@article {pmid38689544,
year = {2024},
author = {Yun, J and Baek, G and Indorf, A and Duong, A},
title = {Incidence of port site complications in relation to timing of bevacizumab infusion.},
journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners},
volume = {},
number = {},
pages = {10781552241245037},
doi = {10.1177/10781552241245037},
pmid = {38689544},
issn = {1477-092X},
abstract = {INTRODUCTION: Bevacizumab is a monoclonal antibody that targets vascular endothelial growth factor, with a serious complication of wound healing complications. The package insert currently does not have recommendations on the management of bevacizumab administration around minor procedures, including port placements. Currently, there are only two trials that have examined the optimal timing of bevacizumab after port placement.

METHODS: This is a single-center retrospective trial aiming to evaluate the rate of wound dehiscence and other port site complications depending on the time between port placement and bevacizumab infusion. Eligible patients who have had at least one port place and have received bevacizumab for an oncologic indication were identified in a study period of 1/1/2016-3/31/2021. The primary outcome of this study was the incidence of wound dehiscence in relation to the timing of bevacizumab infusion.

RESULTS: A total of 243 patients met the inclusion criteria, and 116 port placements had a port site complication. For wound dehiscence, 6% was observed 0 days from port placement, 10% was observed 1 day from port placement, 0% was observed 2 days from port placement, 0% was observed 3-7 days from port placement, 3% was observed 8-14 days from port placement, and 3% was observed 15-30 days from port placement.

CONCLUSIONS: The results of this study show an inverse relationship between the risk of wound dehiscence and port site complication and the timing of bevacizumab infusion to port placement, with an increase in absolute risk of wound dehiscence when bevacizumab is given within 2 days of port placement.},
}

@article {pmid38689480,
year = {2024},
author = {Chambers, M and Andre, AT and Wright, JL and Vakar-Lopez, F and Tretiakova, M and Reder, NP and Haffner, MC and True, LD},
title = {Outcome Analysis of a Series of Mixed-Grade, Non-muscle Invasive, Papillary Carcinomas of the Bladder.},
journal = {International journal of surgical pathology},
volume = {},
number = {},
pages = {10668969241246492},
doi = {10.1177/10668969241246492},
pmid = {38689480},
issn = {1940-2465},
abstract = {Introduction. Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited. Methods. The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers. Results. Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >pT2. Conclusions. The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors.},
}

@article {pmid38688309,
year = {2024},
author = {Cloyd, JM and Colby, S and Guthrie, KA and Lowy, AM and Chiorean, EG and Philip, P and Sohal, D and Ahmad, S},
title = {Failure to Undergo Resection Following Neoadjuvant Therapy for Resectable Pancreatic Cancer: A Secondary Analysis of SWOG S1505.},
journal = {Journal of the National Comprehensive Cancer Network : JNCCN},
volume = {},
number = {},
pages = {1-6},
doi = {10.6004/jnccn.2023.7099},
pmid = {38688309},
issn = {1540-1413},
abstract = {BACKGROUND: Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC), and yet reasons for not undergoing subsequent pancreatectomy are poorly understood. Given the importance of completing multimodality therapy, we investigated factors associated with failure to undergo surgical resection following NT for PDAC.

METHODS: SWOG S1505 was a multicenter phase II randomized trial of preoperative mFOLFIRINOX or gemcitabine/nab-paclitaxel prior to planned pancreatectomy for patients with potentially resectable PDAC. Associations between clinical, demographic, and hospital-level characteristics and receipt of surgical resection were estimated via multiple logistic regression. Differences in overall survival from 18 weeks postrandomization (scheduled time of surgery) according to resection status were assessed via Cox regression models.

RESULTS: Among 102 eligible patients, 73 (71.6%) underwent successful pancreatectomy, whereas 29 (28.4%) did not, primarily because of progression (n=11; 10.8%) or toxicity during NT (n=9; 8.8%). Weight loss during NT (odds ratio [OR], 0.34; 95% CI, 0.11-0.93) and the hospital's city size (small: OR, 0.24 [95% CI, 0.07-0.80] and large: OR, 0.28 [95% CI, 0.10-0.79] compared with midsize) were significantly associated with a lower probability of surgical resection in adjusted models, whereas age, sex, race, body mass index, performance status, insurance type, geographic region, treatment arm, tumor location, chemotherapy delays/modifications, and hospital characteristics were not. Surgical resection following NT was associated with improved overall survival (median, 23.8 vs 10.8 months; P<.01) even after adjusting for grade 3-5 adverse events during NT, performance status, and body mass index (hazard ratio, 0.55; 95% CI, 0.32-0.95).

CONCLUSIONS: Failure to undergo resection following NT was relatively common among patients with potentially resectable PDAC and associated with worse survival. Although few predictive factors were identified in this secondary analysis of the SWOG S1505 randomized trial, further research must focus on risk factors for severe toxicities during NT that preclude surgical resection so that patient-centered interventions can be delivered or alternate treatment sequencing can be recommended.},
}

@article {pmid38688280,
year = {2024},
author = {Benbarche, S and Pineda, JMB and Galvis, LB and Biswas, J and Liu, B and Wang, E and Zhang, Q and Hogg, SJ and Lyttle, K and Dahi, A and Lewis, AM and Sarchi, M and Rahman, J and Fox, N and Ai, Y and Mehta, S and Garippa, R and Ortiz-Pacheco, J and Li, Z and Monetti, M and Stanley, RF and Doulatov, S and Bradley, RK and Abdel-Wahab, O},
title = {GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2024.04.006},
pmid = {38688280},
issn = {1097-4164},
abstract = {Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, yet there is currently no therapeutic means to correct this mis-splicing. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SURP and G-patch domain containing 1 (SUGP1), a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.},
}

@article {pmid38687617,
year = {2024},
author = {Han, D and Labaf, M and Zhao, Y and Owiredu, J and Zhang, S and Patel, K and Venkataramani, K and Steinfeld, JS and Han, W and Li, M and Liu, M and Wang, Z and Besschetnova, A and Patalano, S and Mulhearn, MJ and Macoska, JA and Yuan, X and Balk, SP and Nelson, PS and Plymate, SR and Gao, S and Siegfried, KR and Liu, R and Stangis, MM and Foxa, G and Czernik, PJ and Williams, BO and Zarringhalam, K and Li, X and Cai, C},
title = {Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI168649},
pmid = {38687617},
issn = {1558-8238},
abstract = {One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared to the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remains unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.},
}

@article {pmid38687474,
year = {2024},
author = {Elmore, JG and Lee, CI},
title = {Toward More Equitable Breast Cancer Outcomes.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2024.6052},
pmid = {38687474},
issn = {1538-3598},
}

@article {pmid38687020,
year = {2024},
author = {Crawford, KHD and Selke, S and Pepper, G and Goecker, E and Sobel, A and Wald, A and Johnston, C and Greninger, AL},
title = {Performance characteristics of highly automated HSV-1 and HSV-2 IgG testing.},
journal = {Journal of clinical microbiology},
volume = {},
number = {},
pages = {e0026324},
doi = {10.1128/jcm.00263-24},
pmid = {38687020},
issn = {1098-660X},
abstract = {Herpes simplex virus (HSV) infections are one of the most common and stigmatized infections of humankind, affecting more than 4 billion people around the world and more than 100 million Americans. Yet, most people do not know their infection status, and antibody testing is not recommended, partly due to poor test performance. Here, we compared the test performance of the Roche Elecsys HSV-1 IgG and HSV-2 IgG, DiaSorin LIAISON HSV-1/2 IgG, and Bio-Rad BioPlex 2200 HSV-1 and HSV-2 IgG assays with the gold-standard HSV western blot in 1,994 persons, including 1,017 persons with PCR or culture-confirmed HSV-1 and/or HSV-2 infection. Across all samples, the Bio-Rad and Roche assays had similar performance metrics with low sensitivity (<85%) but high specificity (>97%) for detecting HSV-1 IgG and both high sensitivity (>97%) and high specificity (>98%) for detecting HSV-2 IgG. The DiaSorin assay had a higher sensitivity (92.1%) but much lower specificity (88.7%) for detecting HSV-1 IgG and comparatively poor sensitivity (94.5%) and specificity (94.2%) for detecting HSV-2 IgG. The DiaSorin assay performed poorly at low-positive index values with 60.9% of DiaSorin HSV-1 results and 20.8% of DiaSorin HSV-2 results with positive index values <3.0 yielding false positive results. Based on an estimated HSV-2 seroprevalence of 12% in the United States, positive predictive values for HSV-2 IgG were 96.1% for Roche, 87.4% for Bio-Rad, and 69.0% for DiaSorin, meaning nearly one of every three positive DiaSorin HSV-2 IgG results would be falsely positive. Further development in HSV antibody diagnostics is needed to provide appropriate patient care.IMPORTANCESerological screening for HSV infections is currently not recommended in part due to the poor performance metrics of widely used commercial HSV-1 and HSV-2 IgG assays. Here, we compare three Food and Drug Administration (FDA)-cleared automated HSV-1 and HSV-2 IgG assays to the gold-standard western blot across nearly 2,000 samples. We find that not all commercially available HSV assays are created equal, with comparably low sensitivities for HSV-1 IgG across platforms and high false positivity rates for DiaSorin on HSV-2 IgG. This study is the first large-scale comparison of performance metrics for the Bio-Rad and Roche assays in over 10 years. Our study confirms that there remains room for improvement in HSV serological diagnostic testing-especially in regard to low sensitivities for HSV-1 IgG detection-and highlights that some previously less-studied assays may have better performance metrics than previously considered typical of commercially available HSV-2 IgG assays.},
}

@article {pmid38684898,
year = {2024},
author = {Madden, EB and Hindorff, LA and Bonham, VL and Akintobi, TH and Burchard, EG and Baker, KE and Begay, RL and Carpten, JD and Cox, NJ and Di Francesco, V and Dillard, DA and Fletcher, FE and Fullerton, SM and Garrison, NA and Hammack-Aviran, CM and Hiratsuka, VY and Hildreth, JEK and Horowitz, CR and Hughes Halbert, CA and Inouye, M and Jackson, A and Landry, LG and Kittles, RA and Leek, JT and Limdi, NA and Lockhart, NC and Ofili, EO and Pérez-Stable, EJ and Sabatello, M and Saulsberry, L and Schools, LE and Troyer, JL and Wilfond, BS and Wojcik, GL and Cho, JH and Lee, SS and Green, ED},
title = {Advancing genomics to improve health equity.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38684898},
issn = {1546-1718},
abstract = {Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.},
}

@article {pmid38659968,
year = {2024},
author = {Valint, DJ and Fiedler, TL and Liu, C and Srinivasan, S and Fredricks, DN},
title = {Effect of Metronidazole on Concentrations of Vaginal Bacteria Associated with Risk of HIV Acquisition.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38659968},
support = {R01 AI061628/AI/NIAID NIH HHS/United States ; },
abstract = {Several bacterial vaginosis (BV)-associated bacteria have been associated with elevated risk of HIV acquisition, however susceptibility of these bacteria to antibiotics is poorly understood. Vaginal samples were collected from 22 persons daily for two weeks following BV diagnosis. Metronidazole treatment was prescribed for 5-7 days. Changes in bacterial concentrations were measured with taxon-specific 16S rRNA gene quantitative PCR (qPCR) assays. A culture-based antimicrobial assay confirmed presence of antibiotics in vaginal swab samples. Bacterial DNA concentrations decreased during antibiotic administration for all thirteen bacterial taxa tested. Comparison of bacterial DNA concentrations in samples before administration of antibiotics to samples taken on the last day of antimicrobial assay-confirmed antibiotic presence showed a 2.3-4.5 log10-fold decrease across all taxa. Concentrations were frequently reduced to the qPCR assay's limit of detection, suggesting eradication of bacteria. Mean clearance time varied across taxa (1.2-8.6 days), with several bacteria (e.g., Gemella asaccharolytica, Sneathia spp., Eggerthella-like sp.) taking >7 days to suppress. Metronidazole reduces quantities of bacterial taxa associated with increased HIV acquisition risk. Eradication of high-risk vaginal bacteria using metronidazole is one promising avenue for reducing HIV acquisition risk. A 5-7-day treatment course may not be sufficient to suppress all bacteria.},
}

@article {pmid38684813,
year = {2024},
author = {Radko-Juettner, S and Yue, H and Myers, JA and Carter, RD and Robertson, AN and Mittal, P and Zhu, Z and Hansen, BS and Donovan, KA and Hunkeler, M and Rosikiewicz, W and Wu, Z and McReynolds, MG and Roy Burman, SS and Schmoker, AM and Mageed, N and Brown, SA and Mobley, RJ and Partridge, JF and Stewart, EA and Pruett-Miller, SM and Nabet, B and Peng, J and Gray, NS and Fischer, ES and Roberts, CWM},
title = {Author Correction: Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF.},
journal = {Nature},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41586-024-07402-3},
pmid = {38684813},
issn = {1476-4687},
}

@article {pmid38684704,
year = {2024},
author = {King, DF and Groves, H and Weller, C and Jones, I and Cramer, JP and Gilbert, PB and Goldblatt, D and Gruber, MF and Kampmann, B and Maïga, D and Pasetti, MF and Plotkin, SA and Precioso, A and Wassie, L and Wittke, F and Kaslow, DC},
title = {Realising the potential of correlates of protection for vaccine development, licensure and use: short summary.},
journal = {NPJ vaccines},
volume = {9},
number = {1},
pages = {82},
pmid = {38684704},
issn = {2059-0105},
abstract = {On 27–29[th] of September 2022, Wellcome convened an international multi-stakeholder workshop to discuss the use of Correlates of Protection (CoP) to accelerate vaccine development, the hybrid format meeting was attended by 80 delegates including developers, manufacturers, regulators, public health officials and policy-makers from 17 countries, including 7 LMIC’s.},
}

@article {pmid38684633,
year = {2024},
author = {Greywoode, R and Larson, J and Peraza, J and Clark, R and Allison, MA and Chaudhry, NA and Schnatz, PF and Shadyab, AH and Wallace, RB and Wassertheil-Smoller, S},
title = {Risk of Adverse Cardiovascular Outcomes in Postmenopausal Women with Inflammatory Bowel Disease.},
journal = {Digestive diseases and sciences},
volume = {},
number = {},
pages = {},
pmid = {38684633},
issn = {1573-2568},
support = {UL1TR001073/TR/NCATS NIH HHS/United States ; },
abstract = {BACKGROUND: Individuals with inflammatory bowel disease (IBD) who lack traditional cardiovascular disease (CVD) risk factors, such as young females, are observed to experience adverse CVD outcomes. Whether women with IBD have increased CVD risk after the menopause transition is unclear.

METHODS: We conducted a survival analysis of Women's Health Initiative (WHI) participants and excluded those with missing IBD diagnosis, model covariate data, follow-up data, or a baseline history of the following CVD outcomes: coronary heart disease (CHD), ischemic stroke, venous thromboembolism (VTE), peripheral arterial disease (PAD). Risk of outcomes between IBD and non-IBD women was performed using Cox proportional hazard models, stratified by WHI trial and follow-up. Models were adjusted for age, socio-demographics, comorbidities (e.g., hypertension, diabetes, hypercholesterolemia, etc.), family history, and lifestyle factors (e.g., smoking, alcohol, physical activity, body mass index, etc.).

RESULTS: Of 134,022 WHI participants meeting inclusion criteria, 1367 (1.0%) reported IBD at baseline. Mean baseline age was 63.4 years. After adjusting for age and other confounders, no significant difference was observed between IBD and non-IBD women for the risk of CHD (HR 0.96, 95% CI 0.73-1.24), VTE (HR 1.11, 95% CI 0.81-1.52) or PAD (HR 0.64, 95% CI 0.28-1.42). After adjusting for age, risk of ischemic stroke was significantly higher (HR 1.41, 95% CI 1.06-1.88) in IBD than non-IBD women. With further adjustment, the excess risk of ischemic stroke among IBD women was attenuated and no longer statistically significant (HR 1.31, 95% CI 0.98-1.76).

CONCLUSIONS: Among postmenopausal women with IBD, risk of ischemic stroke may be higher than in non-IBD women.},
}

@article {pmid38684115,
year = {2024},
author = {Kelnhofer-Millevolte, LE and Arnold, EA and Nguyen, DH and Avgousti, DC},
title = {Controlling Much? Viral Control of Host Chromatin Dynamics.},
journal = {Annual review of virology},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-virology-100422-011616},
pmid = {38684115},
issn = {2327-0578},
abstract = {Viruses are exemplary molecular biologists and have been integral to scientific discovery for generations. It is therefore no surprise that nuclear replicating viruses have evolved to systematically take over host cell function through astoundingly specific nuclear and chromatin hijacking. In this review, we focus on nuclear replicating DNA viruses-herpesviruses and adenoviruses-as key examples of viral invasion in the nucleus. We concentrate on critical features of nuclear architecture, such as chromatin and the nucleolus, to illustrate the complexity of the virus-host battle for resources in the nucleus. We conclude with a discussion of the technological advances that have enabled the discoveries we describe and upcoming steps in this burgeoning field.},
}

@article {pmid38683966,
year = {2024},
author = {Krakow, EF and Brault, M and Summers, C and Cunningham, TM and Biernacki, MA and Black, RG and Woodward, KB and Vartanian, N and Kanaan, SB and Yeh, AC and Dossa, RG and Bar, M and Cassaday, RD and Dahlberg, A and Till, BG and Denker, AE and Yeung, CCS and Gooley, TA and Maloney, DG and Riddell, SR and Greenberg, PD and Chapuis, AG and Newell, EW and Furlan, SN and Bleakley, M},
title = {HA-1-targeted T cell receptor (TCR) T cell therapy for recurrent leukemia after hematopoietic stem cell transplantation.},
journal = {Blood},
volume = {},
number = {},
pages = {},
doi = {10.1182/blood.2024024105},
pmid = {38683966},
issn = {1528-0020},
abstract = {Relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (HCT) for leukemia. T cells engineered by gene transfer to express T cell receptors (TCR; TCR-T) specific for hematopoietic-restricted minor histocompatibility (H) antigens may provide a potent selective anti-leukemic effect post-HCT. We conducted a phase I clinical trial employing a novel TCR-T product targeting the minor H antigen HA-1 to treat or consolidate treatment of persistent or recurrent leukemia and myeloid neoplasms. The primary objective was to evaluate the feasibility and safety of administration of HA-1 TCR-T post-HCT. CD8+ and CD4+ T cells expressing the HA-1 TCR and a CD8-co-receptor were successfully manufactured from HA-1 disparate HCT donors. One or more infusions of HA-1 TCR-T following lymphodepleting chemotherapy were administered to nine HCT recipients who had developed disease recurrence post-HCT. TCR-T cells expanded and persisted in vivo after adoptive transfer. No dose-limiting toxicities occurred. Although the study was not designed to assess efficacy, four patients achieved or maintained complete remissions following lymphodepletion and HA-1 TCR-T, with one ongoing at >2 years. Single-cell RNA sequencing of relapsing/progressive leukemia after TCR-T therapy identified upregulated molecules associated with T cell dysfunction or cancer cell survival. HA-1 TCR-T therapy appears feasible and safe and shows preliminary signals of efficacy. This clinical trial is registered at clinicaltrials.gov as NCT03326921.},
}

@article {pmid38659959,
year = {2024},
author = {Larsen, BB and McMahon, T and Brown, JT and Wang, Z and Radford, CE and Crowe, JE and Veesler, D and Bloom, JD},
title = {Functional and antigenic landscape of the Nipah virus receptor binding protein.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38659959},
support = {DP1 AI158186/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; U19 AI142764/AI/NIAID 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 ; },
abstract = {Nipah virus recurrently spills over to humans, causing fatal infections. The viral receptor-binding protein (RBP or G) attaches to host receptors and is a major target of neutralizing antibodies. Here we use deep mutational scanning to measure how all amino-acid mutations to the RBP affect cell entry, receptor binding, and escape from neutralizing antibodies. We identify functionally constrained regions of the RBP, including sites involved in oligomerization, along with mutations that differentially modulate RBP binding to its two ephrin receptors. We map escape mutations for six anti-RBP antibodies, and find that few antigenic mutations are present in natural Nipah strains. Our findings offer insights into the potential for functional and antigenic evolution of the RBP that can inform the development of antibody therapies and vaccines.},
}

@article {pmid38659935,
year = {2024},
author = {Denos, M and Sun, YQ and Brumpton, B and Li, Y and Albanes, D and Burnett-Hartman, A and Campbell, PT and Küry, S and Li, CI and White, E and Samadder, JN and Jenkins, M and Mai, XM},
title = {Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38659935},
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 ; K05 CA154337/CA/NCI NIH HHS/United States ; P30 DK034987/DK/NIDDK NIH HHS/United States ; R21 CA235464/CA/NCI NIH HHS/United States ; U01 CA167551/CA/NCI NIH HHS/United States ; P30 CA076292/CA/NCI NIH HHS/United States ; R01 CA042182/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 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 ; 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 ; 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 ; U01 CA137088/CA/NCI NIH HHS/United States ; R01 CA189184/CA/NCI NIH HHS/United States ; U01 CA167552/CA/NCI NIH HHS/United States ; Z01 CP010200/ImNIH/Intramural NIH HHS/United States ; U24 CA074794/CA/NCI NIH HHS/United States ; R01 CA066635/CA/NCI NIH HHS/United States ; U01 CA206110/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 ; 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 ; 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 ; 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 ; 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 ; K05 CA152715/CA/NCI NIH HHS/United States ; U01 CA122839/CA/NCI NIH HHS/United States ; U01 CA074783/CA/NCI NIH HHS/United States ; KL2 TR000421/TR/NCATS 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 ; 75N92021D00004/WH/WHI NIH HHS/United States ; U19 CA148107/CA/NCI NIH HHS/United States ; U01 AG018033/AG/NIA NIH HHS/United States ; },
abstract = {The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37-0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.},
}

