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Bibliography on: Publications by FHCRC Researchers

RJR-3x

Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 27 Sep 2020 at 01:33 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: 2020-09-25

Crichton DJ, Alphan A, Amos CI, et al (2020)

Cancer Biomarkers and Big Data: A Planetary Science Approach.

Cancer cell pii:S1535-6108(20)30480-3 [Epub ahead of print].

Cancer biomarker research has become a data-intensive discipline requiring innovative approaches for data analysis that can combine traditional and data-driven methods. Significant leveraging can be done transferring methodologies and capabilities across scientific disciplines, such as planetary science and astronomy, each of which are grappling with and developing similar solutions for the analysis of massive scientific data.

RevDate: 2020-09-25

Brent AE, A Rajan (2020)

Insulin and Leptin/Upd2 Exert Opposing Influences on Synapse Number in Fat-Sensing Neurons.

Cell metabolism pii:S1550-4131(20)30477-0 [Epub ahead of print].

Energy-sensing neural circuits decide to expend or conserve resources based, in part, on the tonic, steady-state, energy-store information they receive. Tonic signals, in the form of adipose tissue-derived adipokines, set the baseline level of activity in the energy-sensing neurons, thereby providing context for interpretation of additional inputs. However, the mechanism by which tonic adipokine information establishes steady-state neuronal function has heretofore been unclear. We show here that under conditions of nutrient surplus, Upd2, a Drosophila leptin ortholog, regulates actin-based synapse reorganization to reduce bouton number in an inhibitory circuit, thus establishing a neural tone that is permissive for insulin release. Unexpectedly, we found that insulin feeds back on these same inhibitory neurons to conversely increase bouton number, resulting in maintenance of negative tone. Our results point to a mechanism by which two surplus-sensing hormonal systems, Upd2/leptin and insulin, converge on a neuronal circuit with opposing outcomes to establish energy-store-dependent neuron activity.

RevDate: 2020-09-25

Schünemann HJ, Ventresca M, Crowther M, et al (2020)

Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis.

The Lancet. Haematology, 7(10):e746-e755.

BACKGROUND: Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type.

METHODS: In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526.

FINDINGS: We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93-1·06) and a hazard ratio of 1·01 (95% CI 0·96-1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47-0·71) for venous thromboembolism, 1·27 (0·92-1·74) for major bleeding, and 1·34 (1·19-1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42-0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high.

INTERPRETATION: Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival.

FUNDING: Canadian Institutes of Health Research.

RevDate: 2020-09-25

Gadalla SM, Wang Y, Wang T, et al (2020)

Association of donor IFNL4 genotype and non-relapse mortality after unrelated donor myeloablative haematopoietic stem-cell transplantation for acute leukaemia: a retrospective cohort study.

The Lancet. Haematology, 7(10):e715-e723.

BACKGROUND: The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia.

METHODS: We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts.

FINDINGS: We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset.

INTERPRETATION: Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm.

FUNDING: The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.

RevDate: 2020-09-25

Smith SD, AK Gopal (2020)

Selinexor for relapsed or refractory diffuse large B-cell lymphoma: examining the artifact.

The Lancet. Haematology, 7(10):e707.

RevDate: 2020-09-25

Thangavelu G, Wang C, Loschi M, et al (2020)

Repurposing a novel anti-cancer RXR agonist to attenuate acute GVHD and maintain graft-versus-leukemia responses.

Blood pii:463979 [Epub ahead of print].

The nuclear receptors (NR) retinoid X receptors (RXRs) exert immunomodulatory functions to control inflammation and metabolism via homodimers and heterodimers with several other NRs including retinoic acid receptors. IRX4204 is a novel, highly specific RXR agonist in clinical trials that potently and selectively activates RXR homodimers but not heterodimers. Here, we show that in vivo IRX4204 was compared favorably with FK506 in abrogating acute graft-versus-host disease (GVHD), which was associated with inhibiting allogeneic donor T cell proliferation, reducing T helper 1 differentiation and promoting regulatory T cell (Treg) generation. Recipient IRX4204 treatment reduced intestinal injury and decreased IFN-γ and TNF-α serum levels. Transcriptional analysis of donor T cells isolated from intestines of GVHD mice treated with IRX4204 revealed significant decreases in transcripts regulating pro-inflammatory pathways. In vitro, inducible Treg differentiation from naïve CD4+ T cells was enhanced by IRX4204; in vivo, IRX4204 increased the conversion of donor Foxp3- T cells into peripheral Foxp3+ Tregs in GVHD mice. Using Foxp3 lineage tracer mice in which both the origin and current FoxP3 expression of Tregs can be tracked, we demonstrate that IRX4204 supported Treg stability. Despite favoring Tregs and reducing Th1 differentiation, IRX4204-treated recipients maintained graft-versus-leukemia responses against both leukemia and lymphoma cells. Notably, IRX4204 reduced in vitro human T cell proliferation and enhanced Treg generation in mixed lymphocyte reaction cultures. Collectively, these beneficial effects indicate that targeting RXRs with IRX4204 could be used as a novel approach to prevent acute GVHD in the clinic.

RevDate: 2020-09-25

Jones SM, Henrikson NB, Panattoni L, et al (2020)

A theoretical model of financial burden after cancer diagnosis.

Future oncology (London, England) [Epub ahead of print].

Current models of financial burden after cancer do not adequately define types of financial burden, moderators or causes. We propose a new theoretical model to address these gaps. This model delineates the components of financial burden as material and psychological as well as healthcare-specific (affording treatment) versus general (affording necessities). Psychological financial burden is further divided into worry about future costs and rumination about past and current financial burden. The model hypothesizes costs and employment changes as causes, and moderators include precancer socioeconomic status and post-diagnosis factors. The model outlines outcomes affected by financial burden, including depression and mortality. Theoretically derived measures of financial burden, interventions and policy changes to address the causes of financial burden in cancer are needed.

RevDate: 2020-09-25

Feldstein LR, Self WH, Ferdinands JM, et al (2020)

Incorporating real-time influenza detection into the test-negative design for estimating influenza vaccine effectiveness: The real-time test-negative design (rtTND).

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5911459 [Epub ahead of print].

With rapid and accurate molecular influenza testing now widely available in clinical settings, influenza vaccine effectiveness (VE) studies can prospectively select participants for enrollment based on real-time results rather than enrolling all eligible patients regardless of influenza status, as in the traditional test-negative design (TND). Thus, we explore advantages and disadvantages of modifying the TND for estimating VE by using real-time, clinically available viral testing results paired with acute respiratory infection eligibility criteria for identifying influenza cases and test-negative controls prior to enrollment. This modification, which we have called the real-time test-negative design (rtTND), has the potential to improve influenza VE studies by optimizing the case-to-test-negative control ratio, more accurately classifying influenza status, improving study efficiency, reducing study cost, and increasing study power to adequately estimate VE. Important considerations for limiting biases in the rtTND include the need for comprehensive clinical influenza testing at study sites and accurate influenza tests.

RevDate: 2020-09-25

DeGottardi Q, Gates TJ, Yang J, et al (2020)

Ontogeny of different subsets of yellow fever virus-specific circulatory CXCR5+ CD4+ T cells after yellow fever vaccination.

Scientific reports, 10(1):15686 pii:10.1038/s41598-020-72610-6.

Monitoring the frequency of circulatory CXCR5+ (cCXCR5+) CD4+ T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (TFH) activity within germinal center. However, cCXCR5+ T cells are highly heterogeneous in their expression of ICOS, PD1 and CD38 and the relationship between different cCXCR5 subsets as delineated by these markers remains unclear. We applied class II tetramer reagents and mass cytometry to investigate the ontogeny of different subsets of cCXCR5+ T cell following yellow fever immunization. Through unsupervised analyses of mass cytometry data, we show yellow fever virus-specific cCXCR5 T cells elicited by vaccination were initially CD38+ICOS+PD1+, but then transitioned to become CD38+ICOS-PD1+ and CD38-ICOS-PD1+ before coming to rest as a CD38-ICOS-PD1- subset. These results imply that most antigen-specific cCXCR5+ T cells, including the CD38-ICOS-PD1- CXCR5+ T cells are derived from the CXCR5+CD38+ICOS+PD1+ subset, the subset that most resembles preTFH/TFH in the germinal center.

RevDate: 2020-09-25

Butt J, Blot WJ, Visvanathan K, et al (2020)

Auto-antibodies to p53 and the subsequent development of colorectal cancer in a United States prospective cohort consortium.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-0780 [Epub ahead of print].

BACKGROUND: Auto-antibodies to tumor suppressor p53 are found in a subset of colorectal cancer (CRC) patients. A recent prospective study in the US has reported a significant 1.8-fold increased odds for CRC development with pre-diagnostic sero-positivity to p53. In the present study, we sought to examine this association in a US CRC cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for CRC.

METHODS: Auto-antibodies to p53 were measured in pre-diagnostic blood samples of 3,702 incident CRC cases and 3,702 controls, matched by age, race, and sex, from 9 US prospective cohorts. The association of sero-positivity to p53 with CRC risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression.

RESULTS: Overall, 5% of controls and 7% of cases were sero-positive to p53, resulting in a statistically significant 33% increased CRC risk (OR: 1.33; 95% CI: 1.09, 1.61). By follow-up time, the association was only significant with CRC diagnoses within 4 years after blood draw (OR: 2.27; 95% CI: 1.62, 3.19), but not thereafter (OR: 0.97; 95% CI: 0.76, 1.24).

CONCLUSIONS: In this large consortium of prospective cohorts, we found that pre-diagnostic sero-positivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing CRC within 4 years after blood draw.

IMPACT: Our finding suggests that p53 sero-positivity may not be a useful predictor of long-term CRC risk, however, it might be considered as a marker to aid in the early diagnosis of CRC.

RevDate: 2020-09-24

Barnabas RV, Szpiro AA, van Rooyen H, et al (2020)

Community-based antiretroviral therapy versus standard clinic-based services for HIV in South Africa and Uganda (DO ART): a randomised trial.

The Lancet. Global health, 8(10):e1305-e1315.

BACKGROUND: Community-based delivery of antiretroviral therapy (ART) for HIV, including ART initiation, clinical and laboratory monitoring, and refills, could reduce barriers to treatment and improve viral suppression, reducing the gap in access to care for individuals who have detectable HIV viral load, including men who are less likely than women to be virally suppressed. We aimed to test the effect of community-based ART delivery on viral suppression among people living with HIV not on ART.

METHODS: We did a household-randomised, unblinded trial (DO ART) of delivery of ART in the community compared with the clinic in rural and peri-urban settings in KwaZulu-Natal, South Africa and the Sheema District, Uganda. After community-based HIV testing, people living with HIV were randomly assigned (1:1:1) with mobile phone software to community-based ART initiation with quarterly monitoring and ART refills through mobile vans; ART initiation at the clinic followed by mobile van monitoring and refills (hybrid approach); or standard clinic ART initiation and refills. The primary outcome was HIV viral suppression at 12 months. If the difference in viral suppression was not superior between study groups, an a-priori test for non-inferiority was done to test for a relative risk (RR) of more than 0·95. The cost per person virally suppressed was a co-primary outcome of the study. This study is registered with ClinicalTrials.gov, NCT02929992.

FINDINGS: Between May 26, 2016, and March 28, 2019, of 2479 assessed for eligibility, 1315 people living with HIV and not on ART with detectable viral load at baseline were randomly assigned; 666 (51%) were men. Retention at the month 12 visit was 95% (n=1253). At 12 months, community-based ART increased viral suppression compared with the clinic group (306 [74%] vs 269 [63%], RR 1·18, 95% CI 1·07-1·29; psuperiority=0·0005) and the hybrid approach was non-inferior (282 [68%] vs 269 [63%], RR 1·08, 0·98-1·19; pnon-inferiority=0·0049). Community-based ART increased viral suppression among men (73%, RR 1·34, 95% CI 1·16-1·55; psuperiority<0·0001) as did the hybrid approach (66%, RR 1·19, 1·02-1·40; psuperiority=0·026), compared with clinic-based ART (54%). Viral suppression was similar for men (n=156 [73%]) and women (n=150 [75%]) in the community-based ART group. With efficient scale-up, community-based ART could cost US$275-452 per person reaching viral suppression. Community-based ART was considered safe, with few adverse events.

INTERPRETATION: In high and medium HIV prevalence settings in South Africa and Uganda, community-based delivery of ART significantly increased viral suppression compared with clinic-based ART, particularly among men, eliminating disparities in viral suppression by gender. Community-based ART should be implemented and evaluated in different contexts for people with detectable viral load.

FUNDING: The Bill & Melinda Gates Foundation; the University of Washington and Fred Hutch Center for AIDS Research; the Wellcome Trust; the University of Washington Royalty Research Fund; and the University of Washington King K Holmes Endowed Professorship in STDs and AIDS.

RevDate: 2020-09-24

Sanz-Pamplona R, Melas M, Maoz A, et al (2020)

Lymphocytic infiltration in stage II microsatellite stable colorectal tumors: A retrospective prognosis biomarker analysis.

PLoS medicine, 17(9):e1003292 pii:PMEDICINE-D-19-03830.

BACKGROUND: Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable.

METHODS AND FINDINGS: We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016).

LIMITATIONS: This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival.

CONCLUSION: Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.

RevDate: 2020-09-24

Duke ER, Williamson BD, Borate B, et al (2020)

Cytomegalovirus viral load kinetics as surrogate endpoints after allogeneic transplantation.

The Journal of clinical investigation pii:133960 [Epub ahead of print].

BACKGROUND: Viral load surrogate endpoints transformed development of HIV and hepatitis C therapeutics. Surrogate endpoints for cytomegalovirus (CMV)-related morbidity and mortality could advance development of antiviral treatments. While observational data support using CMV viral load (VL) as a trial endpoint, randomized controlled trials (RCT) demonstrating direct associations between virologic markers and clinical endpoints are lacking.

METHODS: We performed CMV DNA polymerase chain reaction (PCR) on frozen serum samples from the only placebo-controlled RCT of ganciclovir for early treatment of CMV after hematopoietic cell transplantation (HCT). We used established criteria to assess VL kinetics as surrogates for CMV disease or death by weeks 8, 24, and 48 after randomization and quantified antiviral effects captured by each marker. We used ensemble-based machine learning to assess the predictive ability of VL kinetics and performed this analysis on a ganciclovir prophylaxis RCT for validation.

RESULTS: VL suppression with ganciclovir reduced cumulative incidence of CMV disease and death for 20 years after HCT. Mean VL, peak VL, and change in VL during the first five weeks of treatment fulfilled the Prentice definition for surrogacy, capturing > 95% of ganciclovir's effect, and yielded highly sensitive and specific predictions by week 48. In the prophylaxis trial, viral shedding rate satisfied the Prentice definition for CMV disease by week 24.

