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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 22 Jan 2021 at 01:40 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-01-21

Kidzeru E, Gasper MA, Shao D, et al (2021)

Myeloid-derived suppressor cells and their association with vaccine immunogenicity in South African infants.

Journal of leukocyte biology [Epub ahead of print].

The role of Myeloid-Derived Suppressor Cells (MDSC) in infant immune ontogeny is unknown. Here, we evaluated MDSC frequency and relationship with infant vaccine responses throughout the first year of life in a prospective cohort study. Ninety-one South African infant-mother pairs were enrolled at delivery, and blood samples were collected at 0, 6, 10, and 14 weeks, 6 months, 9 months, and 1 year. MDSC frequencies were quantified, and immune responses to the childhood vaccines Bacillus Calmette-Guérin (BCG), hepatitis B (HepB), and combination diphtheria, tetanus, and pertussis (dTaP) were measured by Ag-specific CD4+ T cell proliferation and interferon gamma (IFN-γ) production. Vaccine-specific Ab responses to HepB, dTaP, and Haemophilus influenzae type b (Hib) were quantified via Enzyme-Linked Immunosorbent assay (ELISA). MDSC frequency in mother-infant pairs was strongly correlated; the frequency of MDSC decreased in both mothers and infants during the months after delivery/birth; and by 1 year, infant MDSC frequencies rebounded to birth levels. Higher MDSC frequency at vaccination was associated with a lack of subsequent IFN-γ release in response to vaccine Ags, with the exception of BCG. With the exception of a weak, positive correlation between MDSC frequency at 6 weeks (time of initial vaccination) and peak Hepatitis B surface antigen Ab titer, Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSC) was not correlated with T cell proliferation or Ab responses in this study. The potential for MDSC-mediated suppression of vaccine Ag-specific IFN-γ responses should be explored further, and considered when evaluating candidate infant vaccines.

RevDate: 2021-01-21

Li F, Li YY, Liu MJ, et al (2021)

Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study.

The Lancet. Infectious diseases pii:S1473-3099(20)30981-6 [Epub ahead of print].

BACKGROUND: Wuhan was the first epicentre of COVID-19 in the world, accounting for 80% of cases in China during the first wave. We aimed to assess household transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and risk factors associated with infectivity and susceptibility to infection in Wuhan.

METHODS: This retrospective cohort study included the households of all laboratory-confirmed or clinically confirmed COVID-19 cases and laboratory-confirmed asymptomatic SARS-CoV-2 infections identified by the Wuhan Center for Disease Control and Prevention between Dec 2, 2019, and April 18, 2020. We defined households as groups of family members and close relatives who did not necessarily live at the same address and considered households that shared common contacts as epidemiologically linked. We used a statistical transmission model to estimate household secondary attack rates and to quantify risk factors associated with infectivity and susceptibility to infection, accounting for individual-level exposure history. We assessed how intervention policies affected the household reproductive number, defined as the mean number of household contacts a case can infect.

FINDINGS: 27 101 households with 29 578 primary cases and 57 581 household contacts were identified. The secondary attack rate estimated with the transmission model was 15·6% (95% CI 15·2-16·0), assuming a mean incubation period of 5 days and a maximum infectious period of 22 days. Individuals aged 60 years or older were at a higher risk of infection with SARS-CoV-2 than all other age groups. Infants aged 0-1 years were significantly more likely to be infected than children aged 2-5 years (odds ratio [OR] 2·20, 95% CI 1·40-3·44) and children aged 6-12 years (1·53, 1·01-2·34). Given the same exposure time, children and adolescents younger than 20 years of age were more likely to infect others than were adults aged 60 years or older (1·58, 1·28-1·95). Asymptomatic individuals were much less likely to infect others than were symptomatic cases (0·21, 0·14-0·31). Symptomatic cases were more likely to infect others before symptom onset than after (1·42, 1·30-1·55). After mass isolation of cases, quarantine of household contacts, and restriction of movement policies were implemented, household reproductive numbers declined by 52% among primary cases (from 0·25 [95% CI 0·24-0·26] to 0·12 [0·10-0·13]) and by 63% among secondary cases (from 0·17 [0·16-0·18] to 0·063 [0·057-0·070]).

INTERPRETATION: Within households, children and adolescents were less susceptible to SARS-CoV-2 infection but were more infectious than older individuals. Presymptomatic cases were more infectious and individuals with asymptomatic infection less infectious than symptomatic cases. These findings have implications for devising interventions for blocking household transmission of SARS-CoV-2, such as timely vaccination of eligible children once resources become available.

FUNDING: National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities, US National Institutes of Health, and US National Science Foundation.

RevDate: 2021-01-21

Sohal DPS, Duong M, Ahmad SA, et al (2021)

Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial.

JAMA oncology pii:2775174 [Epub ahead of print].

Importance: Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial.

Objective: To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA.

This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria.

Interventions: Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2).

Main Outcomes and Measures: The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review.

Results: From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2.

Conclusions and Relevance: This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria.

Trial Registration: ClinicalTrials.gov Identifier: NCT02562716.

RevDate: 2021-01-21

Stone D, Long KR, Loprieno MA, et al (2021)

CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice.

Molecular therapy. Methods & clinical development, 20:258-275 pii:S2329-0501(20)30241-2.

Chronic hepatitis B virus (HBV) infection is a major public health problem. New treatment approaches are needed because current treatments do not target covalently closed circular DNA (cccDNA), the template for HBV replication, and rarely clear the virus. We harnessed adeno-associated virus (AAV) vectors and CRISPR-Staphylococcus aureus (Sa)Cas9 to edit the HBV genome in liver-humanized FRG mice chronically infected with HBV and receiving entecavir. Gene editing was detected in livers of five of eight HBV-specific AAV-SaCas9-treated mice, but not control mice, and mice with detectable HBV gene editing showed higher levels of SaCas9 delivery to HBV+ human hepatocytes than those without gene editing. HBV-specific AAV-SaCas9 therapy significantly improved survival of human hepatocytes, showed a trend toward decreasing total liver HBV DNA and cccDNA, and was well tolerated. This work provides evidence for the feasibility and safety of in vivo gene editing for chronic HBV infections, and it suggests that with further optimization, this approach may offer a plausible way to treat or even cure chronic HBV infections.

RevDate: 2021-01-21

Conti DV, Darst BF, Moss LC, et al (2021)

Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

RevDate: 2021-01-21

Chew GL, Bleakley M, Bradley RK, et al (2021)

Short H2A histone variants are expressed in cancer.

Nature communications, 12(1):490.

Short H2A (sH2A) histone variants are primarily expressed in the testes of placental mammals. Their incorporation into chromatin is associated with nucleosome destabilization and modulation of alternate splicing. Here, we show that sH2As innately possess features similar to recurrent oncohistone mutations associated with nucleosome instability. Through analyses of existing cancer genomics datasets, we find aberrant sH2A upregulation in a broad array of cancers, which manifest splicing patterns consistent with global nucleosome destabilization. We posit that short H2As are a class of "ready-made" oncohistones, whose inappropriate expression contributes to chromatin dysfunction in cancer.

RevDate: 2021-01-21

Hung RJ, Warkentin MT, Brhane Y, et al (2021)

Assessing Lung Cancer Absolute Risk Trajectory based on a Polygenic Risk Model.

Cancer research pii:0008-5472.CAN-20-1237 [Epub ahead of print].

Lung cancer is the leading cause of cancer death globally. An improved risk stratification strategy can increase efficiency of low-dose computed tomography (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. Based on 13,119 lung cancer patients and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK biobank data (N=335,931). Absolute risk was estimated based on age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial, N=50,772 participants). The lung cancer odds ratio (ORs) for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 (95%CI=1.92-3.00, P=1.80x10-14) in the validation set (trend p-value of 5.26 x 10-20). The OR per standard deviation of PRS increase was 1.26 (95%CI=1.20-1.32, P=9.69x10-23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status and family history. Collectively, these results suggest that Individual's genetic background may inform the optimal lung cancer LDCT screening strategy.

RevDate: 2021-01-20

Rabinowitch I, Upadhyaya B, Pant A, et al (2021)

Circumventing Neural Damage in a C. elegans Chemosensory Circuit Using Genetically Engineered Synapses.

Cell systems pii:S2405-4712(20)30504-4 [Epub ahead of print].

Neuronal loss can considerably diminish neural circuit function, impairing normal behavior by disrupting information flow in the circuit. Here, we use genetically engineered electrical synapses to reroute the flow of information in a C. elegans damaged chemosensory circuit in order to restore organism behavior. We impaired chemotaxis by removing one pair of interneurons from the circuit then artificially coupled two other adjacent neuron pairs by ectopically expressing the gap junction protein, connexin, in them. This restored chemotaxis in the animals. We expected to observe linear and direct information flow between the connexin-coupled neurons in the recovered circuit but also revealed the formation of new potent left-right lateral electrical connections within the connexin-expressing neuron pairs. Our analysis suggests that these additional electrical synapses help restore circuit function by amplifying weakened neuronal signals in the damaged circuit in addition to emulating the wild-type circuit. A record of this paper's transparent peer review process is included in the Supplemental Information.

RevDate: 2021-01-20

Hu C, Hart SN, Gnanaolivu R, et al (2021)

A Population-Based Study of Genes Previously Implicated in Breast Cancer.

The New England journal of medicine [Epub ahead of print].

BACKGROUND: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.

METHODS: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.

RESULTS: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.

CONCLUSIONS: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).

RevDate: 2021-01-20

Labrecque MP, Brown LG, Coleman IM, et al (2021)

Cabozantinib can block growth of neuroendocrine prostate cancer patient-derived xenografts by disrupting tumor vasculature.

PloS one, 16(1):e0245602 pii:PONE-D-20-11163.

With the advent of potent second-line anti-androgen therapy, we and others have observed an increased incidence of androgen receptor (AR)-null small cell or neuroendocrine prostate cancer (SCNPC) in metastatic castration-resistant prostate cancer (mCRPC). Our study was designed to determine the effect of cabozantinib, a multi-targeted tyrosine kinase inhibitor that inhibits VEGFR2, MET and RET on SCNPC. Transcriptome analysis of the University of Washington rapid autopsy and SU2C mCRPC datasets revealed upregulated MET and RET expression in SCNPCs relative to adenocarcinomas. Additionally, increased MET expression correlated with attenuated AR expression and activity. In vitro treatment of SCNPC patient-derived xenograft (PDX) cells with the MET inhibitor AMG-337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability of LuCaP 93, but not LuCaP 173.1. Notably, MET+/RET+ LuCaP 93 and MET-/RET- LuCaP 173.1 tumor volumes were significantly decreased with cabozantinib treatment in vivo, and this activity was independent of MET or RET expression in LuCaP 173.1. Tissue analysis indicated that cabozantinib did not inhibit tumor cell proliferation (Ki67), but significantly decreased microvessel density (CD31) and increased hypoxic stress and glycolysis (HK2) in LuCaP 93 and LuCaP 173.1 tumors. RNA-Seq and gene set enrichment analysis revealed that hypoxia and glycolysis pathways were increased in cabozantinib-treated tumors relative to control tumors. Our data suggest that the most likely mechanism of cabozantinib-mediated tumor growth suppression in SCNPC PDX models is through disruption of the tumor vasculature. Thus, cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation.

RevDate: 2021-01-20

Jones SMW, Banegas MP, Steiner JF, et al (2021)

Association of Financial Worry and Material Financial Risk with Short-Term Ambulatory Healthcare Utilization in a Sample of Subsidized Exchange Patients.

Journal of general internal medicine [Epub ahead of print].

BACKGROUND: Financial burden can affect healthcare utilization. Few studies have assessed the short-term associations between material (debt, trouble paying rent) and psychological (worry or distress about affording future healthcare) financial risks, and subsequent outpatient and emergency healthcare use. Worry was defined as concerns about affording future healthcare.

OBJECTIVE: Examine whether worry about affording healthcare is associated with healthcare utilization when controlling for material risk and general anxiety DESIGN: Longitudinal observational study PARTICIPANTS: Kaiser Permanente members with exchange-based federally subsidized health insurance (n = 450, 45% response rate) MAIN MEASURES: Survey measures of financial risks (material difficulty paying for medical care and worry about affording healthcare) and general anxiety. Healthcare use (primary care, urgent care, emergency department, and outpatient specialty visits) in the 6 months following survey completion.

KEY RESULTS: Emergency department and primary care visits were not associated with material risk, worry about affording care, or general anxiety in individual and pooled analyses (all 95% confidence intervals (CI) for relative risk (RR) included 1). Although no individual predictor was associated with urgent care use (all 95% CIs for RR included 1), worry about affording prescriptions (relative risk (RR) = 2.01; 95% CI 1.14, 3.55) and general anxiety (RR = 0.38; 95% CI 0.15, 0.95) were significant when included in the same model, suggesting the two confounded each other. Worry about affording healthcare services was associated with fewer specialty care visits (RR = 0.40; 95% CI 0.25, 0.64) even when controlling for material risk and general anxiety, although general anxiety was also associated with more specialty care visits (RR = 1.98; 95% CI, 1.23, 3.18).

CONCLUSIONS: Screening for both general anxiety and financial worry may assist with specialty care utilization. Identifying these concerns may provide more opportunities to assist patients. Future research should examine interventions to reduce worry about cost of care.

RevDate: 2021-01-20

Raiders S, Han T, Scott-Hewitt N, et al (2021)

Engulfed by Glia: Glial Pruning in Development, Function, and Injury across Species.

The Journal of neuroscience : the official journal of the Society for Neuroscience pii:JNEUROSCI.1660-20.2020 [Epub ahead of print].

Phagocytic activity of glial cells is essential for proper nervous system sculpting, maintenance of circuitry, and long-term brain health. Glial engulfment of apoptotic cells and superfluous connections ensures that neuronal connections are appropriately refined, while clearance of damaged projections and neurotoxic proteins in the mature brain protects against inflammatory insults. Comparative work across species and cell types in recent years highlights the striking conservation of pathways that govern glial engulfment. Many signaling cascades used during developmental pruning are re-employed in the mature brain to "fine tune" synaptic architecture and even clear neuronal debris following traumatic events. Moreover, the neuron-glia signaling events required to trigger and perform phagocytic responses are impressively conserved between invertebrates and vertebrates. This review offers a compare-and-contrast portrayal of recent findings that underscore the value of investigating glial engulfment mechanisms in a wide range of species and contexts.

RevDate: 2021-01-20

Maurice NJ, Taber AK, M Prlic (2021)

The Ugly Duckling Turned to Swan: A Change in Perception of Bystander-Activated Memory CD8 T Cells.

Journal of immunology (Baltimore, Md. : 1950), 206(3):455-462.

Memory T cells (Tmem) rapidly mount Ag-specific responses during pathogen reencounter. However, Tmem also respond to inflammatory cues in the absence of an activating TCR signal, a phenomenon termed bystander activation. Although bystander activation was first described over 20 years ago, the physiological relevance and the consequences of T cell bystander activation have only become more evident in recent years. In this review, we discuss the scenarios that trigger CD8 Tmem bystander activation including acute and chronic infections that are either systemic or localized, as well as evidence for bystander CD8 Tmem within tumors and following vaccination. We summarize the possible consequences of bystander activation for the T cell itself, the subsequent immune response, and the host. We highlight when T cell bystander activation appears to benefit or harm the host and briefly discuss our current knowledge gaps regarding regulatory signals that can control bystander activation.

RevDate: 2021-01-19

Wolfson JA, Bhatia S, Ginsberg J, et al (2021)

Expenditures among young adults with acute lymphoblastic leukemia by site of care.

Cancer [Epub ahead of print].

BACKGROUND: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures.

METHODS: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled.

RESULTS: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable.

CONCLUSIONS: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings.

LAY SUMMARY: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.

RevDate: 2021-01-19

Bacchus-Souffan C, Fitch M, Symons J, et al (2021)

Relationship between CD4 T cell turnover, cellular differentiation and HIV persistence during ART.