@article {pmid38502193,
year = {2024},
author = {Appelbaum, J and Price, AE and Oda, K and Zhang, J and Leung, WH and Tampella, G and Xia, D and So, PP and Hilton, SK and Evandy, C and Sarkar, S and Martin, U and Krostag, AR and Leonardi, M and Zak, DE and Logan, R and Lewis, P and Franke-Welch, S and Ngwenyama, N and Fitzgerald, M and Tulberg, N and Rawlings-Rhea, S and Gardner, RA and Jones, K and Sanabria, A and Crago, W and Timmer, J and Hollands, A and Eckelman, B and Bilic, S and Woodworth, J and Lamble, A and Gregory, PD and Jarjour, J and Pogson, M and Gustafson, JA and Astrakhan, A and Jensen, MC},
title = {Drug-regulated CD33-targeted CAR T cells control AML using clinically optimized rapamycin dosing.},
journal = {The Journal of clinical investigation},
volume = {134},
number = {9},
pages = {},
pmid = {38502193},
issn = {1558-8238},
mesh = {Humans ; *Sirolimus/pharmacology/administration & dosage ; Mice ; Animals ; *Leukemia, Myeloid, Acute/immunology/therapy/drug therapy/pathology ; *Sialic Acid Binding Ig-like Lectin 3/immunology/metabolism ; *T-Lymphocytes/immunology/drug effects ; Receptors, Chimeric Antigen/immunology ; Immunotherapy, Adoptive ; Female ; Xenograft Model Antitumor Assays ; Male ; },
abstract = {Chimeric antigen receptor (CAR) designs that incorporate pharmacologic control are desirable; however, designs suitable for clinical translation are needed. We designed a fully human, rapamycin-regulated drug product for targeting CD33+ tumors called dimerizaing agent-regulated immunoreceptor complex (DARIC33). T cell products demonstrated target-specific and rapamycin-dependent cytokine release, transcriptional responses, cytotoxicity, and in vivo antileukemic activity in the presence of as little as 1 nM rapamycin. Rapamycin withdrawal paused DARIC33-stimulated T cell effector functions, which were restored following reexposure to rapamycin, demonstrating reversible effector function control. While rapamycin-regulated DARIC33 T cells were highly sensitive to target antigen, CD34+ stem cell colony-forming capacity was not impacted. We benchmarked DARIC33 potency relative to CD19 CAR T cells to estimate a T cell dose for clinical testing. In addition, we integrated in vitro and preclinical in vivo drug concentration thresholds for off-on state transitions, as well as murine and human rapamycin pharmacokinetics, to estimate a clinically applicable rapamycin dosing schedule. A phase I DARIC33 trial has been initiated (PLAT-08, NCT05105152), with initial evidence of rapamycin-regulated T cell activation and antitumor impact. Our findings provide evidence that the DARIC platform exhibits sensitive regulation and potency needed for clinical application to other important immunotherapy targets.},
}

Humans
*Sirolimus/pharmacology/administration & dosage
Mice
Animals
*Leukemia, Myeloid, Acute/immunology/therapy/drug therapy/pathology
*Sialic Acid Binding Ig-like Lectin 3/immunology/metabolism
*T-Lymphocytes/immunology/drug effects
Receptors, Chimeric Antigen/immunology
Immunotherapy, Adoptive
Female
Xenograft Model Antitumor Assays
Male

@article {pmid38682560,
year = {2024},
author = {Loriot, Y and Kalebasty, AR and Fléchon, A and Jain, RK and Gupta, S and Bupathi, M and Beuzeboc, P and Palmbos, P and Balar, AV and Kyriakopoulos, CE and Pouessel, D and Sternberg, CN and Tonelli, J and Sierecki, M and Zhou, H and Grivas, P and Barthélémy, P and Bangs, R and Tagawa, ST},
title = {A plain language summary of the TROPHY-U-01 study: sacituzumab govitecan use in people with locally advanced or metastatic urothelial cancer.},
journal = {Future oncology (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.2217/fon-2023-1030},
pmid = {38682560},
issn = {1744-8301},
abstract = {WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY[®]) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan.

WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan.

The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious. Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).},
}

@article {pmid38681192,
year = {2024},
author = {Gundle, KR and Rajasekaran, K and Houlton, J and Deutsch, GB and Ow, TJ and Maki, RG and Pang, J and Nathan, CO and Clayburgh, D and Newman, JG and Brinkmann, E and Wagner, MJ and Pollack, SM and Thompson, MJ and Li, RJ and Mehta, V and Schiff, BA and Wenig, BI and Swiecicki, PL and Tang, AL and Davis, JL and van Zante, A and Bertout, JA and Jenkins, W and Turner, A and Grenley, M and Burns, C and Frazier, JP and Merrell, A and Sottero, KHW and Derry, JMJ and Gillespie, KC and Mills, B and Klinghoffer, RA},
title = {Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment.},
journal = {Frontiers in pharmacology},
volume = {15},
number = {},
pages = {1367581},
pmid = {38681192},
issn = {1663-9812},
abstract = {Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO[®]) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.},
}

@article {pmid38680611,
year = {2024},
author = {Anidi, IU and Sakai, S and Brooks, K and Fling, SP and Wagner, MJ and Lurain, K and Lindestam Arlehamn, CS and Sette, A and Knox, KS and Brenchley, JM and Uldrick, TS and Sharon, E and Barber, DL},
title = {Exacerbation of CMV and Nontuberculous Mycobacterial Infections Following PD-1 Blockade for HIV-Associated Kaposi Sarcoma.},
journal = {Open forum infectious diseases},
volume = {11},
number = {5},
pages = {ofae183},
pmid = {38680611},
issn = {2328-8957},
abstract = {Blockade of the co-inhibitory receptor PD-1 enhances antitumor responses by boosting the function of antigen-specific T cells. Although rare, PD-1 blockade in patients with cancer can lead to exacerbation of infection-associated pathology. Here, we detail the case of a 38-year-old man who was enrolled in a clinical trial for assessment of the safety and activity of anti-PD-1 therapy for Kaposi sarcoma in people with HIV well-controlled on antiretroviral therapy. Less than a week after receiving the first dose of anti-PD-1 antibody (pembrolizumab), he presented with severe abdominal pain associated with sudden exacerbations of preexisting cytomegalovirus (CMV) enteritis and nontuberculous mycobacterial mesenteric lymphadenitis. Plasma biomarkers of gastrointestinal tract damage were highly elevated compared with healthy controls, consistent with HIV-associated loss of gut epithelial barrier integrity. Moreover, CMV-specific CD8 T cells expressed high levels of PD-1, and 7 days following PD-1 blockade, there was an increase in the frequency of activated CD38[+] Ki67[+] CMV-specific CD8 T cells. This case highlights the potential for PD-1 blockade to drive rapid exacerbations of inflammatory symptoms when administered to individuals harboring multiple unresolved infections.},
}

@article {pmid38680292,
year = {2024},
author = {Alkassis, S and Fitzsimmons, K and Hurvitz, S},
title = {Pembrolizumab-induced nephrotoxicity in a patient with breast cancer.},
journal = {Therapeutic advances in medical oncology},
volume = {16},
number = {},
pages = {17588359241248362},
pmid = {38680292},
issn = {1758-8340},
abstract = {The introduction of immunotherapy has revolutionized the treatment and improved outcomes of multiple types of cancer. Although breast cancer is a less immune-responsive tumor type, the incorporation of pembrolizumab into chemotherapy regimens in the neoadjuvant and first-line metastatic setting for the triple-negative disease has improved outcomes. However, the use of this type of treatment is associated with a spectrum of adverse events. Although rarely affected, kidneys can be a target for immunotherapy, leading to irreversible injury if not recognized and addressed early. A 52-year-old woman presented with clinical stage II right breast cancer diagnosed at an outside facility. Neoadjuvant docetaxel/carboplatin/pembrolizumab every 3 weeks was started. Given the partial response on MRI after the 4th cycle, treatment was switched to doxorubicin/cyclophosphamide. However, pembrolizumab was held in cycle 2 due to the rash and then resumed in cycle 3 after the resolution of symptoms. Elevated creatinine was noted 3 weeks after the last dose of pembrolizumab without improvement despite adequate fluid resuscitation. Diagnostic workup was unremarkable except for pyuria and minimal albuminuria on urinalysis. In the absence of other risk factors and the temporal relationship between pembrolizumab administration and the onset of acute kidney injury (AKI), immune-related nephrotoxicity was the underlying diagnosis. After initiation of corticosteroids, creatinine decreased back to baseline without the need for kidney biopsy. An addendum to the original pathology report from the outside facility surfaced 5 months after starting treatment, revealing that the second breast lesion had a Fluorescence in situ hybridization (FISH) test performed that was positive. Given this fact, therapy was changed to two cycles of neoadjuvant paclitaxel/carboplatin/trastuzumab/pertuzumab, with approximately 8 weeks between the last pembrolizumab dose and the first dose of trastuzumab. Thereafter, she underwent a right breast mastectomy which showed residual invasive carcinoma with negative margins and lymph nodes. She completed 1 year of trastuzumab. Immune-related AKI is a rare, but potentially serious complication associated with an increase in mortality. Further research is needed in the development and early detection. There is promising research in the development of noninvasive biomarkers which has the added benefit of identifying patients who can be re-challenged with immunotherapy.},
}

@article {pmid38677524,
year = {2024},
author = {Inamdar, VV and Hao, S and Stephan, SB and Stephan, MT},
title = {Biomaterial-based scaffolds for direct in situ programming of tumor-infiltrating T lymphocytes.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jconrel.2024.04.040},
pmid = {38677524},
issn = {1873-4995},
abstract = {Adoptive cell therapy with tumor-infiltrating T cells (TILs) has generated exciting clinical trial results for the treatment of unresectable solid tumors. However, solid tumors remain difficult targets for adoptively transferred T cells, due in part to poor migration of TILs to the tumor, physical barriers to infiltration, and active suppression of TILs by the tumor. Furthermore, a highly skilled team is required to obtain tumor tissue, isolate and expand the TILs ex vivo, and reinfuse them into the patient, which drives up costs and limits patient access. Here, we describe a cell-free polymer implant designed to recruit, genetically reprogram and expand host T cells at tumor lesions in situ. Importantly, the scaffold can be fabricated on a large scale and is stable to lyophilization. Using a mouse breast cancer model, we show that the implants quickly and efficiently amass cancer-specific host lymphocytes at the tumor site in quantities sufficient to bring about long-term tumor regression. Given that surgical care is the mainstay of cancer treatment for many patients, this technology could be easily implemented in a clinical setting as an add-on to surgery for solid tumors. Furthermore, the approach could be broadened to recruit and genetically reprogram other therapeutically desirable host cells, such as macrophages, natural killer cells or dendritic cells, potentially boosting the antitumor effectiveness of the implant even more.},
}

@article {pmid38677521,
year = {2024},
author = {Zhang, Y and Li, Y and Peila, R and Wang, T and Xue, X and Kaplan, RC and Dannenberg, AJ and Qi, Q and Rohan, TE},
title = {Associations of lifestyle and genetic risks with obesity and related chronic diseases in the UK Biobank: a prospective cohort study.},
journal = {The American journal of clinical nutrition},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajcnut.2024.04.025},
pmid = {38677521},
issn = {1938-3207},
abstract = {BACKGROUND: Interplay between lifestyle (LRS) and genetic risk scores (GRS) on obesity and related chronic diseases are under-investigated and necessary for understanding obesity causes and developing prevention strategies.

OBJECTIVES: To investigate independent and joint associations and interactions of LRS and GRS with obesity prevalence and risks of diabetes, cardiovascular disease (CVD), and obesity-related cancer.

METHODS: In this cohort study of 444,957 UK Biobank participants (age: 56.5 ± 8.1 years, body mass index [BMI]: 27.4 ± 4.7 kg/m[2]), LRS included physical activity, dietary score, sedentary behavior, sleep duration, and smoking (range: 0-20, each factor has 5 levels). GRS was calculated based on 941 genetic variants related to BMI. Both scores were categorized into quintiles. Obesity (n=106,301) was defined as baseline BMI≥30 kg/m[2]. Incident diabetes (n=16,311), CVD (n=18,076), and obesity-related cancer (n=17,325) were ascertained through linkage to registries over a median of 12-year follow-up.

RESULTS: The LRS and GRS were independently positively associated with all outcomes. Additive interactions of LRS and GRS were observed for all outcomes (P<0.021). Comparing the top versus bottom LRS quintile, prevalence differences (95% confidence intervals) for obesity were 17.8% (15.9%, 19.7%) in the top GRS quintile and 10.7% (8.3%, 13.1%) in the bottom GRS quintile; for diabetes, CVD, and obesity-related cancer, incidence rate differences associated with per standard deviation increase in LRS were greater in the top compared to the bottom GRS quintile. Participants from top quintiles of both LRS and GRS had 6.16-, 3.81-, 1.56-, and 1.44-fold higher odds/risks of obesity, diabetes, CVD, and obesity-related cancer, respectively, compared with those from bottom quintiles of both scores.

CONCLUSIONS: Higher LRS was associated with higher obesity prevalence and risks of related chronic diseases regardless of GRS, highlighting the broad benefits of healthy lifestyles. Additive gene-lifestyle interactions emphasize the public health importance of lifestyle interventions among people with high genetic risks.},
}

@article {pmid38676662,
year = {2024},
author = {Fauer, AJ and Qiu, W and Huang, IC and Ganz, PA and Casillas, JN and Yabroff, KR and Armstrong, GT and Leisenring, W and Howell, R and Howell, CR and Kirchhoff, AC and Yasui, Y and Nathan, PC},
title = {Financial Hardship & Neighborhood Socioeconomic Disadvantage in Long-term Childhood Cancer Survivors.},
journal = {JNCI cancer spectrum},
volume = {},
number = {},
pages = {},
doi = {10.1093/jncics/pkae033},
pmid = {38676662},
issn = {2515-5091},
abstract = {BACKGROUND: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships.

METHODS: Cross-sectional analysis of data from the Childhood Cancer Survivor Study (CCSS) between 1970 and 1999, and self-reported financial information from 2017-2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material/financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status.

RESULTS: Analysis was restricted to 3,475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 [IQR 33,46] and 47 [39,59] years, respectively. Survivors resided in areas with greater deprivation (ADI ≥ 50: 38.7% survivors vs 31.8% siblings, P < .001). One quintile increases in deprivation were associated with small increases in behavioral (2nd quintile P = .017) and psychological financial hardship (2nd quintile P = .009; 3rd quintile, P = .014). Lower psychological financial hardship was associated with individual factors including greater household income ($60,000+ income, P < .001) and being single (P = .048).

CONCLUSIONS AND RELEVANCE: Childhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Both neighborhood level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships.},
}

@article {pmid38676439,
year = {2024},
author = {Zhang, Y and Win, AK and Makalic, E and Buchanan, DD and Pai, RK and Phipps, AI and Rosty, C and Boussioutas, A and Karahalios, A and Jenkins, MA},
title = {Associations between pathological features and risk of metachronous colorectal cancer.},
journal = {International journal of cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/ijc.34979},
pmid = {38676439},
issn = {1097-0215},
support = {U01 CA167551/CA/NCI NIH HHS/United States ; },
abstract = {Survivors of colorectal cancer (CRC) are at risk of developing another primary colorectal cancer - metachronous CRC. Understanding which pathological features of the first tumour are associated with risk of metachronous CRC might help tailor existing surveillance guidelines. Population-based CRC cases were recruited from the United States, Canada and Australia between 1997 and 2012 and followed prospectively until 2022 by the Colon Cancer Family Registry. Metachronous CRC was defined as a new primary CRC diagnosed at least 1 year after the initial CRC. Those with the genetic cancer predisposition Lynch syndrome or MUTYH mutation carriers were excluded. Cox regression models were fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations. Of 6085 CRC cases, 138 (2.3%) were diagnosed with a metachronous CRC over a median follow-up time of 12 years (incidence: 2.0 per 1000 person-years). CRC cases with a synchronous CRC were 3.4-fold more likely to develop a metachronous CRC (adjusted HR: 3.36, 95% CI: 1.89-5.98) than those without a synchronous tumour. CRC cases with MMR-deficient tumours had a 72% increased risk of metachronous CRC (adjusted HR: 1.72, 95% CI: 1.11-2.64) compared to those with MMR-proficient tumours. Compared to cases who had an adenocarcinoma histologic type, those with an undifferentiated histologic type were 77% less likely to develop a metachronous CRC (adjusted HR: 0.23, 95% CI: 0.06-0.94). Existing surveillance guidelines for CRC survivors could be updated to include increased surveillance for those whose first CRC was diagnosed with a synchronous CRC or was MMR-deficient.},
}

@article {pmid38675841,
year = {2024},
author = {Kampouri, E and Handley, G and Hill, JA},
title = {Human Herpes Virus-6 (HHV-6) Reactivation after Hematopoietic Cell Transplant and Chimeric Antigen Receptor (CAR)- T Cell Therapy: A Shifting Landscape.},
journal = {Viruses},
volume = {16},
number = {4},
pages = {},
pmid = {38675841},
issn = {1999-4915},
mesh = {*Herpesvirus 6, Human/immunology/genetics/physiology ; Humans ; *Hematopoietic Stem Cell Transplantation/adverse effects ; *Virus Activation ; *Roseolovirus Infections/virology/immunology/therapy ; *Receptors, Chimeric Antigen/immunology/genetics ; Immunotherapy, Adoptive/methods/adverse effects ; Graft vs Host Disease/immunology/etiology ; },
abstract = {HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of encephalitis following HCT and is associated with pleiotropic manifestations in this setting, including graft-versus-host disease, myelosuppression, pneumonitis, and CMV reactivation, although the causal link is not always clear. When the virus inserts its genome in chromosomes of germ cells, the chromosomally integrated form (ciHHV6) is inherited by offspring. The condition of ciHHV6 is characterized by the persistent detection of HHV-6 DNA, often confounding diagnosis of reactivation and disease-this has also been associated with adverse outcomes. Recent changes in clinical practice in the field of cellular therapies, including a wider use of post-HCT cyclophosphamide, the advent of letermovir for CMV prophylaxis, and the rapid expansion of novel cellular therapies require contemporary epidemiological studies to determine the pathogenic role and spectrum of disease of HHV-6B in the current era. Research into the epidemiology and clinical significance of HHV-6B in chimeric antigen receptor T cell (CAR-T cell) therapy recipients is in its infancy. No controlled trials have determined the optimal treatment for HHV-6B. Treatment is reserved for end-organ disease, and the choice of antiviral agent is influenced by expected toxicities. Virus-specific T cells may provide a novel, less toxic therapeutic modality but is more logistically challenging. Preventive strategies are hindered by the high toxicity of current antivirals. Ongoing study is needed to keep up with the evolving epidemiology and impact of HHV-6 in diverse and expanding immunocompromised patient populations.},
}

*Herpesvirus 6, Human/immunology/genetics/physiology
Humans
*Hematopoietic Stem Cell Transplantation/adverse effects
*Virus Activation
*Roseolovirus Infections/virology/immunology/therapy
*Receptors, Chimeric Antigen/immunology/genetics
Immunotherapy, Adoptive/methods/adverse effects
Graft vs Host Disease/immunology/etiology

@article {pmid38672531,
year = {2024},
author = {van Dijk, AD and Hoff, FW and Qiu, Y and Hubner, SE and Go, RL and Ruvolo, VR and Leonti, AR and Gerbing, RB and Gamis, AS and Aplenc, R and Kolb, EA and Alonzo, TA and Meshinchi, S and de Bont, ESJM and Horton, TM and Kornblau, SM},
title = {Chromatin Profiles Are Prognostic of Clinical Response to Bortezomib-Containing Chemotherapy in Pediatric Acute Myeloid Leukemia: Results from the COG AAML1031 Trial.},
journal = {Cancers},
volume = {16},
number = {8},
pages = {},
pmid = {38672531},
issn = {2072-6694},
abstract = {The addition of the proteasome inhibitor bortezomib to standard chemotherapy did not improve survival in pediatric acute myeloid leukemia (AML) when all patients were analyzed as a group in the Children's Oncology Group phase 3 trial AAML1031 (NCT01371981). Proteasome inhibition influences the chromatin landscape and proteostasis, and we hypothesized that baseline proteomic analysis of histone- and chromatin-modifying enzymes (HMEs) would identify AML subgroups that benefitted from bortezomib addition. A proteomic profile of 483 patients treated with AAML1031 chemotherapy was generated using a reverse-phase protein array. A relatively high expression of 16 HME was associated with lower EFS and higher 3-year relapse risk after AML standard treatment compared to low expressions (52% vs. 29%, p = 0.005). The high-HME profile correlated with more transposase-accessible chromatin, as demonstrated via ATAC-sequencing, and the bortezomib addition improved the 3-year overall survival compared with standard therapy (62% vs. 75%, p = 0.033). These data suggest that there are pediatric AML populations that respond well to bortezomib-containing chemotherapy.},
}

@article {pmid38671485,
year = {2024},
author = {Zablocki, RW and Hartman, SJ and Di, C and Zou, J and Carlson, JA and Hibbing, PR and Rosenberg, DE and Greenwood-Hickman, MA and Dillon, L and LaCroix, AZ and Natarajan, L},
title = {Using functional principal component analysis (FPCA) to quantify sitting patterns derived from wearable sensors.},
journal = {The international journal of behavioral nutrition and physical activity},
volume = {21},
number = {1},
pages = {48},
pmid = {38671485},
issn = {1479-5868},
support = {R01DK114945/DK/NIDDK NIH HHS/United States ; R01 DK114945/DK/NIDDK NIH HHS/United States ; P01 AG052352/AG/NIA NIH HHS/United States ; P01AG052352/AG/NIA NIH HHS/United States ; R01HL130483/HL/NHLBI NIH HHS/United States ; R01 HL130483/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Female ; *Sedentary Behavior ; *Sitting Position ; Middle Aged ; *Principal Component Analysis ; *Wearable Electronic Devices ; Accelerometry/instrumentation/methods ; Blood Pressure/physiology ; Actigraphy/instrumentation/methods ; Aged ; Overweight ; Postmenopause/physiology ; Exercise/physiology ; Movement ; },
abstract = {BACKGROUND: Sedentary behavior (SB) is a recognized risk factor for many chronic diseases. ActiGraph and activPAL are two commonly used wearable accelerometers in SB research. The former measures body movement and the latter measures body posture. The goal of the current study is to quantify the pattern and variation of movement (by ActiGraph activity counts) during activPAL-identified sitting events, and examine associations between patterns and health-related outcomes, such as systolic and diastolic blood pressure (SBP and DBP).

