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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 05 Jun 2020 at 01:40 Created: 

Publications by FHCRC Researchers

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

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

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

Citations The Papers (from PubMed®)

RevDate: 2020-06-04

Landovitz RJ, Li S, Eron JJ, et al (2020)

Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial.

The lancet. HIV pii:S2352-3018(20)30106-5 [Epub ahead of print].

BACKGROUND: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial.

METHODS: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800.

FINDINGS: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015).

INTERPRETATION: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials.

FUNDING: National Institute of Allergy and Infectious Diseases.

RevDate: 2020-06-04

Melzer AC, Golden SE, Ono SS, et al (2020)

"We Just Never Have Enough Time": Clinician Views of Lung Cancer Screening Processes and Implementation.

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

RATIONALE: Despite a known mortality benefit, lung cancer screening (LCS) implementation has been unexpectedly slow. New programs face barriers to implementation, which may include lack of clinician engagement or beliefs that the intervention is not beneficial.

OBJECTIVE: To evaluate diverse clinician perspectives on their views of LCS and their experience with LCS implementation and processes.

METHODS: We performed a qualitative study of clinicians participating in LCS. Clinicians were drawn from three medical centers, representing diverse specialties and practice settings. All participants practiced at sites with formal lung cancer screening programs. We performed semi-structured interviews with probes designed to elicit opinions of LCS, perceived evidence gaps, and recommendations for improvements. Transcribed interviews were iteratively reviewed and coded using directed content analysis.

RESULTS: Participants (n=24) included LCS coordinators, pulmonologists, physician and non-physician primary care providers (PCPs), a surgeon, and a radiologist. Most clinicians expressed that the evidence supporting LCS was adequate to support clinical adoption, though most PCPs had little direct knowledge and based decisions on local recommendations or endorsement by the US Preventative Services Task Force (USPSTF). Many PCPs endorsed lack of knowledge of eligibility requirements and screening strategy (e.g. annual while eligible). Clinicians with more lung cancer screening knowledge, including several PCPs, identified a number of gaps in the current evidence that tempered enthusiasm, including: unclear ideal screening interval, populations with high cancer risk that do not qualify under USPSTF, indications to stop screening, and the role of serious comorbidities. Support for centralized programs and LCS coordinators was strong, but not uniform. Clinicians were frustrated by time limitations during a patient encounter, costs to the patient, and issues with insurance coverage. Many gaps in informatics support were identified. Clinicians recommended working to improve informatics support, continuing to clarify clinician responsibilities, and working on increasing public awareness of LCS.

CONCLUSIONS: Despite working within programs that have adopted many recommended care processes to support LCS, clinicians identified a number of issues in providing high-quality LCS. Many of these issues are best addressed by improved support of LCS within the electronic health record and continued education of staff and patients.

RevDate: 2020-06-04

Wang Y, Wild AT, Turcan S, et al (2020)

Targeting therapeutic vulnerabilities with PARP inhibition and radiation in IDH-mutant gliomas and cholangiocarcinomas.

Science advances, 6(17):eaaz3221 pii:aaz3221.

Mutations in isocitrate dehydrogenase (IDH) genes occur in multiple cancer types, lead to global changes in the epigenome, and drive tumorigenesis. Yet, effective strategies targeting solid tumors harboring IDH mutations remain elusive. Here, we demonstrate that IDH-mutant gliomas and cholangiocarcinomas display elevated DNA damage. Using multiple in vitro and preclinical animal models of glioma and cholangiocarcinoma, we developed treatment strategies that use a synthetic lethality approach targeting the reduced DNA damage repair conferred by mutant IDH using poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPis). The therapeutic effects are markedly enhanced by cotreatment with concurrent, localized radiation therapy. PARPi-buttressed multimodality therapies may represent a readily applicable approach that is selective for IDH-mutant tumor cells and has potential to improve outcomes in multiple cancers.

RevDate: 2020-06-04

Chi Y, Carter JH, Swanger J, et al (2020)

A novel landscape of nuclear human CDK2 substrates revealed by in situ phosphorylation.

Science advances, 6(16):eaaz9899 pii:aaz9899.

Cyclin-dependent kinase 2 (CDK2) controls cell division and is central to oncogenic signaling. We used an "in situ" approach to identify CDK2 substrates within nuclei isolated from cells expressing CDK2 engineered to use adenosine 5'-triphosphate analogs. We identified 117 candidate substrates, ~40% of which are known CDK substrates. Previously unknown candidates were validated to be CDK2 substrates, including LSD1, DOT1L, and Rad54. The identification of many chromatin-associated proteins may have been facilitated by labeling conditions that preserved nuclear architecture and physiologic CDK2 regulation by endogenous cyclins. Candidate substrates include proteins that regulate histone modifications, chromatin, transcription, and RNA/DNA metabolism. Many of these proteins also coexist in multi-protein complexes, including epigenetic regulators, that may provide new links between cell division and other cellular processes mediated by CDK2. In situ phosphorylation thus revealed candidate substrates with a high validation rate and should be readily applicable to other nuclear kinases.

RevDate: 2020-06-04

Beas AO, Gordon PB, Prentiss CL, et al (2020)

Independent regulation of age associated fat accumulation and longevity.

Nature communications, 11(1):2790 pii:10.1038/s41467-020-16358-7.