CONCLUSION: Our results support using CMV VL kinetics as surrogates for CMV disease, provide a framework for developing CMV preventative and therapeutic agents, and support reductions in viral load as the mechanism through which antivirals reduce CMV disease.

RevDate: 2020-09-24

A'mar T, Beatty JD, Fedorenko C, et al (2020)

Correction: Incorporating Breast Cancer Recurrence Events Into Population-Based Cancer Registries Using Medical Claims: Cohort Study.

JMIR cancer, 6(2):e23821 pii:v6i2e23821.

[This corrects the article DOI: 10.2196/18143.].

RevDate: 2020-09-24

Anderson BO (2020)

NCCN Harmonized Guidelines for Sub-Saharan Africa: A Collaborative Methodology for Translating Resource-Adapted Guidelines Into Actionable In-Country Cancer Control Plans.

JCO global oncology, 6:1419-1421.

RevDate: 2020-09-24

Cuneo A, Mato AR, Rigolin GM, et al (2020)

Efficacy of bendamustine and rituximab in unfit patients with previously untreated chronic lymphocytic leukemia. Indirect comparison with ibrutinib in a real-world setting. A GIMEMA-ERIC and US study.

Cancer medicine [Epub ahead of print].

Limited information is available on the efficacy of front-line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real-world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty-seven patients with creatinine clearance (CrCl) <70 mL/min and/or CIRS score >6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression-free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02-1.10, P < 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33-0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage.

RevDate: 2020-09-24

Kaplan RC, Baldoni PL, Strizich GM, et al (2020)

Current smoking raises risk of incident hypertension: Hispanic Community Health Study - Study of Latinos.

American journal of hypertension pii:5910807 [Epub ahead of print].

BACKGROUND: Hypertension has been implicated as a smoking-related risk factor for cardiovascular disease but the dose-response relationship is incompletely described. Hispanics, who often have relatively light smoking exposures, have been understudied in this regard.

METHODS: We used data from a six-year follow up study of US Hispanic adults aged 18 to 76 to address the dose-response linking cigarette use with incident hypertension, which was defined by measured blood pressure above 140 / 90 mmHg or initiation of antihypertensive medications. Adjustment was performed for potential confounders and mediators, including urinary albumin-to-creatinine ratio which worsened over time among smokers.

RESULTS: Current smoking was associated with incident hypertension, with a threshold effect above five cumulative pack-years of smoking (versus never smokers, hazard ratio for hypertension [95% confidence interval] of 0.95 [0.67, 1.35] for 0-5 pack-years, 1.47 [1.05, 2.06] for 5-10 pack years, 1.40 [1.00, 1.96] for 10-20 pack years, and 1.34 [1.09, 1.66] for >= 20 pack-years, P = 0.037). In contrast to current smokers, former smokers did not appear to have increased risk of hypertension, even at the highest cumulative pack years of past exposure.

CONCLUSIONS: The results confirm that smoking constitutes a hypertension risk factor in Hispanic adults. A relatively modest cumulative dose of smoking, above 5 pack-years of exposure, raises risk of hypertension by over 30%. The increased hypertension risk was confined to current smokers, and did not increase further with higher pack-year levels. The lack of a smoking-hypertension association in former smokers underscores the value of smoking cessation.

RevDate: 2020-09-24

Ghoneim DH, Zhu J, Zheng W, et al (2020)

Mendelian randomization analysis of n-6 polyunsaturated fatty acid levels and pancreatic cancer risk.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-0651 [Epub ahead of print].

BACKGROUND: Whether circulating polyunsaturated fatty acids (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome.

METHODS: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data.

RESULTS: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk (estimates per one standard deviation increase in each PUFA-specific weighted genetic score using summary statistics: Linoleic acid - odds ratio (OR) = 1.00, 95% confidence interval (CI) 0.98-1.02; arachidonic acid - OR = 1.00, 95% CI 0.99-1.01; dihomo-gamma-linolenic acid - OR = 0.95, 95% CI 0.87-1.02). The OR estimates remained virtually unchanged after adjustment for covariates, using of individual level data or summary statistics, or stratification by age and sex.

CONCLUSIONS: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk.

IMPACT: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer.

RevDate: 2020-09-23

Gauthier J, Bezerra ED, Hirayama AV, et al (2020)

Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B cell malignancies.

Blood pii:463850 [Epub ahead of print].

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (ALL, n=14; CLL, n=9; NHL, n=21) who received CART2 on a phase 1/2 trial at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 CRS, 9%; grade ≥3 neurotoxicity, 11%). After CART2, CR was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before CART1 and an increase in the CART2 dose compared to CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received Cy-Flu lymphodepletion before CART1 and a higher CART2 compared to CART1 cell dose. The identification of two modifiable pre-treatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

RevDate: 2020-09-23

Dholaria B, Savani BN, Hamilton BK, et al (2020)

Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy.

The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consistent of both transplant and non-transplant experts was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

RevDate: 2020-09-23

Blue EE, Thornton TA, Kooperberg C, et al (2020)

Non-coding variants in MYH11, FZD3, and SORCS3 are associated with dementia in women.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

INTRODUCTION: Recent studies suggest that both sex-specific genetic risk factors and those shared between dementia and stroke are involved in dementia pathogenesis.

METHODS: We performed both single-variant and gene-based genome-wide association studies of >11,000 whole genome sequences from the Women's Health Initiative cohort to discover loci associated with dementia, with adjustment for age, ethnicity, stroke, and venous thromboembolism status. Evidence for prior evidence of association and differential gene expression in dementia-related tissues and samples was gathered for each locus.

RESULTS: Our multiethnic studies identified significant associations between variants within APOE, MYH11, FZD3, SORCS3, and GOLGA8B and risk of dementia. Ten genes implicated by these loci, including MYH11, FZD3, SORCS3, and GOLGA8B, were differentially expressed in the context of Alzheimer's disease.

DISCUSSION: Our association of MYH11, FZD3, SORCS3, and GOLGA8B with dementia is supported by independent functional studies in human subjects, model systems, and associations with shared risk factors for stroke and dementia.

RevDate: 2020-09-23

Grieshober L, Graw S, Barnett MJ, et al (2020)

AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality.

BMC cancer, 20(1):905 pii:10.1186/s12885-020-07407-x.

BACKGROUND: A low level of methylation at cg05575921 in the aryl-hydrocarbon receptor repressor (AHRR) gene is robustly associated with smoking, and some studies have observed associations between cg05575921 methylation and increased lung cancer risk and mortality. To prospectively examine whether decreased methylation at cg05575921 may identify high risk subpopulations for lung cancer screening among heavy smokers, and mortality in cases, we evaluated associations between cg05575921 methylation and lung cancer risk and mortality, by histotype, in heavy smokers.

METHODS: The β-Carotene and Retinol Efficacy Trial (CARET) included enrollees ages 45-69 with ≥ 20 pack-year smoking histories and/or occupational asbestos exposure. A subset of CARET participants had cg05575921 methylation available from HumanMethylationEPIC assays of blood collected on average 4.3 years prior to lung cancer diagnosis in cases. Cg05575921 methylation β-values were treated continuously for a 10% methylation decrease and as quintiles, where quintile 1 (Q1, referent) represents high methylation and Q5, low methylation. We used conditional logistic regression models to examine lung cancer risk overall and by histotype in a nested case-control study including 316 lung cancer cases (diagnosed through 2005) and 316 lung cancer-free controls matched on age (±5 years), sex, race/ethnicity, enrollment year, current/former smoking, asbestos exposure, and follow-up time. Mortality analyses included 372 lung cancer cases diagnosed between 1985 and 2013 with available methylation data. We used Cox proportional hazards models to examine mortality overall and by histotype.

RESULTS: Decreased cg05575921 methylation was strongly associated with smoking, even in our population of heavy smokers. We did not observe associations between decreased pre-diagnosis cg05575921 methylation and increased lung cancer risk, overall or by histotype. We observed linear increasing trends for lung cancer-specific mortality across decreasing cg05575921 methylation quintiles for adenocarcinoma and small cell carcinoma (P-trends = 0.01 and 0.04, respectively).

CONCLUSIONS: In our study of heavy smokers, decreased cg05575921 methylation was strongly associated with smoking but not increased lung cancer risk. The observed association between cg05575921 methylation and increased mortality in adenocarcinoma and small cell histotypes requires further examination. Our results do not support using decreased cg05575921 methylation as a biomarker for lung cancer screening risk stratification.

RevDate: 2020-09-22

Singal AG, Lok AS, Feng Z, et al (2020)

Conceptual Model for the Hepatocellular Carcinoma Screening Continuum: Current Status and Research Agenda.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association pii:S1542-3565(20)31297-0 [Epub ahead of print].

Hepatocellular carcinoma (HCC) continues to have a dismal prognosis, with 5-year survival below 20%. This poor prognosis can be in part attributed to failures along the cancer screening process continuum such as underuse of screening in at risk patients and appropriate treatments for patients with HCC. Better understanding these process failures, and how they compare to those seen in other cancer types, can help inform potential intervention targets and strategies to reduce HCC-related mortality. Herein, we outline a conceptual model with several discrete steps in the HCC screening process continuum including risk assessment, screening initiation, follow-up of screening results, diagnostic evaluation, and treatment evaluation. The conceptual model illustrates how each step in the screening process is prone to delays or failure, resulting in worse outcomes such as late stage diagnosis or poor survival, and how factors at the patient, provider, and health care system levels can contribute to these failures. We compare cancer screening processes for HCC with those employed in breast and colorectal cancer screening to identify opportunities for improvement. The Translational Liver Cancer consortium was recently established by the National Cancer Institute with the goal of improving early detection of HCC. Studies designed to address failures in the HCC screening process continuum will help accomplish this goal.

RevDate: 2020-09-22

Carlson J, K Harris (2020)

Quantifying and contextualizing the impact of bioRxiv preprints through automated social media audience segmentation.

PLoS biology, 18(9):e3000860 pii:PBIOLOGY-D-20-00622.

Engagement with scientific manuscripts is frequently facilitated by Twitter and other social media platforms. As such, the demographics of a paper's social media audience provide a wealth of information about how scholarly research is transmitted, consumed, and interpreted by online communities. By paying attention to public perceptions of their publications, scientists can learn whether their research is stimulating positive scholarly and public thought. They can also become aware of potentially negative patterns of interest from groups that misinterpret their work in harmful ways, either willfully or unintentionally, and devise strategies for altering their messaging to mitigate these impacts. In this study, we collected 331,696 Twitter posts referencing 1,800 highly tweeted bioRxiv preprints and leveraged topic modeling to infer the characteristics of various communities engaging with each preprint on Twitter. We agnostically learned the characteristics of these audience sectors from keywords each user's followers provide in their Twitter biographies. We estimate that 96% of the preprints analyzed are dominated by academic audiences on Twitter, suggesting that social media attention does not always correspond to greater public exposure. We further demonstrate how our audience segmentation method can quantify the level of interest from nonspecialist audience sectors such as mental health advocates, dog lovers, video game developers, vegans, bitcoin investors, conspiracy theorists, journalists, religious groups, and political constituencies. Surprisingly, we also found that 10% of the preprints analyzed have sizable (>5%) audience sectors that are associated with right-wing white nationalist communities. Although none of these preprints appear to intentionally espouse any right-wing extremist messages, cases exist in which extremist appropriation comprises more than 50% of the tweets referencing a given preprint. These results present unique opportunities for improving and contextualizing the public discourse surrounding scientific research.

RevDate: 2020-09-22

Mendis S, Anand S, Karasinska JM, et al (2020)

Sex representation in clinical trials associated with FDA cancer drug approvals differs between solid and hematologic malignancies.

The oncologist [Epub ahead of print].

BACKGROUND: Proportionate female representation in health research is necessary for scientific rigour and health equity. We aimed to assess the representation of females in clinical trials leading to US Food and Drug Administration (FDA) cancer drug approvals.

METHODS: Trials supporting US FDA cancer drug approvals between July 2008 - June 2018 were sourced from PubMed and ClinicalTrials.gov. The ratio of female to male trial enrollment was compared with cancer incidence and mortality in the US using International Agency for Research on Cancer (IARC) data. Reproductive tract and breast cancers were excluded. Odds ratios (ORs) and 95% confidence intervals (CI) comparing trial enrollment with population incidence and mortality were calculated.

RESULTS: 186 trials leading to 170 FDA cancer drug approvals showed slight female under-representation compared to overall cancer incidence in the US (OR 0.97, 95% CI 0.95-0.98, P<0.0001). Female enrollment between 2008-2013 and 2014-2018 was unchanged (OR 1.02, 95% CI 0.99-1.05, P=0.25). There was slight female underrepresentation in hematological trials (OR 0.95, 95% CI 0.91-0.998, P=0.040 for leukemia; OR 0.95, 95% CI 0.90-0.997, P=0.040 for lymphoma) and significant female underrepresentation in colorectal (OR 0.72, 95% CI 0.69-0.76, P<0.0001), pancreas (OR 0.85, 95% CI 0.78-0.93, P=0.0004), lung (OR 0.77, 95% CI 0.75-0.80, P<0.0001), kidney (OR 0.63, 95% CI 0.60-0.67, P<0.0001) and thyroid cancer trials (OR 0.26, 95% CI 0.23-0.28, P<0.0001) compared to US incidence.

CONCLUSIONS: Female underrepresentation has persisted within solid organ tumor trials but is less notable in hematologic trials. Additional work is required to identify drivers of such disparity.

IMPLICATIONS FOR PRACTICE: Adequate gender representation in clinical trials is a matter of health equity. This study demonstrates that women remain under represented in trials across hematological and solid organ trials compared to cancer incidence and mortality in women, with the disparity worse in a number of solid organ tumor types. There are thus still significant improvements to be made regarding adequate representation of women in trials. Studies exploring the reasons for ongoing disparity in gender representation are warranted, to help clinicians to rectify this.

RevDate: 2020-09-22

Hoff FW, van Dijk AD, Qiu YH, et al (2020)

Heat Shock Factor 1 (HSF1-pSer326) Predicts Response to Bortezomib-Containing Chemotherapy in Pediatric AML: A COG Study.

Blood pii:463802 [Epub ahead of print].

Bortezomib (BTZ) was recently evaluated in a randomized Phase 3 clinical trial which compared standard chemotherapy (cytarabine, daunorubicin, etoposide; ADE) to standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia. While the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefitting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses. We measured total heat shock factor 1 (HSF1) and phosphorylated HSF1 (HSF1-pSer326) in leukemic cells from 483 pediatric patients using Reverse Phase Protein Arrays. HSF1-pSer326 phosphorylation was significantly lower in pediatric AML compared to CD34+ non-malignant cells. We identified a strong correlation between HSF1-pSer326 expression and BTZ sensitivity. BTZ significantly improved outcome of patients with low-HSF1-pSer326 with a 5-year event-free survival of 44% (ADE) vs. 67% for low-HSF1-pSer326 treated with ADEB (P=0.019). To determine the effect of HSF1 expression on BTZ potency in vitro, cell viability with HSF1 gene variants that mimicked phosphorylated (S326A) and non-phosphorylated (S326E) HSF1-pSer326 were examined. Those with increased HSF1 phosphorylation showed clear resistance to BTZ vs. those with wild type or reduced HSF1-phosphorylation. We hypothesize that HSF1-pSer326 expression could identify patients that benefit from BTZ-containing chemotherapy.