METHODS: The current study included 314 overweight postmenopausal women, who were instructed to wear an activPAL (at thigh) and ActiGraph (at waist) simultaneously for 24 hours a day for a week under free-living conditions. ActiGraph and activPAL data were processed to obtain minute-level time-series outputs. Multilevel functional principal component analysis (MFPCA) was applied to minute-level ActiGraph activity counts within activPAL-identified sitting bouts to investigate variation in movement while sitting across subjects and days. The multilevel approach accounted for the nesting of days within subjects.

RESULTS: At least 90% of the overall variation of activity counts was explained by two subject-level principal components (PC) and six day-level PCs, hence dramatically reducing the dimensions from the original minute-level scale. The first subject-level PC captured patterns of fluctuation in movement during sitting, whereas the second subject-level PC delineated variation in movement during different lengths of sitting bouts: shorter (< 30 minutes), medium (30 -39 minutes) or longer (> 39 minute). The first subject-level PC scores showed positive association with DBP (standardized β ^ : 2.041, standard error: 0.607, adjusted p = 0.007), which implied that lower activity counts (during sitting) were associated with higher DBP.

CONCLUSION: In this work we implemented MFPCA to identify variation in movement patterns during sitting bouts, and showed that these patterns were associated with cardiovascular health. Unlike existing methods, MFPCA does not require pre-specified cut-points to define activity intensity, and thus offers a novel powerful statistical tool to elucidate variation in SB patterns and health.

TRIAL REGISTRATION: ClinicalTrials.gov NCT03473145; Registered 22 March 2018; https://clinicaltrials.gov/ct2/show/NCT03473145 ; International Registered Report Identifier (IRRID): DERR1-10.2196/28684.},
}

Humans
Female
*Sedentary Behavior
*Sitting Position
Middle Aged
*Principal Component Analysis
*Wearable Electronic Devices
Accelerometry/instrumentation/methods
Blood Pressure/physiology
Actigraphy/instrumentation/methods
Aged
Overweight
Postmenopause/physiology
Exercise/physiology
Movement

@article {pmid38670944,
year = {2024},
author = {Chen, Z and Guo, X and Tao, R and Huyghe, JR and Law, PJ and Fernandez-Rozadilla, C and Ping, J and Jia, G and Long, J and Li, C and Shen, Q and Xie, Y and Timofeeva, MN and Thomas, M and Schmit, SL and Díez-Obrero, V and Devall, M and Moratalla-Navarro, F and Fernandez-Tajes, J and Palles, C and Sherwood, K and Briggs, SEW and Svinti, V and Donnelly, K and Farrington, SM and Blackmur, J and Vaughan-Shaw, PG and Shu, XO and Lu, Y and Broderick, P and Studd, J and Harrison, TA and Conti, DV and Schumacher, FR and Melas, M and Rennert, G and Obón-Santacana, M and Martín-Sánchez, V and Oh, JH and Kim, J and Jee, SH and Jung, KJ and Kweon, SS and Shin, MH and Shin, A and Ahn, YO and Kim, DH and Oze, I and Wen, W and Matsuo, K and Matsuda, K and Tanikawa, C and Ren, Z and Gao, YT and Jia, WH and Hopper, JL and Jenkins, MA and Win, AK and Pai, RK and Figueiredo, JC and Haile, RW and Gallinger, S and Woods, MO and Newcomb, PA and Duggan, D and Cheadle, JP and Kaplan, R and Kerr, R and Kerr, D and Kirac, I and Böhm, J and Mecklin, JP and Jousilahti, P and Knekt, P and Aaltonen, LA and Rissanen, H and Pukkala, E and Eriksson, JG and Cajuso, T and Hänninen, U and Kondelin, J and Palin, K and Tanskanen, T and Renkonen-Sinisalo, L and Männistö, S and Albanes, D and Weinstein, SJ and Ruiz-Narvaez, E and Palmer, JR and Buchanan, DD and Platz, EA and Visvanathan, K and Ulrich, CM and Siegel, E and Brezina, S and Gsur, A and Campbell, PT and Chang-Claude, J and Hoffmeister, M and Brenner, H and Slattery, ML and Potter, JD and Tsilidis, KK and Schulze, MB and Gunter, MJ and Murphy, N and Castells, A and Castellví-Bel, S and Moreira, L and Arndt, V and Shcherbina, A and Bishop, DT and Giles, GG and Southey, MC and Idos, GE and McDonnell, KJ and Abu-Ful, Z and Greenson, JK and Shulman, K and Lejbkowicz, F and Offit, K and Su, YR and Steinfelder, R and Keku, TO and van Guelpen, B and Hudson, TJ and Hampel, H and Pearlman, R and Berndt, SI and Hayes, RB and Martinez, ME and Thomas, SS and Pharoah, PDP and Larsson, SC and Yen, Y and Lenz, HJ and White, E and Li, L and Doheny, KF and Pugh, E and Shelford, T and Chan, AT and Cruz-Correa, M and Lindblom, A and Hunter, DJ and Joshi, AD and Schafmayer, C and Scacheri, PC and Kundaje, A and Schoen, RE and Hampe, J and Stadler, ZK and Vodicka, P and Vodickova, L and Vymetalkova, V and Edlund, CK and Gauderman, WJ and Shibata, D and Toland, A and Markowitz, S and Kim, A and Chanock, SJ and van Duijnhoven, F and Feskens, EJM and Sakoda, LC and Gago-Dominguez, M and Wolk, A and Pardini, B and FitzGerald, LM and Lee, SC and Ogino, S and Bien, SA and Kooperberg, C and Li, CI and Lin, Y and Prentice, R and Qu, C and Bézieau, S and Yamaji, T and Sawada, N and Iwasaki, M and Le Marchand, L and Wu, AH and Qu, C and McNeil, CE and Coetzee, G and Hayward, C and Deary, IJ and Harris, SE and Theodoratou, E and Reid, S and Walker, M and Ooi, LY and Lau, KS and Zhao, H and Hsu, L and Cai, Q and Dunlop, MG and Gruber, SB and Houlston, RS and Moreno, V and Casey, G and Peters, U and Tomlinson, I and Zheng, W},
title = {Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3557},
pmid = {38670944},
issn = {2041-1723},
support = {R01CA188214//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R37CA227130//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Colorectal Neoplasms/genetics ; *Genetic Predisposition to Disease ; *Genome-Wide Association Study ; *Asian People/genetics ; *White People/genetics ; *Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; Exome Sequencing ; Case-Control Studies ; Transcriptome ; Chromosome Mapping ; Male ; Female ; East Asian People ; },
abstract = {Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.},
}

Humans
*Colorectal Neoplasms/genetics
*Genetic Predisposition to Disease
*Genome-Wide Association Study
*Asian People/genetics
*White People/genetics
*Polymorphism, Single Nucleotide
*Quantitative Trait Loci
Exome Sequencing
Case-Control Studies
Transcriptome
Chromosome Mapping
Male
Female
East Asian People

@article {pmid38670103,
year = {2024},
author = {Martin, CG and Bent, JS and Hill, T and Topalidou, I and Singhvi, A},
title = {Epithelial UNC-23 limits mechanical stress to maintain glia-neuron architecture in C. elegans.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2024.04.005},
pmid = {38670103},
issn = {1878-1551},
abstract = {For an organ to maintain correct architecture and function, its diverse cellular components must coordinate their size and shape. Although cell-intrinsic mechanisms driving homotypic cell-cell coordination are known, it is unclear how cell shape is regulated across heterotypic cells. We find that epithelial cells maintain the shape of neighboring sense-organ glia-neuron units in adult Caenorhabditis elegans (C. elegans). Hsp co-chaperone UNC-23/BAG2 prevents epithelial cell shape from deforming, and its loss causes head epithelia to stretch aberrantly during animal movement. In the sense-organ glia, amphid sheath (AMsh), this causes progressive fibroblast growth factor receptor (FGFR)-dependent disruption of the glial apical cytoskeleton. Resultant glial cell shape alteration causes concomitant shape change in glia-associated neuron endings. Epithelial UNC-23 maintenance of glia-neuron shape is specific both spatially, within a defined anatomical zone, and temporally, in a developmentally critical period. As all molecular components uncovered are broadly conserved across central and peripheral nervous systems, we posit that epithelia may similarly regulate glia-neuron architecture cross-species.},
}

@article {pmid38670099,
year = {2024},
author = {Glass, DR and Mayer-Blackwell, K and Ramchurren, N and Parks, KR and Duran, GE and Wright, AK and Bastidas Torres, AN and Islas, L and Kim, YH and Fling, SP and Khodadoust, MS and Newell, EW},
title = {Multi-omic profiling reveals the endogenous and neoplastic responses to immunotherapies in cutaneous T cell lymphoma.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {101527},
doi = {10.1016/j.xcrm.2024.101527},
pmid = {38670099},
issn = {2666-3791},
abstract = {Cutaneous T cell lymphomas (CTCLs) are skin cancers with poor survival rates and limited treatments. While immunotherapies have shown some efficacy, the immunological consequences of administering immune-activating agents to CTCL patients have not been systematically characterized. We apply a suite of high-dimensional technologies to investigate the local, cellular, and systemic responses in CTCL patients receiving either mono- or combination anti-PD-1 plus interferon-gamma (IFN-γ) therapy. Neoplastic T cells display no evidence of activation after immunotherapy. IFN-γ induces muted endogenous immunological responses, while anti-PD-1 elicits broader changes, including increased abundance of CLA[+]CD39[+] T cells. We develop an unbiased multi-omic profiling approach enabling discovery of immune modules stratifying patients. We identify an enrichment of activated regulatory CLA[+]CD39[+] T cells in non-responders and activated cytotoxic CLA[+]CD39[+] T cells in leukemic patients. Our results provide insights into the effects of immunotherapy in CTCL patients and a generalizable framework for multi-omic analysis of clinical trials.},
}

@article {pmid38669515,
year = {2024},
author = {Beichman, AC and Zhu, L and Harris, K},
title = {The Evolutionary Interplay of Somatic and Germline Mutation Rates.},
journal = {Annual review of biomedical data science},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-biodatasci-102523-104225},
pmid = {38669515},
issn = {2574-3414},
abstract = {Novel sequencing technologies are making it increasingly possible to measure the mutation rates of somatic cell lineages. Accurate germline mutation rate measurement technologies have also been available for a decade, making it possible to assess how this fundamental evolutionary parameter varies across the tree of life. Here, we review some classical theories about germline and somatic mutation rate evolution that were formulated using principles of population genetics and the biology of aging and cancer. We find that somatic mutation rate measurements, while still limited in phylogenetic diversity, seem consistent with the theory that selection to preserve the soma is proportional to life span. However, germline and somatic theories make conflicting predictions regarding which species should have the most accurate DNA repair. Resolving this conflict will require carefully measuring how mutation rates scale with time and cell division and achieving a better understanding of mutation rate pleiotropy among cell types.},
}

@article {pmid38669341,
year = {2024},
author = {Babushok, DV and DeZern, AE and de Castro, C and Rogers, ZR and Beenhouwer, D and Broder, MS and Fanning, S and Gibbs, SN and Hanna, R and Maciejewski, JP and Scott, BL and Tantravahi, SK and Wlodarski, MW and Yermilov, I and Patel, BJ},
title = {Modified Delphi Panel Consensus Recommendations for Management of Severe Aplastic Anemia.},
journal = {Blood advances},
volume = {},
number = {},
pages = {},
doi = {10.1182/bloodadvances.2023011642},
pmid = {38669341},
issn = {2473-9537},
abstract = {Severe aplastic anemia (SAA) is a rare hematologic condition for which there is no clear management algorithm. A panel of 11 adult and pediatric experts on aplastic anemia was assembled and, using the RAND/UCLA modified Delphi panel method, evaluated >600 varying patient care scenarios to develop clinical recommendations for the initial and subsequent management of patients of all ages with SAA. Here we present the panel's recommendations to rule out inherited bone marrow failure (IBMF) syndromes, on supportive care prior to and during first-line therapy, and on first-line (initial management) and second-line (subsequent management) therapy of acquired SAA, focusing on when transplant versus medical therapy is most appropriate. These recommendations represent the consensus of 11 experts informed by published literature and experience. They are intended only as general guidance for experienced clinicians who treat patients with SAA and are in no way intended to supersede individual physician and patient decision-making. Current and future research should validate this consensus using clinical data. Once validated, we hope these expert panel recommendations will improve outcomes for patients with SAA.},
}

@article {pmid38667288,
year = {2024},
author = {Turnham, DJ and Mullen, MS and Bullock, NP and Gilroy, KL and Richards, AE and Patel, R and Quintela, M and Meniel, VS and Seaton, G and Kynaston, H and Clarkson, RWE and Phesse, TJ and Nelson, PS and Haffner, MC and Staffurth, JN and Pearson, HB},
title = {Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer.},
journal = {Cells},
volume = {13},
number = {8},
pages = {},
pmid = {38667288},
issn = {2073-4409},
support = {A27894/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Male ; Humans ; *Prostatic Neoplasms, Castration-Resistant/pathology/genetics/metabolism/drug therapy ; Animals ; *Receptors, Androgen/metabolism/genetics ; Mice ; Xenograft Model Antitumor Assays ; Phenylthiohydantoin/pharmacology/analogs & derivatives/therapeutic use ; Neoplasm Metastasis ; Nitriles/pharmacology ; Disease Models, Animal ; Benzamides/pharmacology ; Phthalazines/pharmacology/therapeutic use ; *Piperazines ; },
abstract = {As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient's treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.},
}

Male
Humans
*Prostatic Neoplasms, Castration-Resistant/pathology/genetics/metabolism/drug therapy
Animals
*Receptors, Androgen/metabolism/genetics
Mice
Xenograft Model Antitumor Assays
Phenylthiohydantoin/pharmacology/analogs & derivatives/therapeutic use
Neoplasm Metastasis
Nitriles/pharmacology
Disease Models, Animal
Benzamides/pharmacology
Phthalazines/pharmacology/therapeutic use
*Piperazines

@article {pmid38666501,
year = {2024},
author = {Kim, SR and Nordlander, A and Xie, H and Kim, YJ and Ogimi, C and Thakar, MS and Leisenring, W and Englund, JA and Boeckh, M and Waghmare, A},
title = {The impact of pre-transplant respiratory virus detection on post-transplant outcomes in children undergoing hematopoietic cell transplantation.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {},
number = {},
pages = {},
doi = {10.1093/cid/ciae216},
pmid = {38666501},
issn = {1537-6591},
abstract = {BACKGROUND: Pre-transplant respiratory virus (RV) infections have been associated with negative transplant outcomes in adult hematopoietic cell transplantation (HCT) recipients. In the era of HCT delay due to high-risk RVs, we examined the impact of pre-transplant RV detection on transplant outcomes in a pediatric HCT recipients.

METHODS: This retrospective cohort study included myeloablative allogeneic HCT recipients from 2010 to 2019. All patients were screened for RV at least once within 90 days before HCT using RT-PCR, regardless of symptoms. Post-transplant outcomes included days alive and out of hospital (DAOH) and progression to lower respiratory tract infection (LRTI).

RESULTS: Among 310 patients, 134 had a RV detected in the 90 days prior to HCT. In univariable analysis, transplant factors including younger age, total body irradiation, umbilical cord blood transplantation, lymphocyte count less than 100/mm3, and HCT comorbidity index score ≥3, and viral factors including symptomatic infection, human rhinovirus (HRV) as a virus type, and symptomatic pre-transplant upper respiratory tract infection (URTI) were associated with fewer DAOH. In multivariable analysis, transplant factors remained significant, but not viral factors. There was a higher incidence of progression to post-transplant LRTI with the same pre-transplant RV if the last positive PCR before HCT was ≤30 days compared to >30 days (p=0.007).

CONCLUSION: In the setting of recommending HCT delay for high-risk RVs, symptomatic URTI, including HRV infections, may lead to increased duration of hospitalization and early progression to LRTI when transplantation is performed within 30 days of the last positive PCR test.},
}

@article {pmid38666065,
year = {2024},
author = {Poston, JN and Brown, SP and Ilich, A and Ginsburg, AS and Herren, H and El Kassar, N and Jensen, CE and Triulzi, DJ and Key, NS and May, S and Gernsheimer, TB},
title = {Fewer severe infections with tranexamic acid in patients with hematologic malignancies.},
journal = {Research and practice in thrombosis and haemostasis},
volume = {8},
number = {2},
pages = {102358},
pmid = {38666065},
issn = {2475-0379},
abstract = {BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding in a multitude of clinical settings from postpartum hemorrhage to trauma. TXA may have clinical effects unrelated to bleeding; plasminogen, the target of TXA, alters immune responses, and TXA appears to decrease the risk of infection in patients undergoing cardiac surgery, as well as joint arthroplasty.

OBJECTIVES: To address whether TXA alters rates of infection and inflammatory outcomes in patients with hematologic malignancies.

METHODS: We performed a post hoc analysis of outcomes of patients randomized to receive either TXA or placebo in the double-blinded, multicenter American Trial to Evaluate Tranexamic Acid Therapy in Thrombocytopenia (Clinicaltrials.gov identifier: NCT02578901).

RESULTS: TXA did not change the overall rate of infections, but the rate of severe infections (Common Toxicology Criteria for Adverse Events grade 3+) was lower in patients who received TXA compared with the placebo group. Patients who experienced grade 3+ infections had higher rates of World Health Organization grade 2+ bleeding and red blood cell transfusion requirements than patients who did not experience a grade 3+ infection, irrespective of treatment group. TXA did not impact other inflammatory outcomes such as mucositis, rash, or graft vs host disease.