PLoS pathogens, 17(1):e1009214 pii:PPATHOGENS-D-20-01673 [Epub ahead of print].

The precise role of CD4 T cell turnover in maintaining HIV persistence during antiretroviral therapy (ART) has not yet been well characterized. In resting CD4 T cell subpopulations from 24 HIV-infected ART-suppressed and 6 HIV-uninfected individuals, we directly measured cellular turnover by heavy water labeling, HIV reservoir size by integrated HIV-DNA (intDNA) and cell-associated HIV-RNA (caRNA), and HIV reservoir clonality by proviral integration site sequencing. Compared to HIV-negatives, ART-suppressed individuals had similar fractional replacement rates in all subpopulations, but lower absolute proliferation rates of all subpopulations other than effector memory (TEM) cells, and lower plasma IL-7 levels (p = 0.0004). Median CD4 T cell half-lives decreased with cell differentiation from naïve to TEM cells (3 years to 3 months, p<0.001). TEM had the fastest replacement rates, were most highly enriched for intDNA and caRNA, and contained the most clonal proviral expansion. Clonal proviruses detected in less mature subpopulations were more expanded in TEM, suggesting that they were maintained through cell differentiation. Earlier ART initiation was associated with lower levels of intDNA, caRNA and fractional replacement rates. In conclusion, circulating integrated HIV proviruses appear to be maintained both by slow turnover of immature CD4 subpopulations, and by clonal expansion as well as cell differentiation into effector cells with faster replacement rates.

RevDate: 2021-01-19

Santiago JC, Goldman JD, Zhao H, et al (2021)

Intra-host changes in Kaposi sarcoma-associated herpesvirus genomes in Ugandan adults with Kaposi sarcoma.

PLoS pathogens, 17(1):e1008594 pii:PPATHOGENS-D-20-00885 [Epub ahead of print].

Intra-host tumor virus variants may influence the pathogenesis and treatment responses of some virally-associated cancers. However, the intra-host variability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma (KS), has to date been explored with sequencing technologies that introduce errors possibly greater than that which occurs in the viral population, and these studies have only studied variable regions. Here, full-length KSHV genomes in tumors and/or oral swabs from 9 Ugandan adults with HIV-associated KS were characterized. Furthermore, we used deep, short-read sequencing using duplex unique molecular identifiers (dUMI)-random double-stranded oligonucleotides that barcode individual DNA molecules before library amplification. This allowed suppression of PCR and sequencing errors to ~10-9/base as well as afforded accurate determination of KSHV genome numbers sequenced in each sample. KSHV genomes were assembled de novo, and rearrangements observed were confirmed by PCR and Sanger sequencing. 131-kb KSHV genome sequences, excluding major repeat regions, were successfully obtained from 23 clinical specimens, averaging 2.3x104 reads/base. Strikingly, KSHV genomes were virtually identical within individuals at the point mutational level. The intra-host heterogeneity that was observed was confined to tumor-associated KSHV mutations and genome rearrangements, all impacting protein-coding sequences. Although it is unclear whether these changes were important to tumorigenesis or occurred as a result of genomic instability in tumors, similar changes were observed across individuals. These included inactivation of the K8.1 gene in tumors of 3 individuals and retention of a region around the first major internal repeat (IR1) in all instances of genomic deletions and rearrangements. Notably, the same breakpoint junctions were found in distinct tumors from 2 individuals, suggesting metastatic spread of rearranged KSHV genomes. These findings define KSHV intra-host heterogeneity in vivo with greater precision than has been possible in the past and suggest the possibility that aberrant KSHV genomes may contribute to aspects of KS tumorigenesis. Furthermore, study of KSHV with use of dUMI provides a proof of concept for utilizing this technique for detailed study of other virus populations in vivo.

RevDate: 2021-01-19

Kistler KE, T Bedford (2021)

Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229E.

eLife, 10: pii:64509 [Epub ahead of print].

Seasonal coronaviruses (OC43, 229E, NL63 and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here, we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively-selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.

RevDate: 2021-01-19

Bellach A, Kosorok MR, Gilbert PB, et al (2020)

General regression model for the subdistribution of a competing risk under left-truncation and right-censoring.

Biometrika, 107(4):949-964 pii:asaa034.

Left-truncation poses extra challenges for the analysis of complex time-to-event data. We propose a general semiparametric regression model for left-truncated and right-censored competing risks data that is based on a novel weighted conditional likelihood function. Targeting the subdistribution hazard, our parameter estimates are directly interpretable with regard to the cumulative incidence function. We compare different weights from recent literature and develop a heuristic interpretation from a cure model perspective that is based on pseudo risk sets. Our approach accommodates external time-dependent covariate effects on the subdistribution hazard. We establish consistency and asymptotic normality of the estimators and propose a sandwich estimator of the variance. In comprehensive simulation studies we demonstrate solid performance of the proposed method. Comparing the sandwich estimator with the inverse Fisher information matrix, we observe a bias for the inverse Fisher information matrix and diminished coverage probabilities in settings with a higher percentage of left-truncation. To illustrate the practical utility of the proposed method, we study its application to a large HIV vaccine efficacy trial dataset.

RevDate: 2021-01-19

Kurilshikov A, Medina-Gomez C, Bacigalupe R, et al (2021)

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nature genetics [Epub ahead of print].

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P < 5 × 10-8) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10-20), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10-10 < P < 5 × 10-8) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.

RevDate: 2021-01-19

Wright M, Smed MK, Nelson JL, et al (2021)

Is gene expression among women with rheumatoid arthritis dysregulated during a postpartum flare?.

Arthritis research & therapy, 23(1):30.

BACKGROUND: To evaluate our hypotheses that, when rheumatoid arthritis (RA) flares postpartum, gene expression patterns are altered compared to (a) healthy women, (b) RA women whose disease activity is low or in remission postpartum, and (c) pre-pregnancy expression profiles.

METHODS: Twelve women with RA and five healthy women were included in this pilot study. RA disease activity and postpartum flare were assessed using the Clinical Disease Activity Index (CDAI). Total RNA from frozen whole blood was used for RNA sequencing. Differential gene expression within the same women (within-group) over time, i.e., postpartum vs. third trimester (T3) or pre-pregnancy (T0), were examined, using a significance threshold of q < 0.05 and fold-change ≥ 2.

RESULTS: Nine of the women with RA experienced a flare postpartum (RAFlare), while three had low disease activity or were in remission (RANoFlare) during that time frame. Numerous immune-related genes were differentially expressed postpartum (vs. T3) during a flare. Fold-changes in expression from T3 to postpartum were mostly comparable between the RAFlare and healthy groups. At 3 months postpartum, compared to healthy women, several genes were significantly differentially expressed only among the RAFlare women, and not among the RANoFlare women. Some of these genes were among those whose "normal" expression was significantly modulated postpartum, and the postpartum expression patterns were significantly altered during the RA flare. There were also some genes that were significantly differentially expressed in RAFlare compared to both healthy and RANoFlare women, even though their expression was not significantly modulated postpartum. Furthermore, while postpartum expression profiles were similar to those at pre-pregnancy among healthy women, significant differences were found between those time points among the RAFlare women.

CONCLUSIONS: The large majority of gene expression changes between T3 and 3 months postpartum among RA women who flared postpartum reflected normal postpartum changes also seen among healthy women. Nonetheless, during a postpartum flare, a set of immune-related genes showed dysregulated expression compared to healthy women and women with RA whose disease activity was low or in remission during the same time frame, while other genes demonstrated significant differences in expression compared to RA pre-pregnancy levels.

RevDate: 2021-01-19

Filice D, Dhahri W, Solan JL, et al (2021)

Correction to: Optical mapping of human embryonic stem cell-derived cardiomyocyte graft electrical activity in injured hearts.

Stem cell research & therapy, 12(1):66.

RevDate: 2021-01-17

Lange PH, Cookson MS, Schellhammer PF, et al (2021)

A history of the Society of Urologic Oncology.

Urologic oncology pii:S1078-1439(20)30648-7 [Epub ahead of print].

This narrative of the history of the Society of Urologic Oncology (SUO) presents the story of the founding and development of this organization and the creation and establishment of its initiatives and programs. It includes a description of how "Urologic Oncology: Seminars and Original Investigations" came to be designated as its "official journal", thus commemorating the anniversary of the Journal's twenty-five years of publication.

RevDate: 2021-01-18

Leisman DE, Ronner L, Pinotti R, et al (2021)

Assessing the importance of interleukin-6 in COVID-19 - Authors' reply.

RevDate: 2021-01-18

Walsh CA, M Al Achkar (2021)

A qualitative study of online support communities for lung cancer survivors on targeted therapies.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer [Epub ahead of print].

BACKGROUND: Due to recent treatment advances, people who have non-small cell lung cancer with oncogenic alterations are an important new group of cancer survivors. Little is known about lung cancer online support communities. This research was guided by two primary questions: (1) How do these lung cancer survivors engage in online support communities? and (2) What are the psychological, social, and physical impacts of such engagement?

METHODS: Qualitative in-depth interviews were conducted with patients with advanced lung cancer (N = 40) to learn about their experiences with the illness. We used qualitative thematic analysis, inductive and deductive, as outlined by Carspecken. We adapted the framework for studying online communities developed by Zhang and colleagues to examine engagement with and impacts of involvement in online lung cancer support communities.

RESULTS: Participants described engaging in the online community through (1) initializing communication through asking questions or sharing resources, (2) responding to others comments or inquiries, or (3) simply observing/reading others posts. Participation had physical, psychological, or social impacts, with benefits (e.g., empowerment) and risks (e.g., feelings of jealousy or misinformation) in each domain. Participants used various strategies to mitigate negative impacts, such as distancing oneself as needed.

CONCLUSIONS: Online lung cancer support communities provide support, camaraderie, and specialized health information. However, there are also risks of online engagement, such as social comparison or accessing misinformation. Understanding the utility of online support communities for lung cancer survivors on targeted therapies and further addressing their risks are urgent tasks, especially in the post-COVID era.

RevDate: 2021-01-16

Tomko EJ, Luyties O, Rimel JK, et al (2021)

The role of XPB/Ssl2 dsDNA translocation processivity in transcription-start-site scanning.

Journal of molecular biology pii:S0022-2836(21)00007-3 [Epub ahead of print].

The general transcription factor TFIIH contains three ATP-dependent catalytic activities. TFIIH functions in nucleotide excision repair primarily as a DNA helicase and in Pol II transcription initiation as a dsDNA translocase and protein kinase. During initiation, the XPB/Ssl2 subunit of TFIIH couples ATP hydrolysis to dsDNA translocation facilitating promoter opening and the kinase module phosphorylates Pol II to facilitate the transition to elongation. These functions are conserved between metazoans and yeast; however, yeast TFIIH also drives transcription start-site scanning in which Pol II scans downstream DNA to locate productive start-sites. The ten-subunit holo-TFIIH from S. cerevisiae has a processive dsDNA translocase activity required for scanning and a structural role in scanning has been ascribed to the three-subunit TFIIH kinase module. Here, we assess the dsDNA translocase activity of ten-subunit holo- and core-TFIIH complexes (i.e. seven subunits, lacking the kinase module) from both S. cerevisiae and H. sapiens. We find that neither holo nor core human TFIIH exhibit processive translocation, consistent with the lack of start-site scanning in humans. Furthermore, in contrast to holo-TFIIH, the S. cerevisiae core-TFIIH also lacks processive translocation and its dsDNA-stimulated ATPase activity was reduced ∼5-fold to a level comparable to the human complexes, potentially explaining the reported upstream shift in start-site observed in vitro in the absence of the S. cerevisiae kinase module. These results suggest that neither human nor S. cerevisiae core-TFIIH can translocate efficiently, and that the S. cerevisiae kinase module functions as a processivity factor to allow for robust transcription start-site scanning.

RevDate: 2021-01-16

Ansell SM, Maris M, Lesokhin AM, et al (2021)

Phase 1 Study of the CD47 Blocker TTI-621 in Patients with Relapsed or Refractory Hematologic Malignancies.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-3706 [Epub ahead of print].

PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase 1 study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies.

EXPERIMENTAL DESIGN: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI‑621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (NHL) or nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoints included overall response rate (ORR).

RESULTS: Overall, 164 patients received TTI‑621: 18 in escalation and 146 in expansion (rituximab combination, n=35; nivolumab combination, n=4). Based on transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20% grade {greater than or equal to}3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI‑621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing.

CONCLUSIONS: TTI-621 was well tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

RevDate: 2021-01-16

Ma W, Chen LS, Özbek U, et al (2019)

Integrative Proteo-genomic Analysis to Construct CNA-protein Regulatory Map in Breast and Ovarian Tumors.

Molecular & cellular proteomics : MCP, 18(8S1):S66-S81.

Recent development in high throughput proteomics and genomics profiling enable one to study regulations of genome alterations on protein activities in a systematic manner. In this article, we propose a new statistical method, ProMAP, to systematically characterize the regulatory relationships between proteins and DNA copy number alterations (CNA) in breast and ovarian tumors based on proteogenomic data from the CPTAC-TCGA studies. Because of the dynamic nature of mass spectrometry instruments, proteomics data from labeled mass spectrometry experiments usually have non-ignorable batch effects. Moreover, mass spectrometry based proteomic data often possesses high percentages of missing values and non-ignorable missing-data patterns. Thus, we use a linear mixed effects model to account for the batch structure and explicitly incorporate the abundance-dependent-missing-data mechanism of proteomic data in ProMAP. In addition, we employ a multivariate regression framework to characterize the multiple-to-multiple regulatory relationships between CNA and proteins. Further, we use proper statistical regularization to facilitate the detection of master genetic regulators, which affect the activities of many proteins and often play important roles in genetic regulatory networks. Improved performance of ProMAP over existing methods were illustrated through extensive simulation studies and real data examples. Applying ProMAP to the CPTAC-TCGA breast and ovarian cancer data sets, we identified many genome regions, including a few novel ones, whose CNA were associated with protein and or phosphoprotein abundances. For example, in breast tumors, a small region in 8p11.21 was recognized as the second biggest hub in the CNA-phosphoprotein regulatory map, and further investigation of the regulatory targets suggests the potential role of 8p11.21 CNA in perturbing oxygen binding and transport activities in tumor cells. This and other findings from our analyses help to characterize the impacts of CNAs on protein activity landscapes and cast light on the genetic regulation mechanisms underlying these tumors.

RevDate: 2021-01-15

Watkins B, Qayed M, McCracken C, et al (2021)

Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD.

METHODS: ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days).

RESULTS: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.

CONCLUSION: Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.

RevDate: 2021-01-15

Menon MP, Niyonzima N, Gralow J, et al (2021)

Breast Cancer Clinical Trials: The Landscape at the Uganda Cancer Institute and Lessons Learned.

JCO global oncology, 7:127-132.

The Uganda Cancer Institute, the sole national comprehensive cancer center in Uganda, has a long and rich history of clinical investigation and locally relevant cancer research. Given the increasing burden of breast cancer in Uganda and elsewhere in sub-Saharan Africa (SSA) and driven by the limited availability of immunohistochemistry (IHC), we launched a clinical trial aimed at evaluating locally available diagnostics to detect the presence of hormone receptors (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2. Preliminary data from 32 women in the diagnostic component of the study reveal high sensitivity and specificity for estrogen receptor and progesterone receptor and high specificity for human epidermal growth factor receptor 2 when comparing reverse transcriptase polymerase chain reaction with the gold standard (IHC). Innovative diagnostic and treatment strategies are required to address the burden of breast cancer that is increasing throughout SSA. Given the costs, infrastructure, and trained personnel associated with IHC, alternative testing options (including reverse transcriptase polymerase chain reaction as tested in our study) may provide an expedited and cost-effective method to determine receptor testing in breast cancer. Clinical trials conducted in the local setting are critical to determining optimal strategies for effective breast cancer management in SSA.