Age-dependent changes in metabolism can manifest as cellular lipid accumulation, but how this accumulation is regulated or impacts longevity is poorly understood. We find that Saccharomyces cerevisiae accumulate lipid droplets (LDs) during aging. We also find that over-expressing BNA2, the first Biosynthesis of NAD+ (kynurenine) pathway gene, reduces LD accumulation during aging and extends lifespan. Mechanistically, this LD accumulation during aging is not linked to NAD+ levels, but is anti-correlated with metabolites of the shikimate and aromatic amino acid biosynthesis (SA) pathways (upstream of BNA2), which produce tryptophan (the Bna2p substrate). We provide evidence that over-expressed BNA2 skews glycolytic flux from LDs towards the SA-BNA pathways, effectively reducing LDs. Importantly, we find that accumulation of LDs does not shorten lifespan, but does protect aged cells against stress. Our findings reveal how lipid accumulation impacts longevity, and how aging cell metabolism can be rewired to modulate lipid accumulation independently from longevity.

RevDate: 2020-06-04

Mays JA, Greninger AL, Jerome KR, et al (2020)

Pre-Procedural Surveillance Testing for SARS-CoV-2 in an Asymptomatic Population in the Seattle Region Shows Low Rates of Positivity.

Seattle region hospitals have been impacted for several months by community spread of the coronavirus disease of 2019 (COVID-19).….

RevDate: 2020-06-04

Barnabas RV, Brown E, Bershteyn A, et al (2020)

Efficacy of hydroxychloroquine for post-exposure prophylaxis to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among adults exposed to coronavirus disease (COVID-19): a structured summary of a study protocol for a randomised controlled trial.

Trials, 21(1):475 pii:10.1186/s13063-020-04446-4.

OBJECTIVES: Primary Objective • To test the efficacy of Hydroxychloroquine (HCQ) (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection Secondary objectives • To determine the safety and tolerability of HCQ as SARS-CoV-2 Post-exposure Prophylaxis (PEP) in adults • To test the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection 2 weeks after completing therapy, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection • To test the efficacy of HCQ to shorten the duration of SARS-CoV-2 shedding among those with SARS-CoV-2 infection in the HCQ PEP group • To test the efficacy of HCQ to prevent incident COVID-19 TRIAL DESIGN: This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the virus.

PARTICIPANTS: This study will enroll up to 2000 asymptomatic adults 18 to 80 years of age (inclusive) at baseline who are close contacts of persons with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. This multisite trial will be conducted at seven sites in Seattle (UW), Los Angeles (UCLA), New Orleans (Tulane), Baltimore (UMB), New York City (NYU), Syracuse (SUNY-Upstate), and Boston (BMC). Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply: 1.Men or women 18 to 80 years of age inclusive, at the time of signing the informed consent2.Willing and able to provide informed consent3.Had a close contact of a person (index) with known PCR-confirmed SARS-CoV-2 infection or index who is currently being assessed for COVID-19 Close contact is defined as: a.Household contact (i.e., residing with the index case in the 14 days prior to index diagnosis or prolonged exposure within a residence/vehicle/enclosed space without maintaining social distance)b.Medical staff, first responders, or other care persons who cared for the index case without personal protection (mask and gloves)4.Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 infection) to the index case5.Access to device and internet for Telehealth visits6.Not planning to take HCQ in addition to the study medication Exclusion criteria Participants are excluded from the study if any of the following criteria apply: 1.Known hypersensitivity to HCQ or other 4-aminoquinoline compounds2.Currently hospitalized3.Symptomatic with subjective fever, cough, or shortness of breath4.Current medications exclude concomitant use of HCQ5.Concomitant use of other anti-malarial treatment or chemoprophylaxis, including chloroquine, mefloquine, artemether, or lumefantrine.6.History of retinopathy of any etiology7.Psoriasis8.Porphyria9.Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K)10.Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen11.Known moderate or severe liver disease12.Known long QT syndrome13.Severe renal impairment14.Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of the study drugs or planned use during the study period INTERVENTION AND COMPARATOR: Households will be randomized 1:1 (at the level of household), with close contact participants receiving one of the following therapies: •HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days •Placebo-like control (ascorbic acid) 500 mg orally daily for 3 days then 250 mg orally daily for 11 days MAIN OUTCOMES: The primary outcome of the study is the incidence of SARS-CoV-2 infection through day 14 among participants who are SARS-CoV-2 negative at baseline by randomization group.

RANDOMISATION: Participants will be randomized in a 1:1 ratio to HCQ or ascorbic acid at the level of the household (all eligible participants in 1 household will receive the same intervention). The randomization code and resulting allocation list will be generated and maintained by the Study Statistician. The list will be blocked and stratified by site and contact type (household versus healthcare worker).

BLINDING (MASKING): This is a blinded study. HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be bitter and ascorbic acid will be sour. The participants will be blinded to their randomization group once assigned. Study team members, apart from the Study Pharmacist and the unblinded statistical staff, will be blinded. Laboratory staff are blinded to the group allocation.

The sample size for the study is N=2 000 participants randomized 1:1 to either HCZ (n=1 000) and ascorbic acid (n=1 000).

TRIAL STATUS: Protocol version: 1.2 05 April 2020 Recruitment is ongoing, started March 31 and anticipated end date is September 30, 2020.

TRIAL REGISTRATION: ClinicalTrials.gov, Protocol Registry Number: NCT04328961 Date of registration: April 1, 2020, retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

RevDate: 2020-06-03

Inamoto Y, Martin PJ, Lee SJ, et al (2020)

Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation.

Blood advances, 4(11):2409-2417.

To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD.

RevDate: 2020-06-03

Manzo T, Prentice BM, Anderson KG, et al (2020)

Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells.

The Journal of experimental medicine, 217(8):.