CONCLUSION: Patients with hematologic malignancies who received TXA had less severe infections than those who received placebo with no difference in overall rate of infection or other inflammatory outcomes. Further investigation is needed on the impact of TXA on infections in this population.},
}

@article {pmid38664404,
year = {2024},
author = {Hurvitz, SA and Bardia, A and Punie, K and Kalinsky, K and Carey, LA and Rugo, HS and Diéras, V and Phan, S and Delaney, R and Zhu, Y and Tolaney, SM},
title = {Subgroup analyses from the phase 3 ASCENT study of sacituzumab govitecan in metastatic triple-negative breast cancer.},
journal = {NPJ breast cancer},
volume = {10},
number = {1},
pages = {33},
pmid = {38664404},
issn = {2374-4677},
abstract = {In this post hoc analysis of the ASCENT study, we compared outcomes with sacituzumab govitecan (SG) vs single-agent chemotherapy in clinically important subgroups of patients with metastatic triple-negative breast cancer (mTNBC). Patients with mTNBC refractory to/relapsing after ≥2 prior chemotherapies (≥1 in the metastatic setting) were randomized 1:1 to receive SG or treatment of physician's choice (TPC) until unacceptable toxicity/progression. The primary endpoint was progression-free survival (PFS) per RECIST 1.1 by central review in patients without brain metastases. Patients with brain metastases were allowed if metastases were stable ≥4 weeks. In the intention-to-treat (ITT) population, 19% of patients were age ≥65 years; 12% were Black, and 12% had brain metastases. SG improved PFS and overall survival (OS), respectively, vs TPC in patients age ≥65 years (7.1 vs 2.4 months and 14.7 vs 8.9 months), or of Black race (5.4 vs 2.2 months and 13.8 vs 8.5 months), consistent with outcomes in the ITT population. Patients with brain metastases had numerically higher median PFS with SG vs TPC, but median OS was similar between treatment groups. SG was well tolerated and had a manageable safety profile consistent with the full safety population across all subgroups; neutropenia and diarrhea were the most common treatment-emergent adverse events. These findings confirm the meaningful clinical benefit of SG vs standard chemotherapy in patient subgroups with high unmet needs. SG should be considered an effective and safe treatment option for patients with mTNBC eligible for second-line or later therapy. ClinicalTrials.gov Number: NCT02574455.},
}

@article {pmid38663768,
year = {2024},
author = {Meyers, G and Bubalo, J and Eckstrom, E and Winsnes, K and Carpenter, PA and Artz, A and Lin, RJ},
title = {Transplant-associated Altered Mentation and Encephalopathy (TAME): A New Classification for Acute Neurocognitive Changes Associated with Hematopoietic Cell Transplantation from the ASTCT Committee on Practice Guidelines.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2024.04.009},
pmid = {38663768},
issn = {2666-6367},
abstract = {Acute encephalopathy, manifesting clinically as delirium, is a common but often unrecognized complication of hematopoietic cell transplant (HCT). Delirium is found in patients of any age and observed after autologous or allogeneic HCT. While primarily studied during initial transplant hospitalizations among recipients of myeloablative conditioning, recent HCT investigations have identified delirium later posttransplant and among those who received reduced intensity conditioning. Acute encephalopathy can be driven by infectious complications, medications, tissue damage and/or organ dysfunction. Altered consciousness, either mild or profound, is often its only clinical manifestation. Identifying delirium is essential to overall HCT care because patients who experience delirium have longer hospitalization and recovery times and are at risk for other poor post-HCT outcomes. Given the critical nature of this common complication and expansion of HCT into more vulnerable populations, the American Society of Transplantation and Cellular Therapy (ASTCT) recommends that it is time to intensify research into post-HCT cognitive changes and to establish standardized definitions that encompass the full spectrum of altered consciousness for clinical care purposes and to provide benchmark endpoints for future research studies. To capture a range of acute neurocognitive changes specifically found in HCT patients (often referred to as acute encephalopathy), ASTCT propose a new diagnosis, Transplant-associated Altered Mentation and Encephalopathy (TAME). The TAME diagnosis includes HCT patients who meet DSM-5 criteria for delirium and those with acute neurocognitive changes who do not meet full DSM-5 criteria for delirium (subsyndromal delirium). Early TAME is defined as occurring during conditioning or ≤100 days post-HCT, while late TAME occurs >100 days post-HCT in patients with additional HCT-related complications. This manuscript will establish clear diagnostic criteria and discuss factors that can potentially impact the development of TAME, as well as work-up and management of TAME.},
}

@article {pmid38662984,
year = {2024},
author = {Raychaudhuri, R and Mo, G and Tuchayi, AM and Graham, L and Gulati, R and Pritchard, CC and Haffner, MC and Yezefski, T and Hawley, JE and Cheng, HH and Yu, EY and Grivas, P and Montgomery, RB and Nelson, PS and Chen, DL and Hope, T and Iravani, A and Schweizer, MT},
title = {Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to [177]Lu-PSMA-617: A Retrospective Multicenter Cohort Study.},
journal = {JCO precision oncology},
volume = {8},
number = {},
pages = {e2300634},
doi = {10.1200/PO.23.00634},
pmid = {38662984},
issn = {2473-4284},
mesh = {Humans ; Male ; Retrospective Studies ; Aged ; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/blood/drug therapy ; *Lutetium/therapeutic use ; *Dipeptides/therapeutic use ; Heterocyclic Compounds, 1-Ring/therapeutic use ; Prostate-Specific Antigen/blood ; Antigens, Surface/genetics ; Cohort Studies ; Glutamate Carboxypeptidase II/genetics ; },
abstract = {PURPOSE: While [177]Lu-PSMA-617 (LuPSMA) is an effective therapy for many patients with metastatic castration-resistant prostate cancer (mCRPC), biomarkers associated with outcomes are not well defined. We hypothesized that prostate cancer mutational profile may associate with clinical activity of LuPSMA. We devised a study to evaluate associations between mCRPC mutational profile with LuPSMA clinical outcomes.

METHODS: This was a multicenter retrospective analysis of patients with mCRPC with next-generation sequencing (NGS) who received LuPSMA. PSA50 response (ie, ≥50% decline in prostate-specific antigen [PSA]) rate, PSA progression free survival (PSA PFS), and overall survival (OS) were compared between genetically defined subgroups.

RESULTS: One hundred twenty-six patients with NGS results who received at least one cycle of LuPSMA were identified. The median age was 73 (IQR, 68-78) years, 124 (98.4%) received ≥1 prior androgen receptor-signaling inhibitor, and 121 (96%) received ≥1 taxane-based chemotherapy regimen. Fifty-eight (46%) patients with a DNA damage repair gene mutation (DNA damage response group) and 59 (46.8%) with a mutation in TP53, RB1, or PTEN tumor suppressor genes (TSG group) were identified. After adjusting for relevant confounders, the presence of ≥1 TSG mutation was associated with shorter PSA PFS (hazard ratio [HR], 1.93 [95% CI, 1.05 to 3.54]; P = .034) and OS (HR, 2.65 [95% CI, 1.15 to 6.11]; P = .023). There was improved OS favoring the DNA damage response group (HR, 0.37 [95% CI, 0.14 to 0.97]; P = .044) on multivariable analysis. Univariate analysis of patients with ATM mutations had significantly higher rates of PSA50 response, PSA PFS, and OS.

CONCLUSION: Outcomes on LuPSMA varied on the basis of mutational profile. Prospective studies to define the clinical activity of LuPSMA in predefined genomic subgroups are justified.},
}

Humans
Male
Retrospective Studies
Aged
*Prostatic Neoplasms, Castration-Resistant/genetics/pathology/blood/drug therapy
*Lutetium/therapeutic use
*Dipeptides/therapeutic use
Heterocyclic Compounds, 1-Ring/therapeutic use
Prostate-Specific Antigen/blood
Antigens, Surface/genetics
Cohort Studies
Glutamate Carboxypeptidase II/genetics

@article {pmid38661186,
year = {2024},
author = {Aitken, SL and Pierce, VM and Pogue, JM and Kline, EG and Tverdek, FP and Shields, RK},
title = {The growing threat of NDM-producing E. coli with penicillin-binding protein 3 mutations in the United States - is there a potential role for durlobactam?.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {},
number = {},
pages = {},
doi = {10.1093/cid/ciae229},
pmid = {38661186},
issn = {1537-6591},
abstract = {We report identification of 5 patients with infections caused by NDM-5-producing E. coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane β-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management.},
}

@article {pmid38657269,
year = {2024},
author = {McCune, JM and Kiem, HP},
title = {Extending Gene Medicines to All in Need.},
journal = {The New England journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1056/NEJMe2403104},
pmid = {38657269},
issn = {1533-4406},
}

@article {pmid38657020,
year = {2024},
author = {Till, C and Goodman, PJ and Tangen, C and Lucia, MS and Thompson, IM},
title = {Letter: Survival After Selenium and Vitamin E Supplementation: Long-Term Followup of the Selenium and Vitamin E Cancer Prevention Trial.},
journal = {The Journal of urology},
volume = {},
number = {},
pages = {101097JU0000000000003937},
doi = {10.1097/JU.0000000000003937},
pmid = {38657020},
issn = {1527-3792},
}

@article {pmid38657001,
year = {2024},
author = {Singh, K and Rubenstein, K and Callier, V and Shaw-Saliba, K and Rupert, A and Dewar, R and Laverdure, S and Highbarger, H and Lallemand, P and Huang, ML and Jerome, KR and Sampoleo, R and Mills, MG and Greninger, AL and Juneja, K and Porter, D and Benson, CA and Dempsey, W and El Sahly, HM and Focht, C and Jilg, N and Paules, CI and Rapaka, RR and Uyeki, TM and Lane, HC and Beigel, J and Dodd, LE and , },
title = {SARS-CoV-2 RNA and nucleocapsid antigen are blood biomarkers associated with severe disease outcomes that improve in response to remdesivir.},
journal = {The Journal of infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1093/infdis/jiae198},
pmid = {38657001},
issn = {1537-6613},
abstract = {BACKGROUND: Although antivirals remain important for the treatment COVID-19, methods to assess treatment efficacy are lacking. Here, we investigated the impact of remdesivir on viral dynamics and their contribution to understanding antiviral efficacy in the multicenter ACTT-1 clinical trial that randomized patients to remdesivir or placebo.

METHODS: Longitudinal specimens collected during hospitalization from a substudy of 642 COVID-19 patients were measured for viral RNA (upper respiratory tract and plasma), viral nucleocapsid antigen (serum), and host immunologic markers. Associations with clinical outcomes and response to therapy were assessed.

RESULTS: Higher baseline plasma viral loads were associated with poorer clinical outcomes, and decreases in viral RNA and antigen in blood but not the upper respiratory tract correlated with enhanced benefit from remdesivir. The treatment effect of remdesivir was most pronounced in patients with elevated baseline nucleocapsid antigen levels: the recovery rate ratio was 1.95 (95%CI 1.40-2.71) for levels >245 pg/ml vs 1.04 (95%CI 0.76-1.42) for levels < 245 pg/ml. Remdesivir also accelerated the rate of viral RNA and antigen clearance in blood, and patients whose blood levels decreased were more likely to recover and survive.

CONCLUSIONS: Reductions in SARS-CoV-2 RNA and antigen levels in blood correlated with clinical benefit from antiviral therapy.},
}

@article {pmid38656285,
year = {2024},
author = {Chen, J and Hart, JE and VoPham, T and Elliott, EG and Birmann, BM and Laden, F},
title = {Association of residential exposure to hazardous air pollutants with risk of non-Hodgkin lymphoma and multiple myeloma.},
journal = {Cancer epidemiology, biomarkers & 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-23-1598},
pmid = {38656285},
issn = {1538-7755},
abstract = {BACKGROUND: Certain hazardous air pollutants (HAPs) are known or suspected to pose immunological or cancer risk to humans, but evidence is limited from the general population.

METHODS: We assessed associations between residential exposure to HAPs at the Census tract level and incident non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) in the Nurses' Health Study (NHS, 1986-2012) and NHSII (1989-2019). We used covariate-adjusted proportional hazards models to estimate hazard ratios (HRs) of NHL, major NHL subtypes, and MM per interquartile range increase in exposure to a given HAP and pooled the cohort-specific estimates using fixed-effects meta-analyses.

RESULTS: There were 810 NHL and 158 MM cases in NHS (1,700,707 person-years), and 379 NHL and 59 MM cases in NHSII (2,820,772 person-years). Most HRs approximated unity. Meta-analyses did not show consistent evidence of associations between any HAP exposure and risk of NHL or MM.

CONCLUSIONS: Exposure to HAPs was not consistently associated with risks of NHL or MM in these nationwide prospective cohorts of women.

IMPACT: This is the first nationwide study assessing associations between residential HAP exposures and risk of lymphoid malignances in prospective cohorts and focuses on women, who have frequently been underrepresented in (primarily occupational) studies of exposure to HAPs.},
}

@article {pmid38655842,
year = {2024},
author = {Riddler, SA and Kelly, CW and Hoesley, CJ and Ho, KS and Piper, JM and Edick, S and Heard, F and Doncel, GF and Johnson, S and Anderson, PL and Brand, RM and Kunjara Na Ayudhya, RP and Bauermeister, JA and Hillier, SL and Hendrix, CW},
title = {A Phase 1 Clinical Trial to Assess the Safety and Pharmacokinetics of a Tenofovir Alafenamide/Elvitegravir Insert Administered Rectally for HIV Prevention.},
journal = {The Journal of infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1093/infdis/jiae211},
pmid = {38655842},
issn = {1537-6613},
abstract = {BACKGROUND: On-demand topical products could be an important tool for HIV prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG; 16 mg/20 mg) insert administered rectally.

METHODS: MTN-039 was a Phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid (RF), and rectal tissue (RT) were collected over 72 hours (hr) following rectal administration of one and two TAF/EVG inserts for each participant. ClinicalTrials.gov Identifier: NCT04047420.

RESULTS: TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. RT EVG peaked at 2-hr (median 2 inserts= 9 ng/mg) but declined to BLQ in the majority of samples at 24-hr, whereas TFV-DP remained high >2,000 fmol/million cells for 72-hr with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each timepoint for both 1 and 2 inserts (p<0.065 and p<0.039, respectively).

DISCUSSION: Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours.},
}

@article {pmid38653906,
year = {2024},
author = {Haas, CB and Chen, H and Harrison, T and Fan, S and Gago-Dominguez, M and Castelao, JE and Bolla, MK and Wang, Q and Dennis, J and Michailidou, K and Dunning, AM and Easton, DF and Antoniou, AC and Hall, P and Czene, K and Andrulis, IL and Mulligan, AM and Milne, RL and Fasching, PA and Haeberle, L and Garcia-Closas, M and Ahearn, T and Gierach, GL and Haiman, C and Maskarinec, G and Couch, FJ and Olson, JE and John, EM and Chenevix-Trench, G and de Gonzalez, AB and Jones, M and Stone, J and Murphy, R and Aronson, KJ and Wernli, KJ and Hsu, L and Vachon, C and Tamimi, RM and Lindström, S},
title = {Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.},
journal = {Breast cancer research and treatment},
volume = {},
number = {},
pages = {},
pmid = {38653906},
issn = {1573-7217},
support = {CA244670//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; },
abstract = {PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR).

METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status.

RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: β = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10[-63]) and inversely associated with dense area (IVW: β = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10[-7]). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (β = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (β =  - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches.

CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.},
}

@article {pmid38653905,
year = {2024},
author = {Chlebowski, RT and Aragaki, AK and Pan, K and Mortimer, JE and Johnson, KC and Wactawski-Wende, J and LeBoff, MS and Lavasani, S and Lane, D and Nelson, RA and Manson, JE},
title = {Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis.},
journal = {Breast cancer research and treatment},
volume = {},
number = {},
pages = {},
pmid = {38653905},
issn = {1573-7217},
support = {R01 CA119171 and R01 CA10921/CA/NCI NIH HHS/United States ; },
abstract = {PURPOSE: In the Women's Health initiative (WHI) randomized clinical trial, conjugated equine estrogen (CEE)-alone significantly reduced breast cancer incidence (P = 0.005). As cohort studies had opposite findings, other randomized clinical trials were identified to conduct a meta-analysis of estrogen-alone influence on breast cancer incidence.

METHODS: We conducted literature searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analysis and reviews. In the meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, the corresponding log-RR = (O - E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP.

RESULTS: Findings from 10 randomized trials included 14,282 participants and 591 incident breast cancers. In 9 smaller trials, with 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. Combining the 10 trials, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo (overall RR 0.77 95% CI 0.65-0.91, P = 0.002).

CONCLUSION: The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use significantly reduces breast cancer incidence.},
}

@article {pmid38653648,
year = {2024},
author = {Chen, EX and Kavan, P and Tehfe, M and Kortmansky, JS and Sawyer, MB and Chiorean, EG and Lieu, CH and Polite, B and Wong, L and Fakih, M and Spencer, K and Chaves, J and Li, C and Leconte, P and Adelberg, D and Kim, R},
title = {Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E.},
journal = {Clinical colorectal cancer},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.clcc.2024.03.002},
pmid = {38653648},
issn = {1938-0674},
abstract = {BACKGROUND: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer.

PATIENTS AND METHODS: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary.

RESULTS: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E.

CONCLUSION: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.},
}

@article {pmid38645152,
year = {2024},
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 Andersson, A and Dann, E and Qin, Q and Otto, DJ and Klein, M and Botvinnik, OB and Deconinck, L and Waldrant, K 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 = {Research square},
volume = {},
number = {},
pages = {},
pmid = {38645152},
support = {/WT_/Wellcome Trust/United Kingdom ; F31 CA257625/CA/NCI NIH HHS/United States ; U24 CA180996/CA/NCI NIH HHS/United States ; },
abstract = {With the growing number of single-cell analysis tools, benchmarks are increasingly important to guide analysis and method development. However, a lack of standardisation and extensibility in current benchmarks limits their usability, longevity, and relevance to the community. We present Open Problems, a living, extensible, community-guided benchmarking platform including 10 current single-cell tasks that we envision will raise standards for the selection, evaluation, and development of methods in single-cell analysis.},
}

@article {pmid38645034,
year = {2024},
author = {Zaidi, S and Park, J and Chan, JM and Roudier, MP and Zhao, JL and Gopalan, A and Wadosky, KM and Patel, RA and Sayar, E and Karthaus, WR and Henry Kates, D and Chaudhary, O and Xu, T and Masilionis, I and Mazutis, L and Chaligné, R and Obradovic, A and Linkov, I and Barlas, A and Jungbluth, A and Rekhtman, N and Silber, J and Manova-Todorova, K and Watson, PA and True, LD and Morrissey, CM and Scher, HI and Rathkopf, D and Morris, MJ and Goodrich, DW and Choi, J and Nelson, PS and Haffner, MC and Sawyers, CL},
title = {Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38645034},
support = {R21 CA277368/CA/NCI NIH HHS/United States ; R01 CA193837/CA/NCI NIH HHS/United States ; P50 CA097186/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA155169/CA/NCI NIH HHS/United States ; P01 CA265768/CA/NCI NIH HHS/United States ; U54 CA224079/CA/NCI NIH HHS/United States ; K08 CA282978/CA/NCI NIH HHS/United States ; R01 CA266452/CA/NCI NIH HHS/United States ; R01 CA234715/CA/NCI NIH HHS/United States ; P50 CA092629/CA/NCI NIH HHS/United States ; },
abstract = {Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.},
}

@article {pmid38653622,
year = {2024},
author = {Psutka, SP and Veleber, S and Siman, J and Holt, SK and Jannat, S and Wright, JL and Lin, DW and Gore, JL and Schade, GR and Annen, Z and Greenlee, H},
title = {Phase 1/2 Randomized Clinical Trial of In-clinic acupuncture Prior to Bacillus Calmette-Guérin in Patients with High-risk Non-muscle-invasive Bladder Cancer.},
journal = {European urology oncology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.euo.2024.04.002},
pmid = {38653622},
issn = {2588-9311},
abstract = {BACKGROUND: Treatment-related dose-limiting dysuria and irritative bladder symptoms are common in patients receiving intravesical bacillus Calmette-Guérin (BCG) to treat non-muscle-invasive bladder cancer (NMIBC). Acupuncture has been shown to reduce pain and urinary urgency/frequency in other patient populations.

OBJECTIVE: To evaluate the feasibility, safety, and tolerability of weekly in-clinic preprocedural acupuncture among patients receiving induction BCG.

Patients with high-risk NMIBC undergoing induction BCG were randomized 2:1 to a standardized acupuncture protocol (acupuncture) versus the standard-of-care control arm.

INTERVENTION: In-office acupuncture prior to each BCG instillation.

Feasibility was assessed via recruitment, retention, and intervention adherence. Acupuncture safety and tolerability were assessed via physician-reported Common Terminology Criteria for Adverse Events version 5.0 and adverse events (AEs). Secondary endpoints included BCG treatment adherence, patient-reported BCG-related toxicity, and bladder cancer-specific and generic (European Organisation for Research and Treatment of Cancer [EORTC]-QLQ-NMIBC-24 and EORTC-QLQ-NMIBC-C30) quality of life (QOL). Subjective assessments of acupuncture acceptability were performed through patient surveys.

RESULTS AND LIMITATIONS: A total of 43 individuals were randomized 2:1 to the acupuncture (n = 28) versus control (n = 15) group. The median age was 70.3 yr, and 76% were male. Week 7 follow-up surveys were completed by 93%; six participants withdrew early due to disease progression, refractory gross hematuria, or preference. Acupuncture was delivered successfully prior to each BCG treatment, with no acupuncture-related AEs or interruptions to induction BCG. BCG-attributed AEs were reported by 91% acupuncture and 100% control individuals, including pain (28% vs 43%, p = 0.34) and urinary symptoms (62% vs 79%, p = 0.31). Comparing acupuncture patients with controls, change in QOL over the study period demonstrated greater improvements in median urinary symptoms (9.5, interquartile range [IQR] 0.0-19.0 vs 0.0, IQR -14.3 to 7.1; p = 0.02) among patients in the acupuncture arm. Of the acupuncture patients, 96% reported that acupuncture was "very/extremely helpful," and 91% would recommend acupuncture to other patients. Limitations include modest sample size and single-institution design.

CONCLUSIONS: Acupuncture prior to induction BCG treatments is feasible and safe. In this phase 1/2 trial, improved urinary function scores were observed among patients undergoing acupuncture. Patients receiving acupuncture reported high degrees of satisfaction with treatments.