RevDate: 2021-01-15

Jang SH, Brown EVR, Lee EJ, et al (2021)

"Blood pressure monitoring should be a habit": adaptation of the Check. Change. Control. program for Asian American older adults, from group-based in-person to one-on-one telephone delivery.

Translational behavioral medicine pii:6100614 [Epub ahead of print].

Asian Americans have the lowest rate of awareness about hypertension, including controlled hypertension, among all racial/ethnic groups in the USA. A high proportion of Asian American older adults have limited English proficiency (LEP) and hypertension. This study adapted the Check. Change. Control. (CCC) program, a community-based intervention for hypertension control delivered in a face-to-face group setting, to phone-based delivery and evaluated the acceptability of the program among Asian American older adults with LEP. Thirteen participants received phone-based educational sessions on hypertension control over 4 months. After 4 months of interventions, we interviewed the 13 Asian American older adults and 4 counselors to examine the acceptability of the adapted CCC program. Both Asian American older adults and counselors found the phone-based delivery of the CCC program to be acceptable, and some participants recommended holding an in-person meeting before telephone delivery to review the program content and clarify information. Future study needs to explore the effectiveness of the phone-based delivery of the program on blood pressure management among larger groups of Asian American older adults.

RevDate: 2021-01-14

Shadman M, C Ujjani (2021)

Vaccinations in CLL: implications for COVID-19.

Blood, 137(2):144-146.

RevDate: 2021-01-14

Nyame YA, Gulati R, Tsodikov A, et al (2021)

Prostate-Specific Antigen Screening and Recent Increases in Advanced Prostate Cancer.

JNCI cancer spectrum, 5(1):pkaa098 pii:pkaa098.

Recent studies show decreasing prostate-specific antigen utilization and increasing incidence of metastatic prostate cancer in the United States after national recommendations against screening in 2012. Yet, whether the increasing incidence of metastatic prostate cancer is consistent in magnitude with the expected impact of decreased screening is unknown. We compared observed incidence of metastatic prostate cancer from the Surveillance, Epidemiology, and End Results program and published effects of continued historical screening and discontinued screening starting in 2013 projected by 2 models of disease natural history, screening, and diagnosis. The observed rate of new metastatic prostate cancer cases in 2017 was 44%-60% of the projected increase under discontinued screening relative to continued screening. Thus, the observed increase in incident metastatic prostate cancer is consistent with the expected impact of reduced screening. Although this comparison does not establish a causal relationship, it highlights the plausible role of decreased screening in the observed trend.

RevDate: 2021-01-14

Tkachev V, Kaminski J, Potter EL, et al (2021)

Spatiotemporal single-cell profiling reveals that invasive and tissue-resident memory donor CD8+ T cells drive gastrointestinal acute graft-versus-host disease.

Science translational medicine, 13(576):.

Organ infiltration by donor T cells is critical to the development of acute graft-versus-host disease (aGVHD) in recipients after allogeneic hematopoietic stem cell transplant (allo-HCT). However, deconvoluting the transcriptional programs of newly recruited donor T cells from those of tissue-resident T cells in aGVHD target organs remains a challenge. Here, we combined the serial intravascular staining technique with single-cell RNA sequencing to dissect the tightly connected processes by which donor T cells initially infiltrate tissues and then establish a pathogenic tissue residency program in a rhesus macaque allo-HCT model that develops aGVHD. Our results enabled creation of a spatiotemporal map of the transcriptional programs controlling donor CD8+ T cell infiltration into the primary aGVHD target organ, the gastrointestinal (GI) tract. We identified the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphodepletion-driven, T cell infiltration. GI-infiltrating donor CD8+ T cells demonstrated a highly activated, cytotoxic phenotype while simultaneously developing a canonical tissue-resident memory T cell (TRM) transcriptional signature driven by interleukin-15 (IL-15)/IL-21 signaling. We found expression of a cluster of genes directly associated with tissue invasiveness, including those encoding adhesion molecules (ITGB2), specific chemokines (CCL3 and CCL4L1) and chemokine receptors (CD74), as well as multiple cytoskeletal proteins. This tissue invasion transcriptional signature was validated by its ability to discriminate the CD8+ T cell transcriptome of patients with GI aGVHD from those of GVHD-free patients. These results provide insights into the mechanisms controlling tissue occupancy of target organs by pathogenic donor CD8+ TRM cells during aGVHD in primate transplant recipients.

RevDate: 2021-01-13

Palumbo PJ, Zhang Y, Clarke W, et al (2021)

Uptake of antiretroviral treatment and viral suppression among men who have sex with men and transgender women in sub-Saharan Africa in an observational cohort study: HPTN 075.

International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases pii:S1201-9712(21)00010-2 [Epub ahead of print].

OBJECTIVES: HPTN 075 enrolled men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa. Persons in HIV care or on antiretroviral treatment (ART) were not eligible to enroll. We evaluated antiretroviral (ARV) drug use, viral suppression, and drug resistance in this cohort over a 12-month follow-up period.

METHODS: Assessments included 64 participants with HIV (39 MSM, 24 TGW, one gender not specified). ARV drugs were detected using a qualitative assay. Viral load (VL) and drug resistance testing were performed using commercial assays.

RESULTS: Over 12 months, the proportion of participants using ARV drugs increased from 28.1% to 59.4% and the proportion with VLs <400 copies/mL increased from 21.9% to 57.8%. The rate of ART failure (detection of drugs without viral suppression) was similar at screening and 12 months (12.0% and 11.1%, respectively) and was similar among MSM and TGW. Two participants developed HIV drug resistance during follow-up.

CONCLUSIONS: Over 12 months, ARV drug use in the cohort more than doubled and viral suppression increased nearly three-fold without a significant increase in ART failure or drug resistance. These results suggest that ART can be successfully scaled up for HIV prevention and treatment in this high-risk population.

RevDate: 2021-01-13

Sadoff J, Le Gars M, Shukarev G, et al (2021)

Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.

The New England journal of medicine [Epub ahead of print].

BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein.

METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 5×1010 viral particles (low dose) or 1×1011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule.

RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 224 to 354) and reached 100% by day 57 with a further increase in titers (GMT, 288 to 488), regardless of vaccine dose or age group. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 14, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3.

CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.).

RevDate: 2021-01-13

Peters BA, Xue X, Wang Z, et al (2021)

Menopausal status and observed differences in the gut microbiome in women with and without HIV infection.

Menopause (New York, N.Y.), Publish Ahead of Print: pii:00042192-900000000-97021 [Epub ahead of print].

OBJECTIVE: Gut microbiota respond to host physiological phenomena, yet little is known regarding shifts in the gut microbiome due to menopausal hormonal and metabolic changes in women. HIV infection impacts menopause and may also cause gut dysbiosis. We therefore sought to determine the association between menopausal status and gut microbiome composition in women with and without HIV.

METHODS: Gut microbiome composition was assessed in stool from 432 women (99 premenopausal HIV+, 71 premenopausal HIV-, 182 postmenopausal HIV+, 80 postmenopausal HIV-) via 16S rRNA gene sequencing. We examined cross-sectional associations of menopause with gut microbiota overall diversity and composition, and taxon and inferred metagenomic pathway abundance. Models were stratified by HIV serostatus and adjusted for age, HIV-related variables, and other potential confounders.

RESULTS: Menopause, ie post- versus premenopausal status, was associated with overall microbial composition only in women with HIV (permutational MANOVA of Jensen Shannon Divergence: P = 0.01). In women with HIV, menopause was associated with enrichment of gram-negative order Enterobacteriales, depletion of highly abundant taxa within Prevotella copri, and alterations in other low-abundance taxa. Additionally, menopause in women with HIV was associated with enrichment of metagenomic pathways related to Enterobacteriales, including degradation of amino acids and phenolic compounds, biosynthesis of enterobactin, and energy metabolism pathways. Menopause-related differences in some low-abundance taxa were also observed in women without HIV.

CONCLUSIONS: A changing gut microbiome may be an overlooked phenomenon of reproductive aging in women with HIV. Longitudinal assessments across all reproductive stages are necessary to confirm these findings and identify health implications.

RevDate: 2021-01-13

Dingens AS, Pratap P, Malone KD, et al (2021)

High-resolution mapping of the neutralizing and binding specificities of polyclonal sera post HIV Env trimer vaccination.

eLife, 10: pii:64281 [Epub ahead of print].

Mapping polyclonal serum responses is critical to rational vaccine design. However, most high-resolution mapping approaches involve isolating and characterizing individual antibodies, which incompletely defines the polyclonal response. Here we use two complementary approaches to directly map the specificities of the neutralizing and binding antibodies of polyclonal anti-HIV-1 sera from rabbits immunized with BG505 Env SOSIP trimers. We used mutational antigenic profiling to determine how all mutations in Env affected viral neutralization and electron microscopy polyclonal epitope mapping (EMPEM) to directly visualize serum Fabs bound to Env trimers. The dominant neutralizing specificities were generally only a subset of the more diverse binding specificities. Additional differences between binding and neutralization reflected antigenicity differences between virus and soluble Env trimer. Further, we refined residue-level epitope specificity directly from sera, revealing subtle differences across sera. Together, mutational antigenic profiling and EMPEM yield a holistic view of the binding and neutralizing specificity of polyclonal sera.

RevDate: 2021-01-13

Mistry D, Litvinova M, Pastore Y Piontti A, et al (2021)

Inferring high-resolution human mixing patterns for disease modeling.

Nature communications, 12(1):323.

Mathematical and computational modeling approaches are increasingly used as quantitative tools in the analysis and forecasting of infectious disease epidemics. The growing need for realism in addressing complex public health questions is, however, calling for accurate models of the human contact patterns that govern the disease transmission processes. Here we present a data-driven approach to generate effective population-level contact matrices by using highly detailed macro (census) and micro (survey) data on key socio-demographic features. We produce age-stratified contact matrices for 35 countries, including 277 sub-national administratvie regions of 8 of those countries, covering approximately 3.5 billion people and reflecting the high degree of cultural and societal diversity of the focus countries. We use the derived contact matrices to model the spread of airborne infectious diseases and show that sub-national heterogeneities in human mixing patterns have a marked impact on epidemic indicators such as the reproduction number and overall attack rate of epidemics of the same etiology. The contact patterns derived here are made publicly available as a modeling tool to study the impact of socio-economic differences and demographic heterogeneities across populations on the epidemiology of infectious diseases.

RevDate: 2021-01-13

Lemmers RJLF, van der Vliet PJ, Blatnik A, et al (2021)

Chromosome 10q-linked FSHD identifies DUX4 as principal disease gene.

Journal of medical genetics pii:jmedgenet-2020-107041 [Epub ahead of print].

BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is an inherited muscular dystrophy clinically characterised by muscle weakness starting with the facial and upper extremity muscles. A disease model has been developed that postulates that failure in somatic repression of the transcription factor DUX4 embedded in the D4Z4 repeat on chromosome 4q causes FSHD. However, due to the position of the D4Z4 repeat close to the telomere and the complex genetic and epigenetic aetiology of FSHD, there is ongoing debate about the transcriptional deregulation of closely linked genes and their involvement in FSHD.

METHOD: Detailed genetic characterisation and gene expression analysis of patients with clinically confirmed FSHD and control individuals.

RESULTS: Identification of two FSHD families in which the disease is caused by repeat contraction and DUX4 expression from chromosome 10 due to a de novo D4Z4 repeat exchange between chromosomes 4 and 10. We show that the genetic lesion causal to FSHD in these families is physically separated from other candidate genes on chromosome 4. We demonstrate that muscle cell cultures from affected family members exhibit the characteristic molecular features of FSHD, including DUX4 and DUX4 target gene expression, without showing evidence for transcriptional deregulation of other chromosome 4-specific candidate genes.

CONCLUSION: This study shows that in rare situations, FSHD can occur on chromosome 10 due to an interchromosomal rearrangement with the FSHD locus on chromosome 4q. These findings provide further evidence that DUX4 derepression is the dominant disease pathway for FSHD. Hence, therapeutic strategies should focus on DUX4 as the primary target.

RevDate: 2021-01-13

Karlsson Q, Brook MN, Dadaev T, et al (2021)

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

European urology oncology pii:S2588-9311(20)30209-1 [Epub ahead of print].

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes.

OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk.

We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry.

Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated.

RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7).

CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families.

PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.

RevDate: 2021-01-13

Sanchez JI, Briant KJ, Wu-Georges S, et al (2021)

Eat Healthy, Be Active Community Workshops implemented with rural Hispanic women.

BMC women's health, 21(1):24.

BACKGROUND: In the U.S., obesity disproportionately affects some racial/ethnic groups more than others; 42.5% of Hispanic adults are obese, compared to 32.6% of non-Hispanic whites (NHW). Research also shows that Mexican American women are 40% more likely to be overweight, as compared to NHW women. With high obesity rates among Hispanics, improving healthier lifestyle practices is an important step for reducing health disparities. The Eat Healthy, Be Active (EHBA) community workshops were developed to assist individuals in translating national nutrition and physical activity recommendations into action. Promotora-led EHBA workshops could be used to promote obesity-related health behavior lifestyle changes among Hispanics.

METHODS: Hispanic women from rural communities in Washington state were recruited to participate in a six-week Promotora-led workshop series. This pilot study used a pre- and post-test study design to examine differences in healthy lifestyle knowledge and practices.

RESULTS: A total of 49 Hispanic women participated in the workshops, of whom 45% were obese. Six-weeks after implementation of EHBA, women had improvements in healthy lifestyle practices, including an increase in nutrition label literacy, decrease in consumption of food eaten in restaurants, and an increase in the number of times a woman performed physical activity long enough to make them sweat.

CONCLUSION: The findings from this pilot study indicate that delivering EHBA workshops through promotoras is a feasible culturally relevant approach to promoting healthier lifestyle practices among Hispanic women. Further, focusing on females, who do the food shopping and preparation in their homes, may help increase awareness among whole families.

RevDate: 2021-01-12

Hua S, Qi Q, Kizer JR, et al (2021)

Association of liver enzymes with incident diabetes in US Hispanic/Latino adults.

Diabetic medicine : a journal of the British Diabetic Association [Epub ahead of print].

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) has been associated with increased risk of incident diabetes. But such evidence is lacking in the Hispanic/Latino population, which has high prevalence of obesity and NAFLD.

METHODS: We conducted a prospective cohort study of 6,928 adults of Hispanic/Latino background who had no diabetes, did not report excessive alcohol use, and no hepatitis B and C infection at baseline (2008-2011). We estimated risk ratios (RR) for incident diabetes, identified from visit 2 examination by glucose measurements or antidiabetic medication use, with baseline liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)).

RESULTS: A total of 738 adults developed diabetes during 6 years of follow-up. After adjusting for participant characteristics at baseline, versus the lowest quartile, highest quartiles of ALT and GGT were associated with risks for incident diabetes (RR for ALT: 1.51 [95% CI 1.03-2.22], P-trend=0.006; RR for GGT: 2.39 [1.60-3.55], P-trend=0.001). Higher GGT levels predicted increased risk of incident diabetes even among those with ALT or AST below the median levels. The associations of ALT and GGT with incident diabetes were similar among most Hispanic background but were not seen among Dominicans (P for interaction<0.05). The association of AST with incident diabetes was found only among light-to-moderate alcohol drinkers (RR=1.50 [1.20-1.86]) but not abstainers (RR=0.91 [0.69-1.20], P for interaction=0.006).

CONCLUSION: Higher ALT and GGT levels are associated with increased risk of developing diabetes among Latinos. Liver enzyme tests might aid in diabetes prevention by identifying high risk individuals.

RevDate: 2021-01-12

O'Brien KM, Tworoger SS, Harris HR, et al (2021)

Genital powder use and risk of uterine cancer: A pooled analysis of prospective studies.

International journal of cancer [Epub ahead of print].