RevDate: 2020-09-22

Gogebakan KC, Berry EG, Geller AC, et al (2020)

Strategizing screening for melanoma in an era of novel treatments: a model-based approach.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-0881 [Epub ahead of print].

BACKGROUND: Benefit-harm tradeoffs of melanoma screening depend on disease risk and treatment efficacy. We developed a model to project outcomes of screening for melanoma in populations with different risks under historic and novel systemic treatments.

METHODS: Computer simulation model of a screening program with specified impact on overall and advanced-stage incidence. Inputs included meta-analyses of treatment trials, cancer registry data, and a melanoma risk prediction study Results: Assuming 50% reduction in advanced stage under screening, the model projected 59 and 38 lives saved per 100,000 men under historic and novel treatments respectively. With 10% increase in Stage 1, the model projects to 2.9 and 4.7 over-diagnosed cases per life saved and number needed to be screened (NNS) equal to 1695 and 2632 under historical and novel treatments. When screening was performed only for the 20% of individuals with highest predicted risk, 34 and 22 lives per 100,000 were saved under historical and novel treatments. Similar results were obtained for women, but lives saved were lower.

CONCLUSIONS: Melanoma early detection programs must shift a substantial fraction of cases from advanced to localized stage to be sustainable. Advances in systemic therapies for melanoma might noticeably reduce benefits of screening, but restricting screening to individuals at highest risk will likely reduce intervention efforts and harms while preserving >50% of the benefit of non-targeted screening.

IMPACT: Our accessible modeling framework will help to guide population melanoma screening programs in an era of novel treatments for advanced disease.

RevDate: 2020-09-22

Bedford T, Greninger AL, Roychoudhury P, et al (2020)

Cryptic transmission of SARS-CoV-2 in Washington State.

medRxiv : the preprint server for health sciences.

Following its emergence in Wuhan, China, in late November or early December 2019, the SARS-CoV-2 virus has rapidly spread throughout the world. On March 11, 2020, the World Health Organization declared Coronavirus Disease 2019 (COVID-19) a pandemic. Genome sequencing of SARS-CoV-2 strains allows for the reconstruction of transmission history connecting these infections. Here, we analyze 346 SARS-CoV-2 genomes from samples collected between 20 February and 15 March 2020 from infected patients in Washington State, USA. We found that the large majority of SARS-CoV-2 infections sampled during this time frame appeared to have derived from a single introduction event into the state in late January or early February 2020 and subsequent local spread, strongly suggesting cryptic spread of COVID-19 during the months of January and February 2020, before active community surveillance was implemented. We estimate a common ancestor of this outbreak clade as occurring between 18 January and 9 February 2020. From genomic data, we estimate an exponential doubling between 2.4 and 5.1 days. These results highlight the need for large-scale community surveillance for SARS-CoV-2 introductions and spread and the power of pathogen genomics to inform epidemiological understanding.

RevDate: 2020-09-21

Bricker JB, Watson NL, Mull KE, et al (2020)

Efficacy of Smartphone Applications for Smoking Cessation: A Randomized Clinical Trial.

JAMA internal medicine pii:2770816 [Epub ahead of print].

Importance: Smoking is a leading cause of premature death globally. Smartphone applications for smoking cessation are ubiquitous and address barriers to accessing traditional treatments, yet there is limited evidence for their efficacy.

Objective: To determine the efficacy of a smartphone application for smoking cessation based on acceptance and commitment therapy (ACT) vs a National Cancer Institute smoking cessation application based on US clinical practice guidelines (USCPG).

A 2-group, stratified, double-blind, individually randomized clinical trial was conducted from May 27, 2017, to September 28, 2018, among 2415 adult cigarette smokers (n = 1214 for the ACT-based smoking cessation application group and n = 1201 for the USCPG-based smoking cessation application group) with 3-, 6-, and 12-month postrandomization follow-up. The study was prespecified in the trial protocol. Follow-up data collection started on August 26, 2017, and ended at the last randomized participant's 12-month follow-up survey on December 23, 2019. Data were analyzed from February 25 to April 3, 2020. The primary analysis was performed on a complete-case basis, with intent-to-treat missing as smoking and multiple imputation sensitivity analyses.

Interventions: iCanQuit, an ACT-based smoking cessation application, which taught acceptance of smoking triggers, and the National Cancer Institute QuitGuide, a USCPG-based smoking cessation application, which taught avoidance of smoking triggers.

Main Outcomes and Measures: The primary outcome was self-reported 30-day point prevalence abstinence (PPA) at 12 months after randomization. Secondary outcomes were 7-day PPA at 12 months after randomization, prolonged abstinence, 30-day and 7-day PPA at 3 and 6 months after randomization, missing data imputed with multiple imputation or coded as smoking, and cessation of all tobacco products (including e-cigarettes) at 12 months after randomization.

Results: Participants were 2415 adult cigarette smokers (1700 women [70.4%]; 1666 White individuals [69.0%] and 868 racial/ethnic minorities [35.9%]; mean [SD] age at enrollment, 38.2 [10.9] years) from all 50 US states. The 3-month follow-up data retention rate was 86.7% (2093), the 6-month retention rate was 88.4% (2136), and the 12-month retention rate was 87.2% (2107). For the primary outcome of 30-day PPA at the 12-month follow-up, iCanQuit participants had 1.49 times higher odds of quitting smoking compared with QuitGuide participants (28.2% [293 of 1040] vs 21.1% [225 of 1067]; odds ratio [OR], 1.49; 95% CI, 1.22-1.83; P < .001). Effect sizes were very similar and statistically significant for 7-day PPA at the 12-month follow-up (OR, 1.35; 95% CI, 1.12-1.63; P = .002), prolonged abstinence at the 12-month follow-up (OR, 2.00; 95% CI, 1.45-2.76; P < .001), abstinence from all tobacco products (including e-cigarettes) at the 12-month follow-up (OR, 1.60; 95% CI, 1.28-1.99; P < .001), 30-day PPA at 3-month follow-up (OR, 2.20; 95% CI, 1.68-2.89; P < .001), 30-day PPA at 6-month follow-up (OR, 2.03; 95% CI, 1.63-2.54; P < .001), 7-day PPA at 3-month follow-up (OR, 2.04; 95% CI, 1.64-2.54; P < .001), and 7-day PPA at 6-month follow-up (OR, 1.73; 95% CI, 1.42-2.10; P < .001).

Conclusions and Relevance: This trial provides evidence that, compared with a USCPG-based smartphone application, an ACT-based smartphone application was more efficacious for quitting cigarette smoking and thus can be an impactful treatment option.

Trial Registration: ClinicalTrials.gov Identifier: NCT02724462.

RevDate: 2020-09-21

Khorana AA, Kuderer NM, McCrae K, et al (2020)

Cancer associated thrombosis and mortality in patients with cancer stratified by khorana score risk levels.

Cancer medicine [Epub ahead of print].

BACKGROUND: The Khorana score (KS) clinical algorithm is used to predict VTE risk in cancer patients. The study objective was to evaluate VTE and survival rates among patients newly diagnosed with cancer and stratified by KS in a real-world population.

METHODS: Data from the Optum® Clinformatics® DataMart database between 01/01/2012-09/30/2017 was used to identify adults with ≥ 1 hospitalization or ≥ 2 outpatient claims with a cancer diagnosis (index date). Only patients who were initiated on chemotherapy or radiation therapy were included. Patients were classified based on KS (KS = 0, 1, 2 or ≥ 3). Time-to-first VTE and survival were evaluated from the index date to the earliest among end of data availability or insurance coverage, death, or 12 months post-index using Kaplan-Meier (KM) analyses.

RESULTS: A total of 2,488 (KS = 0); 2,125 (KS = 1), 1,074 (KS = 2), and 507 (KS ≥ 3) cancer patients were included. The 12-month KM rates of VTE were 3.1%, 5.4%, 7.9%, and 14.9% (associated median time to VTE of 2.7, 3.0, 1.4, and 1.7 months) among KS = 0, 1, 2, and ≥ 3 cohorts, respectively. Corresponding adjusted hazard ratios (95% CIs) relative to the KS = 0 cohort were 1.72 (1.25-2.38), 2.46 (1.73-3.50), and 4.99 (3.40-7.31) for the KS = 1, 2, and ≥ 3 cohorts, respectively (all P < .001). Regardless of KS, patients with VTE had significantly lower survival rates than those without.

CONCLUSIONS: This real-world claims-based cohort study of newly diagnosed cancer patients showed significantly higher rates of VTE with increased KS, confirming its predictive ability. Moreover, VTE was associated with lower survival rates within each KS cohort.

RevDate: 2020-09-21

Merlo LMF, Sprouffske K, Howard TC, et al (2020)

Application of simultaneous selective pressures slows adaptation.

Evolutionary applications, 13(7):1615-1625 pii:EVA13062.

Beneficial mutations that arise in an evolving asexual population may compete or interact in ways that alter the overall rate of adaptation through mechanisms such as clonal or functional interference. The application of multiple selective pressures simultaneously may allow for a greater number of adaptive mutations, increasing the opportunities for competition between selectively advantageous alterations, and thereby reducing the rate of adaptation. We evolved a strain of Saccharomyces cerevisiae that could not produce its own histidine or uracil for ~500 generations under one or three selective pressures: limitation of the concentration of glucose, histidine, and/or uracil in the media. The rate of adaptation was obtained by measuring evolved relative fitness using competition assays. Populations evolved under a single selective pressure showed a statistically significant increase in fitness on those pressures relative to the ancestral strain, but the populations evolved on all three pressures did not show a statistically significant increase in fitness over the ancestral strain on any single pressure. Simultaneously limiting three essential nutrients for a population of S. cerevisiae effectively slows the rate of evolution on any one of the three selective pressures applied, relative to the single selective pressure cases. We identify possible mechanisms for fitness changes seen between populations evolved on one or three limiting nutrient pressures by high-throughput sequencing. Adding multiple selective pressures to evolving disease like cancer and infectious diseases could reduce the rate of adaptation and thereby may slow disease progression, prolong drug efficacy and prevent deaths.

RevDate: 2020-09-21

Klugman M, Hosgood HD, Hua S, et al (2020)

A longitudinal analysis of nondaily smokers: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

Annals of epidemiology, 49:61-67.

PURPOSE: Nondaily smoking is increasing in the United States and common among Hispanic/Latino smokers. We characterized factors related to longitudinal smoking transitions in Hispanic/Latino nondaily smokers.

METHODS: The Hispanic Community Health Study/Study of Latinos is a population-based cohort study of Hispanics/Latinos aged 18-74 years. Multinomial logistic regression assessed the baseline factors (2008-2011) associated with follow-up smoking status (2014-2017) in nondaily smokers (n = 573), accounting for complex survey design.

RESULTS: After ∼6 years, 41% of nondaily smokers became former smokers, 22% became daily smokers, and 37% remained nondaily smokers. Factors related to follow-up smoking status were number of days smoked in the previous month, household smokers, education, income, and insurance. Those smoking 16 or more of the last 30 days had increased risk of becoming a daily smoker [vs. < 4 days; relative risk ratio (RRR) = 5.65, 95% confidence interval (95% CI) = 1.96-16.33]. Greater education was inversely associated with transitioning to daily smoking [>high school vs.
CONCLUSIONS: Many Hispanic/Latino nondaily smokers became daily smokers, which may increase their risk of adverse health outcomes. Addressing different smoking patterns in primary care may be useful to prevent smoking-related diseases.

RevDate: 2020-09-21

de Dieu Tapsoba J, Zangeneh SZ, Appelmans E, et al (2020)

Persistence of oral pre-exposure prophylaxis (PrEP) among adolescent girls and young women initiating PrEP for HIV prevention in Kenya.

AIDS care [Epub ahead of print].

The Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) Initiative aims to reduce HIV infections among adolescent girls and young women (AGYW) in Africa. Oral pre-exposure prophylaxis (PrEP) is offered through DREAMS in Kenya to eligible AGYW in high burden counties including Kisumu and Homa Bay. This study examines PrEP persistence among AGYW in high burden community-based PrEP delivery settings. We evaluated PrEP persistence among AGYW in the DREAMS PrEP program in Kisumu and Homa Bay using survival analysis and programmatic PrEP refill data collected between March through December 2017. Among 1,259 AGYW who initiated PrEP during the study period, the median persistence time in the program was 56 days (95% CI: 49-58 days) and the proportion who persisted 3 months later was 37% (95% CI: 34-40%). Persistence varied by county (p < 0.001), age at PrEP initiation (p = 0.002), marital status (p = 0.008), transactional sex (p = 0.002), gender-based violence (GBV) experience (p = 0.009) and current school attendance (p = 0.001) at DREAMS enrollment. Persistence did not vary with orphan status, food insecurity, condom use, age at first sexual encounter or engagement in age-disparate sex at DREAMS enrollment. Targeted strategies are needed to improve AGYW retention in the PrEP program.

RevDate: 2020-09-21

Rose CM, Gupta S, Buszkiewicz J, et al (2020)

Small increments in diet cost can improve compliance with the Dietary Guidelines for Americans.

Social science & medicine (1982), 266:113359 pii:S0277-9536(20)30578-5 [Epub ahead of print].

Adherence to the Dietary Guidelines for Americans (DGA) may involve higher diet costs. This study assessed the relation between two measures of food spending and diet quality among adult participants (N = 768) in the Seattle Obesity Study (SOS III). All participants completed socio-demographic and food expenditure surveys and the Fred Hutch food frequency questionnaire. Dietary intakes were joined with local supermarket prices to estimate individual-level diet costs. Healthy Eating Index (HEI- 2015) scores measured compliance with DGA. Multiple linear regressions using Generalized Estimating Equations with robust standard errors showed that lower food spending was associated with younger age, Hispanic ethnicity, and lower socioeconomic status. Even though higher HEI-2015 scores were associated with higher diet costs per 2000 kcal, much individual variability was observed. A positive curvilinear relationship was observed in adjusted models. At lower cost diets, a $100/month increase in cost (from $150 to $250) was associated with a 20.6% increase in HEI-2015. For higher levels of diet cost (from $350 to $450) there were diminishing returns (2.8% increase in HEI- 2015). These findings indicate that increases in food spending at the lower end of the range have the most potential to improve diet quality.