PATIENT SUMMARY: We evaluated the safety and feasibility of delivering acupuncture in a urology clinic prior to weekly intravesical bladder cancer treatments with bacillus Calmette-Guérin (BCG) in a randomized controlled trial. We found that acupuncture could be delivered safely prior to weekly BCG instillations and that the use of acupuncture was associated with high patient satisfaction and a decrease in patient-reported urinary symptoms compared with usual care.},
}

@article {pmid38652878,
year = {2024},
author = {Im, C and Neupane, A and Baedke, JL and Lenny, B and Delaney, A and Dixon, SB and Chow, EJ and Mostoufi-Moab, S and Yang, T and Richard, MA and Gramatges, MM and Lupo, PJ and Sharafeldin, N and Bhatia, S and Armstrong, GT and Hudson, MM and Ness, KK and Robison, LL and Yasui, Y and Wilson, CL and Sapkota, Y},
title = {Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2302281},
doi = {10.1200/JCO.23.02281},
pmid = {38652878},
issn = {1527-7755},
abstract = {PURPOSE: Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D.

PATIENTS AND METHODS: Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci.

RESULTS: Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance (P < 5 × 10[-8]). Among these, common variants at 5p15.2 (LINC02112), 2p25.3 (MYT1L), and 19p12 (ZNF492) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: ORAFR, 20.18; P = .023; OREUR, 13.44; P = 1.3 × 10[-9]).

CONCLUSION: Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.},
}

@article {pmid38652672,
year = {2024},
author = {Kwak, SH and Hernandez-Cancela, RB and DiCorpo, DA and Condon, DE and Merino, J and Wu, P and Brody, JA and Yao, J and Guo, X and Ahmadizar, F and Meyer, M and Sincan, M and Mercader, JM and Lee, S and Haessler, J and Vy, HMT and Lin, Z and Armstrong, ND and Gu, S and Tsao, NL and Lange, LA and Wang, N and Wiggins, KL and Trompet, S and Liu, S and Loos, RJF and Judy, R and Schroeder, PH and Hasbani, NR and Bos, MM and Morrison, AC and Jackson, RD and Reiner, AP and Manson, JE and Chaudhary, NS and Carmichael, LK and Chen, YI and Taylor, KD and Ghanbari, M and van Meurs, J and Pitsillides, AN and Psaty, BM and Noordam, R and Do, R and Park, KS and Jukema, JW and Kavousi, M and Correa, A and Rich, SS and Damrauer, SM and Hajek, C and Cho, NH and Irvin, MR and Pankow, JS and Nadkarni, GN and Sladek, R and Goodarzi, MO and Florez, JC and Chasman, DI and Heckbert, SR and Kooperberg, C and Dupuis, J and Malhotra, R and de Vries, PS and Liu, CT and Rotter, JI and Meigs, JB and , },
title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.},
journal = {Diabetes care},
volume = {},
number = {},
pages = {},
doi = {10.2337/dc23-2274},
pmid = {38652672},
issn = {1935-5548},
support = {P30-DK063491/DK/NIDDK NIH HHS/United States ; U01HG011723/HG/NHGRI NIH HHS/United States ; UL1TR001420/TR/NCATS NIH HHS/United States ; },
abstract = {OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD.

RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs11444867 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.},
}

@article {pmid38652659,
year = {2024},
author = {Blest, HTW and Redmond, A and Avissar, J and Barker, J and Bridgeman, A and Fowler, G and Chauveau, L and Hertzog, J and Vendrell, I and Fischer, R and Iversen, MB and Jing, L and Koelle, DM and Paludan, SR and Kessler, BM and Crump, CM and Rehwinkel, J},
title = {HSV-1 employs UL56 to antagonize expression and function of cGAMP channels.},
journal = {Cell reports},
volume = {43},
number = {5},
pages = {114122},
doi = {10.1016/j.celrep.2024.114122},
pmid = {38652659},
issn = {2211-1247},
abstract = {DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.},
}

@article {pmid38652484,
year = {2024},
author = {Martin, PJ},
title = {Steroid tapering after GVHD Rx: not too fast, not too slow.},
journal = {Blood advances},
volume = {8},
number = {8},
pages = {2044-2046},
doi = {10.1182/bloodadvances.2024012850},
pmid = {38652484},
issn = {2473-9537},
mesh = {*Graft vs Host Disease/drug therapy/etiology ; Humans ; Steroids/therapeutic use/administration & dosage ; Hematopoietic Stem Cell Transplantation/adverse effects ; },
}

*Graft vs Host Disease/drug therapy/etiology
Humans
Steroids/therapeutic use/administration & dosage
Hematopoietic Stem Cell Transplantation/adverse effects

@article {pmid38633776,
year = {2024},
author = {Zhang, Y and Lindström, S and Kraft, P and Liu, Y},
title = {Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {38633776},
abstract = {IMPORTANCE: Early-onset cancer (diagnosed under 50 years of age) is associated with aggressive disease characteristics and its rising incidence is a global concern. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants is unknown.

OBJECTIVE: To examine the associations between genetic risk, lifestyle, and risk of early-onset cancers.

We analyzed a prospective cohort of 66,308 white British participants who were under age 50 and free of cancer at baseline in the UK Biobank.

EXPOSURES: Sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs, which summarize smoking status, body mass index [males only], physical activity, alcohol consumption, and diet).

MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer.

RESULTS: A total of 1,247 incident invasive early-onset cancer cases (female: 820, male: 427, breast: 386) were documented. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in females (HR, 95% CI: 1.85, 1.50-2.29) and males (1.94, 1.45-2.59) as well as early-onset breast cancer in females (3.06, 2.20-4.25). An unfavorable lifestyle (highest vs. lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer was stronger in the highest genetic risk category than the lowest: HRs in females and men were 1.85 (1.02, 3.36), 3.27 (0.78, 13.72) in the highest genetic risk category and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40) in the lowest.

CONCLUSIONS AND RELEVANCE: Both genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.},
}

@article {pmid38651213,
year = {2024},
author = {Lockhart, EJ and Horowitz, LF and Rodríguez, A and Zhu, S and Nguyen, T and Mehrabi, M and Gujral, TS and Folch, A},
title = {Drug testing of monodisperse arrays of live microdissected tumors using a valved multiwell microfluidic platform.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d4lc00016a},
pmid = {38651213},
issn = {1473-0189},
abstract = {Cancer drug testing in animals is an extremely poor predictor of the drug's safety and efficacy observed in humans. Hence there is a pressing need for functional testing platforms that better predict traditional and immunotherapy responses in human, live tumor tissue or tissue constructs, and at the same time are compatible with the use of mouse tumor tissue to facilitate building more accurate disease models. Since many cancer drug actions rely on mechanisms that depend on the tumor microenvironment (TME), such platforms should also retain as much of the native TME as possible. Additionally, platforms based on miniaturization technologies are desirable to reduce animal use and sensitivity to human tissue scarcity. Present high-throughput testing platforms that have some of these features, e.g. based on patient-derived tumor organoids, require a growth step that alters the TME. On the other hand, microdissected tumors (μDTs) or "spheroids" that retain an intact TME have shown promising responses to immunomodulators acting on native immune cells. However, difficult tissue handling after microdissection has reduced the throughput of drug testing on μDTs, thereby constraining the inherent advantages of producing numerous TME-preserving units of tissue for drug testing. Here we demonstrate a microfluidic 96-well platform designed for drug treatment of hundreds of similarly-sized, cuboidal μDTs ("cuboids") produced from a single tumor sample. The platform organizes a monodisperse array of four cuboids per well in 384 hydrodynamic traps. The microfluidic device, entirely fabricated in thermoplastics, features 96 microvalves that fluidically isolate each well after the cuboid loading step for straightforward multi-drug testing. Since our platform makes the most of scarce tumor tissue, it can potentially be applied to human biopsies that preserve the human TME while minimizing animal testing.},
}

@article {pmid38647375,
year = {2024},
author = {Dirican, CD and Nelson, PS},
title = {Y Chromosome Loss and Implications for Oncology.},
journal = {Molecular cancer research : MCR},
volume = {},
number = {},
pages = {},
doi = {10.1158/1541-7786.MCR-24-0105},
pmid = {38647375},
issn = {1557-3125},
abstract = {The Y chromosome has recognized functions in promoting male sex determination and regulating aspects of fertility. However, recent work has demonstrated important roles for the Y chromosome and Y-encoded genes in multiple domains of male health, including cancer. It is well-established that males experience shorter life spans than females, and this sex bias on overall mortality is ac-centuated in populations with longer life expectancy, in part related to elevated rates of cancer. The majority of human malignancies exhibit a sex bias with elevated frequencies in males. For many of these cancer types, the disparity has not been explained by environmental risk factors such as tobacco use. Notably, loss of the Y chromosome (LOY) detected in blood cells, termed mosaic LOY (mLOY) is a common event that is related to advancing age and is associated with a shortened lifespan. mLOY is linked to increased incidence and mortality across a range of malignancies. Further, tumors arising in different anatomic sites exhibit different frequencies of partial or complete Y chromosome loss. Causal oncogenic or tumor suppressive roles have been documented for several Y-encoded genes, such as KDM5D, that exert pleiotropic effects on cellular functions by virtue of genome-wide regulation of gene activity. In this review, we discuss aspects of the Y chromosome relevant to oncology. The recent completion of the entire human Y-chromosome sequence provides a reference map of Y-encoded genes and regulatory elements to enable causal molecular studies that may explain and exploit the marked disparity in male cancer risk and mortality.},
}

@article {pmid38647082,
year = {2024},
author = {Chen, KY and Park, H and Subramaniam, AR},
title = {Massively parallel identification of sequence motifs triggering ribosome-associated mRNA quality control.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae285},
pmid = {38647082},
issn = {1362-4962},
support = {R35 GM119835/NH/NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; },
abstract = {Decay of mRNAs can be triggered by ribosome slowdown at stretches of rare codons or positively charged amino acids. However, the full diversity of sequences that trigger co-translational mRNA decay is poorly understood. To comprehensively identify sequence motifs that trigger mRNA decay, we use a massively parallel reporter assay to measure the effect of all possible combinations of codon pairs on mRNA levels in S. cerevisiae. In addition to known mRNA-destabilizing sequences, we identify several dipeptide repeats whose translation reduces mRNA levels. These include combinations of positively charged and bulky residues, as well as proline-glycine and proline-aspartate dipeptide repeats. Genetic deletion of the ribosome collision sensor Hel2 rescues the mRNA effects of these motifs, suggesting that they trigger ribosome slowdown and activate the ribosome-associated quality control (RQC) pathway. Deep mutational scanning of an mRNA-destabilizing dipeptide repeat reveals a complex interplay between the charge, bulkiness, and location of amino acid residues in conferring mRNA instability. Finally, we show that the mRNA effects of codon pairs are predictive of the effects of endogenous sequences. Our work highlights the complexity of sequence motifs driving co-translational mRNA decay in eukaryotes, and presents a high throughput approach to dissect their requirements at the codon level.},
}

@article {pmid38643749,
year = {2024},
author = {Morgenstern, C and Lastres-Becker, I and Demirdöğen, BC and Costa, VM and Daiber, A and Foresti, R and Motterlini, R and Kalyoncu, S and Arioz, BI and Genc, S and Jakubowska, M and Trougakos, IP and Piechota-Polanczyk, A and Mickael, M and Santos, M and Kensler, TW and Cuadrado, A and Copple, IM},
title = {Biomarkers of NRF2 signalling: Current status and future challenges.},
journal = {Redox biology},
volume = {72},
number = {},
pages = {103134},
doi = {10.1016/j.redox.2024.103134},
pmid = {38643749},
issn = {2213-2317},
abstract = {The cytoprotective transcription factor NRF2 regulates the expression of several hundred genes in mammalian cells and is a promising therapeutic target in a number of diseases associated with oxidative stress and inflammation. Hence, an ability to monitor basal and inducible NRF2 signalling is vital for mechanistic understanding in translational studies. Due to some caveats related to the direct measurement of NRF2 levels, the modulation of NRF2 activity is typically determined by measuring changes in the expression of one or more of its target genes and/or the associated protein products. However, there is a lack of consensus regarding the most relevant set of these genes/proteins that best represents NRF2 activity across cell types and species. We present the findings of a comprehensive literature search that according to stringent criteria identifies GCLC, GCLM, HMOX1, NQO1, SRXN1 and TXNRD1 as a robust panel of markers that are directly regulated by NRF2 in multiple cell and tissue types. We assess the relevance of these markers in clinically accessible biofluids and highlight future challenges in the development and use of NRF2 biomarkers in humans.},
}

@article {pmid38643547,
year = {2024},
author = {Moore, M and Zhu, Y and Hirsch, I and White, T and Reiner, RC and Barber, RM and Pigott, D and Collins, JK and Santoni, S and Sobieszczyk, ME and Janes, H},
title = {Estimating vaccine efficacy during open-label follow-up of COVID-19 vaccine trials based on population-level surveillance data.},
journal = {Epidemics},
volume = {47},
number = {},
pages = {100768},
doi = {10.1016/j.epidem.2024.100768},
pmid = {38643547},
issn = {1878-0067},
abstract = {While rapid development and roll out of COVID-19 vaccines is necessary in a pandemic, the process limits the ability of clinical trials to assess longer-term vaccine efficacy. We leveraged COVID-19 surveillance data in the U.S. to evaluate vaccine efficacy in U.S. Government-funded COVID-19 vaccine efficacy trials with a three-step estimation process. First, we used a compartmental epidemiological model informed by county-level surveillance data, a "population model", to estimate SARS-CoV-2 incidence among the unvaccinated. Second, a "cohort model" was used to adjust the population SARS-CoV-2 incidence to the vaccine trial cohort, taking into account individual participant characteristics and the difference between SARS-CoV-2 infection and COVID-19 disease. Third, we fit a regression model estimating the offset between the cohort-model-based COVID-19 incidence in the unvaccinated with the placebo-group COVID-19 incidence in the trial during blinded follow-up. Counterfactual placebo COVID-19 incidence was estimated during open-label follow-up by adjusting the cohort-model-based incidence rate by the estimated offset. Vaccine efficacy during open-label follow-up was estimated by contrasting the vaccine group COVID-19 incidence with the counterfactual placebo COVID-19 incidence. We documented good performance of the methodology in a simulation study. We also applied the methodology to estimate vaccine efficacy for the two-dose AZD1222 COVID-19 vaccine using data from the phase 3 U.S. trial (ClinicalTrials.gov # NCT04516746). We estimated AZD1222 vaccine efficacy of 59.1% (95% uncertainty interval (UI): 40.4%-74.3%) in April, 2021 (mean 106 days post-second dose), which reduced to 35.7% (95% UI: 15.0%-51.7%) in July, 2021 (mean 198 days post-second-dose). We developed and evaluated a methodology for estimating longer-term vaccine efficacy. This methodology could be applied to estimating counterfactual placebo incidence for future placebo-controlled vaccine efficacy trials of emerging pathogens with early termination of blinded follow-up, to active-controlled or uncontrolled COVID-19 vaccine efficacy trials, and to other clinical endpoints influenced by vaccination.},
}

@article {pmid38643166,
year = {2024},
author = {Luo, K and Peters, BA and Moon, JY and Xue, X and Wang, Z and Usyk, M and Hanna, DB and Landay, AL and Schneider, MF and Gustafson, D and Weber, KM and French, A and Sharma, A and Anastos, K and Wang, T and Brown, T and Clish, CB and Kaplan, RC and Knight, R and Burk, RD and Qi, Q},
title = {Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection.},
journal = {Genome medicine},
volume = {16},
number = {1},
pages = {59},
pmid = {38643166},
issn = {1756-994X},
support = {R01HL140976/HL/NHLBI NIH HHS/United States ; U01 AI035004/AI/NIAID NIH HHS/United States ; U01 HL146208/HL/NHLBI NIH HHS/United States ; R01 HL126543/HL/NHLBI NIH HHS/United States ; U01 HL146192/HL/NHLBI NIH HHS/United States ; U01 HL146242/HL/NHLBI NIH HHS/United States ; R01DK119268/DK/NIDDK NIH HHS/United States ; P30 AI124414/AI/NIAID NIH HHS/United States ; U01 HL146194/HL/NHLBI NIH HHS/United States ; U01 HL146241/HL/NHLBI NIH HHS/United States ; P30 AI027767/AI/NIAID NIH HHS/United States ; P30 AI050409/AI/NIAID NIH HHS/United States ; U01 HL146333/HL/NHLBI NIH HHS/United States ; R01 DK126698/DK/NIDDK NIH HHS/United States ; U01 HL146245/HL/NHLBI NIH HHS/United States ; R01 MD011389/MD/NIMHD NIH HHS/United States ; R01 DK119268/DK/NIDDK NIH HHS/United States ; U01 HL146205/HL/NHLBI NIH HHS/United States ; R01 HL095140/HL/NHLBI NIH HHS/United States ; P30 MH116867/MH/NIMH NIH HHS/United States ; R01 HL083760/HL/NHLBI NIH HHS/United States ; R01 HL132794/HL/NHLBI NIH HHS/United States ; K01 HL129892/HL/NHLBI NIH HHS/United States ; R01 HL170904/HL/NHLBI NIH HHS/United States ; P30 AI073961/AI/NIAID NIH HHS/United States ; U01 HL146201/HL/NHLBI NIH HHS/United States ; U01 HL146193/HL/NHLBI NIH HHS/United States ; R01 HL140976/HL/NHLBI NIH HHS/United States ; U01 HL146204/HL/NHLBI NIH HHS/United States ; U01 HL146202/HL/NHLBI NIH HHS/United States ; UL1 TR001881/TR/NCATS NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; UL1 TR000004/TR/NCATS NIH HHS/United States ; U01 HL146240/HL/NHLBI NIH HHS/United States ; U01 HL146203/HL/NHLBI NIH HHS/United States ; K01 HL137557/HL/NHLBI NIH HHS/United States ; UL1 TR003098/TR/NCATS NIH HHS/United States ; P30 AI050410/AI/NIAID NIH HHS/United States ; },
mesh = {Male ; Humans ; Female ; *HIV Infections/drug therapy ; Prospective Studies ; Cohort Studies ; Dysbiosis/complications ; Cross-Sectional Studies ; *Diabetes Mellitus ; Bacteria ; },
abstract = {BACKGROUND: Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear.

METHODS: We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins.

RESULTS: Seven gut bacterial genera were identified to be associated with diabetes (FDR-q <  0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q <  0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV.

CONCLUSION: Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.},
}

Male
Humans
Female
*HIV Infections/drug therapy
Prospective Studies
Cohort Studies
Dysbiosis/complications
Cross-Sectional Studies
*Diabetes Mellitus
Bacteria

@article {pmid38642840,
year = {2024},
author = {Murakami, MA and Connelly-Smith, L and Spitzer, T and Kassim, AA and Penza, SL and Al Malki, MM and Mason, J and Tourville, C and Magliocco, B and Barten, J and Guidry-Groves, H and Margolis, J and Devine, SM and Rennert, WP and Stefanski, HE},
title = {Bone Marrow Harvest: A White Paper of Best Practices by the NMDP Marrow Alliance.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2024.04.010},
pmid = {38642840},
issn = {2666-6367},
abstract = {Data on recent bone marrow harvest collections from the NMDP has shown that bone marrow quality has decreased based on total nucleated cell count in the product. To ensure that quality bone marrow products are available to all recipients, the NMDP Marrow Alliance was formed in April of 2021 to increase the ability for bone marrow collection centers to safely deliver high-quality products consistently and to identify and disseminate guidelines for performing bone marrow harvests. This White Paper describes the best practices of performing a bone marrow harvest as defined by the NMDP Marrow Alliance.},
}

@article {pmid38642459,
year = {2024},
author = {Crawford, DE and Albala, D and Garnick, MB and Hahn, AW and Maroni, P and McKay, RR and Miner, M and Orio Ⅲ, P and Pandit, K and Sellinger, S and Yu, EY and Eckel, RH},
title = {Optimizing outcomes in men with prostate cancer: the cardiovascular event lowering (CaELo) pathways.},
journal = {The Canadian journal of urology},
volume = {31},
number = {2},
pages = {11820-11825},
pmid = {38642459},
issn = {1195-9479},
mesh = {Male ; Humans ; *Prostatic Neoplasms/drug therapy ; Androgen Antagonists/adverse effects ; Androgens ; *Cardiovascular Diseases/etiology/prevention & control ; },
abstract = {INTRODUCTION: Risk of cardiovascular disease is higher among men with prostate cancer than men without, and prostate cancer treatments (especially those that are hormonally based) are associated with increased cardiovascular risk.

MATERIALS AND METHODS: An 11-member panel of urologic, medical, and radiation oncologists (along with a men's health specialist and an endocrinologist/preventive cardiologist) met to discuss current practices and challenges in the management of cardiovascular risk in prostate cancer patients who are taking androgen deprivation therapies (ADT) including LHRH analogues, alone and in combination with androgen-targeted therapies (ATTs).

RESULTS: The panel developed an assessment algorithm to categorize patients by risk and deploy a risk-adapted management strategy, in collaboration with other healthcare providers (the patient's healthcare "village"), with the goal of preventing as well as reducing cardiovascular events. The panel also developed a patient questionnaire for cardiovascular risk as well as a checklist to ensure that all aspects of cardiovascular disease risk reduction are completed and monitored.