When powder is applied to the genital area, it has the potential to reach internal reproductive organs and promote carcinogenesis by irritating and inflaming exposed tissues. While many studies have considered the association between genital powder use and ovarian cancer risk, the relationship between genital powder use and uterine cancer is less well-studied. We pooled data from four large, prospective cohorts (the Nurses' Health Study, the Nurses' Health Study II, the Sister Study, and the Women's Health Initiative - Observational Study). We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI), adjusting for pre-specified confounders. In total, 209 185 women were included, with 37% reporting ever genital powder use. Over a mean 14.5 years of follow-up, 3272 invasive uterine cancers were diagnosed. There was no overall association between ever genital powder use and uterine cancer (HR = 1.01, 95% CI: 0.94-1.09), with little difference observed for frequent (≥1 times/week) vs never use (HR = 1.05, 95% CI: 0.95-1.16; p-for-trend = 0.46). Long-term use (>20 years; HR = 1.12, 95% CI: 0.96-1.31; p-for-trend = 0.14) was associated with a small, but not statistically significant, increase in risk, compared to never use. There were not clear differences by uterine cancer histologic subtypes or across strata of relevant covariates, including race/ethnicity, follow-up time, menopausal status and body mass index. The results of this large, pooled analysis do not support a relationship between use of genital powder and uterine cancer, though the positive associations observed for long-term use may merit further consideration. This article is protected by copyright. All rights reserved.

RevDate: 2021-01-13

Wong RL, EY Yu (2021)

Refining Immuno-Oncology Approaches in Metastatic Prostate Cancer: Transcending Current Limitations.

Current treatment options in oncology, 22(2):13.

OPINION STATEMENT: Due to its immunosuppressive tumor microenvironment, prostate cancer has historically been difficult to treat with immuno-oncology approaches. Other than pembrolizumab, which is now regulatory-approved for all microsatellite instability (MSI)-high and tumor mutational burden (TMB)-high advanced solid tumors, sipuleucel-T is the only immunotherapeutic agent approved by the US Food and Drug Administration (FDA) for prostate cancer. However, sipuleucel-T efficacy is optimal for select patients with indolent metastatic castration-resistant prostate cancer. Although manipulation of immune regulation by blocking immune checkpoints has led to substantial benefit in many cancers, experience with single-agent CTLA-4 and PD-1 or PD-L1 antibodies has shown limited effect for the majority of patients with prostate cancer, especially when administered as monotherapy. Combination therapies are now being attempted, in addition to enrichment strategies employing patient clinicopathologic and biologic characteristics that may heighten responses to immuno-oncology treatment, such as PD-L1 expression, TMB, MSI status, and alterations in CDK12. More work is needed to overcome the immune-exclusive barriers in prostate cancer, such as relatively low TMB, increased activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and defects in major histocompatibility complex (MHC) class I expression and interferon (IFN)-1 signaling. A promising approach and the likely next step in immuno-oncology for prostate cancer involves forced direction to markers expressed by prostate cancer tumor cells, such as prostate-specific membrane antigen (PSMA), that bypass the typical requirements for MHC class I interaction. The future will incorporate bispecific antibodies and chimeric antigen receptor (CAR)-T cells, potentially targeted towards phenotypic markers identified by next-generation PET imaging as part of the next wave of "precision medicine" in prostate cancer. Ultimately, we believe that the immune-exclusive prostate cancer tumor microenvironment can be overcome, and that patient outcomes can be enhanced through these more refined immuno-oncology approaches.

RevDate: 2021-01-12

Perski O, Watson NL, Mull KE, et al (2021)

Identifying content-based engagement patterns in a smoking cessation website and associations with user characteristics and cessation outcomes: A sequence and cluster analysis.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:6089170 [Epub ahead of print].

INTRODUCTION: Using WebQuit as a case study, a smoking cessation website grounded in Acceptance and Commitment Therapy, we aimed to identify sequence clusters of content usage and examine their associations with baseline characteristics, change to a key mechanism of action, and smoking cessation.

METHODS: Participants were adult smokers allocated to the WebQuit arm in a randomized controlled trial (n=1,313). WebQuit contains theory-informed content including goal setting, self-monitoring and feedback, and values- and acceptance-based exercises. Sequence analysis was used to temporally order 30-second website usage segments for each participant. Similarities between sequences were assessed with the optimal matching distance algorithm and used as input in an agglomerative hierarchical clustering analysis. Associations between sequence clusters and baseline characteristics, acceptance of cravings at 3 months and self-reported 30-day point prevalence abstinence at 12 months were examined with linear and logistic regression.

RESULTS: Three qualitatively different sequence clusters were identified. 'Disengagers' (576/1,313) almost exclusively used the goal setting feature. 'Tryers' (375/1,313) used goal setting and two of the values- and acceptance-based components ('Be Aware', 'Be Willing'). 'Committers' (362/1,313) primarily used two of the values- and acceptance-based components ('Be Willing', 'Be Inspired'), goal setting, and self-monitoring and feedback. Compared with Disengagers, Committers demonstrated greater increases in acceptance of cravings (p=.01) and 64% greater odds of quit success (ORadj=1.64, 95% CI=1.18, 2.29, p=.003).

DISCUSSION: WebQuit users were categorised into Disengagers, Tryers and Committers based on their qualitatively different content usage patterns. Committers saw increases in a key mechanism of action and greater odds of quit success.

IMPLICATIONS: This case study demonstrates how employing sequence and cluster analysis of usage data can help researchers and practitioners gain a better understanding of how users engage with a given eHealth intervention over time and use findings to test theory and/or to improve future iterations to the intervention. Future WebQuit users may benefit from being directed to the values- and acceptance-based and the self-monitoring and feedback components via reminders over the course of the program.

RevDate: 2021-01-12

Stefanick ML, King AC, Mackey S, et al (2021)

Women's Health Initiative Strong and Healthy (WHISH) Pragmatic Physical Activity Intervention Trial for Cardiovascular Disease Prevention: Design and Baseline Characteristics.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6089158 [Epub ahead of print].

BACKGROUND: National guidelines promote physical activity to prevent cardiovascular disease (CVD), yet no randomized controlled trial has tested whether physical activity reduces prevent CVD.

METHODS: The Women's Health Initiative (WHI) Strong and Healthy (WHISH) pragmatic trial used a randomized consent design to assign women for whom cardiovascular outcomes were available through WHI data collection (N=18,985) or linkage to the Centers for Medicare and Medicaid Services (N30,346), to a physical activity intervention or "usual activity" comparison, stratified by ages 68-99 years (in tertiles), U.S. geographic region, and outcomes data source. Women assigned to the intervention could "opt out" after receiving initial physical activity materials. Intervention materials applied evidence-based behavioral science principles to promote current national recommendations for older Americans The intervention was adapted to participant input regarding preferences, resources, barriers and motivational drivers and was targetted for three categories of women at lower, middle or higher levels of self-reported physical functioning and physical activity. Physical activity was assessed in both arms through annual questionnaires. The primary outcome is major cardiovascular events, specifically myocardial infarction, stroke, or CVD death; primary safety outcomes are hip fracture and non-CVD death. The trial is monitored annually by an independent Data Safety and Monitoring Board. Final analyses will be based on intention-to-treat in all randomized participants, regardless of intervention engagement.

RESULTS: The 49,331 randomized participants had a mean baseline age of 79.7 years; 84.3% were white, 9.2% black, 3.3% Hispanic, 1.9% Asian/Pacific Islander, 0.3% Native American, and 1% were of unknown race/ethnicity. The mean baseline RAND-36 physical function score was 71.6 (± 25.2 SD). There were no differences between Intervention (N=24,657) and Control (N=24,674) at baseline for age, race/ethnicity, current smoking (2.5%), use of blood pressure or lipid-lowering medications, body mass index, physical function, physical activity, or prior CVD (10.1%).

CONCLUSION: The WHISH trial is rigorously testing whether a physical activity intervention reduces major CV events in a large, diverse cohort of older women.

RevDate: 2021-01-12

Cardozo-Ojeda EF, Duke ER, Peterson CW, et al (2021)

Thresholds for post-rebound SHIV control after CCR5 gene-edited autologous hematopoietic cell transplantation.

eLife, 10: pii:57646.

Autologous, CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplantation is a promising strategy for achieving HIV remission. However, only a fraction of HSPCs can be edited ex vivo to provide protection against infection. To project the thresholds of CCR5-edition necessary for HIV remission, we developed a mathematical model that recapitulates blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted HSPCs are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76-94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur.

RevDate: 2021-01-12

Farland LV, Degnan WJ, Harris HR, et al (2021)

Recreational and residential sun exposure and risk of endometriosis: a prospective cohort study.

Human reproduction (Oxford, England), 36(1):199-210.

STUDY QUESTION: Is recreational and residential sun exposure associated with risk of endometriosis?

SUMMARY ANSWER: Tanning bed use in early adulthood, sunscreen use and history of sunburns were associated with a greater risk of endometriosis; however, higher residential UV exposure was associated with a lower endometriosis risk.

WHAT IS KNOWN ALREADY: Previous research has reported an association between endometriosis and skin cancer, with evidence of shared risk factors between the two diseases. We investigated the potential associations between ultraviolet radiation and endometriosis risk.

STUDY DESIGN, SIZE, DURATION: The Nurses' Health Study II is a prospective cohort of 116 429 female US nurses aged 25-42 years at enrolment in 1989. Participants completed self-administered biennial questionnaires through June 2015.

We investigated self-reported measures of recreational sun-exposure and geocoded residential UV exposure in childhood and adulthood in relation to risk of laparoscopically confirmed endometriosis among premenopausal white women. We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% CIs.

During follow-up, 4791 incident cases of laparoscopically confirmed endometriosis were reported among 1 252 248 person-years. Tanning bed use during high school/college (≥6 times per year vs. never use: HR = 1.19, 95% CI = 1.01-1.40; Ptrend = 0.04) and at ages 25-35 (HR = 1.24, 95% CI = 1.12-1.39; Ptrend ≤ 0.0001), number of sunburns during adolescence (Ptrend = 0.03) and percentage of time using sunscreen in adulthood (Ptrend = 0.002) were positively associated with risk of endometriosis. In contrast, residential UV level at birth (highest vs. lowest quintile: HR = 0.81, 95% CI = 0.72-0.92; Ptrend = 0.0001), at age 15 (HR = 0.79, 95% CI = 0.70-0.88; Ptrend ≤ 0.0001) and at age 30 (HR = 0.90, 95% CI = 0.82-0.99; Ptrend = 0.21) were associated with a decreased risk of endometriosis.

Self-reported endometriosis diagnosis may be prone to misclassification; however, we restricted our definition to laparoscopically confirmed endometriosis, which has been shown to have high validity compared to medical records.

Our results suggest that tanning bed use in early adulthood increases endometriosis risk, potentially through a harmful effect of ultraviolet A wavelengths, and that residential UV exposure reduces risk, possibly via optimal vitamin D synthesis. These findings should be investigated further to enhance our understanding of endometriosis aetiology.

This project was supported by NICHD grants HD48544 and HD52473, HD57210, NIH grant CA50385, CA176726. M.K. was supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme (#PIOF-GA-2011-302078) and is grateful to the Philippe Foundation and the Bettencourt-Schueller Foundation for their financial support. H.R.H. is supported by the National Cancer Institute, National Institutes of Health (K22 CA193860). The authors have nothing to disclose.

TRIAL REGISTRATION NUMBER: N/A.

RevDate: 2021-01-12

Carbone LD, Johnson K, Larson JC, et al (2021)

Association of vitamin D with incident glaucoma: findings from the Women's Health Initiative.

Journal of investigative medicine : the official publication of the American Federation for Clinical Research pii:jim-2020-001645 [Epub ahead of print].

The relationship between vitamin D and glaucoma is controversial. The objective of this study was to examine women from the Women's Health Initiative (WHI) to determine if there is an association between vitamin D and incident glaucoma in postmenopausal women. We examined the association between dietary vitamin D intake, vitamin D supplements and serum 25 hydroxyvitamin D (25(OH)D) levels and the risk of developing glaucoma. 143,389 postmenopausal women from the WHI including a subset with serum 25(OH) D measurements were examined to determine the association of dietary, supplemental and serum levels of vitamin D to the development of glaucoma. Dietary intakes of vitamin D, use of vitamin D supplements and serum levels of 25(OH) D were predictors examined for the main outcome of incident glaucoma. In multivariable models adjusted for demographic, clinical variables and medication use, dietary vitamin D, vitamin D supplements, total vitamin D intake (diet plus supplements) and serum 25 (OH) D measurements were not significantly associated with incident glaucoma. In the CaD placebo-controlled intervention clinical trial, there was also no association in the active intervention arm with glaucoma. We conclude that dietary vitamin D intake, supplements and serum levels are not significantly related to the risk of developing glaucoma in postmenopausal women.

RevDate: 2021-01-12

Smith SD, Lopedote P, Samara Y, et al (2020)

Polatuzumab Vedotin for Relapsed/Refractory Aggressive B-cell Lymphoma: A Multicenter Post-marketing Analysis.

Clinical lymphoma, myeloma & leukemia pii:S2152-2650(20)31019-3 [Epub ahead of print].

INTRODUCTION: Polatuzumab vedotin is approved therapy in the United States for relapsed/refractory diffuse large B-cell lymphoma in combination with bendamustine and rituximab (Pola+BR). However, the safety and efficacy of Pola+BR outside of a clinical trial setting is unknown.

PATIENTS AND METHODS: We analyzed use of pola-based therapy at 5 centers in the United States, including dose, response rates, progression-free survival (PFS), survival, and toxicity.

RESULTS: Sixty-nine patients with aggressive B-cell lymphoma, including 66 with diffuse large B-cell lymphoma/high-grade B-cell lymphoma and 84% refractory to prior therapy, were treated. Responses occurred in of 50%, including 24% complete response. Median duration of response was 5.1 months, PFS was 2.0 months, and survival was 5.3 months, at 4 months median follow-up. Inferior PFS was associated with prior refractory disease (median, 57 days vs. not reached; P = .003) and lack of response to Pola+BR (PFS, 27 days vs. 152 days; P < .001). Discontinuation owing to planned cellular therapy was seen in 36% and owing to toxicity occurred in 12%; unplanned hospitalizations occurred in 36%.

CONCLUSIONS: We conclude that commercial Pola is applied to highly refractory lymphomas at our centers, often with intent to bridge to subsequent therapy. Although some clinical benefit was observed, efficacy was inferior to clinical trial data, especially among those with refractory disease.

RevDate: 2021-01-12

Pollyea DA, Bixby D, Perl A, et al (2021)

NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.

Journal of the National Comprehensive Cancer Network : JNCCN, 19(1):16-27 pii:jnccnGLINS1901.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

RevDate: 2021-01-12

Daly MB, Pal T, Berry MP, et al (2021)

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 19(1):77-102 pii:jnccnGLS1901.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

RevDate: 2021-01-12

Bhattacharya D, Guo R, Tseng CH, et al (2021)

Maternal HBV Viremia and Association With Adverse Infant Outcomes in Women Living With HIV and HBV.

The Pediatric infectious disease journal, 40(2):e56-e61.

BACKGROUND: There is limited information on perinatal outcomes in HIV-hepatitis B virus (HBV) coinfection.

METHODS: HIV Prevention Trials Network (HPTN) 046 was a randomized double-blind placebo-controlled trial of perinatal transmission that evaluated 6 months of infant nevirapine versus placebo among breast-fed infants. Women living with HIV and their infants enrolled in sub-Saharan Africa from 2007 to 2010; 78% received antiretroviral therapy (ART). Maternal samples were tested for hepatitis B surface antigen (HBsAg). High and low HBV viral load (VL) was defined as ≥106 IU/mL and <106 IU/mL. The association between HIV-HBV coinfection and maternal and infant outcomes was assessed using multivariate (MV) logistic and Cox regression.