RevDate: 2020-09-19

Arcuri LJ, Nabhan SK, Cunha R, et al (2020)

Impact of CD34 cell dose and conditioning regimen on outcomes after Haploidentical donor hematopoietic stem cell transplantation with post-transplant cyclophosphamide for relapsed/refractory severe aplastic anemia: Haploidentical HCT with PTCy for SAA.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30595-4 [Epub ahead of print].

Severe aplastic anemia(SAA) is a life-threatening disease that can be cured with allogeneic cell transplantation(HCT). Haploidentical donor transplantation with posttransplant cyclophosphamide(Haplo-PTCy) is an option for patients lacking HLA matched donor. We analyzed 87 patients who received Haplo-PTCy between 2010 and 2019. Median age was 14(range, 1-69), most were heavily transfused and all received previous immunosuppression(25% without ATG). Most(63%) received standard Flu-Cy29-TBI200 conditioning, and the remaining ones received an augmented conditioning: Flu-Cy29-TBI300-400(16%), Flu-Cy50-TBI200(10%) or Flu-Cy50-TBI400(10%). All received PTCy-based GVHD-prophylaxis. Most grafts(93%) were bone marrow(BM). Median follow-up was 2 years and 2 months. Median days of neutrophil recovery was 17 days. Primary graft failure occurred in 15%, and secondary or poor graft function in 5%. Incidences of grade II-IV acute and chronic GVHD were 14% and 9%. Two-year OS and EFS were 79% and 70%. EFS was higher for patients given augmented FluCyTBI(HR=0.28, p=0.02), and in those patients given higher BM CD34 cell dose(>3.2 × 10E6/kg) (HR=0.29, p=0.004). The presence of donor-specific antibodies(DSA) previous to transplant was associate with lower EFS(HR=3.92, p=0.01). Graft failure(HR=7.20, p<0.0001) was associated with a higher risk of death. CMV reactivation was frequent(62%). Haploidentical HCT for SAA is a feasible procedure; outcomes are improved with augmented conditioning regimen and higher BM CD34 cell grafts.

RevDate: 2020-09-19

Hejazi NS, van der Laan MJ, Janes HE, et al (2020)

Efficient nonparametric inference on the effects of stochastic interventions under two-phase sampling, with applications to vaccine efficacy trials.

Biometrics [Epub ahead of print].

The advent and subsequent widespread availability of preventive vaccines has altered the course of public health over the past century. Despite this success, effective vaccines to prevent many high-burden diseases, including HIV, have been slow to develop. Vaccine development can be aided by the identification of immune response markers that serve as effective surrogates for clinically significant infection or disease endpoints. However, measuring immune response marker activity is often costly, which has motivated the usage of two-phase sampling for immune response evaluation in clinical trials of preventive vaccines. In such trials, the measurement of immunological markers is performed on a subset of trial participants, where enrollment in this second phase is potentially contingent on the observed study outcome and other participant-level information. We propose nonparametric methodology for efficiently estimating a counterfactual parameter that quantifies the impact of a given immune response marker on the subsequent probability of infection. Along the way, we fill in theoretical gaps pertaining to the asymptotic behavior of nonparametric efficient estimators in the context of two-phase sampling, including a multiple robustness property enjoyed by our estimators. Techniques for constructing confidence intervals and hypothesis tests are presented, and an open source software implementation of the methodology, the txshift R package, is introduced. We illustrate the proposed techniques using data from a recent preventive HIV vaccine efficacy trial.

RevDate: 2020-09-21

Joseph V, Jones A, Canidate S, et al (2020)

Factors associated with current and severe pain among people living with HIV: results from a statewide sample.

BMC public health, 20(1):1424 pii:10.1186/s12889-020-09474-y.

BACKGROUND: People living with HIV (PLHIV) are more likely to suffer from pain compared to the general public. Pain often clusters with mental health symptoms and substance use. This study sought to evaluate mental health and substance use factors associated with any pain and severe pain intensities among PLHIV.

METHODS: Data were derived from HIV+ adults (N = 733) recruited from community health centers across Florida who completed questionnaires regarding demographics, chronic pain, HIV clinical outcomes, mental health symptoms, and substance use information. Pain was assessed using the Brief Pain Inventory (BPI) short form. Multivariate logistic regression analysis was utilized to assess the relationship between selected covariates and pain.

RESULTS: Approximately half (45.0%) of participants reported having any current pain while 16.1% reported severe pain. The odds of having any current pain were 2.49 (CI 95% 1.48, 4.18, p < 0.01) times greater among PLHIV reporting anxiety and 1.69 (CI 95% 1.11, 2.57, p = 0.01) times greater among PLHIV reporting PTSD compared to those without those factors. The odds of having severe pain were 2.03 (CI 95% 1.03, 4.01, p = 0.04) times greater among PLHIV reporting anxiety and 2.02 (CI 95% 1.26, 3.24, p < 0.01) times greater among female participants compared to PLHIV without those factors respectively. Factors including depression, alcohol consumption, and marijuana use were not statistically associated with any current pain nor with severe pain.

CONCLUSION: The relationship between pain and mental health is complex. Thus, future research is needed to determine if pain treatments may reduce mental health symptoms or if treatments can be targeted to address both issues simultaneously.

RevDate: 2020-09-18

de Bruyn G, Gordon DL, Steiner T, et al (2020)

Safety, immunogenicity, and efficacy of a Clostridioides difficile toxoid vaccine candidate: a phase 3 multicentre, observer-blind, randomised, controlled trial.

The Lancet. Infectious diseases pii:S1473-3099(20)30331-5 [Epub ahead of print].

BACKGROUND: In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate.

METHODS: We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated.

FINDINGS: Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group.

INTERPRETATION: In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped.

FUNDING: Sanofi Pasteur.

RevDate: 2020-09-18

Gutierrez A, Kim JO, Umbreit NT, et al (2020)

Cdk1 Phosphorylation of the Dam1 Complex Strengthens Kinetochore-Microtubule Attachments.

Current biology : CB pii:S0960-9822(20)31244-6 [Epub ahead of print].

To ensure the faithful inheritance of DNA, a macromolecular protein complex called the kinetochore sustains the connection between chromosomes and force-generating dynamic microtubules during cell division. Defects in this process lead to aneuploidy, a common feature of cancer cells and the cause of many developmental diseases [1-4]. One of the major microtubule-binding activities in the kinetochore is mediated by the conserved Ndc80 complex (Ndc80c) [5-7]. In budding yeast, the retention of kinetochores on dynamic microtubule tips also depends on the essential heterodecameric Dam1 complex (Dam1c) [8-15], which binds to the Ndc80c and is proposed to be a functional ortholog of the metazoan Ska complex [16, 17]. The load-bearing activity of the Dam1c depends on its ability to oligomerize, and the purified complex spontaneously self-assembles into microtubule-encircling oligomeric rings, which are proposed to function as collars that allow kinetochores to processively track the plus-end tips of microtubules and harness the forces generated by disassembling microtubules [10-15, 18-22]. However, it is unknown whether there are specific regulatory events that promote Dam1c oligomerization to ensure accurate segregation. Here, we used a reconstitution system to discover that Cdk1, the major mitotic kinase that drives the cell cycle, phosphorylates the Ask1 component of the Dam1c to increase its residence time on microtubules and enhance kinetochore-microtubule attachment strength. We propose that Cdk1 activity promotes Dam1c oligomerization to ensure that kinetochore-microtubule attachments are stabilized as kinetochores come under tension in mitosis.

RevDate: 2020-09-18

Wang LT, Pereira LS, Flores-Garcia Y, et al (2020)

A Potent Anti-Malarial Human Monoclonal Antibody Targets Circumsporozoite Protein Minor Repeats and Neutralizes Sporozoites in the Liver.

Immunity pii:S1074-7613(20)30371-X [Epub ahead of print].

Discovering potent human monoclonal antibodies (mAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on sporozoites (SPZ) and elucidating their mechanisms of neutralization will facilitate translation for passive prophylaxis and aid next-generation vaccine development. Here, we isolated a neutralizing human mAb, L9 that preferentially bound NVDP minor repeats of PfCSP with high affinity while cross-reacting with NANP major repeats. L9 was more potent than six published neutralizing human PfCSP mAbs at mediating protection against mosquito bite challenge in mice. Isothermal titration calorimetry and multiphoton microscopy showed that L9 and the other most protective mAbs bound PfCSP with two binding events and mediated protection by killing SPZ in the liver and by preventing their egress from sinusoids and traversal of hepatocytes. This study defines the subdominant PfCSP minor repeats as neutralizing epitopes, identifies an in vitro biophysical correlate of SPZ neutralization, and demonstrates that the liver is an important site for antibodies to prevent malaria.

RevDate: 2020-09-18

Triplette M, Thayer JH, Kross EK, et al (2020)

The Impact of Smoking and Screening Results on Adherence to Follow-up in an Academic Multisite Lung Cancer Screening Program.

Annals of the American Thoracic Society [Epub ahead of print].

RevDate: 2020-09-18

Powles T, Park SH, Voog E, et al (2020)

Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma.

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

BACKGROUND: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.

METHODS: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety.

RESULTS: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively.

CONCLUSIONS: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).

RevDate: 2020-09-18

Mithraprabhu S, Kalff A, Gartlan KH, et al (2020)

Phase II trial of single-agent panobinostat consolidation improves responses after sub-optimal transplant outcomes in multiple myeloma.

British journal of haematology [Epub ahead of print].

Panobinostat is a pan-deacetylase inhibitor that modulates the expression of oncogenic and immune-mediating genes involved in tumour cell growth and survival. We evaluated panobinostat-induced post-transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three-times weekly (TIW) on alternate weeks of 28-day cycles commencing 8-12 weeks post-transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9-9·7) months of panobinostat. In responders, T-lymphocyte histone acetylation increased after both three cycles (P < 0·05) and six cycles (P < 0·01) of panobinostat when compared to baseline, with no differences in non-responders. The reduction in the proportion of CD127+ CD8+ T cells and CD4:CD8 ratio was significantly greater, after three and six cycles of panobinostat compared to pre-transplant, in non-responders when compared to responders. Whole marrow RNA-seq revealed widespread transcriptional changes only in responders with baseline differences in genes involved in ribosome biogenesis, oxidative phosphorylation and metabolic pathways. This study confirmed the efficacy of panobinostat as a single agent in multiple myeloma and established acetylation of lymphocyte histones, modulation of immune subsets and transcriptional changes as pharmacodynamic biomarkers of clinical benefit.

RevDate: 2020-09-19

Ujjani C, Mato A, Hill BT, et al (2020)

The Impact of Age on Survival in CLL Patients Receiving Ibrutinib as Initial Therapy.

Blood and lymphatic cancer : targets and therapy, 10:1-5.

Introduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.

Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.

Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients >65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).

Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.

RevDate: 2020-09-17

Mohon AN, Oberding L, Hundt J, et al (2020)

Optimization and clinical validation of dual-target RT-LAMP for SARS-CoV-2.

Journal of virological methods pii:S0166-0934(20)30224-X [Epub ahead of print].

A novel reverse-transcriptase loop mediated amplification (RT-LAMP) method targeting genes encoding the Spike (S) protein and RNA-dependent RNA polymerase (RdRP) of SARS-CoV-2 has been developed. The LAMP assay achieves a comparable limit of detection (25 copies per reaction) as commonly used RT-PCR protocols using clinical samples quantified by digital droplet PCR. Precision, cross-reactivity, inclusivity, and limit of detection studies were performed according to regulatory standards. Clinical validation of dual-target RT-LAMP (S and RdRP gene) achieved a PPA of 98.48% (95% CI 91.84% to 99.96%) and NPA 100.00% (95% CI 93.84% to 100.00%) based on the E gene and N2 gene reference RT-PCR methods. The method has implications for development of point of care technology using isothermal amplification.

RevDate: 2020-09-17

Broder GB, Lucas JP, Davis J, et al (2020)

Standardized metrics can reveal region-specific opportunities in community engagement to aid recruitment in HIV prevention trials.

PloS one, 15(9):e0239276 pii:PONE-D-20-04045.

Good Participatory Practice (GPP) guidelines support and direct community engagement practices in biomedical HIV prevention trials, however no standardized metrics define the implementation and evaluation of these practices. Collaboratively, the Community Program staff of the HIV Vaccine Trials Network (HVTN) and the HIV Prevention Trials Network (HPTN) created a metric to describe, monitor, and evaluate one component of GPP, recruitment practices, in two HIV monoclonal Antibody Mediated Prevention (AMP) clinical trials, HVTN 703/HPTN 081 and HVTN 704/HPTN 085. Through consultation with community representatives from each clinical research site (hereafter "site(s)"), who made up the study Community Working Groups, recruitment strategy descriptors were developed for both trials to characterize responses to "How did you hear about the AMP study?" The Community Working Groups also helped to define and establish time points that were selected to allow comparisons across sites. Data were collected by 43 of 46 clinical research sites from January 1, 2017 to February 28, 2018. All 43 sites used multiple recruitment strategies successfully, but strategies varied by region. Globally, referrals was the most efficient and effective recruitment strategy as evidenced by the screening: enrollment ratio of 2.2:1 in Africa, and 2.1:1 in the Americas/Switzerland. Print materials were also valuable globally (3:1 Africa, 4.2:1 Americas/Switzerland). In Africa, in-person outreach was also quite effective (2.3:1) and led to the most enrollments (748 of 1186, 63%). In the Americas/Switzerland, outreach was also effective (2.6:1), but internet use resulted in the most screens (1893 of 4275, 44%) and enrollments (677 of 1531, 44%), compared to 12 of 2887 (0.4%) and 2 of 1204 (0.1%) in Africa, respectively. Standardized metrics and data collection aid meaningful comparisons of optimal community engagement methods for trial enrollment. Internet strategies had better success in the Americas/Switzerland than in sub-Saharan African countries. Data are essential in outreach staff efforts to improve screening-to-enrollment ratios. Because the effectiveness of recruitment strategies varies by region, it is critical that clinical research sites tailor community engagement and recruitment strategies to their local environment, and that they are supported with resources enabling use of a range of approaches.

RevDate: 2020-09-18

Zager RA, ACM Johnson (2020)

The NRF2 stimulating agent, tin protoporphyrin, activates protective cytokine pathways in healthy human subjects and in patients with chronic kidney disease.

Physiological reports, 8(18):e14566.

BACKGROUND: Tin protoporphyrin (SnPP), a heme oxygenase 1 (HO-1) inhibitor, triggers adaptive tissue responses that confer potent protection against acute renal- and extra-renal tissue injuries. This effect is mediated, in part, via SnPP-induced activation of the cytoprotective Nrf2 pathway. However, it remains unclear as to whether SnPP can also upregulate humoral cytokine defenses, either in healthy human subjects or in patients with CKD. If so, then systemically derived cytokines could contribute SnPP-induced tissue protection.