CD8+ T cells are master effectors of antitumor immunity, and their presence at tumor sites correlates with favorable outcomes. However, metabolic constraints imposed by the tumor microenvironment (TME) can dampen their ability to control tumor progression. We describe lipid accumulation in the TME areas of pancreatic ductal adenocarcinoma (PDA) populated by CD8+ T cells infiltrating both murine and human tumors. In this lipid-rich but otherwise nutrient-poor TME, access to using lipid metabolism becomes particularly valuable for sustaining cell functions. Here, we found that intrapancreatic CD8+ T cells progressively accumulate specific long-chain fatty acids (LCFAs), which, rather than provide a fuel source, impair their mitochondrial function and trigger major transcriptional reprogramming of pathways involved in lipid metabolism, with the subsequent reduction of fatty acid catabolism. In particular, intrapancreatic CD8+ T cells specifically exhibit down-regulation of the very-long-chain acyl-CoA dehydrogenase (VLCAD) enzyme, which exacerbates accumulation of LCFAs and very-long-chain fatty acids (VLCFAs) that mediate lipotoxicity. Metabolic reprogramming of tumor-specific T cells through enforced expression of ACADVL enabled enhanced intratumoral T cell survival and persistence in an engineered mouse model of PDA, overcoming one of the major hurdles to immunotherapy for PDA.

RevDate: 2020-06-03

Dai JY, M LeBlanc (2019)

Case-only trees and random forests for exploring genotype-specific treatment effects in randomized clinical trials with dichotomous endpoints.

Journal of the Royal Statistical Society. Series C, Applied statistics, 68(5):1371-1391.

Discovering gene-treatment interactions in clinical trials is of rising interest in the era of precision medicine. Nonparametric statistical learning methods such as trees and random forests are useful tools for building prediction rules. In this article, we introduce trees and random forests to the recently proposed case-only approach for discovering gene-treatment interactions and estimating marker-specific treatment effects for a dichotomous trial endpoints. The motivational example is a case-control genetic association study in the Prostate Cancer Prevention Trial (PCPT), which tested the hypothesis whether finasteride can prevent prostate cancer. We compare this novel approach to the interaction tree method previously proposed. Because of the modeling simplicity - directly targeting at interaction - and the statistical efficiency of the case-only approach, case-only trees and random forests yield more accurate prediction of heterogeneous treatment effects and better measure of variable importance, relative to the interaction tree method which uses data from both cases and controls. Application of the proposed case-only trees and random forests to the PCPT study yielded a discovery of genotypes that may influence the prevention effect of finasteride.

RevDate: 2020-06-03

Medeiros-Fonseca B, Mestre VF, Estêvão D, et al (2020)

HPV16 induces penile intraepithelial neoplasia and squamous cell carcinoma in transgenic mice: first mouse model for HPV-related penile cancer.

The Journal of pathology [Epub ahead of print].

Penile cancer is an under-studied disease that occurs more commonly in developing countries and 30-50% of cases show high-risk human papillomavirus (HPV) infection. Therapeutic advances are slow, largely due to the absence of animal models for translational research. Here, we report the first mouse model for HPV-related penile cancer. Ten-week-old mice expressing all the HPV16 early genes under control of the cytokeratin 14 (Krt14) gene promoter and matched wild-type controls were exposed topically to dimethylbenz(o)anthracene (DMBA) or vehicle for 16 weeks. At 30 weeks of age mice were sacrificed for histological analysis. Expression of Ki67, cytokeratin 14 and of the HPV16 oncogenes E6 and E7 was confirmed using immunohistochemistry and quantitative PCR, respectively. HPV16-transgenic mice developed intraepithelial lesions including condylomas and penile intraepithelial neoplasia (PeIN). Lesions expressed cytokeratin 14 and the HPV16 oncogenes E6 and E7 and showed deregulated cell proliferation, demonstrated by Ki67-positive supra-basal cells. HPV16-transgenic mice exposed to DMBA showed increased penile intraepithelial neoplasia (PeIN) incidence and squamous cell carcinoma. Malignant lesions showed varied histological features closely resembling those of HPV-associated human penile cancers. Wild-type mice showed no malignant or pre-malignant lesions even when exposed to DMBA. These observations provide the first experimental evidence to support the etiological role of HPV16 in penile carcinogenesis. Importantly, this is the first mouse model to recapitulate key steps of HPV-related penile carcinogenesis and to reproduce morphological and molecular features of human penile cancer, providing a unique in vivo tool for studying its biology and advancing basic and translational research. This article is protected by copyright. All rights reserved.

RevDate: 2020-06-03

Kang JH, VoPham T, Laden F, et al (2020)

Cohort Study of Nonmelanoma Skin Cancer and the Risk of Exfoliation Glaucoma.

Journal of glaucoma, 29(6):448-455.

PRECIS: In a cohort study of 120,307 participants with 25+ years of follow-up, a history of nonmelanoma skin cancer (NMSC) was associated with a 40% higher exfoliation glaucoma (XFG) risk.

PURPOSE: The purpose of this study was to evaluate the relationship between NMSC (a marker of ultraviolet radiation exposure) and XFG.

METHODS: We performed a cohort study of US women (n=79,102; 1980-2014) and men (n=41,205; 1986-2014), aged 40+ years and at risk for glaucoma who reported eye examinations. From 1984 (women)/1988 (men), we asked about basal cell carcinoma or squamous cell carcinoma history separately; in prior years, we asked about any NMSC history in a single question. Squamous cell carcinoma was confirmed with histopathology reports while basal cell carcinoma and any early (<1984/<1988) NMSC history was self-reported. Incident XFG cases (362 women and 83 men) were confirmed with medical records. Using pooled data, we estimated multivariable-adjusted relative risks [MVRRs; 95% confidence intervals (CIs)] with Cox proportional hazards models that were stratified by age (in mo), 2-year time period at risk and average lifetime residential latitude.