RESULTS: Among 2025 women, 88 (4.3%) had HBV. HIV-HBV women with high HBV VL had lower median CD4, versus HIV alone or HIV-HBV women with low HBV VL [320, 490 and 434 cells/mm3, respectively (P < 0.007)]. In MV analysis, adjusted for maternal CD4, age and maternal ART, infants born to women with high HBV VL were more likely to be low birth weight (LBW), versus HIV+/HBV- and low HBV VL women: [30% (3/10) vs. 10% (194/1953) vs. 6% (5/78), respectively, P = 0.03). High HBV VL was associated with HIV perinatal transmission [(hazard ratio 6.75 (95% confidence interval (CI): 1.86 - 24.50)]. There was no impact on infant mortality or maternal outcomes at 18 months.

CONCLUSIONS: In HIV-HBV women, high HBV viral loads increase the risk of LBW and potentially HIV perinatal transmission. Reduction of antepartum HBV viremia may have beneficial effects beyond the prevention of HBV perinatal transmission.

RevDate: 2021-01-12
CmpDate: 2012-07-31

Lu Q, Krull KR, Leisenring W, et al (2011)

Pain in long-term adult survivors of childhood cancers and their siblings: a report from the Childhood Cancer Survivor Study.

Pain, 152(11):2616-2624.

Little is known about pain among long-term adult survivors of childhood cancers. The study investigated pain prevalence in this population compared with sibling controls and examined pain-related risk factors. Three self-reported pain outcomes including pain conditions, prescription analgesics used, and pain attributed to cancer and treatment were assessed among 10,397 cancer survivors and 3034 sibling controls from the Childhood Cancer Survivor Study. Pain conditions (pain/abnormal sensation, migraines, and other headaches) were reported by 12.3%, 15.5%, and 20.5% of survivors, respectively; 16.7% of survivors reported use of prescription analgesics, and 21% attributed pain to cancer and treatment. Risks of reporting pain conditions and using prescription analgesics were higher among survivors than siblings, adjusting for sociodemographic factors. Younger age at diagnosis and a history of non-Hodgkin lymphoma, Wilms tumor, or neuroblastoma (compared to leukemia) were associated with greater risk of reporting pain conditions. A history of bone cancer or soft tissue sarcoma (compared to leukemia) was associated with greater risks of using prescription analgesics and cancer-related pain attribution. Non-brain-directed scatter irradiation was associated with elevated risk for migraines and cancer-related pain attribution. Female gender and lower educational attainment were associated with increased reports of all 3 pain outcomes; minority status, unemployment, and being single were associated with greater risks for reporting pain conditions. These findings contribute to the understanding of pain and associated risk factors among adult survivors of childhood cancer and suggest areas of focus for pain intervention.

RevDate: 2021-01-08
CmpDate: 2009-04-14

Reed SD, Voigt LF, Newton KM, et al (2009)

Progestin therapy of complex endometrial hyperplasia with and without atypia.

Obstetrics and gynecology, 113(3):655-662.

OBJECTIVE: To assess the likelihood of histologic persistence/progression of complex hyperplasia and atypical hyperplasia among women treated with progestin compared with those not treated, with attention to type, dose, and duration.

METHODS: This was a cohort study at an integrated health plan of women, ages 18-85 years, with complex or atypical hyperplasia on independent pathology review with a second endometrial specimen in the 2-6 months after the index diagnosis. Progestin therapy between index diagnosis and follow-up biopsy was determined from the pharmacy database. Medical record abstraction was performed. Relative risks (RRs), adjusted for age and body mass index, were calculated.

RESULTS: Among 185 women, average age 55.9 years, follow-up 16.1 weeks, 115 had complex and 70 had atypical hyperplasia. Among women with complex hyperplasia, 28.4% of those treated with progestin and 30.0% of those not treated had persistence/progression (RR 1.20, 95% confidence interval [CI] 0.53-2.72). Among women with atypical hyperplasia, 26.9% of those treated with progestin and 66.7% of those not treated had persistence/progression (RR 0.39, 95% CI 0.21-0.70); there was a suggestion that use of at least a medium dose, or a duration of at least 3 months, was associated with a particularly low probability of persistence/progression.

CONCLUSION: Although progestin treatment of women with atypical hyperplasia was associated with a substantial increase in the likelihood of regression of the lesion during the ensuing 2-6 months, persistence/progression was nonetheless present in more than one quarter of treated women. Regression of complex hyperplasia without atypia was common whether progestin had or had not been used.

RevDate: 2021-01-08
CmpDate: 2009-02-24

Kudish BI, Iglesia CB, Sokol RJ, et al (2009)

Effect of weight change on natural history of pelvic organ prolapse.

Obstetrics and gynecology, 113(1):81-88.

OBJECTIVE: To evaluate the relationship between change in weight and pelvic organ prolapse (POP) progression/regression in women during a 5-year period.

METHODS: Postmenopausal women with uteri (N=16,608), ages 50 to 79, who were enrolled in the Women's Health Initiative (WHI) Estrogen plus Progestin Clinical Trial between 1993 and 1998 were included in this secondary analysis. Baseline pelvic examination, repeated annually, assessed uterine prolapse, cystocele, and rectocele using the WHI Prolapse Classification System. Statistical analyses included univariate and multiple logistic regression methods.

RESULTS: During the 5-year time period, the majority of women (9,251, 55.7%) gained weight (mean 4.43 kg, +/-5.95 kg), and the overall rate of prolapse (WHI Prolapse Classification System: grades 1-3) increased from 40.9% at baseline to 43.8% at year 5 of evaluation. Controlling for age, parity, race, and other health/physical variables, being overweight (body mass index [BMI] between 25 and 29.9) or obese (BMI of at least 30) at baseline was associated with progression in cystocele, rectocele, and uterine prolapse compared with women with healthy BMIs (BMI is calculated as weight (kg)/[height (m)]). Specifically, the risk of prolapse progression in overweight and obese women as compared with the participants with healthy BMIs increased by 32% and 48% for cystocele, by 37% and 58% for rectocele, and by 43% and 69% for uterine prolapse, respectively. Adjusting for women with prolapse at baseline and baseline BMI, a 10% weight change was associated with minimal change in overall POP. Specifically, a 10% weight loss was associated with a borderline worsening of uterine prolapse (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.88-0.97) and a minimal regression of cystocele (OR 1.03, 95% CI 1.00-1.05) and rectocele (OR 1.04, 95% CI 1.01-1.07).

CONCLUSION: Being overweight or obese is associated with progression of POP. Weight loss does not appear to be significantly associated with regression of POP, suggesting that damage to the pelvic floor related to weight gain might be irreversible.

LEVEL OF EVIDENCE: II.

RevDate: 2021-01-07
CmpDate: 2009-02-24

Paramsothy P, Jamieson DJ, Heilig CM, et al (2009)

The effect of highly active antiretroviral therapy on human papillomavirus clearance and cervical cytology.

Obstetrics and gynecology, 113(1):26-31.

OBJECTIVE: To examine the association of highly active antiretroviral therapy (HAART) with human papillomavirus (HPV) clearance and progression or regression of cervical cytological abnormalities in women with human immunodeficiency virus (HIV).

METHODS: Five hundred thirty-seven women with HIV participating in the HIV Epidemiology Research Study, an observational, multisite cohort study, were evaluated semiannually from 1996 to 2000. Cervical Pap tests were collected for cervical cytology. Testing for HPV was conducted by polymerase chain reaction. Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals (CIs). Number needed to treat (NNT) at 2 years was calculated for HAART.

RESULTS: Among women with cervical squamous intraepithelial lesions, HAART was associated with an increased likelihood of HPV clearance (hazard ratio 4.5, 95% CI 1.2-16.3, NNT 22.4). Use of HAART was not associated with an increased likelihood of HPV clearance among women with normal cervical cytology (hazard ratio 1.7, 95% CI 0.9-3.1, NNT 6.5) or atypical squamous cells of undetermined significance cytology (hazard ratio 1.0, 95% CI 0.4-2.5, NNT 174.0). Use of HAART was not significantly associated with an increased likelihood of cervical cytologic regression (hazard ratio 1.3, 95% CI 1.0-1.7, NNT 10.9) or cervical cytologic progression (hazard ratio 0.7, 95% CI 0.6-1.0, NNT 12.8).

CONCLUSION: Among women with preexisting abnormal cervical cytology, HAART was associated with enhanced HPV clearance but not with Pap test regression. Close monitoring of women with HIV for cervical cytologic abnormalities, regardless of HAART treatment status, is warranted.

LEVEL OF EVIDENCE: II.

RevDate: 2021-01-11

Szulzewsky F, Holland EC, V Vasioukhin (2021)

YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance.

Developmental biology pii:S0012-1606(21)00004-X [Epub ahead of print].

YAP1 is a transcriptional co-activator whose activity is controlled by the Hippo signaling pathway. In addition to important functions in normal tissue homeostasis and regeneration, YAP1 has also prominent functions in cancer initiation, aggressiveness, metastasis, and therapy resistance. In this review we are discussing the molecular functions of YAP1 and its roles in cancer, with a focus on the different mechanisms of de-regulation of YAP1 activity in human cancers, including inactivation of upstream Hippo pathway tumor suppressors, regulation by intersecting pathways, miRNAs, and viral oncogenes. We are also discussing new findings on the function and biology of the recently identified family of YAP1 gene fusions, that constitute a new type of activating mutation of YAP1 and that are the likely oncogenic drivers in several subtypes of human cancers. Lastly, we also discuss different strategies of therapeutic inhibition of YAP1 functions.

RevDate: 2021-01-11

Hill GR, Betts BC, Tkachev V, et al (2021)

Current Concepts and Advances in Graft-Versus-Host Disease Immunology.

Annual review of immunology [Epub ahead of print].

Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host/donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

RevDate: 2021-01-11

Kared H, Redd AD, Bloch EM, et al (2021)

SARS-CoV-2-specific CD8+ T cell responses in convalescent COVID-19 individuals.

The Journal of clinical investigation pii:145476 [Epub ahead of print].

Characterization of the T cell response in individuals who recover from SARS-CoV-2 infection is critical to understand its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 COVID-19 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis, humoral and inflammatory responses. There were 132 SARS-CoV-2-specific CD8+ T cell responses detected across six different HLAs, corresponding to 52 unique epitope reactivities. CD8+ T cell responses were detected in almost all convalescent individuals and were directed against several structural and non-structural target epitopes from the entire SARS-CoV-2 proteome. A unique phenotype for SARS-CoV-2-specific T cells was observed that was distinct from other common virus-specific T cells detected in the same cross-sectional sample and characterized by early differentiation kinetics. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem-cell and transitional memory states, subsets, which may be key to developing durable protection.

RevDate: 2021-01-11

Barber-Axthelm IM, Barber-Axthelm V, Sze KY, et al (2021)

Stem cell-derived CAR T cells traffic to HIV reservoirs in macaques.

JCI insight, 6(1): pii:141502.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with CCR5- donor cells is the only treatment known to cure HIV-1 in patients with underlying malignancy. This is likely due to a donor cell-mediated graft-versus-host effect targeting HIV reservoirs. Allo-HSCT would not be an acceptable therapy for most people living with HIV due to the transplant-related side effects. Chimeric antigen receptor (CAR) immunotherapies specifically traffic to malignant lymphoid tissues (lymphomas) and, in some settings, are able to replace allo-HSCT. Here, we quantified the engraftment of HSC-derived, virus-directed CAR T cells within HIV reservoirs in a macaque model of HIV infection, using potentially novel IHC assays. HSC-derived CAR cells trafficked to and displayed multilineage engraftment within tissue-associated viral reservoirs, persisting for nearly 2 years in lymphoid germinal centers, the brain, and the gastrointestinal tract. Our findings demonstrate that HSC-derived CAR+ cells reside long-term and proliferate in numerous tissues relevant for HIV infection and cancer.

RevDate: 2021-01-11

Doepker LE, Danon S, Harkins E, et al (2021)

Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies.

eLife, 10: pii:63444 [Epub ahead of print].

A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naïve antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of broadly active ADCC antibodies may require mutations that enable high affinity antigen recognition along with mutations that optimize factors contributing to functional ADCC activity.

RevDate: 2021-01-11

Cannon P, Asokan A, Czechowicz A, et al (2021)

Safe and Effective In Vivo Targeting and Gene Editing in Hematopoietic Stem Cells: Strategies for Accelerating Development National Institutes of Health/Bill & Melinda Gates Foundation Expert Scientific Roundtable Webinar Meeting.

Human gene therapy [Epub ahead of print].

Introduction On May 11, 2020, the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation (Gates Foundation) held an exploratory expert scientific roundtable to inform an NIH-Gates Foundation collaboration on the development of scalable, sustainable, and accessible HIV and sickle cell disease (SCD) therapies based on in vivo gene editing of hematopoietic stem cells (HSC). A particular emphasis was on how such therapies could be developed for low-resource settings in sub-Saharan Africa. Paula Cannon, Ph.D., of the University of Southern California and Hans-Peter Kiem, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center served as roundtable co-chairs. Welcoming remarks were provided by the leadership of NIH, NHLBI, and BMGF, who cited the importance of assessing the state of the science and charting a path toward finding safe, effective, and durable gene-based therapies for HIV and sickle cell disease. These remarks were followed by three sessions in which participants heard presentations on and discussed the therapeutic potential of modified HSCs, leveraging HSC biology and differentiation, and in vivo HSC targeting approaches. This roundtable serves as the beginning of an ongoing discussion among NIH, the Gates Foundation, research and patient communities, and the public at large. As this collaboration progresses, these communities will be engaged as we collectively navigate the complex scientific and ethical issues surrounding in vivo HSC targeting and editing. Summarized excerpts from each of the presentations are below, reflecting the individual views and perspectives of each presenter.

RevDate: 2021-01-11

Moralez EA, Thompson B, Englund K, et al (2020)

The Health Disparities Field Experience: College students and community health workers in the field.

Journal of education and health promotion, 9:323 pii:JEHP-9-323.

CONTEXT: Immersing students studying health promotion and disease prevention into community settings facing health disparities is an essential supplement to their academic experience. As part of many public health professions, these students will likely need to understand the values and beliefs of different cultures so that decisions of appropriate health promotion and treatment can be made equitably. This paper evaluates an education immersion program that was part of a National Cancer Institute funded collaboration supporting the recruitment and training of university students in cancer research. The primary aim of the Health Disparities Field Experience (HDFE) was to facilitate an experience for students pursuing a health-related degree to understand the conceptual issues in border/rural health and the cultural contexts related to health disparities among medically and financially indigent populations in the region.

SUBJECTS AND METHODS: This study was conducted using qualitative research methods using a variation of the content analysis approach using open codes to categorize the data. Six students were selected to participate in the HDFE (five graduate students and one undergraduate) and all six of the participants completed pre- and post-test surveys.

RESULTS: From the analysis of the data, posttest qualitative responses indicated that three participants saw racism as a primary cause of cancer-related disparities, a change from their pretest responses. When asked about the personal impact of the HDFE, respondents mentioned the importance of the experiential component.

CONCLUSIONS: Participants learned about health disparities from the HDFE and expressed high satisfaction with this approach to education.

RevDate: 2021-01-11

Khaki AR, Li A, Diamantopoulos LN, et al (2021)

A New Prognostic Model in Patients with Advanced Urothelial Carcinoma Treated with First-line Immune Checkpoint Inhibitors.

European urology oncology pii:S2588-9311(20)30214-5 [Epub ahead of print].

BACKGROUND: While immune checkpoint inhibitors (ICIs) are approved in the first-line (1L) setting for cisplatin-unfit patients with programmed death-ligand 1 (PD-L1)-high tumors or for platinum (cisplatin/carboplatin)-unfit patients, response rates remain modest and outcomes vary with no clinically useful biomarkers (except for PD-L1).

OBJECTIVE: We aimed to develop a prognostic model for overall survival (OS) in patients receiving 1L ICIs for advanced urothelial cancer (aUC) in a multicenter cohort study.

Patients treated with 1L ICIs for aUC across 24 institutions and five countries (in the USA and Europe) outside clinical trials were included in this study.