METHODS: SnPP (90 mg IV) was administered over 2 hr to six healthy human volunteers (HVs) and 12 subjects with stage 3-4 CKD. Plasma samples were obtained from baseline upto 72 hr post injection. Two representative anti-inflammatory cytokines (IL-10, TGFβ1), and a pro-inflammatory cytokine (TNF-α), were assayed. Because IL-6 has been shown to induce tissue preconditioning, its plasma concentrations were also assessed. In complementary mouse experiments, SnPP effects on renal, splenic, and hepatic IL-10, IL-6, TGFβ1, and TNF-α production (as gauged by their mRNAs) were tested. Tissue HO-1 mRNA served as an Nrf2 activation marker.

RESULTS: SnPP induced marked (~5-7x) increases in plasma IL-10 and IL-6 concentrations within 24-48 hr, and to equal degrees in HVs and CKD patients. SnPP modestly raised plasma TGFβ1 without impacting plasma TNF-α levels. In mouse experiments, SnPP did not affect IL-6, IL-10, TNF-α, or TGFβ1 mRNAs in kidney despite marked renal Nrf2 activation. Conversely, SnPP increased splenic IL-10 and hepatic IL-6/TGFβ1 mRNA levels, suggesting these organs as sites of extra-renal cytokine generation.

CONCLUSIONS: SnPP can trigger cytoprotective cytokine production, most likely in extra-renal tissues. With ready glomerular cytokine filtration, extra-renal/renal "organ cross talk" can result. Thus, humoral factors seemingly can contribute to SnPP's cytoprotective effects.

RevDate: 2020-09-17

Ilozumba MN, Cheng TD, Neuhouser ML, et al (2020)

Associations between Plasma Choline Metabolites and Genetic Polymorphisms in One-Carbon Metabolism in Postmenopausal Women: The Women's Health Initiative Observational Study.

The Journal of nutrition pii:5906633 [Epub ahead of print].

BACKGROUND: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites.

OBJECTIVES: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites.

METHODS: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined.

RESULTS: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration.

CONCLUSIONS: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

RevDate: 2020-09-17

Glorioso JC, Cohen JB, Goins WF, et al (2020)

Oncolytic HSV Vectors and Anti-Tumor Immunity.

Current issues in molecular biology, 41:381-468 pii:v41/381 [Epub ahead of print].

The therapeutic promise of oncolytic viruses (OVs) rests on their ability to both selectively kill tumor cells and induce anti-tumor immunity. The potential of tumors to be recognized and eliminated by an effective anti-tumor immune response has been spurred on by the discovery that immune checkpoint inhibition can overcome tumor-specific cytotoxic T cell (CTL) exhaustion and provide durable responses in multiple tumor indications. OV-mediated tumor destruction is now recognized as a powerful means to assist in the development of anti-tumor immunity for two important reasons: (i) OVs, through the elicitation of an anti-viral response and the production of type I interferon, are potent stimulators of inflammation and can be armed with transgenes to further enhance anti-tumor immune responses; and (ii) lytic activity can promote the release of tumor-associated antigens (TAAs) and tumor neoantigens that function as in situ tumor-specific vaccines to elicit adaptive immunity. Oncolytic herpes simplex viruses (oHSVs) are among the most widely studied OVs for the treatment of solid malignancies, and Amgen's oHSV Imlygic® for the treatment of melanoma is the only OV approved in major markets. Here we describe important biological features of HSV that make it an attractive OV, clinical experience with HSV-based vectors, and strategies to increase applicability to cancer treatment.

RevDate: 2020-09-17

Mandrycky C, Hadland B, Y Zheng (2020)

3D curvature-instructed endothelial flow response and tissue vascularization.

Science advances, 6(38): pii:6/38/eabb3629.

Vascularization remains a long-standing challenge in engineering complex tissues. Particularly needed is recapitulating 3D vascular features, including continuous geometries with defined diameter, curvature, and torsion. Here, we developed a spiral microvessel model that allows precise control of curvature and torsion and supports homogeneous tissue perfusion at the centimeter scale. Using this system, we showed proof-of-principle modeling of tumor progression and engineered cardiac tissue vascularization. We demonstrated that 3D curvature induced rotation and mixing under laminar flow, leading to unique phenotypic and transcriptional changes in endothelial cells (ECs). Bulk and single-cell RNA-seq identified specific EC gene clusters in spiral microvessels. These mark a proinflammatory phenotype associated with vascular development and remodeling, and a unique cell cluster expressing genes regulating vascular stability and development. Our results shed light on the role of heterogeneous vascular structures in differential development and pathogenesis and provide previously unavailable tools to potentially improve tissue vascularization and regeneration.

RevDate: 2020-09-16

Joung J, Ladha A, Saito M, et al (2020)

Detection of SARS-CoV-2 with SHERLOCK One-Pot Testing.

RevDate: 2020-09-16

Wei XX, Werner L, Teo MY, et al (2020)

Sequencing of PD-1/L1 Inhibitors and Carboplatin-Based Chemotherapy for Cisplatin-Ineligible Metastatic Urothelial Carcinoma.

The Journal of urology [Epub ahead of print].

PURPOSE: Current first-line treatment options in patients with metastatic urothelial carcinoma (mUC) unfit to receive cisplatin-containing chemotherapy include PD-1/L1 inhibitors and carboplatin-containing chemotherapy. However, the optimal sequencing of these therapies remains unclear.

MATERIAL AND METHODS: We conducted a multicenter retrospective analysis. Consecutive cisplatin-ineligible patients with mUC treated with first-line carboplatin-containing chemotherapy followed sequentially by second-line PD-1/L1 inhibitor, or the reverse order, were included. Patient demographics, objective response, time to treatment failure for first-line (TTF1) and second-line (TTF2) therapy, interval between end of first-line and initiation of second-line treatment (Interval1L-2L), and overall survival (OS) were collected. Multivariate analysis was conducted to examine the association of sequencing on OS.

RESULTS: In this multicenter retrospective study, we identified 146 cisplatin-ineligible patients with mUC treated with first-line (1L) PD-1/L1 inhibitor therapy followed by second-line (2L) carboplatin-containing chemotherapy (Group 1, n=43) or the reverse sequence (Group 2, n=103). In the overall cohort, median age was 72, 76% were men, and 18% had liver metastasis. In both groups, objective response rates were higher with carboplatin-containing chemotherapy (45.6% 1L, 44.2% 2L) compared to PD-1/L1 inhibitors (9.3% 1L, 21.3% 2L). On multivariate analysis, treatment sequence was not associated with overall survival (HR 1.05, p=0.85). Site of metastasis was the only factor significantly associated with overall survival (p=0.002).

CONCLUSIONS: In this biomarker-unselected cohort of cisplatin-ineligible patients with mUC, PD-1/L1 inhibitor followed by carboplatin-containing chemotherapy and the reverse sequence had comparable OS.

RevDate: 2020-09-16

Hall ET, Sridhar D, Singhal S, et al (2020)

Perceptions of time spent pursuing cancer care among patients, caregivers, and oncology professionals.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-020-05763-9 [Epub ahead of print].

PURPOSE: Patients with cancer spend significant time receiving treatment and recovering from side effects. Little is known about how patients and their caregivers perceive time spent receiving cancer treatment and how this impacts health-related quality of life (HRQoL). Our study aims to characterize perceptions of time invested in receiving cancer therapy as experienced by patients, caregivers, and oncology professionals.

METHODS: We conducted semi-structured interviews with patients undergoing treatment for advanced lung cancer and melanoma, their informal caregivers, and oncology professionals (physicians, nurses, social workers, and chaplains). Participants received and provided care at a tertiary cancer center. Interviews were audiorecorded and transcribed verbatim. Transcripts were analyzed qualitatively using predominantly inductive coding to identify themes relating to time perception and cancer care.

RESULTS: We interviewed 29 participants (11 patients, 7 informal caregivers, and 11 oncology professionals) and found they consistently differentiated between time remaining in life ("existential time") and time required to manage cancer treatment and symptoms ("chronological time"). Patients and caregivers reported distress around the mechanics of oncologic care that interrupted their daily lives (hobbies, activities). Participants described the impact of time invested in cancer care on dimensions of quality of life, ranging from minimal to substantial negative impact.

CONCLUSIONS: We found that the time spent undergoing cancer treatment affects well-being and often prevents patients and caregivers from participating in meaningful activities. The investment of personal time undergoing cancer therapy for patients with advanced solid tumors merits further study and can enhance communication between patients, caregivers, and their oncologists.

RevDate: 2020-09-15

Rogers JH, Link AC, McCulloch D, et al (2020)

Characteristics of COVID-19 in Homeless Shelters : A Community-Based Surveillance Study.

Annals of internal medicine [Epub ahead of print].

BACKGROUND: Homeless shelters are a high-risk setting for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission because of crowding and shared hygiene facilities.

OBJECTIVE: To investigate SARS-CoV-2 case counts across several adult and family homeless shelters in a major metropolitan area.

DESIGN: Cross-sectional, community-based surveillance study. (ClinicalTrials.gov: NCT04141917).

SETTING: 14 homeless shelters in King County, Washington.

PARTICIPANTS: A total of 1434 study encounters were done in shelter residents and staff, regardless of symptoms.

INTERVENTION: Two strategies were used for SARS-CoV-2 testing: routine surveillance and contact tracing ("surge testing") events.

MEASUREMENTS: The primary outcome measure was test positivity rate of SARS-CoV-2 infection at shelters, determined by dividing the number of positive cases by the total number of participant encounters, regardless of symptoms. Sociodemographic, clinical, and virologic variables were assessed as correlates of viral positivity.

RESULTS: Among 1434 encounters, 29 (2% [95% CI, 1.4% to 2.9%]) cases of SARS-CoV-2 infection were detected across 5 shelters. Most (n = 21 [72.4%]) were detected during surge testing events rather than routine surveillance, and most (n = 21 [72.4% {CI, 52.8% to 87.3%}]) were asymptomatic at the time of sample collection. Persons who were positive for SARS-CoV-2 were more frequently aged 60 years or older than those without SARS-CoV-2 (44.8% vs. 15.9%). Eighty-six percent of persons with positive test results slept in a communal space rather than in a private or shared room.

LIMITATION: Selection bias due to voluntary participation and a relatively small case count.

CONCLUSION: Active surveillance and surge testing were used to detect multiple cases of asymptomatic and symptomatic SARS-CoV-2 infection in homeless shelters. The findings suggest an unmet need for routine viral testing outside of clinical settings for homeless populations.

PRIMARY FUNDING SOURCE: Gates Ventures.

RevDate: 2020-09-15

Vargas CE, Thorpe CS, Dueck AC, et al (2020)

Impact of adjuvant trastuzumab on locoregional failure rates in a randomized clinical trial: North Central Cancer Treatment Group N9831 (alliance) study.

Cancer [Epub ahead of print].

BACKGROUND: The goal of this study was to assess the impact of trastuzumab on locoregional failure.

METHODS: The analysis included 2763 patients with HER2-positive (HER2+) breast cancer who were randomly assigned to adjuvant doxorubicin (A), cyclophosphamide (C), paclitaxel (T) and trastuzumab (H) (arm A, AC→T [n = 922]; arm B, AC→T→H [n = 988]; arm C, AC→T+H→H [n = 853]). Radiotherapy was given after AC→T concurrently with H. Radiotherapy was given after lumpectomy (L) or after mastectomy (M) with ≥4 positive lymph nodes but was optional for 1 to 3 positive lymph nodes. Locoregional failures at 10 years (LFR10) as first events were compared using competing risk analysis.

RESULTS: The median follow-up was 13.0 years. The first site of failure was local-only in 96 cases, locoregional in 16 cases, regional in 32 cases, and not specified in 2 cases; LFR10 was 4.8% (95% CI 4.1%-5.7%). LFR10 was 5.5% (95% CI 4.3%-7.2%), 4.9% (95% CI 3.7%-6.4%), and 2.8% (95% CI 1.9%-4.1%) in arms A, B, and C (B vs A: hazard ratio [HR] 0.91, P = .62; C vs A: HR 0.72, P = .12). For estrogen receptor-positive patients, LFR10 was 3.7% (95% CI 2.8%-4.8%) and for estrogen receptor-negative patients, it was 6.1% (95% CI 5.0%-7.4%; HR 0.61, P = .004). Local treatment included L+RT (n = 1044 [38%]), M+RT (n = 1025 [37%]), and M (n = 694 [25%]). LFR10 was 6.% (95% CI 5.0%-7.8%), 3.0% (95% CI 2.1%-4.3%), and 5.5% (95% CI 4.0%-7.4%) for L+RT, M+RT, and M, respectively (M+RT vs L+RT: HR 0.43, P < .001; M vs L+RT: HR 0.88, P = .57). For 1 to 3 positive lymph nodes, LFR10 was 6.5% (95% CI 4.8%-8.9%), 4.1% (95% CI 2.4%-7.0%), and 4.3% (95% CI 2.9%-6.5%) in L+RT, M+RT, and M, respectively (M vs L+RT: HR 0.68, P = .14; M vs M+RT: HR 1.2, P = .6).

CONCLUSION: Low 10-year LFRs were seen regardless of trastuzumab use. Differences in local therapy in patients with 1 to 3 positive lymph nodes did not appear to improve local control. Local therapy studies for HER2+ and other tumor characteristics are important as the role of local therapies continues to evolve.

RevDate: 2020-09-16

Tenthorey JL, Young C, Sodeinde A, et al (2020)

Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races.

eLife, 9: pii:59988.

Host antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5α uses its rapidly evolving 'v1' loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. However, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. Using deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restriction of divergent retroviruses. Unexpectedly, we found that the majority of mutations increase weak antiviral function. Moreover, most random mutations do not disrupt potent viral restriction, even when it is newly acquired via a single adaptive substitution. Our results indicate that TRIM5α's adaptive landscape is remarkably broad and mutationally resilient, maximizing its chances of success in evolutionary arms races with retroviruses.

RevDate: 2020-09-15

Karunamuni RA, Huynh-Le MP, Fan CC, et al (2020)

African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

International journal of cancer [Epub ahead of print].

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46), showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify SNPs that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6,253 men with African genetic ancestry. Ten iterations of a ten-fold cross-validation search were conducted, to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African were compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890, and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47 to 4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65 to 0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-15

Kizub DA, Miao J, Schubert MM, et al (2020)

Risk factors for bisphosphonate-associated osteonecrosis of the jaw in the prospective randomized trial of adjuvant bisphosphonates for early-stage breast cancer (SWOG 0307).

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-020-05748-8 [Epub ahead of print].

PURPOSE: Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis.

METHODS: SWOG 0307 randomized women with stage I-III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided.

RESULTS: Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ.

CONCLUSION: ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this.

CLINICAL TRIAL NUMBER: NCT00127205 REGISTRATION DATE: July 2005.