RESULTS: In multivariable-adjusted analyses, we observed a 40% higher XFG risk with any NMSC history (MVRR=1.40; 95% CI=1.08-1.82); the association was observed even with 4 and 8-year lags in NMSC history. Also, the NMSC association was stronger in younger (below 65 y; MVRR=2.56; 95% CI=1.62-4.05) versus older participants (65 y and above; MVRR=1.25; 95% CI=0.94-1.66; P for interaction=0.01) and those living in the northern latitudes (≥42°N; MVRR=1.92; 95% CI=1.28-2.88) versus more southern latitudes (<42°N; MVRR=1.19; 95% CI=0.86-1.66; P for interaction=0.04).

CONCLUSION: NMSC was associated with higher XFG risk, particularly among younger participants and those living in the Northern US.

RevDate: 2020-06-03

Gentles LE, Wan H, Eichelberger MC, et al (2020)

Antibody Neutralization of an Influenza Virus that Uses Neuraminidase for Receptor Binding.

Viruses, 12(6): pii:v12060597.

Influenza virus infection elicits antibodies against the receptor-binding protein hemagglutinin (HA) and the receptor-cleaving protein neuraminidase (NA). Because HA is essential for viral entry, antibodies targeting HA often potently neutralize the virus in single-cycle infection assays. However, antibodies against NA are not potently neutralizing in such assays, since NA is dispensable for single-cycle infection. Here we show that a modified influenza virus that depends on NA for receptor binding is much more sensitive than a virus with receptor-binding HA to neutralization by some anti-NA antibodies. Specifically, a virus with a receptor-binding G147R N1 NA and a binding-deficient HA is completely neutralized in single-cycle infections by an antibody that binds near the NA active site. Infection is also substantially inhibited by antibodies that bind NA epitopes distant from the active site. Finally, we demonstrate that this modified virus can be used to efficiently select mutations in NA that escape antibody binding, a task that can be laborious with typical influenza viruses that are not well neutralized by anti-NA antibodies. Thus, viruses dependent on NA for receptor binding allow for sensitive in vitro detection of antibodies binding near the catalytic site of NA and enable the selection of viral escape mutants.

RevDate: 2020-06-02

Shankaran V, Unger JM, Darke AK, et al (2020)

Design, data linkage, and implementation considerations in the first cooperative group led study assessing financial outcomes in cancer patients and their informal caregivers.

Contemporary clinical trials pii:S1551-7144(20)30115-4 [Epub ahead of print].

BACKGROUND: Few studies have assessed the financial impact of cancer diagnosis on patients and caregivers in diverse clinical settings. S1417CD, led by the SWOG Cancer Research Network, is the first prospective longitudinal cohort study assessing financial outcomes conducted in the NCI Community Oncology Research Program (NCORP). We report our experience navigating design and implementation barriers.

METHODS: Patients age ≥ 18 within 120 days of metastatic colorectal cancer diagnosis were considered eligible and invited to identify a caregiver to participate in an optional substudy. Measures include 1) patient and caregiver surveys assessing financial status, caregiver burden, and quality of life and 2) patient credit reports obtained from the credit agency TransUnion through a linkage requiring social security numbers and secure data transfer processes. The primary endpoint is incidence of treatment-related financial hardship, defined as one or more of the following: debt accrual, selling or refinancing home, ≥20% income decline, or borrowing money. Accrual goal was n = 374 patients in 3 years.

RESULTS: S1417CD activated on Apr 1, 2016 and closed on Feb 1, 2019 after reaching its accrual goal sooner than anticipated. A total of 380 patients (median age 59.7 years) and 155 caregivers enrolled across 548 clinical sites. Credit data were not obtainable for 76 (20%) patients due to early death, lack of credit, or inability to match records.

CONCLUSIONS: Robust accrual to S1417CD demonstrates patients' and caregivers' willingness to improve understanding of financial toxicity despite perceived barriers such as embarrassment and fears that disclosing financial status could influence treatment recommendations.

RevDate: 2020-06-02

Watson NL, Heffner JL, Mull KE, et al (2020)

Which method of assessing depression and anxiety best predicts smoking cessation: Screening instruments or self-reported conditions?.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:5850354 [Epub ahead of print].

INTRODUCTION: Affective disorders and symptoms (ADS) are predictive of lower odds of quitting smoking. However, it is unknown which approach to assessing ADS best predicts cessation. This study compared a battery of ADS screening instruments with a single, self-report question on predicting cessation. Among those who self-reported ADS, we also examined if an additional question regarding whether participants believed the condition(s) might interfere with their ability to quit added predictive utility to the single-item question.

METHODS: Participants (N=2,637) enrolled in a RCT of web-based smoking treatments completed a battery of five ADS screening instruments and answered a single-item question about having ADS. Those with a positive self-report on the single-item question were also asked about their interference beliefs. The primary outcome was complete-case, self-reported 30-day point prevalence abstinence at 12 months.

RESULTS: Both assessment approaches significantly predicted cessation. Screening positive for ≥ one ADS in the battery was associated with 23% lower odds of quitting than not screening positive for any (p=.023); those with a positive self-report on the single-item had 39% lower odds of quitting than self-reporting no mental health conditions (p<.001). AUCROC values for the two assessment approaches were similar (p=.136). Adding the interference belief question to the single-item assessment significantly increased the AUCROC value (p=.042).

CONCLUSIONS: The single-item question assessing ADS had as much predictive validity, and possibly more, than the battery of screening instruments for identifying participants at risk for failing to quit smoking. Adding a question about interference beliefs significantly increased the predictive utility of the single-item question.

RevDate: 2020-06-02

Engel JA, Lee HJ, Williams CG, et al (2020)

Single-cell transcriptomics of allo-reactive CD4+ T cells over time reveals divergent fates during gut GVHD.

JCI insight pii:137990 [Epub ahead of print].