We used a stepwise, hypothesis-driven approach using clinician-selected covariates to develop a new risk score for patients receiving ICIs in the 1L setting. Demographics, clinicopathologic data, treatment patterns, and OS were collected uniformly. Univariate Cox regression was performed on 18 covariates hypothesized to be associated with OS based on published data. Variables were retained for multivariate analysis (MVA) if they correlated with OS (p < 0.2) and were included in the final model if p < 0.05 on MVA. Retained covariates were assigned points based on the beta coefficient to create a risk score. Stratified median OS and C-statistic were calculated.

RESULTS AND LIMITATIONS: Among 984 patients, 357 with a mean age of 71 yr were included in the analysis, 27% were female, 68% had pure UC, and 13% had upper tract UC. Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases were significant prognostic factors on MVA and were included in the risk score. C index for new 1L risk score was 0.68 (95% confidence interval 0.65-0.71). Limitations include retrospective nature and lack of external validation.

CONCLUSIONS: We developed a new 1L ICI risk score for OS based on data from patients with aUC treated with ICIs in the USA and Europe outside of clinical trials. The score components highlight readily available factors related to tumor biology and treatment response. External validation is being pursued.

PATIENT SUMMARY: With multiple new treatments under development and approved for advanced urothelial carcinoma, it can be difficult to identify the best treatment sequence for each patient. The risk score may help inform treatment discussions and estimate outcomes in patients treated with first-line immune checkpoint inhibitors, while it can also impact clinical trial design and endpoints. TAKE HOME MESSAGE: A new risk score was developed for advanced urothelial carcinoma treated with first-line immune checkpoint inhibitors. The score assigned Eastern Cooperative Oncology Group performance status ≥2, albumin <3.5 g/dl, neutrophil:lymphocyte ratio >5, and liver metastases each one point, with a higher score being associated with worse overall survival.

RevDate: 2021-01-10

Lees B, Hampton JM, Trentham-Dietz A, et al (2021)

A population-based study of causes of death after endometrial cancer according to major risk factors.

Gynecologic oncology pii:S0090-8258(20)34223-2 [Epub ahead of print].

OBJECTIVE: To identify the most common causes of death and potentially modifiable risk factors in endometrial cancer patients.

METHODS: 745 women diagnosed with incident endometrial cancer were enrolled in a population-based study from 1991 to 1994. Participants completed structured interviews about 1 year after diagnosis. Study files were linked with the National Death Index to identify dates and causes of death through 2016. Proportional hazards regression was used to estimate hazard rate ratios for cause of death adjusting for age and stage of disease. Hazard ratios were also examined according to comorbidities.

RESULTS: Of the 745 women, 450 were deceased after a median of 19.9 years. The two most common causes of death were cardiovascular disease (N = 145, 32%) and any cancer (N = 135, 30%), with only 10% of women dying from endometrial cancer (N = 46). Obesity, diabetes and smoking increased risk of all-cause mortality (HRR 1.77, 95%CI 1.36-2.31; HRR 1.74, 95%CI 1.34-2.27; HRR 1.59, 95%CI 1.16-2.17). Diabetes also increased risk of cardiovascular disease-specific mortality (HRR 1.98, 95%CI 1.38-3.08), but not endometrial cancer mortality (HRR 0.55, 95%CI 0.21-1.48). Neither obesity nor smoking was associated with increased risk of cardiovascular disease-specific mortality (HRR 1.46, 95%CI 0.92-2.32; HRR 1.21, 95%CI 0.67-2.18) nor endometrial-cancer specific mortality (HRR 1.81, 95%CI 0.83-3.93; HRR 0.61, 95%CI 0.17-2.15).

CONCLUSIONS: Endometrial cancer patients were 3 times more likely to die of cardiovascular disease than endometrial cancer. Obesity, smoking and diabetes increase the risk of death in these patients and are potentially modifiable. Clinical trials should be developed that incorporate counseling regarding these risk factors into survivorship care to determine impact on mortality.

RevDate: 2021-01-09

Aapro M, Lyman GH, Bokemeyer C, et al (2020)

Supportive care in patients with cancer during the COVID-19 pandemic.

ESMO open, 6(1):100038 pii:S2059-7029(20)32904-5 [Epub ahead of print].

Cancer care has been profoundly impacted by the global pandemic of severe acute respiratory syndrome coronavirus 2 disease (coronavirus disease 2019, COVID-19), resulting in unprecedented challenges. Supportive care is an essential component of cancer treatment, seeking to prevent and manage chemotherapy complications such as febrile neutropenia, anaemia, thrombocytopenia/bleeding, thromboembolic events and nausea/vomiting, all of which are common causes of hospitalisation. These adverse events are an essential consideration under routine patient management, but particularly so during a pandemic, a setting in which clinicians aim to minimise patients' risk of infection and need for hospital visits. Professional medical oncology societies have been providing updated guidelines to support health care professionals with the management, treatment and supportive care needs of their patients with cancer under the threat of COVID-19. This paper aims to review the recommendations made by the most prominent medical oncology societies for devising and modifying supportive care strategies during the pandemic.

RevDate: 2021-01-09

Nørskov KH, Yi JC, Crouch ML, et al (2021)

Social support as a moderator of healthcare adherence and distress in long-term hematopoietic cell transplantation survivors.

Journal of cancer survivorship : research and practice [Epub ahead of print].

BACKGROUND: Treatment with hematopoietic cell transplantation (HCT) has potentially severe effects on physical and psychosocial functioning. Poor social support has been linked with physical morbidity and mortality as well as psychological distress in HCT survivors. This study tested a theory-driven hypothesis that social support buffers adverse effects of health stressors of comorbidities and graft-versus-host disease (cGVHD) on distress and adherence to recommended healthcare among long-term HCT survivors.

METHODS: This cross-sectional study analyzed baseline data from a randomized controlled trial in adult survivors 3-18 years post-HCT. Data included medical records and patient-reported outcomes including cancer and treatment distress (CTXD), healthcare adherence (HCA), comorbidity index, cGVHD, ENRICHD Social Support Instrument (ESSI), Social Activity Log, and Health Self-Efficacy. We tested hypothesized models for HCA and CTXD using blocked hierarchical linear regressions.

RESULTS: Among the 781 HCT survivors completing baseline assessment, 38% had > 3 comorbidities, 8% had moderate-severe cGVHD, 30% reported low social support, 30% reported elevated distress, and 49% reported low healthcare adherence. Social support and self-efficacy were directly related to both adherence and distress. Regression models supported the hypothesized moderated relationships for distress but not for healthcare adherence.

CONCLUSIONS: The two tested models confirm that the health stressors of comorbidities and cGVHD are moderated by better social support and self-efficacy in their associations with lower distress but without moderating effects for healthcare adherence.

Social support and self-efficacy confer protective benefits on healthcare adherence and psychological distress. Interventions are needed that focus on maintaining social networks or finding new networks if necessary.

NCT00799461.

RevDate: 2021-01-09

Zhang E, Chai JC, Deik AA, et al (2021)

Plasma lipidomic profiles and risk of diabetes: two prospective cohorts of HIV-infected and HIV-uninfected individuals.

The Journal of clinical endocrinology and metabolism pii:6073670 [Epub ahead of print].

OBJECTIVES: Antiretroviral therapy (ART) use is associated with disrupted lipid and glucose metabolism in people with HIV-infection. We aimed to identify plasma lipid species associated with risk of diabetes in the context of HIV infection.

RESEARCH DESIGN AND METHODS: We profiled 211 plasma lipid species in 491 HIV-infected and 203 HIV-uninfected participants aged 35-55 years from the Women's Interagency HIV study and the Multicenter AIDS Cohort Study. Cox proportional hazards model was used to examine associations between baseline lipid species and incident diabetes (166 diabetes cases were identified during a median follow-up of 12.6 years).

RESULTS: We identified 11 lipid species, representing independent signals for 8 lipid classes/subclasses, associated with risk of diabetes (P<0.05 after FDR correction). After adjustment for multiple covariates, cholesteryl ester (CE)(22:4), lysophosphatidylcholine (LPC)(18:2), phosphatidylcholine (PC)(36:4), phosphatidylcholine-plasmalogen(34:3), and phosphatidylethanolamine (PE)(38:2) were associated with decreased risk of diabetes (HRs=0.70 to 0.82 per SD increment), while diacylglycerol(32:0), LPC(14:0), PC(38:3), PE(36:1), and triacylglycerol(50:1) were associated with increased risk of diabetes (HRs=1.26 to 1.56 per SD increment). HIV serostatus did not modify any lipid-diabetes associations; however, most of these lipid species were positively associated with HIV and/or ART use, including 3 diabetes-decreased (CE(22:4), LPC(18:2), PE(38:2)) and all 5 diabetes-increased lipid species.

CONCLUSIONS: This study identified multiple plasma lipid species associated with incident diabetes. Regardless of the directions of their associations with diabetes, most diabetes-associated lipid species were elevated in ART-treated people with HIV-infection. This suggests a complex role of lipids in the link between ART and diabetes in HIV infection.

RevDate: 2021-01-09

Karunamuni RA, Huynh-Le MP, Fan CC, et al (2021)

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate cancer and prostatic diseases [Epub ahead of print].

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

RevDate: 2021-01-09

Jin Q, Shi N, Aroke D, et al (2021)

Insulinemic and Inflammatory Dietary Patterns Show Enhanced Predictive Potential for Type 2 Diabetes Risk in Postmenopausal Women.

Diabetes care pii:dc20-2216 [Epub ahead of print].

OBJECTIVE: The empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores assess the insulinemic and inflammatory potentials of habitual dietary patterns, irrespective of the macronutrient content, and are based on plasma insulin response or inflammatory biomarkers, respectively. The glycemic index (GI) and glycemic load (GL) assess postprandial glycemic potential based on dietary carbohydrate content. We tested the hypothesis that dietary patterns promoting hyperinsulinemia, chronic inflammation, or hyperglycemia may influence type 2 diabetes risk.

RESEARCH DESIGN AND METHODS: We calculated dietary scores from baseline (1993-1998) food frequency questionnaires among 73,495 postmenopausal women in the Women's Health Initiative, followed through March 2019. We used multivariable-adjusted Cox regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes risk. We also estimated multivariable-adjusted absolute risk of type 2 diabetes.

RESULTS: During a median 13.3 years of follow-up, 11,009 case subjects with incident type 2 diabetes were diagnosed. Participants consuming the most hyperinsulinemic or proinflammatory dietary patterns experienced greater risk of type 2 diabetes; HRs (95% CI) comparing highest to lowest dietary index quintiles were: EDIH 1.49 (1.32-1.68; Ptrend < 0.0001) and EDIP 1.45 (1.29-1.63; Ptrend < 0.0001). The absolute excess incidence for the same comparison was 220 (EDIH) and 271 (EDIP) case subjects per 100,000 person-years. GI and GL were not associated with type 2 diabetes risk: GI 0.99 (0.88-1.12; Ptrend = 0.46) and GL 1.01 (0.89-1.16; Ptrend = 0.30).

CONCLUSIONS: Our findings in this diverse cohort of postmenopausal women suggest that lowering the insulinemic and inflammatory potentials of the diet may be more effective in preventing type 2 diabetes than focusing on glycemic foods.

RevDate: 2021-01-09

Son YM, Cheon IS, Wu Y, et al (2021)

Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses.

Science immunology, 6(55):.

Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.

RevDate: 2021-01-09
CmpDate: 2019-01-16

Jones SMW, Chennupati S, Nguyen T, et al (2019)

Comorbidity is associated with higher risk of financial burden in Medicare beneficiaries with cancer but not heart disease or diabetes.

Medicine, 98(1):e14004.

The aim of the study was to examine how multimorbidity influences the prevalence of financial burden among older adults with heart disease, diabetes, or cancer.The study was a cross-sectional analysis of prospective observational cohort survey study.Older adults (age 65 or older) who did not report 1/6 major chronic illnesses (n = 2773; reference group), reported 1/3 major chronic illnesses without comorbidity (heart disease n = 206; diabetes n = 460; cancer n = 417), and reported 1/3 major chronic illnesses with comorbidity (heart disease n = 232; diabetes n = 202; cancer n = 109).The measures were presence of chronic diseases (heart disease, diabetes, cancer), comorbid chronic diseases (stroke, lung disease, dementia), medical-related financial burden (credit card debt due to medical costs, paying medical bills over time), and overall financial burden (financial help from family, credit card debt, help with food, utilities, and other necessities).The proportion reporting financial burden ranged from 15% to 27% across samples. Heart disease was unrelated to medical or overall financial burden, regardless of comorbidity. Diabetes was unrelated to financial burden except diabetes without comorbidity was associated with lower odds of overall financial burden compared to healthy older adults (odds ratio [OR] = 0.655, 95% confidence interval [CI]: 0.468-0.917). Cancer with comorbidity, but not cancer without comorbidity, was associated with greater odds of medical related (OR = 1.678, 95% CI: 1.057-2.664) and overall financial burden (OR = 1.748, 95% CI: 1.064-2.872).The association of multimorbidity with financial burden likely varies based on specific diseases. Future research on financial burden should focus on specific disease combinations such as cancer with comorbidity.

RevDate: 2021-01-08

Lin BM, Grinde KE, Brody JA, et al (2021)

Whole genome sequence analyses of eGFR in 23,732 people representing multiple ancestries in the NHLBI trans-omics for precision medicine (TOPMed) consortium.

EBioMedicine, 63:103157 pii:S2352-3964(20)30533-8 [Epub ahead of print].

BACKGROUND: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants.

METHODS: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity.

FINDINGS: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10-11; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10-9; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10-9). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10-9, nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10-9, CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants.

INTERPRETATION: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry.

RevDate: 2021-01-08

Liu M, Liu Y, Wu MC, et al (2021)

A Method for Subtype Analysis with Somatic Mutations.

Bioinformatics (Oxford, England) pii:6069547 [Epub ahead of print].

MOTIVATION: Cancer is a highly heterogeneous disease, and virtually all types of cancer have subtypes. Understanding the association between cancers subtypes and genetic variations is fundamental to the development of targeted therapies for patients. Somatic mutation plays important roles in tumor development and has emerged as a new type of genetic variations for studying the association with cancer subtypes. However, the low prevalence of individual mutations poses a tremendous challenge to the related statistical analysis.

RESULTS: In this article, we propose an approach, SASOM, for the association analysis of cancer subtypes with somatic mutations. Our approach tests the association between a set of somatic mutations (from a genetic pathway) and subtypes, while incorporating functional information of the mutations into the analysis. We further propose a robust p-value combination procedure, DAPC, to synthesize statistical significance from different sources. Simulation studies show that the proposed approach has correct type I error and tends to be more powerful than possible alternative methods. In a real data application, we examine the somatic mutations from a cutaneous melanoma dataset, and identify a genetic pathway that is associated with immune-related subtypes.

The SASOM R package is available at https://github.com/rksyouyou/SASOM-pkg. R scripts and data are available at https://github.com/rksyouyou/SASOM-analysis.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RevDate: 2021-01-07

Wu NL, S Hingorani (2021)

Outcomes of kidney injury including dialysis and kidney transplantation in pediatric oncology and hematopoietic cell transplant patients.

Pediatric nephrology (Berlin, Germany) [Epub ahead of print].

Pediatric oncology and hematopoietic cell transplant (HCT) patients are susceptible to both acute kidney injury (AKI) and chronic kidney disease (CKD). The etiologies of AKI vary but include tumor infiltration, radiation, drug-induced toxicity, and fluid and electrolyte abnormalities including tumor lysis syndrome. HCT patients can also have additional complications such as sinusoidal obstructive syndrome, graft-versus-host disease, or thrombotic microangiopathy. For patients with severe AKI requiring dialysis, multiple modalities can be used successfully, although continuous kidney replacement therapy (CKRT) is often the principal modality for critically ill patients. While increasing numbers of pediatric cancer and HCT patients are now surviving long term, they remain at risk for a number of chronic medical conditions, including CKD. Certain high-risk patients, due to underlying risk factors or treatment-related complications, eventually develop kidney failure and may require kidney replacement therapies. Management of co-morbidities and complications associated with kidney failure, including use of erythropoietin for anemia and potential need for ongoing cancer-related treatment while on dialysis, is an additional consideration in this patient population. Kidney transplantation can be successfully performed in pediatric cancer survivors, although additional features such as specific cancer diagnosis and duration of remission should be considered.