RevDate: 2020-09-15

Uy GL, Aldoss I, Foster MC, et al (2020)

Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia.

Blood pii:463757 [Epub ahead of print].

Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after <6 months (early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML. Eighty-eight AML patients were enrolled, 42 in dose-finding and 46 at the recommended phase 2 dose (RP2D) of 500ng/kg/day. Consistent with flotetuzumab's mode of action, the most frequent adverse events were infusion-related reactions (IRR)/cytokine release syndrome (CRS), the majority as grade 1-2. Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability. Clinical benefit accrued to PIF/ER AML patients, who showed an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the CR/CRh rate was 26.7%, with an overall response rate (CR/CRh/CRi) of 30.0%. In PIF/ER patients who achieved CR/CRh, median OS was 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95%CI, 0.450-1.05) and 50% (95%CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted complete responses to flotetuzumab (AUROC=0.904 versus 0.672 for the ELN risk classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.

RevDate: 2020-09-15

Czartoski J, Lemos MP, Fong Y, et al (2020)

Rapid Collection of Human Rectal Secretions Using OriCol Devices Is Suitable for Measurement of Mucosal Ig without Blood Contamination.

Journal of immunology (Baltimore, Md. : 1950) pii:jimmunol.2000320 [Epub ahead of print].

Measurements of IgG and IgA in human rectal secretions are used to evaluate the Abs elicited by HIV vaccines or the bioaccumulation following immunoprophylaxis at the sites of HIV exposure. To improve sampling methods and tolerability of the procedure, we optimized a balloon device (OriCol) for rectal microbiome sampling requiring 10 second inflation and compared this method to a 5 minute collection using sponges. Lubrication of the device did not interfere with IgG, IgA, or hemoglobin ELISA. Lubricated OriCols inflated to 30 cc minimized hemoglobin contamination (<4.68 ng/ml) compared with collections with two sponge types (Weck-Cel: 267.2 ng/ml, p < 0.0001; and Merocel: 59.38 ng/ml, p = 0.003). Median human serum albumin for OriCols was 14.9 μg/ml, whereas Merocels and Weck-Cels were 28.57 μg/ml (p = 0.0005) and 106.2 μg/ml (p = 0.0002), respectively. Consistent with reduced systemic contamination, the median IgG measured in OriCol-collected rectal secretions (986 ng) was lower than secretions from sponges (Weck-Cel: 8588 ng, p < 0.0001; Merocel: 2509 ng, p = 0.0389). The median IgA yield of samples using the OriCol method (75,253 ng) was comparable to that using Merocel (71,672 ng; p = 0.6942) but significantly higher than Weck-Cel sponges (16,173 ng, p = 0.0336). Median recovery volumes for OriCols were 800 μl, whereas Merocels and Weck-Cels were 615 μl (p = 0.0010) and 655 μl (p = 0.0113), respectively. The balloon device was acceptable among 23 participants, as 85.1% experiencing their first collection ranked it as "seven: acceptable - a lot" or "six: acceptable - somewhat" in a seven-point Likert scale. Therefore, lubricated OriCols inflated to 30 cc allowed for a rapid, well-tolerated, blood-free collection of human rectal secretions.

RevDate: 2020-09-15

Huang M, O'Shaughnessy J, Zhao J, et al (2020)

Association of Pathological Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-analysis.

Cancer research pii:0008-5472.CAN-20-1792 [Epub ahead of print].

Pathological complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer (BC). The magnitude of this association varies by BC subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation of the association between pCR and survival outcomes in triple-negative BC (TNBC). A literature review identified neoadjuvant studies, including clinical trials, real-world cohort studies and studies that pooled multiple trials or cohorts, which reported EFS/OS results by pCR in early-stage TNBC patients. Meta-analyses were performed to evaluate the association between pCR and EFS/OS and to predict long-term survival outcomes based on pCR status. Sensitivity analyses were conducted to assess the impact of cross-study variations. Twenty-five studies with over 4000 TNBC patients were identified. A synthesis of evidence from these studies suggested substantial improvement in EFS and OS for pCR vs. non-pCR (EFS HR [95% confidence interval]: 0.24 [0.20; 0.29]; OS: 0.19 [0.15; 0.24]); consistent results were reported in sensitivity analyses. Collectively, our findings suggest that adjuvant therapy is associated with improved EFS/OS in TNBC patients who received neoadjuvant therapy, regardless of pCR status.

RevDate: 2020-09-15

Mossavar-Rahmani Y, Hua S, Qi Q, et al (2020)

Are sedentary behavior and physical activity independently associated with cardiometabolic benefits? The Hispanic Community Health Study/Study of Latinos.

BMC public health, 20(1):1400 pii:10.1186/s12889-020-09497-5.

BACKGROUND: Whether physical activity can reduce cardiometabolic risk particularly in understudied populations such as US Hispanics/Latinos is of public health interest. We prospectively examined the association of physical activity and cardiometabolic biomarkers in n = 8049 participants of the Hispanic Community Health Study/Study of Latinos, a community-based cohort study of 16,415 adults aged 18-74 yr who self-identified as Hispanic/Latino from four US urban centers.

METHODS: We assessed physical activity using accelerometry in 2008-2011 at visit 1. We assessed cardiometabolic biomarkers twice: once at visit 1 and collected a second measure in 2014-2017 at visit 2. We used survey linear regression models with changes in cardiometabolic markers as the dependent variables and quartiles of sedentary behavior or whether adults met guidelines for moderate-to-vigorous physical activity as the independent variables.

RESULTS: In normoglycemic adults without cardiovascular disease, but not in adults with evidence of cardiometabolic disease, those who were in the lowest quartile for sedentary behavior (< 10.08 h/day) had a significant decline in mean LDL-cholesterol of - 3.94 mg/dL (95% CI: - 6.37, - 1.52) compared to adults in the highest quartile (≥13.0 h/day) who exhibited a significant increase in LDL-cholesterol of 0.14 mg/dL (95% CI, - 2.15,2.42) over the six year period (P < 0.02 in fully adjusted models.) There was also a trend toward lower mean increase in HbA1c comparing the lowest with the highest quartile of sedentary behavior. Overall regardless of glycemic level or evidence of cardiometabolic disease, adults who met guidelines for moderate-to-vigorous physical activity at visit 1, had significantly lower mean increases in level of fasting glucose compared to adults not meeting guidelines in fully adjusted models.

CONCLUSIONS: In this cohort of Hispanics/Latinos, being free of cardiometabolic disease and having low levels of sedentary behavior were associated with health benefits. Among all adults regardless of cardiometabolic disease, meeting guidelines for moderate-to-vigorous physical activity was associated with health benefits. Overall these data suggest that an active lifestyle may blunt the association of advancing age with worsening cardiometabolic risk factors.

RevDate: 2020-09-21

Lui GYL, Shaw R, Schaub FX, et al (2020)

BET, SRC, and BCL2 family inhibitors are synergistic drug combinations with PARP inhibitors in ovarian cancer.

EBioMedicine, 60:102988 pii:S2352-3964(20)30364-9 [Epub ahead of print].

BACKGROUND: Homologous recombination deficiencies (HRD) are present in approximately half of epithelial ovarian cancers, for which PARP inhibitors (PARPi) are becoming a preferred treatment option. However, a considerable proportion of these carcinomas acquire resistance or harbour de novo resistance, posing a significant challenge to treatment.

METHODS: To identify new combinatorial therapeutics to overcome resistance to PARPi, we employed high-throughput conditional RNAi and drug screening of patient-derived ovarian cancer cells. To prioritise clinically relevant drug combinations, we integrated empirical validation with analysis of The Cancer Genome Atlas (TCGA) and Genomics of Drug Sensitivity in Cancer (GDSC) datasets to nominate candidate targets and drugs, reaching three main findings.

FINDINGS: Firstly, we found that the PARPi rucaparib enhanced the effect of BET inhibitors (CPI-203 & CPI-0610) irrespective of clinical subtype or HRD status. Additional drug combination screens identified that dasatinib, a non-receptor tyrosine kinase inhibitor, augmented the effects of rucaparib and BET inhibitors, proposing a potential broadly applicable triple-drug combination for high-grade serous and clear cell ovarian carcinomas. Secondly, rucaparib synergised with the BCL2 family inhibitor navitoclax, with preferential activity in ovarian carcinomas that harbour alterations in BRCA1/2, BARD1, or MSH2/6. Thirdly, we identified potentially antagonistic drug combinations between the PARPi rucaparib and vinca alkaloids, anthracyclines, and antimetabolites, cautioning their use in the clinic.

INTERPRETATION: These findings propose therapeutic strategies to address PARP inhibitor resistance using agents that are already approved or are in clinical development, with the potential for rapid translation to benefit a broad population of ovarian cancer patients.

RevDate: 2020-09-21

Brooks JD, Boice JD, Shore RE, et al (2020)

A case-control study of the joint effect of reproductive factors and radiation treatment for first breast cancer and risk of contralateral breast cancer in the WECARE study.

Breast (Edinburgh, Scotland), 54:62-69 pii:S0960-9776(20)30149-1 [Epub ahead of print].

OBJECTIVE: To examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC).

METHODS: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N = 1521) and controls are women with unilateral breast cancer (N = 2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0-<1Gy, ≥1Gy]) and reproductive factors (e.g., parity).

RESULTS: Nulliparous women treated with RT (≥1Gy dose) were at increased risk of CBC compared with nulliparous women not treated with RT, although this relationship did not reach statistical significance (RR = 1.34, 95% CI 0.87, 2.07). Women treated with RT who had an interval pregnancy (i.e., pregnancy after first diagnosis and before second diagnosis [in cases]/reference date [in controls]) had an increased risk of CBC compared with those who had an interval pregnancy with no RT (RR = 4.60, 95% CI 1.16, 18.28). This was most apparent for women with higher radiation doses to the contralateral breast.

CONCLUSION: Among young female survivors of breast cancer, we found some evidence suggesting that having an interval pregnancy could increase a woman's risk of CBC following RT for a first breast cancer. While sampling variability precludes strong interpretations, these findings suggest a role for pregnancy and hormonal factors in radiation-associated CBC.

RevDate: 2020-09-14

Deeg HJ (2020)

Individuals, Boundaries and GVHD.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30586-3 [Epub ahead of print].

Hematopoietic cell transplantation generates new individuals, transplant chimeras, composed of two genetic partners - the patient and donor-derived cells - no longer restricted by their original genomes. Interactions of donor-derived and recipient cells occur prominently at the boundary of the recipient with a third partner, the microbiome, in particular skin and intestinal tract, leading to disruption of microbiome homeostasis. These interactions of donor and patient cells at the boundary set the stage for the development of graft versus host disease, an expression of the defense of individuality by recipient and donor. Establishment of tolerance and return of homeostasis at the boundary will allow for the survival of the new integrated, physiological individual.

RevDate: 2020-09-14

Ustun C, Morgan EA, Ritz EM, et al (2020)

Core-binding factor acute myeloid leukemia with inv(16): Older age and high white blood cell count are risk factors for treatment failure.

RevDate: 2020-09-14

Cespedes Feliciano EM, Hohensee C, Rosko AE, et al (2020)

Association of Prediagnostic Frailty, Change in Frailty Status, and Mortality After Cancer Diagnosis in the Women's Health Initiative.

JAMA network open, 3(9):e2016747 pii:2770549.

Importance: Understanding changes in frailty in relation to cancer diagnosis can inform optimal selection of cancer treatments and survivorship care.

Objective: To investigate associations of prediagnostic frailty and change in frailty status with mortality after a cancer diagnosis.

This multicenter, prospective cohort study included 7257 community-dwelling, postmenopausal women in the United States who had frailty assessed at the Women's Health Initiative (WHI) enrollment (1993-1998) and the 3-year visit who were subsequently diagnosed as having invasive cancer. The data were analyzed from January 7, 2019, to June, 8, 2020.

Exposure: Frailty scores were defined from validated questionnaire items conceptually aligned with the Fried frailty phenotype, including at least 3 of the following characteristics: self-reported unintentional weight loss, exhaustion, low physical activity, and muscle weakness or impaired walking. Physical function components of the frailty score were updated a median of 10 (range, 1-18) times.

Main Outcomes and Measures: Using multivariable-adjusted Cox proportional hazards models, this study examined associations of prediagnostic frailty (at the 3-year visit, before cancer diagnosis) and prediagnostic changes in frailty (from enrollment to the 3-year visit) with mortality. Women were followed up beginning from cancer diagnosis for mortality outcomes through March 2018. In linear mixed-effects models with frailty scores as a function of time since cancer diagnosis, this study evaluated whether the time slope, ie, the rate of change in frailty score, increased after cancer diagnosis.

Results: This study included 7257 women in the WHI cohort who completed frailty assessments at enrollment and the 3-year WHI visit before cancer diagnosis and subsequently developed cancer. Cancer cases included 2644 breast cancers (36%), 822 lung cancers (11%), 691 colorectal cancers (10%), 445 endometrial cancers (6%), and 286 ovarian cancers (4%). At the 3-year visit, prior to cancer diagnosis, the mean (SD) age was 63 (7) years, and 1161 of 7257 (16%) of participating women met criteria for frailty; 2129 of 7257 (29%) were prefrail, and 3967 of 7257 (55%) were nonfrail. Over a median follow-up of 5.8 years after cancer diagnosis (range, 1 day to 19.9 years), 3056 women died. After multivariable adjustment, women who were frail (vs nonfrail) before cancer diagnosis had an increased risk of mortality after cancer diagnosis (hazard ratio [HR], 1.40; 95% CI, 1.26-1.55; P for trend <.001). Sustained frailty (21% [1537 of 7257] of women) or worsening frailty (22% [1578 of 7257]) vs being consistently nonfrail (45% [3266 of 7257]) before cancer diagnosis increased the risk of mortality after cancer diagnosis (HR, 1.25; 95% CI, 1.14-1.38 and 1.22; 95% CI, 1.11-1.34, respectively; P for trend <.001). In linear mixed-effects models, the rate of increase in physical frailty over time was statistically significantly higher after cancer diagnosis.

Conclusions and Relevance: Sustained and worsening frailty before cancer diagnosis was associated with an increased risk of mortality after cancer diagnosis in postmenopausal women. Furthermore, the rate of decline in physical function accelerated after cancer diagnosis. Frailty assessment could provide valuable information and perhaps prompt interventions to reduce and preempt worsening of physical frailty after cancer diagnosis.

RevDate: 2020-09-14

Dhakal B, Wang T, Kuxhausen M, et al (2020)

Prognostic impact of serum CXC chemokine ligands 4 and 7 on myelodysplastic syndromes post allogeneic hematopoietic cell transplant.

RevDate: 2020-09-14

Sun R, Xu M, Li X, et al (2020)

Integration of multiomic annotation data to prioritize and characterize inflammation and immune-related risk variants in squamous cell lung cancer.