Acute gastrointestinal Graft-versus-Host-Disease (GVHD) is a primary determinant of mortality after allogeneic hematopoietic stem-cell transplantation (alloSCT). It is mediated by alloreactive donor CD4+ T cells that differentiate into pathogenic subsets expressing IFNγ, IL-17A or GM-CSF, and is regulated by subsets expressing IL-10 and/or Foxp3. Developmental relationships between T-helper states during priming in mesenteric lymph nodes (mLN) and effector function in the GI tract remain undefined at genome-scale. We applied scRNA-seq and computational modelling to a mouse model of donor DC-mediated GVHD exacerbation, creating an atlas of putative CD4+ T-cell differentiation pathways in vivo. Computational trajectory inference suggested emergence of pathogenic and regulatory states along a single developmental trajectory in mLN. Importantly, we inferred an unexpected second trajectory, categorised by little proliferation or cytokine expression, reduced glycolysis, and high tcf7 expression. TCF1hi cells upregulated α4β7 prior to gut migration and failed to express cytokines therein. Nevertheless, they exhibited recall potential and plasticity following secondary transplantation, including cytokine or Foxp3 expression, but reduced TCF1. Thus, scRNA-seq suggested divergence of allo-reactive CD4+ T cells into quiescent and effector states during gut GVHD exacerbation by donor DC, reflecting putative heterogenous priming in vivo. These findings, the first at a single-cell level during GVHD over time, may assist in examination of T cell differentiation in patients undergoing alloSCT.

RevDate: 2020-06-02

Petersdorf EW, Stevenson P, Bengtsson M, et al (2020)

HLA-B Leader and Survivorship after HLA-Mismatched Unrelated Donor Transplantation.

Blood pii:460604 [Epub ahead of print].

Hematopoietic-cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B-mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 11872 patients transplanted between 1988 and 2016 from unrelated donors with one HLA-A -B,-C,-DRB1 or -DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A,-B,-C,-DRB1 or -DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Non-relapse mortality was higher among HLA-DQB1-mismatched MM patients compared to HLA-DQB1-mismatched TT patients (hazard ratio 1.35; P = .01). Grades III-IV GVHD risk was higher among HLA-DRB1-mismatched MM or MT patients compared to HLA-DRB1-mismatched TT patients (odds ratio 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's given leader genotype.

RevDate: 2020-06-02

Zviran A, Schulman RC, Shah M, et al (2020)

Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring.

Nature medicine pii:10.1038/s41591-020-0915-3 [Epub ahead of print].

In many areas of oncology, we lack sensitive tools to track low-burden disease. Although cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low-disease-burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole-genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10-5. The WGS approach enabled dynamic tumor burden tracking and postoperative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome-wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance and empowering treatment optimization in low-disease-burden oncology care.

RevDate: 2020-06-02

Becht E, Zhao E, Amezquita R, et al (2020)

Aggregating transcript-level analyses for single-cell differential gene expression.

RevDate: 2020-06-02

Leman JK, Weitzner BD, Lewis SM, et al (2020)

Macromolecular modeling and design in Rosetta: recent methods and frameworks.

Nature methods pii:10.1038/s41592-020-0848-2 [Epub ahead of print].

The Rosetta software for macromolecular modeling, docking and design is extensively used in laboratories worldwide. During two decades of development by a community of laboratories at more than 60 institutions, Rosetta has been continuously refactored and extended. Its advantages are its performance and interoperability between broad modeling capabilities. Here we review tools developed in the last 5 years, including over 80 methods. We discuss improvements to the score function, user interfaces and usability. Rosetta is available at http://www.rosettacommons.org.

RevDate: 2020-06-01

Yang L, Emerman M, Malik HS, et al (2020)

Retrocopying expands the functional repertoire of APOBEC3 antiviral proteins in primates.

eLife, 9: pii:58436.

Host-virus arms races are inherently asymmetric; viruses evolve much more rapidly than host genomes. Thus, there is high interest in discovering mechanisms by which host genomes keep pace with rapidly evolving viruses. One family of restriction factors, the APOBEC3 (A3) cytidine deaminases, has undergone positive selection and expansion via segmental gene duplication and recombination. Here, we show that new copies of A3 genes have also been created in primates by reverse transcriptase-encoding elements like LINE-1 or endogenous retroviruses via a process termed retrocopying. First, we discovered that all simian primate genomes retain the remnants of an ancient A3 retrocopy: A3I. Furthermore, we found that some New World monkeys encode up to ten additional APOBEC3G (A3G) retrocopies. Some of these A3G retrocopies are transcribed in a variety of tissues and able to restrict retroviruses. Our findings suggest that host genomes co-opt retroelement activity in the germline to create new host restriction factors as another means to keep pace with the rapid evolution of viruses. (163).

RevDate: 2020-06-01

Petersdorf EW, Bengtsson M, De Santis D, et al (2020)

Role of HLA-DP Expression in Graft-Versus-Host Disease After Unrelated Donor Transplantation.

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

PURPOSE: The main aim of this study was to evaluate the significance of HLA-DPB1 expression in acute graft-versus-host disease (GVHD) after hematopoietic cell transplantation (HCT) from HLA-A, -B, -C, -DRB1, -DQB1-matched and -mismatched unrelated donors.

PATIENTS AND METHODS: Between January 1, 2017, and January 10, 2019, we assessed 19,136 patients who received HCT from an HLA-A, -B, -C, -DRB1, -DQB1-matched or -mismatched unrelated donor performed in Australia, the European Union, Japan, North America, and the United Kingdom between 1988 and 2016. Among transplant recipients with one HLA-DPB1 mismatch, the patient's mismatched HLA-DPB1 allotype was defined as low or high expression. Multivariable regression models were used to assess risks of GVHD associated with high expression relative to low expression HLA-DPB1 mismatches. The effect of increasing numbers of HLA-DPB1 mismatches on clinical outcome was assessed in HLA-mismatched transplant recipients.

