0;.02), family history (p&#xa0;=&#xa0;.02), and performance status (p&#xa0;=.007) were significantly associated with the severity of depression. Relative to the no-symptomatology group, the hazard ratios (overall p&#xa0;=&#xa0;.04) for DFS were 1.34 (95% confidence interval [CI], 1.03-1.76) for women with mild-to-moderate depression and 1.34 (95% CI, 0.96-1.87) for those with severe depression. Relative to the no-symptomatology group, the hazard ratios (overall p&#xa0;=&#xa0;.008) for OS were 1.68 for mild-to-moderate depression (95% CI, 1.15-2.44) and 1.67 for those with severe depression (95% CI, 1.05-2.66).<br><br>CONCLUSIONS: In premenopausal women with hormone-responsive early BC, depression at baseline is a risk factor for poorer DFS and OFS. Further investigation of the underlying interactive processes is needed.<br><br>TRIAL REGISTRATION: Clinicaltrials.gov NCT00066703 (SOFT) and NCT00066690 (TEXT).}, }
@article {pmid40987290, year = {2025}, author = {Reeves, DB and Rigau, DN and Romero, A and Zhang, H and Simonetti, FR and Varriale, J and Hoh, R and Zhang, L and Smith, KN and Montaner, LJ and Rubin, LH and Gange, SJ and Roan, NR and Tien, PC and Margolick, JB and Peluso, MJ and Deeks, SG and Schiffer, JT and Siliciano, JD and Siliciano, RF and Antar, AAR}, title = {Mild HIV-specific selective forces overlaying natural CD4+ T cell dynamics explain the clonality and decay dynamics of HIV reservoir cells.}, journal = {Cell systems}, volume = {16}, number = {10}, pages = {101402}, pmid = {40987290}, issn = {2405-4720}, support = {UM1 AI126620/AI/NIAID NIH HHS/United States ; K25 AI155224/AI/NIAID NIH HHS/United States ; R01 AI150500/AI/NIAID NIH HHS/United States ; L30 AI126550/AI/NIAID NIH HHS/United States ; U01 HL146242/HL/NHLBI NIH HHS/United States ; R01 AI186721/AI/NIAID NIH HHS/United States ; U01 HL146193/HL/NHLBI NIH HHS/United States ; DP5 OD031834/OD/NIH HHS/United States ; P30 AI027757/AI/NIAID NIH HHS/United States ; R21 AI186783/AI/NIAID NIH HHS/United States ; UL1 TR003098/TR/NCATS NIH HHS/United States ; U01 AI177211/AI/NIAID NIH HHS/United States ; K23 AI157875/AI/NIAID NIH HHS/United States ; P30 AI094189/AI/NIAID NIH HHS/United States ; K08 AI143391/AI/NIAID NIH HHS/United States ; U01 HL146201/HL/NHLBI NIH HHS/United States ; UM1 AI164566/AI/NIAID NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; }, mesh = {Humans ; *CD4-Positive T-Lymphocytes/virology/immunology ; *HIV Infections/immunology/virology/drug therapy ; *HIV-1/immunology ; Proviruses/immunology ; Female ; Viral Load ; Male ; }, abstract = {To determine whether HIV persistence arises from the natural dynamics of memory (m)CD4+ T cells, we compare clonal dynamics of HIV proviruses and mCD4+ T cells from the same people living with HIV (PWH) on antiretroviral therapy and from matched HIV-seronegative people (N = 51). HIV proviruses are more clonal than mCD4+ T cells but similarly clonal to antigen-specific cells. Increasing reservoir clonality over time and differential decay of intact and defective proviruses are not explained by mCD4+ T cell kinetics alone. We develop and validate a stochastic model trained on 10 quantitative data metrics, which shows that negative selection against HIV-infected cells is necessary to explain all metrics. We estimate the strength of negative selection, finding that death of cells harboring intact and defective proviruses is infrequently (∼6% and ∼2% on average) due to HIV-specific factors. Thus, our data indicate that HIV persistence is mostly, but not entirely, driven by natural mCD4+ kinetics.}, }