CONCLUSIONS: Prostate cancer patients receiving ADT with or without ATT need to be more zealously assessed for prevention and aggressively managed to reduce cardiovascular events. This can and should include participation from the entire multidisciplinary healthcare team.},
}

Male
Humans
*Prostatic Neoplasms/drug therapy
Androgen Antagonists/adverse effects
Androgens
*Cardiovascular Diseases/etiology/prevention & control

@article {pmid38640253,
year = {2024},
author = {Minnie, SA and Waltner, OG and Zhang, P and Takahashi, S and Nemychenkov, NS and Ensbey, KS and Schmidt, CR and Legg, SRW and Comstock, M and Boiko, JR and Nelson, E and Bhise, SS and Wilkens, AB and Koyama, M and Dhodapkar, MV and Chesi, M and Riddell, SR and Green, DJ and Spencer, A and Furlan, SN and Hill, GR},
title = {TIM-3[+] CD8 T cells with a terminally exhausted phenotype retain functional capacity in hematological malignancies.},
journal = {Science immunology},
volume = {9},
number = {94},
pages = {eadg1094},
doi = {10.1126/sciimmunol.adg1094},
pmid = {38640253},
issn = {2470-9468},
support = {T32 CA009351/CA/NCI NIH HHS/United States ; U01 CA244291/CA/NCI NIH HHS/United States ; P50 CA186781/CA/NCI NIH HHS/United States ; KL2 TR002317/TR/NCATS NIH HHS/United States ; R01 CA272426/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Hepatitis A Virus Cellular Receptor 2 ; *Multiple Myeloma/metabolism ; CD8-Positive T-Lymphocytes ; Phenotype ; *Hematologic Neoplasms ; Tumor Microenvironment ; },
abstract = {Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (TPHEX), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ[+] TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ[+] TPHEX. We also observed IFN-γ[+] TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19[+] leukemia cells. An IFN-γ[+] TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ[+] TPHEX represent a potential target for immunotherapy of blood cancers.},
}

Humans
Hepatitis A Virus Cellular Receptor 2
*Multiple Myeloma/metabolism
CD8-Positive T-Lymphocytes
Phenotype
*Hematologic Neoplasms
Tumor Microenvironment

@article {pmid38617337,
year = {2024},
author = {Grinde, KE and Browning, BL and Reiner, AP and Thornton, TA and Browning, SR},
title = {Adjusting for principal components can induce spurious associations in genome-wide association studies in admixed populations.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38617337},
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 ; HHSN268201300048C/HL/NHLBI NIH HHS/United States ; HHSN268201300049C/HL/NHLBI NIH HHS/United States ; HHSN268201800001C/HL/NHLBI NIH HHS/United States ; HHSN268201300046C/HL/NHLBI NIH HHS/United States ; R01 HL117626/HL/NHLBI NIH HHS/United States ; 75N92021D00004/WH/WHI NIH HHS/United States ; U01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL089897/HL/NHLBI NIH HHS/United States ; 75N92021D00001/HL/NHLBI NIH HHS/United States ; U01 HL089856/HL/NHLBI NIH HHS/United States ; R01 HG010869/HG/NHGRI NIH HHS/United States ; 75N92021D00003/WH/WHI NIH HHS/United States ; HHSN268201300047C/HL/NHLBI NIH HHS/United States ; HHSN268201300050C/HL/NHLBI NIH HHS/United States ; },
abstract = {Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.},
}

@article {pmid38295282,
year = {2024},
author = {Lineburg, KE and Leveque-El Mouttie, L and Hunter, CR and Le Texier, L and McGirr, C and Teal, B and Blazar, BR and Lane, SW and Hill, GR and Lévesque, JP and MacDonald, KPA},
title = {Autophagy prevents graft failure during murine graft-versus-host disease.},
journal = {Blood advances},
volume = {8},
number = {8},
pages = {2032-2043},
doi = {10.1182/bloodadvances.2023010972},
pmid = {38295282},
issn = {2473-9537},
support = {R01 HL056067/HL/NHLBI NIH HHS/United States ; R01 HL118979/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; *Graft vs Host Disease/etiology/prevention & control ; Mice ; *Autophagy ; *Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cells/metabolism/cytology ; Disease Models, Animal ; Transplantation, Homologous ; Graft Rejection ; Cytokines/metabolism ; },
abstract = {Autophagy is an intracellular survival process that has established roles in the long-term survival and function of hematopoietic stem cells (HSC). We investigated the contribution of autophagy to HSC fitness during allogeneic transplantation and graft-versus-host disease (GVHD). We demonstrate in vitro that both tumor necrosis factor and IL-1β, major components of GVHD cytokine storm, synergistically promote autophagy in both HSC and their more mature hematopoietic progenitor cells (HPC). In vivo we demonstrate that autophagy is increased in donor HSC and HPC during GVHD. Competitive transplant experiments demonstrated that autophagy-deficient cells display reduced capacity to reconstitute the hematopoietic system compared to wild-type counterparts. In a major histocompatibility complex-mismatched model of GVHD and associated cytokine dysregulation, we demonstrate that autophagy-deficient HSC and progenitors fail to establish durable hematopoiesis, leading to primary graft failure and universal transplant related mortality. Using several different models, we confirm that autophagy activity is increased in early progenitor and HSC populations in the presence of T-cell-derived inflammatory cytokines and that these HSC populations require autophagy to survive. Thus, autophagy serves as a key survival mechanism in HSC and progenitor populations after allogeneic stem cell transplant and may represent a therapeutic target to prevent graft failure during GVHD.},
}

Animals
*Graft vs Host Disease/etiology/prevention & control
Mice
*Autophagy
*Hematopoietic Stem Cell Transplantation/adverse effects
Hematopoietic Stem Cells/metabolism/cytology
Disease Models, Animal
Transplantation, Homologous
Graft Rejection
Cytokines/metabolism

@article {pmid38639810,
year = {2024},
author = {Oswald, LB and Bloomer, A and Li, X and Jean-Baptiste, E and Trujillo, G and Felder, S and Small, BJ and Ose, J and Hardikar, S and Strehli, I and Huang, LC and Mooney, K and Mutch, MG and Chao, D and Cohen, SA and Karchi, M and Wood, EH and Damerell, V and Loroña, NC and Gong, J and Toriola, AT and Li, CI and Shibata, D and Schneider, M and Gigic, B and Figueiredo, JC and Jim, HSL and Ulrich, CM and Siegel, EM},
title = {Functional quality of life among newly diagnosed young adult colorectal cancer survivors compared to older adults: results from the ColoCare Study.},
journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer},
volume = {32},
number = {5},
pages = {298},
pmid = {38639810},
issn = {1433-7339},
support = {U01CA206110//National Institutes of Health, National Cancer Institute/ ; U01CA206110//National Institutes of Health, National Cancer Institute/ ; R01CA254108//National Institutes of Health, National Cancer Institute/ ; U01CA206110//National Institutes of Health, National Cancer Institute/ ; U01CA206110//National Institutes of Health, National Cancer Institute/ ; U01CA206110//National Institutes of Health, National Cancer Institute/ ; 01KT1503//German Ministry of Education and Research/ ; 01KT1503//German Ministry of Education and Research/ ; R01NR018762//National Institutes of Health, National Institute of Nursing Research/ ; 09BN-13//Florida Department of Health Bankhead Coley Award/ ; },
mesh = {Aged ; Humans ; Young Adult ; *Cancer Survivors/psychology ; *Colorectal Neoplasms/therapy/psychology ; Emotions ; Quality of Life/psychology ; Survivors/psychology ; Adolescent ; Adult ; Middle Aged ; },
abstract = {PURPOSE: Colorectal cancer (CRC) incidence and mortality are increasing among young adults (YAs) aged 18-39. This study compared quality of life (QOL) between YA and older adult CRC survivors in the ColoCare Study.

METHODS: Participants were grouped by age (years) as follows: 18-39 (YA), 40-49, 50-64, and 65 + . Functional QOL (physical, social, role, emotional, cognitive) and global QOL were assessed with the EORTC-QLQ-C30 at enrollment, 3, 6, and 12 months. Average scores were compared between groups over time using longitudinal mixed-effect modeling. Proportions with clinically meaningful QOL impairment were calculated using age-relevant thresholds and compared between groups over time using logistic regression with mixed effects.

RESULTS: Participants (N = 1590) were n = 81 YAs, n = 196 aged 40-49, n = 627 aged 50-64, and n = 686 aged 65 + . Average physical function was better among YAs than participants aged 50-64 (p = 0.010) and 65 + (p < 0.001), and average social function was worse among YAs than aged 65 + (p = 0.046). Relative to YAs, all age groups were less likely to report clinically meaningful social dysfunction (aged 40-49 OR = 0.13, 95%CI = 0.06-0.29; aged 50-64 OR = 0.10, 95%CI = 0.05-0.21; aged 65 + OR = 0.07, 95%CI = 0.04-0.15) and role dysfunction (aged 40-49 OR = 0.36, 95%CI = 0.18-0.75; aged 50-64 OR = 0.41, 95%CI = 0.22-0.78; aged 65 + OR = 0.32, 95%CI = 0.17-0.61). Participants aged 40-49 were also less likely to report physical dysfunction (OR = 0.42, 95%CI = 0.19-0.93).

CONCLUSION: YA CRC survivors reported better physical and worse social function compared to older CRC survivors, and YA CRC survivors were more likely to report clinically meaningful social, role, and physical disfunction. Future work should further investigate QOL using age-relevant benchmarks to inform best practices for CRC survivorship care.

TRIAL REGISTRATION: NCT02328677, registered December 2014.},
}

Aged
Humans
Young Adult
*Cancer Survivors/psychology
*Colorectal Neoplasms/therapy/psychology
Emotions
Quality of Life/psychology
Survivors/psychology
Adolescent
Adult
Middle Aged

@article {pmid38638362,
year = {2023},
author = {Harrison, J and Stokes, T and Hahne, J and Shen, M},
title = {Ca-HELP: Adaptation of a Communication Tool to Help Geriatric Cancer Patients in Rural Settings Talk to Their Doctors About Pain.},
journal = {Innovation in aging},
volume = {7},
number = {10},
pages = {igad087},
pmid = {38638362},
issn = {2399-5300},
abstract = {BACKGROUND AND OBJECTIVES: Among the older adult population living in the rural United States, undertreated cancer pain is very common. The need for interventions targeting pain management communication between older adults with cancer in rural communities and their doctors outpaces the current evidence base. Adaptation of existing pain interventions may improve the speed at which clinicians can respond to pain in this vulnerable population.

RESEARCH DESIGN AND METHODS: The Cancer Health Empowerment for Living without Pain (Ca-HELP) is an evidence-based communication tool that coaches patients to communicate about pain by asking questions, making requests, and signaling distress to their physicians in order to achieve improved pain control. Guided by the Method for Program Adaptation through Community Engagement (M-PACE) model, which utilizes detailed stakeholder feedback to guide the adaptation of an intervention for an appropriate target audience, we proactively adapted the Ca-HELP and its delivery for use among geriatric cancer patients living in rural settings using qualitative feedback from patients, informal caregivers, and providers as a planned step in a multiphase pilot study.

RESULTS: All stakeholders agreed that the Ca-HELP was a promising candidate intervention to improve pain among older adults with cancer. They suggested modifications to the delivery, context, and content of the intervention. A multidisciplinary team of nurse leaders and researchers evaluated stakeholder feedback and recommendations before determining which adaptations were made. Adaptations were cataloged and reported using the Framework for Reporting Adaptations and Modifications-Enhanced model.

DISCUSSION AND IMPLICATIONS: Our multistakeholder team proactively modified the Ca-HELP intervention tool using end-user feedback with a goal to optimize fit for use by older adults with cancer in rural settings without compromising the active ingredients. Documenting and reporting modifications to interventions are critical to their implementation and will lay the groundwork for further testing of the efficacy of the adapted Ca-HELP intervention.},
}

@article {pmid38637498,
year = {2024},
author = {Keller, MD and Hanley, PJ and Chi, YY and Aguayo-Hiraldo, P and Dvorak, CC and Verneris, MR and Kohn, DB and Pai, SY and Dávila Saldaña, BJ and Hanisch, B and Quigg, TC and Adams, RH and Dahlberg, A and Chandrakasan, S and Hasan, H and Malvar, J and Jensen-Wachspress, MA and Lazarski, CA and Sani, G and Idso, JM and Lang, H and Chansky, P and McCann, CD and Tanna, J and Abraham, AA and Webb, JL and Shibli, A and Keating, AK and Satwani, P and Muranski, P and Hall, E and Eckrich, MJ and Shereck, E and Miller, H and Mamcarz, E and Agarwal, R and De Oliveira, SN and Vander Lugt, MT and Ebens, CL and Aquino, VM and Bednarski, JJ and Chu, J and Parikh, S and Whangbo, J and Lionakis, M and Zambidis, ET and Gourdine, E and Bollard, CM and Pulsipher, MA},
title = {Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3258},
pmid = {38637498},
issn = {2041-1723},
support = {U01 AI126612/AI/NIAID NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; KL2 TR002492/TR/NCATS NIH HHS/United States ; UG1 HL069254/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; Child ; *Epstein-Barr Virus Infections ; Herpesvirus 4, Human ; *Virus Diseases ; Risk Factors ; *Hematopoietic Stem Cell Transplantation/adverse effects ; },
abstract = {Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.},
}

Humans
Child
*Epstein-Barr Virus Infections
Herpesvirus 4, Human
*Virus Diseases
Risk Factors
*Hematopoietic Stem Cell Transplantation/adverse effects

@article {pmid38617334,
year = {2024},
author = {Lane, DD and Gottimukkala, KSV and Cunningham, RA and Jwa, S and Cassidy, ME and Castelli, JMP and Adair, JE},
title = {Cas9 RNP Physiochemical Analysis for Enhanced CRISPR-AuNP Assembly and Function.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38617334},
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 ; },
abstract = {CRISPR therapy for hematological disease has proven effective for transplant dependent beta thalassemia and sickle cell anemia, with additional disease targets in sight. The success of these therapies relies on high rates of CRISPR-induced double strand DNA breaks in hematopoietic stem and progenitor cells (HSPC). To achieve these levels, CRISPR complexes are typically delivered by electroporation ex vivo which is toxic to HSPCs. HSPCs are then cultured in stimulating conditions that promote error-prone DNA repair, requiring conditioning with chemotherapy to facilitate engraftment after reinfusion. In vivo delivery by nanocarriers of CRISPR gene editing tools has the potential to mitigate this complexity and toxicity and make this revolutionary therapy globally available. To achieve in vivo delivery, the inherent restriction factors against oligonucleotide delivery into HSPCs, that make ex vivo manipulation including electroporation and stimulation essential, must be overcome. To this end, our group developed a CRISPR carrying gold nanoparticle (CRISPR-AuNP) capable of delivering either Cas9 or Cas12a CRISPRs as ribonucleoprotein complexes (RNP) without compromising HSPC fitness. However, the most commonly used CRISPR, Cas9, demonstrated inconsistent activity in this delivery system, with lower activity relative to Cas12a. Investigation of Cas9 RNP biophysics relative to Cas12a revealed duplex RNA instability during the initial loading onto Au cores, resulting in undetectable Cas9 loading to the particle surface. Here we demonstrate preformation of RNP before loading, coupled with optimization of the loading chemistry and conditions, resulted in 39.6 ± 7.0 Cas9 RNP/AuNP without compromising RNP activity in both in vitro assays and primary human HSPC. The same alterations improved Cas12a RNP/AuNP loading 10-fold over previously reported levels. To achieve particle stability, the reported polyethyleneimine outer coating was altered to include PEGylation and the resulting 2[nd] generation CRISPR-AuNP demonstrates favorable nanoformulation characteristics for in vivo administration, with a hydrophilic, more neutral nanoparticle surface. Direct treatment of HSPC in vitro showed 72.5 ± 7.37% uptake of 2[nd] generation CRISPR-AuNP in primary human HSPC, but with endosomal accumulation and low rates of gene editing consistent with low levels of endosomal escape.},
}

@article {pmid38636793,
year = {2024},
author = {Sidahmed, E and Freedland, SJ and Wang, M and Wu, K and Albanes, D and Barnett, M and van den Brandt, PA and Cook, MB and Giles, GG and Giovannucci, E and Haiman, CA and Larsson, SC and Key, TJ and Loftfield, E and Männistö, S and McCullough, ML and Milne, RL and Neuhouser, ML and Platz, EA and Perez-Cornago, A and Sawada, N and Schenk, JM and Sinha, R and Tsugane, S and Visvanathan, K and Wang, Y and White, KK and Willett, WC and Wolk, A and Ziegler, RG and Genkinger, JM and Smith-Warner, SA},
title = {Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.},
journal = {Journal of the Academy of Nutrition and Dietetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jand.2024.04.006},
pmid = {38636793},
issn = {2212-2672},
abstract = {BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited.

OBJECTIVE: To examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC.

DESIGN: Pooled analysis of the primary data in 15 cohorts in three continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study.

PARTICIPANTS/SETTING: 842,149 men were followed for up to 9-22 years between 1985-2009 across studies.

MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), high grade (Gleason score ≥8 or poorly differentiated/undifferentiated) PC, and PC mortality.

STATISTICAL ANALYSIS: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models.

RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n=4,863), advanced restricted (n=2,978), or high-grade PC (n=9,673) or PC mortality (n=3,097). Dietary fiber intake from grains was inversely associated with advanced PC (MVHR comparing the highest vs. lowest quintile=0.84, 95% confidence interval [CI] 0.76-0.93), advanced restricted PC (MVHR=0.85, 95%CI 0.74-0.97), and PC mortality (MVHR=0.78, 95%CI 0.68-0.89); statistically significant trends were noted for each of these associations (p≤0.03), while a null association was observed for high grade PC for the same comparison (MVHR=1.00, 95%CI 0.93-1.07). The comparable results were 1.06 (95%CI 1.01-1.10, p-value, test for trend=0.002) for localized (n=35,199) and 1.05 (95%CI 0.99-1.11, , p-value, test for trend=0.04) for low/intermediate grade (n=34,366) PC.

CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.},
}

@article {pmid38636510,
year = {2024},
author = {Sun, Q and Yang, Y and Rosen, JD and Chen, J and Li, X and Guan, W and Jiang, MZ and Wen, J and Pace, RG and Blackman, SM and Bamshad, MJ and Gibson, RL and Cutting, GR and O'Neal, WK and Knowles, MR and Kooperberg, C and Reiner, AP and Raffield, LM and Carson, AP and Rich, SS and Rotter, JI and Loos, RJF and Kenny, E and Jaeger, BC and Min, YI and Fuchsberger, C and Li, Y},
title = {MagicalRsq-X: A cross-cohort transferable genotype imputation quality metric.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2024.04.001},
pmid = {38636510},
issn = {1537-6605},
abstract = {Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed markers from the same cohort and outperforms Rsq as a QC metric. In this work, we extended the original MagicalRsq to allow cross-cohort model training and named the new model MagicalRsq-X. We removed the cohort-specific estimated minor allele frequency and included linkage disequilibrium scores and recombination rates as additional features. Leveraging whole-genome sequencing data from TOPMed, specifically participants in the BioMe, JHS, WHI, and MESA studies, we performed comprehensive cross-cohort evaluations for predominantly European and African ancestral individuals based on their inferred global ancestry with the 1000 Genomes and Human Genome Diversity Project data as reference. Our results suggest MagicalRsq-X outperforms Rsq in almost every setting, with 7.3%-14.4% improvement in squared Pearson correlation with true R[2], corresponding to 85-218 K variant gains. We further developed a metric to quantify the genetic distances of a target cohort relative to a reference cohort and showed that such metric largely explained the performance of MagicalRsq-X models. Finally, we found MagicalRsq-X saved up to 53 known genome-wide significant variants in one of the largest blood cell trait GWASs that would be missed using the original Rsq for QC. In conclusion, MagicalRsq-X shows superiority for post-imputation QC and benefits genetic studies by distinguishing well and poorly imputed lower-frequency variants.},
}

@article {pmid38635788,
year = {2024},
author = {Kampouri, E and Krantz, EM and Xie, H and Ibrahimi, SS and Kiem, ES and Sekhon, MK and Liang, EC and Cowan, AJ and Portuguese, AJ and Green, DJ and Albittar, A and Huang, JJ and Gauthier, J and Pérez-Osorio, AC and Jerome, KR and Zerr, D and Boeckh, MJ and Hill, JA},
title = {Human Herpesvirus-6 Reactivation and Disease Are Infrequent in Chimeric Antigen Receptor T-cell Therapy Recipients.},
journal = {Blood},
volume = {},
number = {},
pages = {},
doi = {10.1182/blood.2024024145},
pmid = {38635788},
issn = {1528-0020},
abstract = {Human herpesvirus-6B (HHV-6B) reactivation and disease are increasingly reported after CAR-T-cell therapy (CARTx). HHV-6 reactivation in the CAR-T-cell product was recently reported, raising questions about product and patient management. Due to overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide two lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks post-infusion, HHV-6B reactivation occurred in eight of 89 participants; three had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval (CI), 2.2-12.5%). HHV-6B detection was low level (median peak, 435 copies/mL; IQR, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in blood and/or cerebrospinal fluid (CSF) within 12 weeks post-infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing with detection in one. Among 34 patients with CSF HHV-6 testing, one patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94%), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.},
}