RESULTS: In HLA-A, -B, -C, -DRB1,-DQB1-matched transplant recipients, donor mismatching against one high-expression patient HLA-DPB1 increased moderate (odds ratio [OR], 1.36; P = .001) and severe acute GVHD (OR, 1.32; P = .0016) relative to low-expression patient mismatches, regardless of the expression level of the donor's mismatched HLA-DPB1. Among transplant recipients with one HLA-A, -B, -C, -DRB1, or -DQB1 mismatch, the odds of acute GVHD increased with increasing numbers of HLA-DPB1 mismatches (OR, 1.23 for one; OR, 1.40 for two mismatches relative to zero mismatches for moderate GVHD; OR, 1.19 for one; OR, 1.40 for two mismatches relative to zero for severe GVHD), but not with the level of expression of the patient's mismatched HLA-DPB1 allotype.

CONCLUSION: The level of expression of patient HLA-DPB1 mismatches informs the risk of GVHD after HLA-A, -B, -C, -DRB1, -DQB1-matched unrelated HCT, and the total number of HLA-DPB1 mismatches informs the risk of GVHD after HLA-mismatched unrelated HCT. Prospective consideration of HLA-DPB1 may help to lower GVHD risks after transplantation.

RevDate: 2020-06-01

Unger JM, Blanke CD, LeBlanc M, et al (2020)

Association of the Coronavirus Disease 2019 (COVID-19) Outbreak With Enrollment in Cancer Clinical Trials.

JAMA network open, 3(6):e2010651 pii:2766577.

RevDate: 2020-06-01

Lieberman JA, Mays JA, Wells C, et al (2020)

Expedited SARS-CoV-2 Screening of Donors and Recipients Supports Continued Solid Organ Transplant.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons [Epub ahead of print].

Universal screening of potential organ donors and recipients for SARS-CoV-2 is now recommended prior to transplantation in the United States during the COVID-19 pandemic. Challenges have included limited testing capacity, short windows of organ viability, brief lead time for notification of potential organ recipients, and the need to test lower respiratory donor specimens to optimize sensitivity. In an early US epicenter of the outbreak, we designed and implemented a system to expedite this testing and here report results from the first three weeks. The process included a Laboratory Medicine designee for communication with organ recovery and transplant clinical staff, specialized sample labeling and handoff, and priority processing. Thirty-two organs recovered from 14 of 17 screened donors were transplanted versus 70 recovered from 23 donors during the same period in 2019. No pre-transplant or organ donors tested positive for SARS-CoV-2. Median turnaround time from specimen receipt was 6.8h (donors), 6.5h (recipients): 4.5h faster than daily inpatient median. No organ recoveries or transplants were disrupted by a lack of SARS-CoV-2 testing. Waitlist inactivations for COVID-19 precautions were reduced in our region. Systems that include specialized ordering pathways and adequate testing capacity can support continued organ transplantation even in a SARS-CoV-2 hyperendemic area.

RevDate: 2020-05-31

Fiorenza S, Ritchie DS, Ramsey SD, et al (2020)

Value and affordability of CAR T-cell therapy in the United States.

Bone marrow transplantation pii:10.1038/s41409-020-0956-8 [Epub ahead of print].

In the United States the increasing number of Food and Drug Administration (FDA)-approved, innovative, and potentially effective commercial cancer therapies pose a significant financial burden on public and private payers. Chimeric antigen receptor (CAR) T cells are prototypical of this challenge. In 2017 and 2018, tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite) were approved by the FDA for use after showing groundbreaking results in relapsed/refractory B-cell malignancies. In 2020 and 2021, four further submissions to the FDA are expected for CAR T-cell therapies for indolent and aggressive B-cell malignancies and plasma cell myeloma. Yet, with marketed prices of over $350,000 per infusion for the two FDA-approved therapies and similar price tags expected for the coming products, serious concerns are raised over value and affordability. In this review we summarize recent, peer-reviewed cost-effectiveness studies of tisagenlecleucel and axicabtagene ciloleucel in the United States; discuss key issues concerning the health plan budget impact of CAR T-cell therapy; and review policy, payment and scientific approaches that may improve the value and affordability of CAR T-cell therapy.

RevDate: 2020-05-31

Kuderer NM, Choueiri TK, Shah DP, et al (2020)

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

Lancet (London, England) pii:S0140-6736(20)31187-9 [Epub ahead of print].

BACKGROUND: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.

METHODS: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.

FINDINGS: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.

INTERPRETATION: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.

FUNDING: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

RevDate: 2020-05-30

Miron PM, M Fang (2020)

The evolving clinical testing landscape of genomic aberrations in solid tumors and hematological malignancies - Insights from evidence-based reviews for B-ALL and breast, brain, and renal cell neoplasia.

RevDate: 2020-05-30

Millstein J, Budden T, Goode EL, et al (2020)

Prognostic gene expression signature for high-grade serous ovarian cancer.

Annals of oncology : official journal of the European Society for Medical Oncology pii:S0923-7534(20)39841-0 [Epub ahead of print].

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is approximately four years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for overall survival in HGSOC patients.

PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, were measured using NanoString technology from formalin-fixed, paraffin-embedded (FFPE) tumour tissue from 3,769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from fifteen studies and evaluated on an independent set of 1067 tumours from six studies.

RESULTS: Expression levels of 276 genes were associated with OS [false discovery rate (FDR) < 0.05] in covariate-adjusted single gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1, and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score (GES) conferred a greater than two-fold increase in risk of death [HR = 2.35 (2.02, 2.71); P < 0.001]. Median survival by GES quintile was 9.5 (8.3, --), 5.4 (4.6, 7.0), 3.8 (3.3, 4.6), 3.2 (2.9, 3.7) and 2.3 (2.1, 2.6) years.

CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

RevDate: 2020-05-30

Toran PT, Wohlfahrt M, Foye J, et al (2020)

ASSESSMENT, AND STREAMLINED PREPARATION OF LOW CYTOTOXICITY LENTIVIRAL VECTORS FOR MOBILIZED HUMAN HEMATOPOIETIC STEM CELL TRANSDUCTION.

Experimental hematology pii:S0301-472X(20)30187-9 [Epub ahead of print].

As important vectors for ectopic protein expression, gene silencing and progenitor cell barcoding, lentiviruses continue to emerge as versatile research and clinical tools. For studies employing cell types that are relatively resistant to transduction, high titer lentivirus preparations with low cytotoxicity are required. During lentivirus production, carryover plasmid DNA endotoxins, transfection reagents, damaged packaging cells, and virus concentration procedures are potential sources of cytotoxicity. As an often unevaluated property of lentivirus preparations, cytotoxicity can unwittingly skew estimates of functional titers, and complicate interpretations of transduced cell phenotypes. By employing hematopoietic UT7epo cells cultured in EPO below maximal dosing, we first define a sensitive flow cytometric bioassay for critically assessing cytotoxicities (and titers) of lentivirus preparations. When custom preparations of research- grade lentiviruses from six commercial sources were bioassayed, substantial cytotoxicity unexpectedly was revealed (with certain preparations additionally registering titers several logs below designated values). To overcome such limiting properties, we further report on unique, efficient workflows for reproducibly preparing and processing high titer low cytotoxicity (HTLC) lentiviruses at research scale. These HTLC lentiviruses reliably transduce PB-HSPCs at ≥40% frequencies, with low cytotoxicity. In addition, by employing cyclosporin-H (to inhibit IFITM3), PB-HSPC can be transduced at heightened efficiency with nominal cytotoxicity. Overall, this work provides straightforward approaches to: 1) critically assess the cytotoxicity of lentivirus preparations; 2) reproducibly generate (and concentrate) high quality lentiviruses via a streamlined workflow; and 3) transduce PB-HSPC at benchmark levels with nominal cytotoxicity.

RevDate: 2020-05-30

LaCourse SM, Kachikis A, Blain M, et al (2020)

Low prevalence of SARS-CoV-2 among pregnant and postpartum patients with universal screening in Seattle, Washington.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5848913 [Epub ahead of print].

We found a low prevalence of SARS-CoV-2 (2.7% [5/188]) among pregnant and postpartum patients after initiating universal testing. Prevalence among symptomatic patients (22.2% [4/18]) was similar to initial targeted screening approaches (19.1% [8/42]). Among 170 asymptomatic patients, two were positive or inconclusive, respectively; repeat testing at 24 hours was negative.

RevDate: 2020-05-29

Perchetti GA, Nalla AK, Huang ML, et al (2020)

Validation of SARS-CoV-2 detection across multiple specimen types.

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 128:104438 pii:S1386-6532(20)30180-3 [Epub ahead of print].

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused considerable disruption across the world, resulting in more than 235,000 deaths since December 2019. SARS-CoV-2 has a wide tropism and detection of the virus has been described in multiple specimen types, including various respiratory secretions, cerebrospinal fluid, and stool.

OBJECTIVE: To evaluate the accuracy and sensitivity of a laboratory modified CDCbased SARS-CoV-2 N1 and N2 assay across a range of sample types. Study Design We compared the matrix effect on the analytical sensitivity of SARS-CoV-2 detection by qRT-PCR in nasal swabs collected in viral transport medium (VTM), bronchoalveolar lavage (BAL), sputum, plasma, cerebral spinal fluid (CSF), stool, VTM, phosphate buffered saline (PBS), and Hanks' Balanced Salt Solution (HBSS). Initial limits of detection (LoD) were subsequently narrowed to confirm an LoD for each specimen type and target gene.

RESULTS: LoDs were established using a modified CDC-based laboratory developed test and ranged from a mean CT cut-off of 33.8-35.7 (10-20 copies/reaction) for the N1 gene target, and 34.0-36.2 (1-10 copies/reaction) for N2. Alternatives to VTM such as PBS and HBSS had comparable LoDs. The N2 gene target was found to be most sensitive in CSF.

CONCLUSION: A modified CDC-based laboratory developed test is able to detect SARSCoV- 2 accurately with similar sensitivity across all sample types tested.

RevDate: 2020-05-29

Augert A, Mathsyaraja H, Ibrahim AH, et al (2020)

MAX Functions as a Tumor Suppressor and Rewires Metabolism in Small Cell Lung Cancer.

Cancer cell pii:S1535-6108(20)30215-4 [Epub ahead of print].

Small cell lung cancer (SCLC) is a highly aggressive and lethal neoplasm. To identify candidate tumor suppressors we applied CRISPR/Cas9 gene inactivation screens to a cellular model of early-stage SCLC. Among the top hits was MAX, the obligate heterodimerization partner for MYC family proteins that is mutated in human SCLC. Max deletion increases growth and transformation in cells and dramatically accelerates SCLC progression in an Rb1/Trp53-deleted mouse model. In contrast, deletion of Max abrogates tumorigenesis in MYCL-overexpressing SCLC. Max deletion in SCLC resulted in derepression of metabolic genes involved in serine and one-carbon metabolism. By increasing serine biosynthesis, Max-deleted cells exhibit resistance to serine depletion. Thus, Max loss results in metabolic rewiring and context-specific tumor suppression.

RevDate: 2020-05-29

Li T, Cheng GS, Pipavath S, et al (2020)

The Novel Coronavirus Disease (COVID-19) Complicated by Pulmonary Embolism and Acute Respiratory Distress Syndrome.

Journal of medical virology [Epub ahead of print].