Genetic epidemiology [Epub ahead of print].

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

RevDate: 2020-09-16

Labadie JD, Harrison TA, Banbury B, et al (2020)

Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location.

JNCI cancer spectrum, 4(5):pkaa042.

Background: Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location.

Methods: We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided.

Results: Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors.

Conclusions: We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

RevDate: 2020-09-16

Morton LM, Karyadi DM, Hartley SW, et al (2020)

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

JCO precision oncology, 4:.

PURPOSE: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

PATIENTS AND METHODS: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10-5.

RESULTS: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10-5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10-5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10-5), another gene implicated in DNA double-strand break repair.

CONCLUSION: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

RevDate: 2020-09-20

Steineck A, Krumm N, Sarthy JF, et al (2019)

Response to Pembrolizumab in a Patient With Xeroderma Pigmentosum and Advanced Squamous Cell Carcinoma.

JCO precision oncology, 3:.

RevDate: 2020-09-16

Dasgupta S, Y Huang (2020)

Selecting Biomarkers for building optimal treatment selection rules using Kernel Machines.

Journal of the Royal Statistical Society. Series C, Applied statistics, 69(1):69-88.

Optimal biomarker combinations for treatment-selection can be derived by minimizing total burden to the population caused by the targeted disease and its treatment. However, when multiple biomarkers are present, including all in the model can be expensive and hurt model performance. To remedy this, we consider feature selection in optimization by minimizing an extended total burden that additionally incorporates biomarker costs. Formulating it as a 0-norm penalized weighted-classification, we develop various procedures for estimating linear and nonlinear combinations. Through simulations and a real data example, we demonstrate the importance of incorporating feature-selection and marker cost when deriving treatment-selection rules.

RevDate: 2020-09-14

Halpern AB, Othus M, Howard NP, et al (2020)

Comparison of outpatient care following intensive induction versus post-remission chemotherapy for adults with acute myeloid leukemia and other high-grade myeloid neoplasms.

RevDate: 2020-09-21

Andreatos N, Iyer G, P Grivas (2020)

Emerging biomarkers in urothelial carcinoma: Challenges and opportunities.

Cancer treatment and research communications, 25:100179 pii:S2468-2942(20)30016-2 [Epub ahead of print].

Advanced urothelial carcinoma (UC) is a very important cause of cancer-related morbidity and mortality with, until recently, only a few available therapeutic options. The treatment landscape has dramatically changed in recent years with the introduction of immune checkpoint inhibitors and the development of novel targeted agents, such as erdafitinib, and antibody-drug conjugates, such as enfortumab vedotin. Cost-effective utilization of this rapidly expanding therapeutic armamentarium can be further optimized via the identification and validation of reliable prognostic and predictive biomarkers that inform prognostication and patient selection. In this review, we aim to summarize examples of recent developments in the rapidly expanding field of emerging biomarkers in UC, outlining challenges and opportunities.

RevDate: 2020-09-12

Dong J, Maj C, Tsavachidis S, et al (2020)

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

Gastroenterology pii:S0016-5085(20)35130-1 [Epub ahead of print].

BACKGROUND AND AIMS: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

METHODS: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in three separate studies and then used fixed-effects meta-analysis to provide summary estimates for > 9 million variants for males and females. A series of downstream analyses were conducted separately in males and females to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

RESULTS: We included 6,758 male BE/EA cases, 7,489 male controls, 1,670 female BE/EA cases and 6,174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified one variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, PBONF = 0.039) that was statistically significantly associated with BE/EA risk in males only, and one variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, PBONF = 0.057) associated, at borderline significance, with BE/EA risk in females only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in males and obesity in females.

CONCLUSIONS: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.

RevDate: 2020-09-12

Chiotos K, Hayes M, Kimberlin DW, et al (2020)

Multicenter interim guidance on use of antivirals for children with COVID-19/SARS-CoV-2.

Journal of the Pediatric Infectious Diseases Society pii:5904884 [Epub ahead of print].

BACKGROUND: Although Coronavirus Disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data evaluating agents with potential antiviral activity continue to expand, such that updated guidance is needed regarding use of these agents in children.

METHODS: A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.

RESULTS: Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for non-invasive or invasive mechanical ventilation or extra-corporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or non-invasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.

CONCLUSIONS: Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

RevDate: 2020-09-12

Stephens DM, Li H, Schoder H, et al (2020)

Reply to: Interim PET assessment of advanced Hodgkin Lymphoma: is it sufficient?.

Journal of nuclear medicine : official publication, Society of Nuclear Medicine pii:jnumed.120.242685 [Epub ahead of print].

RevDate: 2020-09-12

Yaghootkar H, Zhang Y, Spracklen CN, et al (2020)

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Diabetes pii:db20-0070 [Epub ahead of print].

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14 The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10-16, n=3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

RevDate: 2020-09-12

Oluoch LM, Roxby A, Mugo N, et al (2020)

Does providing laboratory confirmed STI results impact uptake of HIV pre-exposure prophylaxis (PrEP) uptake among Kenyan adolescents girls and young women? A descriptive analysis.

Sexually transmitted infections pii:sextrans-2020-054637 [Epub ahead of print].

RevDate: 2020-09-15

Shental N, Levy S, Wuvshet V, et al (2020)

Efficient high-throughput SARS-CoV-2 testing to detect asymptomatic carriers.

Science advances, 6(37): pii:sciadv.abc5961.

Recent reports suggest that 10 to 30% of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infected patients are asymptomatic and that viral shedding may occur before symptom onset. Therefore, there is an urgent need to increase diagnostic testing capabilities to prevent disease spread. We developed P-BEST, a method for Pooling-Based Efficient SARS-CoV-2 Testing, which identifies all positive subjects within a set of samples using a single round of testing. Each sample is assigned into multiple pools using a combinatorial pooling strategy based on compressed sensing. We pooled sets of 384 samples into 48 pools, providing both an eightfold increase in testing efficiency and an eightfold reduction in test costs, while identifying up to five positive carriers. We then used P-BEST to screen 1115 health care workers using 144 tests. P- BEST provides an efficient and easy-to-implement solution for increasing testing capacity that can be easily integrated into diagnostic laboratories.

RevDate: 2020-09-12

Liang X, Harris HR, Hendryx M, et al (2020)

Sleep characteristics and risk of ovarian cancer among postmenopausal women.

Cancer prevention research (Philadelphia, Pa.) pii:1940-6207.CAPR-20-0174 [Epub ahead of print].

Several studies have assessed the relationship between sleep duration and ovarian cancer risk, but the results are conflicting. Importantly, no studies addressed the relationship between sleep disturbance or sleep quality and ovarian cancer incidence. Moreover, few studies have examined the relationships between sleep measures and subtypes of ovarian cancer. This study included 109,024 postmenopausal women aged 50-79 from the Women's Health Initiative (WHI) during 1993-1998 and followed through 2018. The Cox proportional hazards model was used to estimate adjusted hazard ratios for the associations between sleep habits and the incidence of ovarian cancer and its subtypes. No association was observed between sleep duration, sleep quality, sleep disturbance, or insomnia and risk of overall ovarian cancer, serous/non-serous or Type I/Type II ovarian cancer subtype. However, compared with women with average sleep quality, women with restful or very restful sleep quality had a significantly lower risk of invasive serous subtype (HR: 0.73, 95% CI: 0.60-0.90) while insomnia was associated with a higher risk of invasive serous subtype (HR: 1.36, 95% CI: 1.12-1.66). Associations with insomnia differed significantly by serous and non-serous subtypes, and Type I and Type II subtypes (Pheterogeneity=0.001 and Pheterogeneity<0.001, respectively). This study provides no evidence on association between sleep habits and overall ovarian cancer risk among postmenopausal women. However, restful or very restful sleep quality was associated with a lower risk of invasive serous ovarian cancer, and insomnia was associated with a higher risk of invasive serous ovarian cancer. Associations with insomnia differed by subtypes.

RevDate: 2020-09-11

Stephens DS, MJ McElrath (2020)

COVID-19 and the Path to Immunity.

JAMA pii:2770758 [Epub ahead of print].

RevDate: 2020-09-11

Zhou W, Liu G, Hung RJ, et al (2020)

Causal Relationships between Body Mass Index, Smoking, and Lung Cancer: Univariable and Multivariable Mendelian Randomization.

International journal of cancer [Epub ahead of print].

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes, based on an aggregated genome wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 x 10-4). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = 0.011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = 0.008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = 0.036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = 0.746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-11

Kaya-Okur HS, Janssens DH, Henikoff JG, et al (2020)

Efficient low-cost chromatin profiling with CUT&Tag.

Nature protocols pii:10.1038/s41596-020-0373-x [Epub ahead of print].

We recently introduced Cleavage Under Targets & Tagmentation (CUT&Tag), an epigenomic profiling strategy in which antibodies are bound to chromatin proteins in situ in permeabilized nuclei. These antibodies are then used to tether the cut-and-paste transposase Tn5. Activation of the transposase simultaneously cleaves DNA and adds adapters ('tagmentation') for paired-end DNA sequencing. Here, we introduce a streamlined CUT&Tag protocol that suppresses DNA accessibility artefacts to ensure high-fidelity mapping of the antibody-targeted protein and improves the signal-to-noise ratio over current chromatin profiling methods. Streamlined CUT&Tag can be performed in a single PCR tube, from cells to amplified libraries, providing low-cost genome-wide chromatin maps. By simplifying library preparation CUT&Tag requires less than a day at the bench, from live cells to sequencing-ready barcoded libraries. As a result of low background levels, barcoded and pooled CUT&Tag libraries can be sequenced for as little as $25 per sample. This enables routine genome-wide profiling of chromatin proteins and modifications and requires no special skills or equipment.

RevDate: 2020-09-11

Bedford T, Greninger AL, Roychoudhury P, et al (2020)

Cryptic transmission of SARS-CoV-2 in Washington state.

Science (New York, N.Y.) pii:science.abc0523 [Epub ahead of print].

Following its emergence in Wuhan, China, in late November or early December 2019, the SARS-CoV-2 virus has rapidly spread globally. Genome sequencing of SARS-CoV-2 allows reconstruction of its transmission history, although this is contingent on sampling. We have analyzed 453 SARS-CoV-2 genomes collected between 20 February and 15 March 2020 from infected patients in Washington State, USA. We find that most SARS-CoV-2 infections sampled during this time derive from a single introduction in late January or early February 2020 which subsequently spread locally before active community surveillance was implemented.

RevDate: 2020-09-10

Chen GC, Qi Q, Hua S, et al (2020)

Accelerometer-assessed physical activity and incident diabetes in a population covering the adult life span: the Hispanic Community Health Study/Study of Latinos.

The American journal of clinical nutrition pii:5903730 [Epub ahead of print].

BACKGROUND: The association between accelerometer-assessed physical activity and risk of diabetes remains unclear, especially among US Hispanic/Latino adults who have lower levels of physical activity and a higher diabetes burden compared with other racial/ethnical populations in the country.

OBJECTIVES: To examine the association between accelerometer-assessed physical activity and incident diabetes in a US Hispanic/Latino population.

METHODS: We included 7280 participants of the Hispanic Community Health Study/Study of Latinos who aged 18-74 y and free of diabetes at baseline. Data on moderate-to-vigorous physical activity (MVPA) were collected using a 7-d accelerometer measurement. Incident diabetes was assessed after a mean ± SD of 6.0 ± 0.8 y using standard procedures including blood tests. RRs and 95% CIs of diabetes associated with MVPA were estimated using survey Poisson regressions. The associations of MVPA with 6-y changes in adiposity measures were also examined.

RESULTS: A total of 871 incident cases of diabetes were identified. MVPA was inversely and nonlinearly associated with risk of diabetes (P-nonlinearity = 0.006), with benefits accruing rapidly at the lower end of MVPA range (<30 min/d) and leveling off thereafter. The association differed by population age (P-interaction = 0.006). Higher MVPA was associated with lower risk of diabetes among individuals older than 50 y (RRQ4 versus Q1 = 0.50; 95% CI: 0.35, 0.73; P-trend < 0.001) but not among younger individuals (RRQ4 versus Q1 = 0.98; 95% CI: 0.66, 1.47; P-trend = 0.92). An inverse association between MVPA and 6-y gain in waist circumference was also limited to the older group (P-interaction with age < 0.001).

CONCLUSIONS: Among US Hispanic/Latino adults, baseline accelerometer-derived MVPA was inversely associated with incident diabetes only among individuals aged 50 y and older. Further studies are needed to confirm our findings and to clarify potential mechanisms underlying the possible age differences in the MVPA-diabetes association. This study was registered at clinicaltrials.gov as NCT02060344.

RevDate: 2020-09-10

Pollack SM, Redman MW, Baker KK, et al (2020)

Assessment of Doxorubicin and Pembrolizumab in Patients With Advanced Anthracycline-Naive Sarcoma: A Phase 1/2 Nonrandomized Clinical Trial.

JAMA oncology pii:2770032 [Epub ahead of print].

Importance: Anthracycline-based therapy is standard first-line treatment for most patients with advanced and metastatic sarcomas. Although multiple trials have attempted to show improved outcomes in patients with soft-tissue sarcoma over doxorubicin monotherapy, each has fallen short of demonstrating improved outcomes.

Objective: To evaluate the safety and efficacy of doxorubicin in combination with pembrolizumab in patients with advanced, anthracycline-naive sarcomas.

This nonrandomized clinical trial used a 2-stage phase 2 design and was performed at a single, academic sarcoma specialty center. Patients were adults with good performance status and end-organ function. Patients with all sarcoma subtypes were allowed to enroll with the exception of osteosarcoma, Ewing sarcoma, and alveolar and embryonal rhabdomyosarcoma.

Interventions: Two dose levels of doxorubicin (45 and 75 mg/m2) were tested for safety in combination with pembrolizumab.

Main Outcomes and Measures: Objective response rate (ORR) was the primary end point. Overall survival (OS) and progression-free survival (PFS) were secondary end points. Correlative studies included immunohistochemistry, gene expression, and serum cytokines.

Results: A total of 37 patients (22 men; 15 women) were treated in the combined phase 1/2 trial. The median (range) patient age was 58.4 (25-80) years. The most common histologic subtype was leiomyosarcoma (11 patients). Doxorubicin plus pembrolizumab was well tolerated without significant unexpected toxic effects. The ORR was 13% for phase 2 patients and 19% overall. Median PFS was 8.1 (95% CI, 7.6-10.8) months. Median OS was 27.6 (95% CI, 18.7-not reached) months at the time of this analysis. Two of 3 patients with undifferentiated pleomorphic sarcoma and 2 of 4 patients with dedifferentiated liposarcoma had durable partial responses. Tumor-infiltrating lymphocytes were present in 21% of evaluable tumors and associated with inferior PFS (log-rank P = .03). No dose-limiting toxic effects were observed.