@article {pmid38635762,
year = {2024},
author = {Locke, FL and Siddiqi, T and Jacobson, CA and Ghobadi, A and Ahmed, S and Miklos, DB and Perales, MA and Munoz, J and Fingrut, WB and Pennisi, M and Gauthier, J and Shadman, M and Gowda, L and Mirza, AS and Abid, MB and Hong, S and Majhail, NS and Kharfan-Dabaja, MA and Khurana, A and Badar, T and Lin, Y and Bennani, NN and Herr, MM and Hu, ZH and Wang, H and Baer, A and Baro, E and Miao, H and Spooner, C and Xu, H and Pasquini, MC},
title = {Real-World and Clinical Trial Outcomes in Large B-cell Lymphoma with Axicabtagene Ciloleucel Across Race and Ethnicity.},
journal = {Blood},
volume = {},
number = {},
pages = {},
doi = {10.1182/blood.2023023447},
pmid = {38635762},
issn = {1528-0020},
abstract = {Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting the use of axi-cel in patients with LBCL, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients with R/R LBCL who received axi-cel between 2017-2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 clinical trials, respectively. Adjusted odds ratio (OR) and hazard ratio (HR) for race and ethnicity groups are reported. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37, [95% CI, 0.22-0.63]) and lower complete response rate (OR, 0.57, [95% CI, 0.33-0.97]) than NH-white patients. NH-Black patients also had a shorter progression-free survival versus NH-white (HR, 1.41, [95% CI, 1.04-1.90]) and NH-Asian patients (HR, 1.67, [95% CI, 1.08-2.59]). NH-Asian patients had a longer duration of response compared with NH-white (HR, 0.56, [95% CI, 0.33-0.94]) and Hispanic patients (HR, 0.54, [95% CI, 0.30-0.97]). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade ICANS were observed in NH-white patients compared with other patients. These results provide important context when treating patients with R/R LBCL with axi-cel across different racial and ethnic groups. ZUMA-1 (NCT02348216) and ZUMA-7 (NCT03391466), both registered on ClinicalTrials.gov.},
}

@article {pmid38635416,
year = {2024},
author = {Larouche, JD and Laumont, CM and Trofimov, A and Vincent, K and Hesnard, L and Brochu, S and Côté, C and Humeau, JF and Bonneil, É and Lanoix, J and Durette, C and Gendron, P and Laverdure, JP and Richie, ER and Lemieux, S and Thibault, P and Perreault, C},
title = {Transposable elements regulate thymus development and function.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
pmid = {38635416},
issn = {2050-084X},
support = {FDN 148400/CAPMC/CIHR/Canada ; },
abstract = {Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDCs). In mTECs, transcriptomic data suggest that TEs interact with transcription factors essential for mTEC development and function (e.g., PAX1 and REL), and immunopeptidomic data showed that TEs generate MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 regulate small yet non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large numbers of TEs that likely form dsRNA, which can activate innate immune receptors, potentially explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study highlights the diversity of interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. Therefore, we propose that orchestrating TE expression in thymic cells is critical to prevent autoimmunity in vertebrates.},
}

@article {pmid38635241,
year = {2024},
author = {Tosoian, JJ and Zhang, Y and Xiao, L and Xie, C and Samora, NL and Niknafs, YS and Chopra, Z and Siddiqui, J and Zheng, H and Herron, G and Vaishampayan, N and Robinson, HS and Arivoli, K and Trock, BJ and Ross, AE and Morgan, TM and Palapattu, GS and Salami, SS and Kunju, LP and Tomlins, SA and Sokoll, LJ and Chan, DW and Srivastava, S and Feng, Z and Sanda, MG and Zheng, Y and Wei, JT and Chinnaiyan, AM and , },
title = {Development and Validation of an 18-Gene Urine Test for High-Grade Prostate Cancer.},
journal = {JAMA oncology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoncol.2024.0455},
pmid = {38635241},
issn = {2374-2445},
abstract = {IMPORTANCE: Benefits of prostate cancer (PCa) screening with prostate-specific antigen (PSA) alone are largely offset by excess negative biopsies and overdetection of indolent cancers resulting from the poor specificity of PSA for high-grade PCa (ie, grade group [GG] 2 or greater).

OBJECTIVE: To develop a multiplex urinary panel for high-grade PCa and validate its external performance relative to current guideline-endorsed biomarkers.

RNA sequencing analysis of 58 724 genes identified 54 markers of PCa, including 17 markers uniquely overexpressed by high-grade cancers. Gene expression and clinical factors were modeled in a new urinary test for high-grade PCa (MyProstateScore 2.0 [MPS2]). Optimal models were developed in parallel without prostate volume (MPS2) and with prostate volume (MPS2+). The locked models underwent blinded external validation in a prospective National Cancer Institute trial cohort. Data were collected from January 2008 to December 2020, and data were analyzed from November 2022 to November 2023.

EXPOSURE: Protocolized blood and urine collection and transrectal ultrasound-guided systematic prostate biopsy.

MAIN OUTCOMES AND MEASURES: Multiple biomarker tests were assessed in the validation cohort, including serum PSA alone, the Prostate Cancer Prevention Trial risk calculator, and the Prostate Health Index (PHI) as well as derived multiplex 2-gene and 3-gene models, the original 2-gene MPS test, and the 18-gene MPS2 models. Under a testing approach with 95% sensitivity for PCa of GG 2 or greater, measures of diagnostic accuracy and clinical consequences of testing were calculated. Cancers of GG 3 or greater were assessed secondarily.

RESULTS: Of 761 men included in the development cohort, the median (IQR) age was 63 (58-68) years, and the median (IQR) PSA level was 5.6 (4.6-7.2) ng/mL; of 743 men included in the validation cohort, the median (IQR) age was 62 (57-68) years, and the median (IQR) PSA level was 5.6 (4.1-8.0) ng/mL. In the validation cohort, 151 (20.3%) had high-grade PCa on biopsy. Area under the receiver operating characteristic curve values were 0.60 using PSA alone, 0.66 using the risk calculator, 0.77 using PHI, 0.76 using the derived multiplex 2-gene model, 0.72 using the derived multiplex 3-gene model, and 0.74 using the original MPS model compared with 0.81 using the MPS2 model and 0.82 using the MPS2+ model. At 95% sensitivity, the MPS2 model would have reduced unnecessary biopsies performed in the initial biopsy population (range for other tests, 15% to 30%; range for MPS2, 35% to 42%) and repeat biopsy population (range for other tests, 9% to 21%; range for MPS2, 46% to 51%). Across pertinent subgroups, the MPS2 models had negative predictive values of 95% to 99% for cancers of GG 2 or greater and of 99% for cancers of GG 3 or greater.

CONCLUSIONS AND RELEVANCE: In this study, a new 18-gene PCa test had higher diagnostic accuracy for high-grade PCa relative to existing biomarker tests. Clinically, use of this test would have meaningfully reduced unnecessary biopsies performed while maintaining highly sensitive detection of high-grade cancers. These data support use of this new PCa biomarker test in patients with elevated PSA levels to reduce the potential harms of PCa screening while preserving its long-term benefits.},
}

@article {pmid38634730,
year = {2024},
author = {Konecny, AJ and Mage, PL and Tyznik, AJ and Prlic, M and Mair, F},
title = {OMIP-102: 50-color phenotyping of the human immune system with in-depth assessment of T cells and dendritic cells.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {},
number = {},
pages = {},
doi = {10.1002/cyto.a.24841},
pmid = {38634730},
issn = {1552-4930},
support = {R01 AI123323/AI/NIAID NIH HHS/United States ; R56 DE032009/DE/NIDCR NIH HHS/United States ; },
abstract = {We report the development of an optimized 50-color spectral flow cytometry panel designed for the in-depth analysis of the immune system in human blood and tissues, with the goal of maximizing the amount of information that can be collected using currently available flow cytometry platforms. We established and tested this panel using peripheral blood mononuclear cells (PBMCs), but included CD45 to enable its future use for the analysis of human tissue samples. The panel contains lineage markers for all major immune cell subsets, and an extensive set of phenotyping markers focused on the activation and differentiation status of the T cell and dendritic cell (DC) compartment. We outline the biological insight that can be gained from the simultaneous measurement of such a large number of proteins and propose that this approach provides a unique opportunity for the comprehensive exploration of the immune status in human samples with a limited number of cells. Of note, we tested the panel to be compatible with cell sorting for further downstream applications. Furthermore, to facilitate the wide-spread implementation of such a panel across different cohorts and samples, we established a trimmed-down 45-color version which can be used with different spectral cytometry platforms. Finally, to generate this panel, we utilized not only existing panel design guidelines, but also developed new metrics to systematically identify the optimal combination of 50 fluorochromes and evaluate fluorochrome-specific resolution in the context of a 50-color unmixing matrix.},
}

@article {pmid38634655,
year = {2024},
author = {De Rosa, SC and Mahnke, YD},
title = {Setting the gold standard: Commentary on designing and optimizing high-parameter flow cytometry panels.},
journal = {Cytometry. Part A : the journal of the International Society for Analytical Cytology},
volume = {},
number = {},
pages = {},
doi = {10.1002/cyto.a.24844},
pmid = {38634655},
issn = {1552-4930},
support = {/NH/NIH HHS/United States ; },
}

@article {pmid38633407,
year = {2024},
author = {Webster, AP and Ecker, S and Moghul, I and Liu, X and Dhami, P and Marzi, S and Paul, DS and Kuxhausen, M and Lee, SJ and Spellman, SR and Wang, T and Feber, A and Rakyan, V and Peggs, KS and Beck, S},
title = {Donor whole blood DNA methylation is not a strong predictor of acute graft versus host disease in unrelated donor allogeneic haematopoietic cell transplantation.},
journal = {Frontiers in genetics},
volume = {15},
number = {},
pages = {1242636},
pmid = {38633407},
issn = {1664-8021},
abstract = {Allogeneic hematopoietic cell transplantation (HCT) is used to treat many blood-based disorders and malignancies, however it can also result in serious adverse events, such as the development of acute graft-versus-host disease (aGVHD). This study aimed to develop a donor-specific epigenetic classifier to reduce incidence of aGVHD by improving donor selection. Genome-wide DNA methylation was assessed in a discovery cohort of 288 HCT donors selected based on recipient aGVHD outcome; this cohort consisted of 144 cases with aGVHD grades III-IV and 144 controls with no aGVHD. We applied a machine learning algorithm to identify CpG sites predictive of aGVHD. Receiver operating characteristic (ROC) curve analysis of these sites resulted in a classifier with an encouraging area under the ROC curve (AUC) of 0.91. To test this classifier, we used an independent validation cohort (n = 288) selected using the same criteria as the discovery cohort. Attempts to validate the classifier failed with the AUC falling to 0.51. These results indicate that donor DNA methylation may not be a suitable predictor of aGVHD in an HCT setting involving unrelated donors, despite the initial promising results in the discovery cohort. Our work highlights the importance of independent validation of machine learning classifiers, particularly when developing classifiers intended for clinical use.},
}

@article {pmid38632891,
year = {2024},
author = {Patterson, JG and McQuoid, J and Heffner, JL and Ye, Q and Ennis, AC and Ganz, O and Tan, ASL},
title = {Resonating with Pride: Considerations for Tailoring Tobacco Interventions for LGBTQ+ Communities.},
journal = {Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco},
volume = {},
number = {},
pages = {},
doi = {10.1093/ntr/ntae087},
pmid = {38632891},
issn = {1469-994X},
}

@article {pmid38630732,
year = {2024},
author = {Banack, HR and Wactawski-Wende, J and Ochs-Balcom, HM and Feliciano, EMC and Caan, B and Lee, C and Anderson, G and Shankaran, M and Evans, WJ},
title = {A protocol for remote collection of skeletal muscle mass via D3-creatine dilution in community-dwelling postmenopausal women from the Women's Health Initiative.},
journal = {PloS one},
volume = {19},
number = {4},
pages = {e0300140},
pmid = {38630732},
issn = {1932-6203},
abstract = {BACKGROUND: There is emerging evidence that cancer and its treatments may accelerate the normal aging process, increasing the magnitude and rate of decline in functional capacity. This accelerated aging process is hypothesized to hasten the occurrence of common adverse age-related outcomes in cancer survivors, including loss of muscle mass and decrease in physical function. However, there is no data describing age-related loss of muscle mass and its relation to physical function in the long-term in cancer survivors.

METHODS: This study protocol describes the use of a novel method of muscle mass measurement, D3-creatine dilution method (D3Cr), in a large sample (n~6000) of community dwelling postmenopausal women from the Women's Health Initiative (WHI). D3Cr will be used to obtain a direct measure of muscle mass remotely. Participants will be drawn from two sub-cohorts embedded within the WHI that have recently completed an in-home visit. Cancer survivors will be drawn from the Life and Longevity After Cancer (LILAC) cohort, and cancer-free controls will be drawn from the WHI Long Life Study 2. The overall objective of this study is to examine the antecedents and consequences of low muscle mass in cancer survivors. The study aims are to: 1) create age-standardized muscle mass percentile curves and z-scores to characterize the distribution of D3- muscle mass in cancer survivors and non-cancer controls, 2) compare muscle mass, physical function, and functional decline in cancer survivors and non- cancer controls, and 3) use machine learning approaches to generate multivariate risk-prediction algorithms to detect low muscle mass.

DISCUSSION: The D3Cr method will transform our ability to measure muscle mass in large-scale epidemiologic research. This study is an opportunity to advance our understanding of a key source of morbidity among older and long-term female cancer survivors. This project will fill knowledge gaps, including the antecedents and consequences of low muscle mass, and use innovative methods to overcome common sources of bias in cancer research. The results of this study will be used to develop interventions to mitigate the harmful effects of low muscle mass in older adults and promote healthy survivorship in cancer survivors in the old (>65) and oldest-old (>85) age groups.},
}

@article {pmid38629238,
year = {2024},
author = {Greteman, BB and Del Vecchio, NJ and Garcia-Auguste, CJ and Kahl, AR and Gryzlak, BM and Chrischilles, EA and Charlton, ME and Nash, SH},
title = {Identifying predictors of COVID-related delays in cancer-specific medical care.},
journal = {Cancer medicine},
volume = {13},
number = {8},
pages = {e7183},
pmid = {38629238},
issn = {2045-7634},
support = {HHSN261201800012I/HHSN26100001/3P30CA086862/CA/NCI NIH HHS/United States ; COVID-19 Supplement Grant 3P30CA086862-19S5/CA/NCI NIH HHS/United States ; },
mesh = {Male ; Humans ; *COVID-19/epidemiology ; Pandemics ; Delivery of Health Care ; Patient Care ; *Neoplasms/epidemiology/therapy ; },
abstract = {PURPOSE: Evidence of the impact of the COVID-19 pandemic on cancer prevention and control is growing, but little is known about patient-level factors associated with delayed care. We analyzed data from a survey focused on Iowan cancer patients' COVID-19 experiences in the early part of the pandemic.

METHODS: Participants were recruited from the University of Iowa Holden Comprehensive Cancer Center's Patients Enhancing Research Collaborations at Holden (PERCH) program. We surveyed respondents on demographic characteristics, COVID-19 experiences and reactions, and delays in any cancer-related health care appointment, or cancer-related treatment appointments. Two-sided significance tests assessed differences in COVID-19 experiences and reactions between those who experienced delays and those who did not.

RESULTS: There were 780 respondents (26% response), with breast, prostate, kidney, skin, and colorectal cancers representing the majority of respondents. Delays in cancer care were reported by 29% of respondents. In multivariable-adjusted models, rural residents (OR 1.47; 95% CI 1.03, 2.11) and those experiencing feelings of isolation (OR 2.18; 95% CI 1.37, 3.47) were more likely to report any delay, where experiencing financial difficulties predicted delays in treatment appointments (OR 5.72; 95% CI 1.96, 16.67). Health insurance coverage and concern about the pandemic were not statistically significantly associated with delays.

CONCLUSION: These findings may inform cancer care delivery during periods of instability when treatment may be disrupted by informing clinicians about concerns that patients have during the treatment process. Future research should assess whether delays in cancer care impact long-term cancer outcomes and whether delays exacerbate existing disparities in cancer outcomes.},
}

Male
Humans
*COVID-19/epidemiology
Pandemics
Delivery of Health Care
Patient Care
*Neoplasms/epidemiology/therapy

@article {pmid38627946,
year = {2024},
author = {Ergas, IJ and Cheng, RK and Roh, JM and Kushi, LH and Kresovich, JK and Iribarren, C and Nguyen-Huynh, M and Rana, JS and Rillamas-Sun, E and Laurent, CA and Lee, VS and Quesenberry, CP and Greenlee, H and Kwan, ML},
title = {Diet quality and cardiovascular disease risk among breast cancer survivors in the Pathways Study.},
journal = {JNCI cancer spectrum},
volume = {8},
number = {2},
pages = {},
pmid = {38627946},
issn = {2515-5091},
support = {R01CA214057/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Female ; *Breast Neoplasms/epidemiology ; *Cardiovascular Diseases/epidemiology ; Prospective Studies ; *Cancer Survivors ; Diet/adverse effects ; *Heart Failure ; Arrhythmias, Cardiac ; },
abstract = {BACKGROUND: Women with breast cancer are at higher risk of cardiovascular disease (CVD) compared with women without breast cancer. Whether higher diet quality at breast cancer diagnosis lowers this risk remains unknown. We set out to determine if higher diet quality at breast cancer diagnosis was related to lower risk of CVD and CVD-related death.

METHODS: This analysis included 3415 participants from the Pathway Study, a prospective cohort of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California between 2005 and 2013 and followed through December 31, 2021. Scores from 5 diet quality indices consistent with healthy eating were obtained at the time of breast cancer diagnosis. Scores were categorized into ascending quartiles of concordance for each diet quality index, and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. P values were 2-sided.

RESULTS: The Dietary Approaches to Stop Hypertension diet quality index was associated with lower risk of heart failure (HR = 0.53, 95% CI = 0.33 to 0.87; Ptrend = .03), arrhythmia (HR = 0.77, 95% CI = 0.62 to 0.94; Ptrend = .008), cardiac arrest (HR = 0.77, 95% CI = 0.61 to 0.96; Ptrend = .02), valvular heart disease (HR = 0.79, 95% CI = 0.64 to 0.98; Ptrend = .046), venous thromboembolic disease (HR = 0.75, 95% CI = 0.60 to 0.93; Ptrend = .01), and CVD-related death (HR = 0.70, 95% CI = 0.50 to 0.99; Ptrend = .04), when comparing the highest with lowest quartiles. Inverse associations were also found between the healthy plant-based dietary index and heart failure (HR = 0.60, 95% CI = 0.39 to 0.94; Ptrend = .02), as well as the alternate Mediterranean dietary index and arrhythmia (HR = 0.74, 95% CI = 0.60 to 0.93; Ptrend = .02).