@article {pmid40991382, year = {2026}, author = {Faulk, KE and Kairalla, JA and Hibbitts, E and Long-Boyle, J and Devidas, M and August, A and Gore, L and Raetz, E and Hunger, SP and Loh, ML and Teachey, DT and Brown, P and Breese, EH and Kotecha, RS and Guest, E}, title = {Age-based pegaspargase dosing is safe and achieves therapeutic levels in infants with ALL: report from COG AALL15P1.}, journal = {Blood advances}, volume = {10}, number = {1}, pages = {70-74}, pmid = {40991382}, issn = {2473-9537}, support = {U10 CA180886/CA/NCI NIH HHS/United States ; U10 CA180899/CA/NCI NIH HHS/United States ; }, }
@article {pmid40991418, year = {2025}, author = {Matsuk, VY and Khatib, TO and Marcus, LJ and Robinson, IE and Liu, Y and Pasupathy, JK and Shanmugam, M and Mouw, JK and Marcus, AI}, title = {Metabolic programming defines oxygen-sensitive subpopulation hierarchies and patterning in collective invasion.}, journal = {Molecular biology of the cell}, volume = {36}, number = {11}, pages = {ar137}, pmid = {40991418}, issn = {1939-4586}, support = {R50 CA265345/CA/NCI NIH HHS/United States ; }, mesh = {*Metabolic Reprogramming/genetics ; *Oxygen/metabolism ; Neoplasm Invasiveness/diagnosis/genetics/pathology ; *Carcinoma, Non-Small-Cell Lung/diagnosis/genetics/pathology ; *Lung Neoplasms/diagnosis/genetics/pathology ; Cell Line, Tumor ; Membrane Potential, Mitochondrial ; *Mitochondria/metabolism/pathology ; Interleukin-13 Receptor alpha2 Subunit/analysis/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Cell Movement/genetics ; Flow Cytometry ; Biomarkers, Tumor/analysis/metabolism ; }, abstract = {Phenotypic heterogeneity-distinct molecular and behavioral variations within a population-significantly influences collective invasion and tumor progression. Here, we use a molecular approach to explore how the underlying metabolic heterogeneity in non-small cell lung cancer (NSCLC) influences invasion and pack patterning. Assessment of three-dimensional (3D) pack patterning revealed invasive heterogeneity across NSCLC cell lines and patient-derived samples. Flow cytometry identified IL13RA2 as a biomarker for invasive potential, enabling isolation of subpopulations with distinct invasive characteristics. By integrating a cell surface biomarker (IL13RA2±) with mitochondrial membrane potential (TMRM), we identified and isolated three distinct subpopulations. Two-dimensional (2D) analyses revealed differences in mitochondrial polarity and transcriptional programs associated with migration and oxygensensitivity. In 3D, these subpopulations invaded with distinct patterns, from contiguous circular packs to structured chains. Assessments under varied oxygen tension demonstrated that oxygen availability and subpopulation metabolism together influence collective invasion patterning. When recombined at ratios recapitulating the original population, both stochastic and opportunistic cooperative dynamics emerged, dependent on subpopulation composition and oxygen levels. Our molecular approach, integrating cell surface and metabolic characteristics, enables the isolation of unique subpopulations and demonstrates that phenotypic and metabolic heterogeneity, population composition, and oxygen availability collectively pattern invasion packs and drive collective invasion.}, }