RevDate: 2021-01-07

Carlson DS, Grivas P, Wei W, et al (2021)

The Effectiveness of Shared Compared to Informed Decision Making for Prostate Cancer Screening in a High-Risk African American Population: A Randomized Control Trial.

Cancer investigation [Epub ahead of print].

BACKGROUND: Prostate cancer incidence and mortality in the United States in African Americans (AA) are higher than in Caucasians. Eastern Cuyahoga County in Ohio is majority AA and is considered an underserved population particularly vulnerable to healthcare disparities. There is a paucity of data about shared decision making among high-risk AA men with regard to prostate cancer screening. This study aims to examine shared versus informed decision making (SDM versus IDM) in a randomized, control trial among a large, high-risk AA population.

METHODS: Patients were included in annual one-day outreach events, each held over 3 years (2017-2019), and were randomized at each event into IDM (control) and SDM (investigational) groups and then were offered screening via prostate specific antigen (PSA) and digital rectal exam (DRE). The primary endpoints were proportion of participants over 40 who did not demonstrate decisional conflict about prostate cancer screening measured by the SURE score, as well as change of knowledge score about prostate cancer screening.

RESULTS: Overall, 175 patients were enrolled in the trial; 79 in the SDM arm and 96 in the IDM arm. The investigational (SDM) arm had 3/79 (3.9%) conflict versus 6/96 (6.4%) in the control (IDM) arm (p = 0.74). With regard to knowledge improvement, the SDM cohort demonstrated improvement following educational tools for 66/79 (81%) of participants versus 76/96 (79%) in the IDM cohort (p = 0.85). There was no difference in the proportion (63%) of participants in either group who found the information very helpful (using a Likert scale).

CONCLUSIONS: Our education-based study showed no significant difference between SDM and IDM with regard to decisional conflict about prostate cancer screening. The study also demonstrated significant improvement in knowledge about prostate cancer screening in a high-risk AA population in both groups. Our results should be interpreted with caution due to several limitations; however, the study can serve as a benchmark for future studies in this very important topic.

RevDate: 2021-01-07

McLeod C, Gout AM, Zhou X, et al (2021)

St. Jude Cloud-a Pediatric Cancer Genomic Data Sharing Ecosystem.

Cancer discovery pii:2159-8290.CD-20-1230 [Epub ahead of print].

Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival of pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem for accessing, analyzing and visualizing genomic data from >10,000 pediatric cancer patients and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes and 2,202 transcriptomes. The resource is expanding rapidly with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the pediatric cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes.

RevDate: 2021-01-06

Sun J, Mathias BJ, Laronga C, et al (2021)

Impact of Axillary Dissection Among Patients With Sentinel Node-Positive Breast Cancer Undergoing Mastectomy.

Journal of the National Comprehensive Cancer Network : JNCCN, 19(1):40-47 pii:jnccn19315.

BACKGROUND: Results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial supports omission of completion axillary lymph node dissection (CLND) after breast-conservation surgery with a positive sentinel lymph node biopsy (SLNB). We hypothesized that CLND also does not impact outcomes in women with clinically node-negative (cN0), pathologically node-positive breast cancer undergoing mastectomy.

MATERIALS AND METHODS: A single-institution retrospective review was performed of patients with SLN-positive breast cancer treated from July 1999 through May 2018. Clinicopathologic and outcome data were collected. Patients with SLNBs were compared with those receiving SLNB and CLND. The Kruskal-Wallis, chi-square, and Fisher exact tests were used to assess for differences between continuous and categorical variables. The log-rank test was used for time-to-event analyses, and Cox proportional hazards models were fit for locoregional and distant recurrence and overall survival (OS).

RESULTS: Of 329 patients with SLN-positive breast cancer undergoing mastectomy, 60% had CLND (n=201). Median age at diagnosis was 53 years (interquartile range [IQR], 46-62 years). The median number of SLNs sampled was 3 (IQR, 2-4), and the median number of positive SLNs was 1 (IQR, 1-2). Patients receiving CLND had higher tumor grades (P=.02) and a higher proportion of hormone receptor negativity (estrogen receptor, 19%; progesterone receptor, 27%; both P=.007). A total of 44 patients (22%) had increased N stage after CLND. Median follow-up was 51 months (IQR, 29-83 months). No association was found between CLND and change in OS and locoregional or distant recurrence. Completion of postmastectomy radiotherapy was associated with improved OS (P=.04).

CONCLUSIONS: CLND is not significantly correlated with reduced recurrence or improved OS among patients who have cN0, SLN-positive breast cancer treated with mastectomy. CLND was significantly correlated with receipt of adjuvant systemic therapy. Completion of postmastectomy radiotherapy was associated with improved OS.

RevDate: 2021-01-06

Martin PJ (2021)

Sitagliptin to Prevent Acute Graft-versus-Host Disease.

The New England journal of medicine, 384(1):70-71.

RevDate: 2021-01-06

Polaski JT, Udy DB, Escobar-Hoyos LF, et al (2021)

The origins and consequences of UPF1 variants in pancreatic adenosquamous carcinoma.

eLife, 10: pii:62209 [Epub ahead of print].

Pancreatic adenosquamous carcinoma (PASC) is an aggressive cancer whose mutational origins are poorly understood. An early study reported high-frequency somatic mutations affecting UPF1, a nonsense-mediated mRNA decay (NMD) factor, in PASC, but subsequent studies did not observe these lesions. The corresponding controversy about whether UPF1 mutations are important contributors to PASC has been exacerbated by a paucity of functional studies. Here, we modeled two UPF1 mutations in human and mouse cells to find no significant effects on pancreatic cancer growth, acquisition of adenosquamous features, UPF1 splicing, UPF1 protein, or NMD efficiency. We subsequently discovered that 45% of UPF1 mutations reportedly present in PASCs are identical to standing genetic variants in the human population, suggesting that they may be non-pathogenic inherited variants rather than pathogenic mutations. Our data suggest that UPF1 is not a common functional driver of PASC and motivate further attempts to understand the genetic origins of these malignancies.

RevDate: 2021-01-06

Petrick JL, Pfeiffer RM, Liao LM, et al (2021)

Circulating MicroRNAs in Relation to Esophageal Adenocarcinoma Diagnosis and Survival.

Digestive diseases and sciences [Epub ahead of print].

BACKGROUND AND AIMS: Tissue miRNA can discriminate between esophageal adenocarcinoma (EA) and normal epithelium. However, no studies have examined a comprehensive panel of circulating miRNAs in relation to EA diagnosis and survival.

METHODS: We used all 62 EA cases from the US Multi-Center case-control study with available serum matched 1:1 to controls. Cases were followed for vital status. MiRNAs (n = 2064) were assessed using the HTG EdgeSeq miRNA Whole Transcriptome Assay. Differential expression analysis of miRNAs in relation to case-control status was conducted. In cases, Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality. P values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control. Predictive performance was assessed using cross-validation.

RESULTS: Sixty-eight distinct miRNAs were significantly upregulated between cases and controls (e.g., miR-1255b-2-3p fold change = 1.74, BH-adjusted P = 0.01). Assessing the predictive performance of these significantly upregulated miRNAs yielded 60% sensitivity, 65% specificity, and 0.62 AUC. miR-4253 and miR-1238-5p were associated with risk of mortality after EA diagnosis (HR = 4.85, 95% CI: 2.30-10.23, BH-adjusted P = 0.04 and HR = 3.81, 95% CI: 2.02-7.19, BH-adjusted P = 0.04, respectively).

CONCLUSIONS: While they require replication, these findings suggest that circulating miRNAs may be associated with EA diagnosis and survival.

RevDate: 2021-01-05

Dowsett IT, Sneeden JL, Olson BJ, et al (2021)

Rate volatility and asymmetric segregation diversify mutation burden in cells with mutator alleles.

Communications biology, 4(1):21.

Mutations that compromise mismatch repair (MMR) or DNA polymerase ε or δ exonuclease domains produce mutator phenotypes capable of fueling cancer evolution. Here, we investigate how combined defects in these pathways expands genetic heterogeneity in cells of the budding yeast, Saccharomyces cerevisiae, using a single-cell resolution approach that tallies all mutations arising from individual divisions. The distribution of replication errors present in mother cells after the initial S-phase was broader than expected for a single uniform mutation rate across all cell divisions, consistent with volatility of the mutator phenotype. The number of mismatches that then segregated to the mother and daughter cells co-varied, suggesting that each division is governed by a different underlying genome-wide mutation rate. The distribution of mutations that individual cells inherit after the second S-phase is further broadened by the sequential actions of semiconservative replication and mitotic segregation of chromosomes. Modeling suggests that this asymmetric segregation may diversify mutation burden in mutator-driven tumors.

RevDate: 2021-01-05

Sillah A, Tykodi SS, Hall ET, et al (2021)

Predictive lifestyle markers for efficacy of cancer immune checkpoint inhibitors: a commentary.

Lifestyle factors could plausibly modulate the host immune system, the tumor microenvironment and, hence, immune checkpoint inhibitor (ICI) response. As such, these factors should be considered in ICI studies.

RevDate: 2021-01-07
CmpDate: 2017-05-10

Lee AW, Ness RB, Roman LD, et al (2016)

Association Between Menopausal Estrogen-Only Therapy and Ovarian Carcinoma Risk.

Obstetrics and gynecology, 127(5):828-836.

OBJECTIVE: To describe the association between postmenopausal estrogen-only therapy use and risk of ovarian carcinoma, specifically with regard to disease histotype and duration and timing of use.

METHODS: We conducted a pooled analysis of 906 women with ovarian carcinoma and 1,220 women in a control group; all 2,126 women included reported having had a hysterectomy. Ten population-based case-control studies participating in the Ovarian Cancer Association Consortium, an international consortium whose goal is to combine data from many studies with similar methods so reliable assessments of risk factors can be determined, were included. Self-reported questionnaire data from each study were harmonized and conditional logistic regression was used to examine estrogen-only therapy's histotype-specific and duration and recency of use associations.

RESULTS: Forty-three and a half percent of the women in the control group reported previous use of estrogen-only therapy. Compared with them, current or recent estrogen-only therapy use was associated with an increased risk for the serous (51.4%, odds ratio [OR] 1.63, 95% confidence interval [CI] 1.27-2.09) and endometrioid (48.6%, OR 2.00, 95% CI 1.17-3.41) histotypes. In addition, statistically significant trends in risk according to duration of use were seen among current or recent postmenopausal estrogen-only therapy users for both ovarian carcinoma histotypes (Ptrend<.001 for serous and endometrioid). Compared with women in the control group, current or recent users for 10 years or more had increased risks of serous ovarian carcinoma (36.8%, OR 1.73, 95% CI 1.26-2.38) and endometrioid ovarian carcinoma (34.9%, OR 4.03, 95% CI 1.91-8.49).

CONCLUSION: We found evidence of an increased risk of serous and endometrioid ovarian carcinoma associated with postmenopausal estrogen-only therapy use, particularly of long duration. These findings emphasize that risk may be associated with extended estrogen-only therapy use.

RevDate: 2021-01-07
CmpDate: 2012-06-07

Win AK, Dowty JG, Antill YC, et al (2011)

Body mass index in early adulthood and endometrial cancer risk for mismatch repair gene mutation carriers.

Obstetrics and gynecology, 117(4):899-905.

OBJECTIVE: To investigate the association of body mass index (BMI) in early adulthood and endometrial cancer risk for carriers of a germline mutation in a DNA mismatch repair gene.

METHODS: We estimated the association between BMI at age 18-20 years and endometrial cancer risk for mismatch repair gene mutation carriers and, as a comparison group, noncarriers using 601 female carriers of a germline mutation in a mismatch repair gene (245 MLH1, 299 MSH2, 38 MSH6, and 19 PMS2) and 533 female noncarriers from the Colon Cancer Family Registry using a weighted Cox proportional hazards regression.

RESULTS: During 51,693 person-years of observation, we observed diagnoses of endometrial cancer for 126 carriers and eight noncarriers. For carriers, there was no evidence of an association between BMI at age 20 years and endometrial cancer (adjusted hazard ratio 0.73 per 5 kg/m²; 95% confidence interval [CI], 0.40-1.34; P=.31). For noncarriers, endometrial cancer risk increased by 74% for each 5-kg/m² increment in BMI (adjusted hazard ratio 1.74; 95% CI 1.27-2.37; P<.001). The hazard ratio for BMI and endometrial cancer for noncarriers was greater than for carriers (P=.04).

CONCLUSION: The effect of body mass on endometrial cancer risk depends on the woman's mismatch repair gene mutation carrier status, suggesting obesity-independent endometrial carcinogenesis for carriers.

LEVEL OF EVIDENCE: II.

RevDate: 2021-01-07
CmpDate: 2010-07-01

Gardella C, Huang ML, Wald A, et al (2010)

Rapid polymerase chain reaction assay to detect herpes simplex virus in the genital tract of women in labor.

Obstetrics and gynecology, 115(6):1209-1216.

OBJECTIVE: To develop a rapid quantitative real-time polymerase chain reaction (PCR) to detect herpes simplex virus (HSV) in the genital secretions of women that may be used in labor.

METHODS: Samples of genital secretions from women in labor, swabs of active genital lesions, and swabs of buffer solution were analyzed using a newly developed rapid HSV PCR assay to detect HSV glycoprotein B gene and quantitate virion copy number. A previously validated TaqMan PCR to detect HSV glycoprotein B gene was performed as the comparator gold standard. Positivity determination that optimized sensitivity and specificity was determined with receiver operating characteristic curves.

RESULTS: The median time to result for rapid HSV PCR was 2 hours (range 1.5-3.5 hours). A positivity determination rule that required both wells of the rapid test to detect 150 copies or greater of HSV per milliliter maximized specificity (96.7%) without appreciable loss of sensitivity (99.6%). Among positive samples, the correlation between the rapid test and TaqMan for the quantity of HSV isolated was excellent (R=0.96, P<.001). The rapid test had a positive predictive value of 96.7% and a negative predictive value of 99.6% in a population with HSV shedding prevalence of 10.8%, based on the prevalence of genital HSV previously found among HSV-2 seropositive women in labor.

CONCLUSION: Rapid HSV PCR provides results with excellent sensitivity and specificity within a timeframe that could inform clinical decision making for identifying neonates at risk of neonatal HSV infection.

LEVEL OF EVIDENCE: II.

RevDate: 2021-01-07
CmpDate: 2010-07-01

Theiler RN, Farr SL, Karon JM, et al (2010)

High-risk human papillomavirus reactivation in human immunodeficiency virus-infected women: risk factors for cervical viral shedding.

Obstetrics and gynecology, 115(6):1150-1158.

OBJECTIVE: To evaluate the presence of and estimate risk factors for reactivation of latent high-risk human papillomavirus (HPV) cervical infection in human immunodeficiency virus (HIV)-infected and HIV-uninfected women.

METHODS: Data from 898 women in the HIV Epidemiology Research Study (HERS) were used to evaluate cervical HPV latency and reactivation. Prior exposure to HPV types (16, 18, 31, 35, and 45) was determined by serologic testing at enrollment, and cervical shedding of HPV was detected by polymerase chain reaction at 6-month intervals. Human papillomavirus cervical shedding and sexual history were used to estimate rates of reactivation and recurrence. Repeated measures survival analysis was used to estimate hazard ratios and 95% confidence intervals for reactivation and recurrence. Rates of total HPV shedding (recurrence and reactivation) during follow-up were assessed by HIV status and rate ratios were calculated.