Conclusions and Relevance: In this nonrandomized clinical trial, doxorubicin plus pembrolizumab was well tolerated. Although the primary end point for ORR was not reached, the PFS and OS observed compared favorably with prior published studies. Further studies are warranted, especially those focusing on undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

Trial Registration: ClinicalTrials.gov Identifier: NCT02888665.

RevDate: 2020-09-10

Zhao Y, Feng X, Chen Y, et al (2020)

5-fluorouracil enhances the anti-tumor activity of the glutaminase inhibitor CB-839 against PIK3CA-mutant colorectal cancers.

Cancer research pii:0008-5472.CAN-20-0600 [Epub ahead of print].

PIK3CA encodes the p110α catalytic subunit of PI3 kinase and is frequently mutated in human cancers, including ~30% of colorectal cancer (CRC). Oncogenic mutations in PIK3CA render CRCs more dependent on glutamine. Here we report that the glutaminase inhibitor CB-839 preferentially inhibits xenograft growth of PIK3CA-mutant, but not wild-type (WT), CRCs. Moreover, the combination of CB-839 and 5-fluorouracil (5-FU) induces PIK3CA-mutant tumor regression in xenograft models. CB-839 treatment increased reactive oxygen species and caused nuclear translocation of Nrf2, which in turn up-regulated mRNA expression of uridine phosphorylase 1 (UPP1). UPP1 facilitated the conversion of 5-FU to its active compound, thereby enhancing the inhibition of thymidylate synthase. Consistently, knockout of UPP1 abrogated the tumor inhibitory effect of combined CB-839 and 5-FU administration. A phase I clinical trial showed that the combination of CB-839 and capecitabine, a prodrug of 5-FU, was well tolerated at biologically-active doses. Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA-mutant CRC patients might derive greater benefit from this treatment strategy as compared to PIK3CA WT CRC patients. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant CRCs and warrants further clinical evaluation.

RevDate: 2020-09-12

Kinsella S, JA Dudakov (2020)

When the Damage Is Done: Injury and Repair in Thymus Function.

Frontiers in immunology, 11:1745.

Even though the thymus is exquisitely sensitive to acute insults like infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation-therapy, it also has a remarkable capacity for repair. This phenomenon of endogenous thymic regeneration has been known for longer even than its primary function to generate T cells, however, the underlying mechanisms controlling the process have been largely unstudied. Although there is likely continual thymic involution and regeneration in response to stress and infection in otherwise healthy people, acute and profound thymic damage such as that caused by common cancer cytoreductive therapies or the conditioning regimes as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines with age as a function of thymic involution; which even at steady state leads to reduced capacity to respond to new pathogens, vaccines, and immunotherapy. Consequently, there is a real clinical need for strategies that can boost thymic function and enhance T cell immunity. One approach to the development of such therapies is to exploit the processes of endogenous thymic regeneration into novel pharmacologic strategies to boost T cell reconstitution in clinical settings of immune depletion such as HCT. In this review, we will highlight recent work that has revealed the mechanisms by which the thymus is capable of repairing itself and how this knowledge is being used to develop novel therapies to boost immune function.

RevDate: 2020-09-09

Lam T, VoPham T, Munger KL, et al (2020)

Long-term effects of latitude, ambient temperature, and ultraviolet radiation on the incidence of multiple sclerosis in two cohorts of US women.

Environmental epidemiology (Philadelphia, Pa.), 4(4):e0105.

Background: Differences in multiple sclerosis (MS) risk by latitude have been observed worldwide; however, the exposures driving these associations are unknown. Ultraviolet radiation (UV) has been explored as a risk factor, and ambient temperature has been correlated with disease progression. However, no study has examined the impact of all three exposures. We examined the association between these exposures and incidence of MS within two nationwide prospective cohorts of women, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).

Methods: Both cohorts were followed with biennial questionnaires to ascertain new diagnoses and risk factors. Time-varying exposures to latitude, cumulative average July temperature (°C), and cumulative average July erythemal UV (mW/m2) were predicted at each participant's biennially updated residential addresses. Using Cox proportional hazards models adjusted for MS risk factors, we calculated hazard ratios (HR) and 95% confidence intervals (CIs) within each cohort and pooled via meta-analyses.

Results: In multivariable models, there were suggestions that decreasing latitude (meta-analysis multivariable-adjusted HR = 0.72; 95% CI 0.55, 0.94 for women living <35.73° compared with those ≥42.15°, P-for-trend = 0.007) and increasing cumulative average July temperature (meta-analysis multivariable-adjusted HR = 0.81; 95% CI 0.72, 0.91 for each interquartile range increase [3.91°]) were associated with decreasing risk of MS. There was no evidence of heterogeneity between cohorts. We did not observe consistent associations with cumulative average UV.

Conclusion: Our results suggest that adult exposures to decreasing latitude and increasing temperature, but not UV, were associated with reduced MS risk in these two cohorts of women. Studies of MS incidence may want to consider temperature as a risk factor.

RevDate: 2020-09-09

Sarthy JF, Meers MP, Janssens DH, et al (2020)

Histone deposition pathways determine the chromatin landscapes of H3.1 and H3.3 K27M oncohistones.

eLife, 9: pii:61090 [Epub ahead of print].

Lysine 27-to-methionine (K27M) mutations in the H3.1 or H3.3 histone genes are characteristic of pediatric diffuse midline gliomas (DMGs). These oncohistone mutations dominantly inhibit histone H3K27 trimethylation and silencing, but it is unknown how oncohistone type affects gliomagenesis. We show that the genomic distributions of H3.1 and H3.3 oncohistones in human patient-derived DMG cells are consistent with the DNA replication-coupled deposition of histone H3.1 and the predominant replication-independent deposition of histone H3.3. Although H3K27 trimethylation is reduced for both oncohistone types, H3.3K27M-bearing cells retain some domains, and only H3.1K27M-bearing cells lack H3K27 trimethylation. Neither oncohistone interferes with PRC2 binding. Using Drosophila as a model, we demonstrate that inhibition of H3K27 trimethylation occurs only when H3K27M oncohistones are deposited into chromatin and only when expressed in cycling cells. We propose that oncohistones inhibit the H3K27 methyltransferase as chromatin patterns are being duplicated in proliferating cells, predisposing them to tumorigenesis.

RevDate: 2020-09-09

Sutherland MW, Ma X, Reboussin BA, et al (2020)

Socioeconomic position is associated with glycemic control in youth and young adults with type 1 diabetes.

Pediatric diabetes [Epub ahead of print].

OBJECTIVE: Health inequities persist in youth and young adults(YYA) with type 1diabetes in achieving optimal glycemic control. The purpose of this study was to assess the contribution of multiple indicators of social needto these inequities.

RESEARCH DESIGN AND METHODS: 222YYAwithtype 1 diabetes enrolled in the SEARCH Food Insecurity Study in South Carolina and Washington between the years 2013-2015 were included. Latent class analysis was used to identify socioeconomic profiles based on household income, parental education, health insurance,household food insecurity, and food assistance. Profileswere evaluated in relation to glycemic control using multivariable linear andlogistic regression, with HbA1c > 9%(75 mmol/mol) defined as high-riskglycemic control.

RESULTS: Twoprofiles were identified: alower socioeconomic profile included YYA whose parents had lower income and/or education,and weremore likely to be uninsured, receive food assistance, and be food insecure.A higher socioeconomic profileincluded YYA whose circumstances were opposite to those in the lower socioeconomic profile.Those with a lower socioeconomic profile were more likely to have high-riskglycemic control relative to thosewith a higher socioeconomic profile (OR = 2.24, 95%CI = 1.16-4.33).

CONCLUSIONS: Lower socioeconomic profilesare associated with high-riskglycemic controlamong YYA with type 1 diabetes. This supports recommendations that care providers of YYA with type 1 diabetes assess individual social needs in tailoring diabetes management plans to the social context of the patient. This article is protected by copyright. All rights reserved.

RevDate: 2020-09-09

Suzuki T, Uruno A, Yumoto A, et al (2020)

Nrf2 contributes to the weight gain of mice during space travel.

Communications biology, 3(1):496 pii:10.1038/s42003-020-01227-2.

Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.

RevDate: 2020-09-15
CmpDate: 2020-09-15

Loes AN, Gentles LE, Greaney AJ, et al (2020)

Attenuated Influenza Virions Expressing the SARS-CoV-2 Receptor-Binding Domain Induce Neutralizing Antibodies in Mice.

Viruses, 12(9): pii:v12090987.

An effective vaccine is essential for controlling the spread of the SARS-CoV-2 virus. Here, we describe an influenza virus-based vaccine for SARS-CoV-2. We incorporated a membrane-anchored form of the SARS-CoV-2 spike receptor binding domain (RBD) in place of the neuraminidase (NA) coding sequence in an influenza virus also possessing a mutation that reduces the affinity of hemagglutinin for its sialic acid receptor. The resulting ΔNA(RBD)-Flu virus can be generated by reverse genetics and grown to high titers in cell culture. A single-dose intranasal inoculation of mice with ΔNA(RBD)-Flu elicits serum neutralizing antibody titers against SAR-CoV-2 comparable to those observed in humans following natural infection (~1:200). Furthermore, ΔNA(RBD)-Flu itself causes no apparent disease in mice. It might be possible to produce a vaccine similar to ΔNA(RBD)-Flu at scale by leveraging existing platforms for the production of influenza vaccines.

RevDate: 2020-09-08

Samuelson Bannow BT, Warad D, Jones C, et al (2020)

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis.

Blood pii:463714 [Epub ahead of print].

Heparin-induced thrombocytopenia (HIT) is a life-threatening, pro-thrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays such as the Platelet Factor 4-Heparin ELISAs lack specificity, and the "gold standard" C14-labeled serotonin release assay (SRA) is of limited value for early patient management due to availability only through reference laboratories. Recent studies demonstrate that "pathogenic" HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin Expression Assay (PEA), may provide an option for rapid and conclusive results. Four hundred and nine consecutive adults suspected of HIT were classified as disease-positive, -negative or -indeterminate based upon predefined criteria that combined 4Ts scores and HIT ELISA results. Patients deemed "HIT-indeterminate" were considered disease-negative in the primary analysis and disease-positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (Area under the curve [AUC] of 0.94; 0.87-1.0, 95% CI) and similar to that of SRA (0.91; 0.82-1.0, 95% CI). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (0.78-0.98, 95% CI) and 0.86 (0.77-0.96, 95% CI), respectively. The PEA, a technically simple non-radioactive assay that uses ~20-fold fewer platelets compared to the SRA had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.

RevDate: 2020-09-17
CmpDate: 2020-09-17

Lieberman NAP, Peddu V, Xie H, et al (2020)

In vivo antiviral host transcriptional response to SARS-CoV-2 by viral load, sex, and age.

PLoS biology, 18(9):e3000849 pii:PBIOLOGY-D-20-01861.

Despite limited genomic diversity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shown a wide range of clinical manifestations in different patient populations. The mechanisms behind these host differences are still unclear. Here, we examined host response gene expression across infection status, viral load, age, and sex among shotgun RNA sequencing profiles of nasopharyngeal (NP) swabs from 430 individuals with PCR-confirmed SARS-CoV-2 and 54 negative controls. SARS-CoV-2 induced a strong antiviral response with up-regulation of antiviral factors such as OAS1-3 and IFIT1-3 and T helper type 1 (Th1) chemokines CXCL9/10/11, as well as a reduction in transcription of ribosomal proteins. SARS-CoV-2 culture in human airway epithelial (HAE) cultures replicated the in vivo antiviral host response 7 days post infection, with no induction of interferon-stimulated genes after 3 days. Patient-matched longitudinal specimens (mean elapsed time = 6.3 days) demonstrated reduction in interferon-induced transcription, recovery of transcription of ribosomal proteins, and initiation of wound healing and humoral immune responses. Expression of interferon-responsive genes, including ACE2, increased as a function of viral load, while transcripts for B cell-specific proteins and neutrophil chemokines were elevated in patients with lower viral load. Older individuals had reduced expression of the Th1 chemokines CXCL9/10/11 and their cognate receptor CXCR3, as well as CD8A and granzyme B, suggesting deficiencies in trafficking and/or function of cytotoxic T cells and natural killer (NK) cells. Relative to females, males had reduced B cell-specific and NK cell-specific transcripts and an increase in inhibitors of nuclear factor kappa-B (NF-κB) signaling, possibly inappropriately throttling antiviral responses. Collectively, our data demonstrate that host responses to SARS-CoV-2 are dependent on viral load and infection time course, with observed differences due to age and sex that may contribute to disease severity.

RevDate: 2020-09-08

Schweizer MT, Cheng HH, Nelson PS, et al (2020)

Two Steps Forward and One Step Back for Precision in Prostate Cancer Treatment.

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

RevDate: 2020-09-08

Thakur J, S Henikoff (2020)

Architectural RNA in chromatin organization.

Biochemical Society transactions pii:226363 [Epub ahead of print].

RNA plays a well-established architectural role in the formation of membraneless interchromatin nuclear bodies. However, a less well-known role of RNA is in organizing chromatin, whereby specific RNAs have been found to recruit chromatin modifier proteins. Whether or not RNA can act as an architectural molecule for chromatin remains unclear, partly because dissecting the architectural role of RNA from its regulatory role remains challenging. Studies that have addressed RNA's architectural role in chromatin organization rely on in situ RNA depletion using Ribonuclease A (RNase A) and suggest that RNA plays a major direct architectural role in chromatin organization. In this review, we will discuss these findings, candidate chromatin architectural long non-coding RNAs and possible mechanisms by which RNA, along with RNA binding proteins might be mediating chromatin organization.

RevDate: 2020-09-09

Moodley J, Naidoo S, Kelly C, et al (2020)

The Impact of Male Partner Circumcision on Women's Health Outcomes.

AIDS education and prevention : official publication of the International Society for AIDS Education, 32(4):356-366.

Medical male circumcision is a proven method of HIV risk reduction in men with no known direct benefit to women. We investigated the benefit of partner circumcision on women's health. We conducted a secondary analysis of 5,029 women enrolled in the Vaginal and Oral Interventions to Control the Epidemic trial across 15 African sites, to look at the impact of partner circumcision status on sexually transmitted infections, pregnancy, frequency of sex, and condom use in women. Of 4,982 participants with a baseline response, 31% had circumcised partners. Women with circumcised partners had a significantly reduced risk of syphilis acquisition, hazard ratio 0.51 (0.26, 1.00), p value = .05. Participants with uncircumcised partners were significantly less likely to have used a condom at the last sex act than the other two groups, adj. relative risk 0.86 (0.80, 0.92), adj. p value < .0001. We found no evidence of sexual risk compensation in women with circumcised partners.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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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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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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