@article {pmid40991892, year = {2025}, author = {Dorovini-Zis, K and Li, H and Zhe, C and Zhang, B and Small, D and Taylor, TE}, title = {Mapping the expression of endothelial adhesion receptors for Plasmodium falciparum-infected erythrocytes in fatal cerebral malaria in Malawian children.}, journal = {Journal of neuropathology and experimental neurology}, volume = {84}, number = {12}, pages = {1113-1134}, pmid = {40991892}, issn = {1554-6578}, support = {R01 AI034969/AI/NIAID NIH HHS/United States ; 5R01AI34969/NH/NIH HHS/United States ; 5R01AI34969//US National Institutes of Health/ ; }, mesh = {Humans ; *Malaria, Cerebral/pathology/metabolism ; Male ; Malawi/epidemiology ; Female ; *Erythrocytes/parasitology/metabolism ; Child, Preschool ; *Plasmodium falciparum ; Child ; Infant ; Brain/pathology/metabolism ; Intercellular Adhesion Molecule-1/metabolism ; *Endothelial Cells/metabolism ; CD36 Antigens/metabolism ; *Malaria, Falciparum/pathology ; }, abstract = {We investigated the expression and distribution of 5 cytoadhesion receptors for the Plasmodium falciparum erythrocyte membrane protein 1 in 12 regions of post-mortem brains of 50 Malawian children, that is, 27 with the clinical and pathological diagnosis of cerebral malaria (CM) and 23 with a non-malarial cause of death. We quantified the expression of each receptor by microvascular endothelium and the colocalization of receptor-expressing microvessels with sequestered infected red blood cells (iRBC) and calculated a receptor-independent sequestration ratio. There were differences in the level of expression and regional distribution of the five receptors: ICAM-1 was the most widely expressed receptor, followed by CD36, VCAM-1, E-selectin, and thrombospondin. Receptor-expressing microvessels were most numerous in the frontal lobe and least numerous in the brainstem and cerebellum. Colocalization of receptor-expressing endothelial cells with iRBC was present in all brain regions; it was highest for ICAM-1 and CD36 and greatest in the frontal lobe. The sequestration ratios were close to 100% for all receptors across all brain regions and were similar in cerebral and extracerebral microvessels. Receptor expression and colocalization ratios were greater in the brain than in the lung, heart, liver, spleen, and subcutaneous tissue. These differences in cerebral endothelial expression of cytoadhesion receptors and their preferential regional distribution may underpin differences in iRBC sequestration and lesion development in CM. Moreover, greater expression of these receptors in the brain vs peripheral organs may explain a comparatively greater degree of iRBC sequestration in the brain.}, }
@article {pmid40993182, year = {2025}, author = {Sarnowski, C and Zhang, Y and Ammous, F and Shade, LMP and DiCorpo, D and Jian, X and Arnett, DK and Austin, TR and Beiser, A and Bis, JC and Blangero, J and Boerwinkle, E and Bressler, J and Curran, JE and DeCarli, CS and Doddapaneni, H and Dupuis, J and Fardo, DW and Florez, JC and Gabriel, S and Gibbs, RA and Glahn, DC and Gupta, N and González, HM and González, KA and Hatzikotoulas, K and Hayden, KM and Heckbert, SR and Hidalgo, B and Huerta-Chagoya, A and Hughes, TM and Kardia, SLR and Kooperberg, CL and Launer, LJ and Longstreth, WT and ,  and ,  and Mandla, R and Mathias, RA and Morris, AP and Mosley, TH and Nasrallah, IM and Nyquist, P and Psaty, BM and Qi, Q and Raffield, LM and Rayner, NW and Reiner, AP and Satizabal, CL and Selvin, E and Sevilla-Gonzalez, MDR and Smith, AV and Smith, JA and Smith, K and Snively, BM and Southam, L and Sofer, T and Suzuki, K and Taylor, HJ and Udler, MS and Viaud-Martinez, KA and Wassertheil-Smoller, S and Wood, AC and Yanek, LR and Yin, X and Manning, AK and Rotter, JI and Rich, SS and Meigs, JB and Fornage, M and Seshadri, S and Morrison, AC and ,  and , }, title = {Association of genetic scores related to insulin resistance with neurological outcomes in ancestrally diverse cohorts from the Trans-Omics for Precision Medicine (TOPMed) program.}, journal = {Communications biology}, volume = {8}, number = {1}, pages = {1352}, pmid = {40993182}, issn = {2399-3642}, support = {KL2 TR002646/TR/NCATS NIH HHS/Un