CONCLUSION: Among newly diagnosed breast cancer patients, higher diet quality at diagnosis was associated with lower risk of CVD events and death.},
}

Humans
Female
*Breast Neoplasms/epidemiology
*Cardiovascular Diseases/epidemiology
Prospective Studies
*Cancer Survivors
Diet/adverse effects
*Heart Failure
Arrhythmias, Cardiac

@article {pmid38627450,
year = {2024},
author = {Liang, EC and Rejeski, K and Fei, T and Albittar, A and Huang, JJ and Portuguese, AJ and Wu, Q and Raj, S and Subklewe, M and Shouval, R and Gauthier, J},
title = {Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.},
journal = {Bone marrow transplantation},
volume = {},
number = {},
pages = {},
pmid = {38627450},
issn = {1476-5365},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; },
abstract = {Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.},
}

@article {pmid38626801,
year = {2024},
author = {Schaeffer, EM and Srinivas, S and Adra, N and An, Y and Bitting, R and Chapin, B and Cheng, HH and D'Amico, AV and Desai, N and Dorff, T and Eastham, JA and Farrington, TA and Gao, X and Gupta, S and Guzzo, T and Ippolito, JE and Karnes, RJ and Kuettel, MR and Lang, JM and Lotan, T and McKay, RR and Morgan, T and Pow-Sang, JM and Reiter, R and Roach, M and Robin, T and Rosenfeld, S and Shabsigh, A and Spratt, D and Szmulewitz, R and Teply, BA and Tward, J and Valicenti, R and Wong, JK and Snedeker, J and Freedman-Cass, DA},
title = {Prostate Cancer, Version 3.2024.},
journal = {Journal of the National Comprehensive Cancer Network : JNCCN},
volume = {22},
number = {3},
pages = {140-150},
doi = {10.6004/jnccn.2024.0019},
pmid = {38626801},
issn = {1540-1413},
mesh = {Male ; Humans ; *Prostatic Neoplasms/diagnosis/therapy ; Risk Assessment ; *Neoplasms, Second Primary ; },
abstract = {The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.},
}

Male
Humans
*Prostatic Neoplasms/diagnosis/therapy
Risk Assessment
*Neoplasms, Second Primary

@article {pmid38626800,
year = {2024},
author = {Wierda, WG and Brown, J and Abramson, JS and Awan, F and Bilgrami, SF and Bociek, G and Brander, D and Cortese, M and Cripe, L and Davis, RS and Eradat, H and Fakhri, B and Fletcher, CD and Gaballa, S and Hamid, MS and Hill, B and Kaesberg, P and Kahl, B and Kamdar, M and Kipps, TJ and Ma, S and Mosse, C and Nakhoda, S and Parikh, S and Schorr, A and Schuster, S and Seshadri, M and Siddiqi, T and Stephens, DM and Thompson, M and Ujjani, C and Valdez, R and Wagner-Johnston, N and Woyach, JA and Sundar, H and Dwyer, M},
title = {Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024.},
journal = {Journal of the National Comprehensive Cancer Network : JNCCN},
volume = {22},
number = {3},
pages = {175-204},
doi = {10.6004/jnccn.2024.0018},
pmid = {38626800},
issn = {1540-1413},
mesh = {Humans ; *Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/drug therapy/genetics ; Prognosis ; Immunotherapy ; },
abstract = {Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.},
}

Humans
*Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/drug therapy/genetics
Prognosis
Immunotherapy

@article {pmid38623592,
year = {2024},
author = {Wang, L and Slaughter, F and Nguyen, AT and Smith, S and Prabhu, S and Beima-Sofie, K and Wallace, S and Crane, HM and Simoni, JM and Graham, SM},
title = {Impact of the COVID-19 pandemic on mental health and viral suppression among persons living with HIV in western Washington.},
journal = {AIDS care},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/09540121.2024.2341220},
pmid = {38623592},
issn = {1360-0451},
abstract = {The COVID-19 pandemic and social distancing measures elevated stress levels globally, exacerbating mental health challenges for people with HIV (PWH). We examined the effect of COVID-19-related stress on mental health among PWH in western Washington, exploring whether social support and coping self-efficacy were protective. Data on COVID-19-related stress, mental health, social support, and coping self-efficacy were collected using online surveys during the pandemic. Pre-COVID-19 mental health data were available for a subset of participants and were linked with the survey data. In the total sample (N = 373), COVID-19-stress was associated with elevated depression (PHQ-8, β = 0.21, 95%CI [0.10, 0.32]) and anxiety (GAD-7, β = 0.28, 95%CI [0.17, 0.39]). Among the subset of respondents with pre-pandemic mental health data (N = 103), COVID-19-related stress was associated with elevated PHQ-8 scores (β = 0.35, 95%CI [0.15, 0.56]) and GAD-7 scores (β = 0.35, 95%CI [0.16, 0.54]), adjusted for baseline mental health and other confounders. Coping self-efficacy was negatively associated with GAD-7 scores (β = -0.01, 95%CI [-0.01, 0.00]), while social support was negatively associated with PHQ-8 scores (β = -0.06, 95%CI [-0.12, -0.01]). Viral suppression before and during the pandemic did not differ among participants with available data. While COVID-19-related stress predicted elevated depression and anxiety symptoms among PWH, social support and coping self-efficacy were protective.},
}

@article {pmid38623380,
year = {2024},
author = {Persky, V and Abasilim, C and Tsintsifas, K and Day, T and Sargis, RM and Daviglus, M and Cai, J and Freels, S and Kaplan, R and Isasi, CR and Pirzada, A and Meyer, ML and Talavera, GA and Thyagarajan, B and Agarwal, S and Chavez, N and Grieco, A and Turyk, ME},
title = {Thyroid Hormones and Diabetes in Euthyroid Hispanic/Latino Adults of Diverse Backgrounds: HCHS/SOL.},
journal = {Journal of the Endocrine Society},
volume = {8},
number = {6},
pages = {bvae039},
pmid = {38623380},
issn = {2472-1972},
abstract = {CONTEXT: Previous studies have demonstrated associations of endogenous thyroid hormones with diabetes; less is known about stages of diabetes development at which they are operative, mechanisms of associations, and the role of the hypothalamic-pituitary-thyroid axis.

OBJECTIVE: This study examined associations of thyroid hormones with incident prediabetes and diabetes and with changes in glycemic traits in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the largest cohort of Hispanic/Latino adults with diverse backgrounds in the United States.

METHODS: The study includes 592 postmenopausal euthyroid women and 868 euthyroid men aged 45 to 74 years without diabetes at baseline participating in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Baseline hormones included thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (T3), and indices calculated from thyroid hormones evaluating pituitary sensitivity to thyroid hormone. Transitions to diabetes and prediabetes, and changes in glycemic traits determined at the 6-year follow-up visit, were examined using multivariable Poisson and linear regressions.

RESULTS: Among women, T3 (incident rate ratio [IRR] = 1.65; 95% CI, 1.22-2.24; P = .001) and TSH (IRR = 2.09; 95% CI, 1.01-4.33; P = .047) were positively, while FT4 (IRR = 0.59; 95% CI, 0.39-0.88; P = .011) was inversely, associated with transition from prediabetes to diabetes. Among men, the T3/FT4 ratio was positively associated with transition from normoglycemia to prediabetes but not from prediabetes to diabetes. Indices measuring sensitivity of the pituitary to thyroid hormone suggested increased sensitivity in men who transitioned from prediabetes to diabetes.

CONCLUSION: Positive associations in women of T3 and TSH and inverse associations of FT4, as well as inverse associations of thyroid indices in men with transition from prediabetes to diabetes, but not from normoglycemia to diabetes, suggest decreased pituitary sensitivity to thyroid hormones in women and increased sensitivity in men later in the development of diabetes.},
}

@article {pmid38622850,
year = {2024},
author = {Lim, JJ and Chen, EY and Schaub, SK and Wagner, MJ},
title = {Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma.},
journal = {Molecular genetics & genomic medicine},
volume = {12},
number = {4},
pages = {e2423},
pmid = {38622850},
issn = {2324-9269},
mesh = {Female ; Humans ; Adult ; *Protein-Tyrosine Kinases/genetics ; Anaplastic Lymphoma Kinase/genetics ; In Situ Hybridization, Fluorescence ; Proto-Oncogene Proteins/genetics ; *Sarcoma/drug therapy/genetics/pathology ; High-Throughput Nucleotide Sequencing ; Ubiquitin Thiolesterase/genetics ; Vesicular Transport Proteins/genetics ; },
abstract = {BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial.

METHODS AND RESULTS: We report a case of a metastatic sarcoma in a 34-year-old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG-ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG-ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit.

CONCLUSIONS: We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.},
}

Female
Humans
Adult
*Protein-Tyrosine Kinases/genetics
Anaplastic Lymphoma Kinase/genetics
In Situ Hybridization, Fluorescence
Proto-Oncogene Proteins/genetics
*Sarcoma/drug therapy/genetics/pathology
High-Throughput Nucleotide Sequencing
Ubiquitin Thiolesterase/genetics
Vesicular Transport Proteins/genetics

@article {pmid38618958,
year = {2024},
author = {Hansen, UK and Church, CD and Carnaz Simões, AM and Frej, MS and Bentzen, AK and Tvingsholm, SA and Becker, JC and Fling, SP and Ramchurren, N and Topalian, SL and Nghiem, PT and Hadrup, SR},
title = {T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma.},
journal = {The Journal of clinical investigation},
volume = {134},
number = {8},
pages = {},
doi = {10.1172/JCI177082},
pmid = {38618958},
issn = {1558-8238},
mesh = {Humans ; Antigens, Viral, Tumor ; *Carcinoma, Merkel Cell/drug therapy/genetics ; Programmed Cell Death 1 Receptor/genetics ; CD8-Positive T-Lymphocytes ; *Skin Neoplasms/drug therapy/genetics ; },
abstract = {Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.},
}

Humans
Antigens, Viral, Tumor
*Carcinoma, Merkel Cell/drug therapy/genetics
Programmed Cell Death 1 Receptor/genetics
CD8-Positive T-Lymphocytes
*Skin Neoplasms/drug therapy/genetics

@article {pmid38617425,
year = {2024},
author = {VoPham, T and Ton, M and Weaver, MD},
title = {Spatiotemporal light exposure modeling for environmental circadian misalignment and solar jetlag.},
journal = {Environmental epidemiology (Philadelphia, Pa.)},
volume = {8},
number = {2},
pages = {e301},
pmid = {38617425},
issn = {2474-7882},
abstract = {BACKGROUND: Light exposure is the most powerful resetting signal for circadian rhythms. The objective of this study was to develop and validate a high-resolution geospatial light exposure model that measures environmental circadian misalignment (or solar jetlag) as the mismatch between the social clock and sun clock, which occurs from geographic variation in light exposure leading to delayed circadian phase from relatively less morning light exposure and greater evening light exposure with increasing westward position within a time zone.

METHODS: The light exposure model (30 m[2] spatial resolution) incorporated geospatial data across the United States on time zones, elevation (using Google Earth Engine), sunrise time, and sunset time to estimate solar jetlag scores (higher values indicate higher environmental circadian misalignment). The validation study compared the light exposure model in 2022, which was linked with geocoded residential addresses of n = 20 participants in Boston, MA (eastern time zone position) and Seattle, WA (western time zone position) using a geographic information system, with illuminance values captured from wearable LYS light sensors and with sun times from the Solar Calculator.

RESULTS: Western versus eastern positions within a time zone were associated with higher solar jetlag scores from the light exposure model (P < 0.01) and relatively larger differences in sunset time measured using light sensors (social clock) and the Solar Calculator (sun clock) (P = 0.04).

CONCLUSION: We developed and validated a geospatial light exposure model, enabling high spatiotemporal resolution and comprehensive characterization of geographic variation in light exposure potentially impacting circadian phase in epidemiologic studies.},
}

@article {pmid38615031,
year = {2024},
author = {Wagner, C and Kistler, KE and Perchetti, GA and Baker, N and Frisbie, LA and Torres, LM and Aragona, F and Yun, C and Figgins, M and Greninger, AL and Cox, A and Oltean, HN and Roychoudhury, P and Bedford, T},
title = {Positive selection underlies repeated knockout of ORF8 in SARS-CoV-2 evolution.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3207},
pmid = {38615031},
issn = {2041-1723},
support = {S10 OD020069/OD/NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; },
mesh = {Humans ; *COVID-19/genetics ; SARS-CoV-2/genetics ; Exercise ; Phylogeny ; Pressure ; },
abstract = {Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.},
}

Humans
*COVID-19/genetics
SARS-CoV-2/genetics
Exercise
Phylogeny
Pressure

@article {pmid38613330,
year = {2024},
author = {Baek, G and Kim, M and Lee, M and O'Connor, S and Held, L and van der Laan, L and Cassaday, RD},
title = {Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.},
journal = {Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners},
volume = {},
number = {},
pages = {10781552241246104},
doi = {10.1177/10781552241246104},
pmid = {38613330},
issn = {1477-092X},
abstract = {INTRODUCTION: Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity.

METHODS: A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted.

RESULTS: Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities.

CONCLUSION: Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.},
}

@article {pmid38607625,
year = {2024},
author = {Wagner, MJ and Ravi, V and Schaub, SK and Kim, EY and Sharib, J and Mogal, H and Park, M and Tsai, M and Duarte-Bateman, D and Tufaro, A and Loggers, ET and Cranmer, LD and Chau, B and Hassett, MJ and Grilley-Olson, J and Paulson, KG},
title = {Incidence and Presenting Characteristics of Angiosarcoma in the US, 2001-2020.},
journal = {JAMA network open},
volume = {7},
number = {4},
pages = {e246235},
pmid = {38607625},
issn = {2574-3805},
mesh = {Male ; Humans ; Female ; Aged ; Incidence ; *Hemangiosarcoma/epidemiology ; Cross-Sectional Studies ; Retrospective Studies ; *Breast Neoplasms ; },
abstract = {IMPORTANCE: Angiosarcoma is an aggressive vascular malignant neoplasm presenting either as a primary or secondary cancer, often arising after radiotherapy or in the context of preexisting lymphedema. Comprehensive data describing its incidence and presentation patterns are needed.

OBJECTIVE: To describe the incidence, presenting characteristics, and change over time of angiosarcoma in the US.

This retrospective cross-sectional study used data from the US Cancer Statistics (USCS) National Program of Cancer Registries-Surveillance, Epidemiology, and End Results Combined Database, which captures more than 99% of newly diagnosed cancers in the US. The study included all 19 289 patients in the US with a new diagnosis of angiosarcoma between 2001 and 2020 captured in the USCS database. Statistical analysis was performed from June to September 2023.

MAIN OUTCOMES AND MEASURES: Incidence of angiosarcoma, demographics of patients with angiosarcoma, and extent of disease at presentation.

RESULTS: The study included 19 289 patients (median age, 71 years [IQR, 59-80 years]; 10 506 women [54.5%]) with a new diagnosis of angiosarcoma. The US incidence of angiosarcoma doubled between 2001 (657 cases) and 2019 (1312 cases), reflecting both an increase in the adjusted incidence rate of 1.6% per year (P = .001), to 3.3 cases per 1 000 000 person-years (95% CI, 3.1-3.5 cases per 1 000 000 person-years), and an increase in the population at risk. In 2020, the reported incidence rate (3.0 cases per 1 000 000 person-years) and cases of angiosarcoma (n = 1159) were modestly lower than in 2019. Overall, 72.3% of cases of angiosarcoma (n = 13 955) were cutaneous, subcutaneous, or breast angiosarcomas; 24.4% were visceral (n = 4701); and 3.3% were located in unknown or rare primary sites (n = 633). Secondary breast and chest wall angiosarcomas among women represented the largest contribution to increasing incidence. Among breast angiosarcomas, 99.2% (2684 of 2705) were in women and 71.9% (1944 of 2705) were secondary. A total of 80.4% of chest wall or thorax cases among women (1861 of 2316) were secondary vs 26.5% among men (112 of 422), and 63.9% of upper extremity cases among women (205 of 321) were secondary vs 26.8% (56 of 209) among men (P = .001). Rates of secondary angiosarcoma in the abdomen and lower extremities were similar between men and women. The incidence rate of visceral angiosarcoma was also found to be increasing (1.5% per year; P = .001).

CONCLUSIONS AND RELEVANCE: This cross-sectional study describes angiosarcoma presentation patterns and incidence rates in the US over a 20-year period and shows that the number of cases in men and women increased, with the greatest increase among women with secondary angiosarcoma of the chest, breast, and upper extremity. These data increase awareness of a rare but highly morbid disease and highlight the need for improved early detection of angiosarcoma among patients at high risk, such as women with a history of breast cancer.},
}

Male
Humans
Female
Aged
Incidence
*Hemangiosarcoma/epidemiology
Cross-Sectional Studies
Retrospective Studies
*Breast Neoplasms

@article {pmid38606632,
year = {2024},
author = {Liu, M and Su, YR and Liu, Y and Hsu, L and He, Q},
title = {Structured testing of genetic association with mixed clinical outcomes.},
journal = {Genetic epidemiology},
volume = {},
number = {},
pages = {},
doi = {10.1002/gepi.22560},
pmid = {38606632},
issn = {1098-2272},
support = {R01CA223498/NH/NIH HHS/United States ; R01CA189532/NH/NIH HHS/United States ; R01HL152439/NH/NIH HHS/United States ; R01GM105785/NH/NIH HHS/United States ; },
abstract = {Genetic factors play a fundamental role in disease development. Studying the genetic association with clinical outcomes is critical for understanding disease biology and devising novel treatment targets. However, the frequencies of genetic variations are often low, making it difficult to examine the variants one-by-one. Moreover, the clinical outcomes are complex, including patients' survival time and other binary or continuous outcomes such as recurrences and lymph node count, and how to effectively analyze genetic association with these outcomes remains unclear. In this article, we proposed a structured test statistic for testing genetic association with mixed types of survival, binary, and continuous outcomes. The structured testing incorporates known biological information of variants while allowing for their heterogeneous effects and is a powerful strategy for analyzing infrequent genetic factors. Simulation studies show that the proposed test statistic has correct type I error and is highly effective in detecting significant genetic variants. We applied our approach to a uterine corpus endometrial carcinoma study and identified several genetic pathways associated with the clinical outcomes.},
}

@article {pmid38604173,
year = {2024},
author = {Ahmad, K and Brahma, S and Henikoff, S},
title = {Response to "Learning from chromatin reconstitution: Pioneering factors enabling nucleosome remodelers".},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2024.03.020},
pmid = {38604173},
issn = {1097-4164},
}

@article {pmid38604127,
year = {2024},
author = {Jin, J and Zhan, J and Zhang, J and Zhao, R and O'Connell, J and Jiang, Y and , and Buyske, S and Gignoux, C and Haiman, C and Kenny, EE and Kooperberg, C and North, K and Koelsch, BL and Wojcik, G and Zhang, H and Chatterjee, N},
title = {MUSSEL: Enhanced Bayesian polygenic risk prediction leveraging information across multiple ancestry groups.},
journal = {Cell genomics},
volume = {4},
number = {4},
pages = {100539},
doi = {10.1016/j.xgen.2024.100539},
pmid = {38604127},
issn = {2666-979X},
mesh = {Humans ; Animals ; *Multifactorial Inheritance/genetics ; Genome-Wide Association Study/methods ; Bayes Theorem ; Phenotype ; Genetic Risk Score ; *Bivalvia ; },
abstract = {Polygenic risk scores (PRSs) are now showing promising predictive performance on a wide variety of complex traits and diseases, but there exists a substantial performance gap across populations. We propose MUSSEL, a method for ancestry-specific polygenic prediction that borrows information in summary statistics from genome-wide association studies (GWASs) across multiple ancestry groups via Bayesian hierarchical modeling and ensemble learning. In our simulation studies and data analyses across four distinct studies, totaling 5.7 million participants with a substantial ancestral diversity, MUSSEL shows promising performance compared to alternatives. For example, MUSSEL has an average gain in prediction R[2] across 11 continuous traits of 40.2% and 49.3% compared to PRS-CSx and CT-SLEB, respectively, in the African ancestry population. The best-performing method, however, varies by GWAS sample size, target ancestry, trait architecture, and linkage disequilibrium reference samples; thus, ultimately a combination of methods may be needed to generate the most robust PRSs across diverse populations.},
}

Humans
Animals
*Multifactorial Inheritance/genetics
Genome-Wide Association Study/methods
Bayes Theorem
Phenotype
Genetic Risk Score
*Bivalvia

@article {pmid38598658,
year = {2024},
author = {Sherman, A and Tuan, J and Cantos, VD and Adeyiga, O and Mahoney, S and Ortega-Villa, AM and Tillman, A and Whitaker, J and Woodward Davis, AS and Leav, B and Hirsch, I and Sadoff, J and Dunkle, LM and Gilbert, PB and Janes, HE and Kublin, JG and Goepfert, PA and Kotloff, K and Rouphael, N and Falsey, AR and El Sahly, HM and Sobieszczyk, ME and Huang, Y and Neuzil, KM and Corey, L and Grinsztejn, B and Gray, G and Nason, M and Baden, LR and Gay, CL},
title = {COVID-19 vaccine efficacy in participants with weakened immune systems from four randomized-controlled trials.},
journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America},
volume = {},
number = {},
pages = {},
doi = {10.1093/cid/ciae192},
pmid = {38598658},
issn = {1537-6591},
abstract = {BACKGROUND: Although the SARS-CoV-2 vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions.

METHODS: A post-hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, COVID-19 vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS (NTIS) individuals starting at 14 days after completion of the primary series through the blinded phase for each of the four trials. An analysis of participants living with well-controlled HIV was conducted using the same methods.

RESULTS: 3,852/30,351 (12.7%) Moderna participants, 3,088/29,868 (10.3%) Novavax participants, 3,549/32,380 (11.0%) AstraZeneca participants, and 5,047/43,788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (versus placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants vs NTIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with HIV.

CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared to those with non-tempered immune systems in the four COVID-19 vaccine randomized controlled efficacy trials.},
}

@article {pmid38598634,
year = {2024},
author = {Hiatt, JB and Doebley, AL and Arnold, HU and Adil, M and Sandborg, H and Persse, TW and Ko, M and Wu, F and Quintanal Villalonga, A and Santana-Davila, R and Eaton, K and Dive, C and Rudin, CM and Thomas, A and Houghton, AM and Ha, G and MacPherson, D},
title = {Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions.},
journal = {Science advances},
volume = {10},
number = {15},
pages = {eadk2082},
pmid = {38598634},
issn = {2375-2548},
mesh = {Humans ; *Small Cell Lung Carcinoma/metabolism ; *Lung Neoplasms/metabolism ; *Cell-Free Nucleic Acids ; *Carcinoma, Non-Small-Cell Lung/pathology ; Regulatory Sequences, Nucleic Acid ; Gene Expression Regulation, Neoplastic ; },
abstract = {We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) for small cell lung cancer (SCLC). In SCLC, differential activation of transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. We designed a targeted capture panel that identifies chromatin organization signatures at 1535 TF binding sites and 13,240 gene transcription start sites and detects exonic mutations in 842 genes. Sequencing of cfDNA from SCLC patient-derived xenograft models captured TF activity and gene expression and revealed individual highly informative loci. Prediction models of ASCL1 and NEUROD1 activity using informative loci achieved areas under the receiver operating characteristic curve (AUCs) from 0.84 to 0.88 in patients with SCLC. As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types.},
}

Humans
*Small Cell Lung Carcinoma/metabolism
*Lung Neoplasms/metabolism
*Cell-Free Nucleic Acids
*Carcinoma, Non-Small-Cell Lung/pathology
Regulatory Sequences, Nucleic Acid
Gene Expression Regulation, Neoplastic