RESULTS: Reactivation of latent HPV infections was observed in HIV-infected women, but few reactivation events were identified in HIV-uninfected women. Factors consistently associated with reactivation in HIV-infected women included CD4 count less than 200/mm and age younger than 35 years. Women infected with HIV had 1.8 to 8.2 times higher rates of viral shedding (reactivation plus recurrence) compared with HIV-uninfected women.

CONCLUSION: Women with a history of cervical HPV infection may be at risk of reactivation of latent viral infection even in the absence of sexual activity, and this risk is higher in women with HIV infection.

LEVEL OF EVIDENCE: II.

RevDate: 2021-01-07
CmpDate: 2009-05-28

Shah CA, Goff BA, Lowe K, et al (2009)

Factors affecting risk of mortality in women with vaginal cancer.

Obstetrics and gynecology, 113(5):1038-1045.

OBJECTIVE: To estimate the current effect of demographics, pathology, and treatment on mortality among women with vaginal cancer.

METHODS: Using data from 17 population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results program, 2,149 women diagnosed with primary vaginal cancer between 1990 and 2004 were identified. The association between various demographic factors, tumor characteristics, and treatments and risk of vaginal cancer mortality were evaluated using Cox proportional hazards modeling.

RESULTS: The mean age+/-standard deviation at diagnosis was 65.7+/-14.3 years. Approximately 66% of all cases were non-Hispanic whites. Incidence was highest among African-American women (1.24 per 100,000 person-years). The 5-year disease-specific survival was 84% (stage I), 75% (stage II), and 57% (stage III/IV). In a multivariate adjusted model, women with tumors greater than 4 cm and advanced disease had elevated risks of mortality (hazard ratios 1.71 and 4.67, respectively). Compared with women with squamous cell carcinomas, patients with vaginal melanoma had a 1.51-fold (95% confidence interval 1.07-2.41) increased risk of mortality. Surgery alone as a treatment modality had the lowest risk of mortality. The risk of mortality has decreased over time, as women diagnosed after 2000 had an adjusted 17% decrease in their risk of death compared with women from 1990-1994.

CONCLUSION: Stage, tumor size, histology, and treatment modality significantly affect a woman's risk of mortality from vaginal cancer. There seems to be a survival advantage that is temporally related to the advent of chemoradiation.

RevDate: 2021-01-07
CmpDate: 2009-05-28

Schwarz EB, Ray RM, Stuebe AM, et al (2009)

Duration of lactation and risk factors for maternal cardiovascular disease.

Obstetrics and gynecology, 113(5):974-982.

OBJECTIVE: To examine dose-response relationships between the cumulative number of months women lactated and postmenopausal risk factors for cardiovascular disease.

METHODS: We examined data from 139,681 postmenopausal women (median age 63 years) who reported at least one live birth on enrolling in the Women's Health Initiative observational study or controlled trials. Multivariable models were used to control for sociodemographic (age, parity, race, education, income, age at menopause), lifestyle, and family history variables when examining the effect of duration of lactation on risk factors for cardiovascular disease, including obesity (body mass index [BMI] at or above 30), hypertension, self-reported diabetes, hyperlipidemia, and prevalent and incident cardiovascular disease.

RESULTS: Dose-response relationships were seen; in fully adjusted models, women who reported a lifetime history of more than 12 months of lactation were less likely to have hypertension (odds ratio [OR] 0.88, P<.001), diabetes (OR 0.80, P<.001), hyperlipidemia (OR 0.81, P<.001), or cardiovascular disease (OR 0.91, P=.008) than women who never breast-fed, but they were not less likely to be obese. In models adjusted for all above variables and BMI, similar relationships were seen. Using multivariate adjusted prevalence ratios from generalized linear models, we estimate that among parous women who did not breast-feed compared with those who breast-fed for more than 12 months, 42.1% versus 38.6% would have hypertension, 5.3% versus 4.3% would have diabetes, 14.8% versus 12.3% would have hyperlipidemia, and 9.9% versus 9.1% would have developed cardiovascular disease when postmenopausal. Over an average of 7.9 years of postmenopausal participation in the Women's Health Initiative, women with a single live birth who breast-fed for 7-12 months were significantly less likely to develop cardiovascular disease (hazard ratio 0.72, 95% confidence interval 0.53-0.97) than women who never breast-fed.

CONCLUSION: Among postmenopausal women, increased duration of lactation was associated with a lower prevalence of hypertension, diabetes, hyperlipidemia, and cardiovascular disease.

RevDate: 2021-01-05

Farland LV, Degnan WJ, Harris HR, et al (2021)

A prospective study of endometriosis and risk of type 2 diabetes.

Diabetologia [Epub ahead of print].

AIMS/HYPOTHESIS: The objective of this study was to investigate the association between laparoscopically confirmed endometriosis and risk of type 2 diabetes.

METHODS: We used data from the Nurses' Health Study II, a prospective cohort of female nurses followed for >25 years (N = 112,037). We used Cox proportional hazards models to estimate the HRs and 95% CIs of incident, confirmed type 2 diabetes (n = 8496 participants) adjusted a priori for confounding factors. We additionally investigated differences in the relationship between endometriosis and type 2 diabetes by age (<50 or ≥50 years), BMI (<30 or ≥30 kg/m2), infertility history, menopausal status and history of gestational diabetes mellitus (GDM; restricted to parous women).

RESULTS: We saw no association between laparoscopically confirmed endometriosis and risk of type 2 diabetes in multivariable confounder-adjusted models (HR 1.06 [95% CI 0.98, 1.13]) or models accounting for potential mediating factors (HR 0.94 [95% CI 0.87, 1.00]). However, we observed modest differences in the association between endometriosis and type 2 diabetes by BMI group, history of infertility and history of GDM. Among non-obese women (HR 1.17 [95% CI 1.02, 1.35]), women who never experienced infertility (HR 1.14 [95% CI 1.04, 1.25]) and women who never experienced GDM (HR 1.11 [95% CI 1.01, 1.22]), endometriosis was associated with greater risk of type 2 diabetes.

CONCLUSIONS/INTERPRETATION: Overall, women with endometriosis were not at increased risk of type 2 diabetes. However, among subgroups at low risk for type 2 diabetes (i.e. non-obese women and women with no prior history of infertility or GDM), endometriosis was associated with a modest increased risk of type 2 diabetes.

RevDate: 2021-01-05

Hyacinth HI, Franceschini N, Seals SR, et al (2021)

Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.

JAMA network open, 4(1):e2030435 pii:2774578.

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).

Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.

This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.

Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.

Main Outcomes and Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).

Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).

Conclusions and Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.

RevDate: 2021-01-05

Bonm AV, Gibson AW, Holmberg LA, et al (2021)

A single-center retrospective analysis of outcome measures and consolidation strategies for relapsed and refractory primary CNS lymphoma.

Journal of neuro-oncology [Epub ahead of print].

BACKGROUND: Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management.

METHODS: We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded.

RESULTS: During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2-88.5) months and median PFS was 11.0 (0.2-73.9) months. At diagnosis (r2 = 0.85, p < 0.001), first relapse (r2 = 0.69, p < 0.001), multiple relapses (r2 = 0.97, p < 0.001) PFS was highly correlated with OS. In contrast, there was no correlation between the duration of subsequent progression-free intervals. No difference in PFS or OS was seen between CSF or intraocular relapse and parenchymal relapse. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7%. Consolidation with autologous stem cell transplant (ASCT) was associated with longer PFS compared to either no consolidation (p = 0.01) and trended to longer PFS when compared to other consolidation strategies (p = 0.06). OS was similarly improved in patients consolidated with ASCT compared with no consolidation (p = 0.04), but not compared with other consolidation (p = 0.22). Although patients receiving ASCT were younger, KPS, sex, and number of recurrences were similar between consolidation groups. A multivariate analysis confirmed an independent effect of consolidation group on PFS (p = 0.01), but not OS.

CONCLUSIONS: PFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.

RevDate: 2021-01-05

Conti DV, Darst BF, Moss LC, et al (2021)

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Nature genetics [Epub ahead of print].

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

RevDate: 2021-01-04

Barnabas RV, A Wald (2021)

A Public Health COVID-19 Vaccination Strategy to Maximize the Health Gains for Every Single Vaccine Dose.

RevDate: 2021-01-04

Sundaram V, Gould MK, VS Nair (2020)

A Comparison of the PanCan Model and Lung-RADS to Assess Cancer Probability Among People With Screening-Detected, Solid Lung Nodules.

Chest pii:S0012-3692(20)34935-7 [Epub ahead of print].

BACKGROUND: The Pan-Canadian Early Detection of Lung Cancer (PanCan) risk model and the Lung CT Screening Reporting & Data System (Lung-RADS) estimate cancer probability for screening-detected nodules. The accuracy and agreement of these models require further study.

RESEARCH QUESTION: What is the performance of the PanCan model and Lung-RADS to estimate the probability of cancer in screening-detected solid nodules?

STUDY DESIGN AND METHODS: We analyzed data for newly identified, solid nodules detected on any screening round in the low-dose CT arm of the National Lung Screening Trial to assign a PanCan risk and Lung-RADS score. We compared PanCan risk with the corresponding Lung-RADS category according to the expected prevalence of cancer and examined accuracy using logistic regression and between-test agreement. We also analyzed baseline screen-detected nodules only, high (defined as ≥ 5% probability of cancer) vs low-risk nodules, "risk-gap" nodules with a 3% to 5% PanCan probability and no equivalent Lung-RADS category, and procedure use by model.

RESULTS: Participants with solid nodules (6,956) had a calculable PanCan risk and Lung-RADS score. PanCan accuracy by cancer probabilities < 1%, 1% to 2%, 5% to 15%, and > 15% was similar to corresponding Lung-RADS categories 2, 3, 4A, and 4B for any solid nodule (area under the curve, 0.84 vs 0.84; P = .95) and for nodules identified at baseline (area under the curve, 0.85 vs 0.84; P = .17). When dichotomized by high/low risk, PanCan and Lung-RADS were discordant (P < .001). Participants with risk-gap nodules (n = 543) were distributed across Lung-RADS categories 2 through 4; 41 (8%) had invasive procedures with 23 (4%) having unnecessary invasive procedure use for solid, benign nodules.

INTERPRETATION: PanCan and Lung-RADS had similar overall accuracy for assessing cancer in screening-detected, solid lung nodules with evidence of discordance by subgroup. The existence of Lung-RADS category 4 nodules with a ≥ 3% to 5% PanCan risk may result in unnecessary procedures.

RevDate: 2021-01-04

Sandoval M, Ying Z, S Beronja (2021)

Interplay of opposing fate choices stalls oncogenic growth in murine skin epithelium.

eLife, 10: pii:54618 [Epub ahead of print].

Skin epithelium can accumulate a high burden of oncogenic mutations without morphological or functional consequences. To investigate the mechanism of oncogenic tolerance, we induced HrasG12V in single murine epidermal cells and followed them long-term. We observed that HrasG12V promotes an early and transient clonal expansion driven by increased progenitor renewal that is replaced with an increase in progenitor differentiation leading to reduced growth. We attribute this dynamic effect to emergence of two populations within oncogenic clones: renewing progenitors along the edge and differentiating ones within the central core. As clone expansion is accompanied by progressive enlargement of the core and diminishment of the edge compartment, the intra-clonal competition between the two populations results in stabilized oncogenic growth. To identify the molecular mechanism of HrasG12V-driven differentiation, we screened known Ras-effector in vivo, and identified Rassf5 as a novel regulator of progenitor fate choice that is necessary and sufficient for oncogene-specific differentiation.

RevDate: 2021-01-04

Pan K, Larson JC, Prentice RL, et al (2020)

Protein Intake by Source and Breast Cancer Incidence and Mortality: The Women's Health Initiative.

JNCI cancer spectrum, 4(6):pkaa101 pii:pkaa101.

Background: Prior studies of dietary protein intake and breast cancer have been mixed and were limited by dietary self-report measurement error.

Methods: Biomarker-calibrated total protein intake and estimated vegetable protein and animal protein intake were determined from baseline food frequency questionnaires in 100 024 Women's Health Initiative participants. Associations between total, animal, and vegetable protein intake and breast cancer incidence, deaths from breast cancer, and deaths after breast cancer were estimated using Cox proportional hazards regression. Breast cancers were verified by medical record review and survival outcomes enhanced by National Death Index queries. All statistical tests were 2-sided.

Results: After 14 years of follow-up, there were 6340 incident breast cancers, 764 deaths from breast cancer, and 2059 deaths after breast cancer. In multivariable analyses, higher calibrated total protein intake was not associated with breast cancer incidence or deaths from or after breast cancer. Vegetable protein intake was associated with statistically significantly lower breast cancer incidence (hazard ratio [HR] = 0.98, 95% confidence interval [CI] = 0.96 to 0.99, Ptrend = .006) and statistically significantly lower risk of death after breast cancer (HR = 0.93, 95% CI = 0.91 to 0.97, Ptrend < .001) but not with deaths from breast cancer. In contrast, higher animal protein intake was associated with statistically significantly higher breast cancer incidence (HR = 1.03, 95% CI = 1.01 to 1.06, Ptrend = .02) but not with deaths from or after breast cancer.

Conclusions: Calibrated total protein intake was not associated with breast cancer incidence or mortality. Higher vegetable protein intake was associated with lower breast cancer incidence and lower risk of death after breast cancer. Higher animal protein intake was associated with higher breast cancer incidence.

RevDate: 2021-01-04

Gust J, Ponce R, Liles WC, et al (2020)

Cytokines in CAR T Cell-Associated Neurotoxicity.

Frontiers in immunology, 11:577027.

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.

RevDate: 2021-01-04

Hamilton RJ, Ding K, Crook JM, et al (2020)

The Association Between Statin Use and Outcomes in Patients Initiating Androgen Deprivation Therapy.

European urology pii:S0302-2838(20)31017-4 [Epub ahead of print].

BACKGROUND: Studies have conflicting results regarding the association between statin use and biochemical recurrence for prostate cancer (PCa). A limited number of studies examining statins in advanced stages report positive results, with a few specifically examining statins and androgen deprivation therapy (ADT).

OBJECTIVE: To perform a post hoc secondary analysis of a randomised controlled trial (RCT) of men initiating ADT to examine the association between statin use and outcomes.

Patients with prostate-specific antigen (PSA) >3 ng/ml >1 yr following primary/salvage radiotherapy were enrolled in an RCT of intermittent androgen deprivation (IAD) versus continuous ADT (NCT00003653). Baseline and on-study statin use was modelled as a time-dependent covariate.

The primary endpoint was overall survival. Models were adjusted for age, time from radiotherapy to ADT, baseline PSA, and prior ADT.

RESULTS AND LIMITATIONS: Of 1364 patients, statin users (585; 43%) were younger (72.7 vs 73.8 yr, p = 0.001) and less likely to have PSA >15 ng/ml (20% vs 25%, p = 0.04). After a median follow-up of 6.9 yr, statin use was associated with reduced overall (hazard ratio [HR]: 0.64; 95% confidence interval [CI] 0.53-0.78, p < 0.001) and PCa-specific (HR: 0.65, 95% CI 0.48-0.87, p = 0.004) mortality. Statin users had 13% longer time to castration resistance, but this did not reach statistical significance (p = 0.15). As an exploratory endpoint, in the IAD arm, statin users had longer time off treatment (median: 0.85 vs 0.64 yr, p = 0.06). Limitations include potential for residual confounding between statin users and nonusers, and confounding by indication.

CONCLUSIONS: In men treated with ADT following primary or salvage radiotherapy, statin use was associated with improved overall and PCa-specific survival. In patients treated with IAD, statin use was associated with a trend towards longer time off treatment. A prospective trial of statins in men commencing ADT is warranted.

PATIENT SUMMARY: We found a favourable association between statin use and survival outcomes in patients initiating androgen deprivation therapy.

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In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

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In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

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Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

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With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Papers in Classical Genetics

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Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

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Selected Bibliographies

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