Acute respiratory distress syndrome and coagulopathy played an important role in morbidity and mortality of severe COVID-19 patients. A higher frequency of PE than expected in COVID-19 patients was recently reported. The presenting symptoms for PE were untypical including dyspnea, which is one of the major symptoms in severe COVID-19, especially in those patients with ARDS. We reported two COVID-19 cases with coexisting complications of PE and ARDS, aiming to consolidate the emerging knowledge of this global health emergency and raise the awareness that the hypoxemia or severe dyspnea in COVID-19 may be related to PE and not necessarily always due to the parenchymal disease. This article is protected by copyright. All rights reserved.

RevDate: 2020-05-29

Mpendo J, Mutua G, Nanvubya A, et al (2020)

Acceptability and tolerability of repeated intramuscular electroporation of Multi-antigenic HIV (HIVMAG) DNA vaccine among healthy African participants in a phase 1 randomized controlled trial.

PloS one, 15(5):e0233151 pii:PONE-D-19-22032.

INTRODUCTION: Intramuscular electroporation (IM/EP) is a vaccine delivery technique that improves the immunogenicity of DNA vaccines. We evaluated the acceptability and tolerability of electroporation among healthy African study participants.

METHODS: Forty-five participants were administered a DNA vaccine (HIV-MAG) or placebo by electroporation at three visits occurring at four week-intervals. At the end of each visit, participants were asked to rate pain at four times: (1) when the device was placed on the skin and vaccine injected, before the electrical stimulation, (2) at the time of electrical stimulation and muscle contraction, and (3) at 10 minutes and (4) 30 minutes after the procedure was completed. For analyses, pain level was dichotomized as either "acceptable" (none/slight/uncomfortable) or "too much" (Intense, severe, and very severe) and examined over time using repeated measures models. Optional brief comments made by participants were summarized anecdotally.

RESULTS: All 45 participants completed all three vaccination visits; none withdrew from the study due to the electroporation procedure. Most (76%) reported pain levels as acceptable at every time point across all vaccination visits. The majority of "unacceptable" pain was reported at the time of electrical stimulation. The majority of the participants (97%) commented that they preferred electroporation to standard injection.

CONCLUSION: Repeated intramuscular electroporation for vaccine delivery was found to be acceptable and feasible among healthy African HIV vaccine trial participants. The majority of participants reported an acceptable pain level at all vaccination time points. Further investigation may be warranted into the value of EP to improve immunization outcomes. ClinicalTrials.gov NCT01496989.

RevDate: 2020-05-29

Chen GC, Chai JC, Yu B, et al (2020)

Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

The American journal of clinical nutrition pii:5848527 [Epub ahead of print].

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1 = 2.40; 95% CI: 1.24, 4.65; P-trend = 0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1 = 3.15; 95% CI: 1.75, 5.67; P-trend <0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1 = 1.98; 95% CI: 1.09, 3.59; P-trend = 0.031).

CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.

RevDate: 2020-05-29

Esopi D, Graham MK, Brosnan-Cashman JA, et al (2020)

Pervasive promoter hypermethylation of silenced TERT alleles in human cancers.

Cellular oncology (Dordrecht) pii:10.1007/s13402-020-00531-7 [Epub ahead of print].

BACKGROUND: In cancers, maintenance of telomeres often occurs through activation of the catalytic subunit of telomerase, encoded by TERT. Yet, most cancers show only modest levels of TERT gene expression, even in the context of activating hotspot promoter mutations (C228T and C250T). The role of epigenetic mechanisms, including DNA methylation, in regulating TERT gene expression in cancer cells is as yet not fully understood.

METHODS: Here, we have carried out the most comprehensive characterization to date of TERT promoter methylation using ultra-deep bisulfite sequencing spanning the CpG island surrounding the core TERT promoter in 96 different human cell lines, including primary, immortalized and cancer cell types, as well as in control and reference samples.

RESULTS: In general, we observed that immortalized and cancer cell lines were hypermethylated in a region upstream of the recurrent C228T and C250T TERT promoter mutations, while non-malignant primary cells were comparatively hypomethylated in this region. However, at the allele-level, we generally found that hypermethylation of promoter sequences in cancer cells is associated with repressed expression, and the remaining unmethylated alleles marked with open chromatin are largely responsible for the observed TERT expression in cancer cells.

CONCLUSIONS: Our findings suggest that hypermethylation of the TERT promoter alleles signals transcriptional repression of those alleles, leading to attenuation of TERT activation in cancer cells. This type of fine tuning of TERT expression may account for the modest activation of TERT expression in most cancers.

RevDate: 2020-05-28

Bettampadi D, Sirak BA, Fulp WJ, et al (2020)

Oral HPV prevalence assessment by Linear Array vs. SPF10 PCR-DEIA-LiPA25 system in the human papillomavirus Infection in Men (HIM) study.

Papillomavirus research (Amsterdam, Netherlands) pii:S2405-8521(20)30013-6 [Epub ahead of print].

INTRODUCTION: Oral human papillomavirus (HPV) attributable oropharyngeal cancers are on the rise in many countries. Oral HPV infections among healthy individuals are commonly detected using oral gargle samples. However, the optimal method for HPV genotyping oral gargle specimens in research studies has not been previously evaluated.

MATERIALS AND METHODS: Oral gargle samples from 1,455 HPV Infection in Men (HIM) study participants were HPV genotyped using two different methods: Linear Array and the SPF10 PCR-DEIA-LiPA25. The sensitivity of the two tests for detecting individual HPV types and grouped HPV types, high-risk HPV, low-risk HPV, grouped 4-HPV-vaccine types, and grouped 9-vaccine-types, and the degree of concordance between the two tests was assessed. We also examined whether socio-demographic-behavioral factors were associated with concordance between the two assays.

RESULTS: The sensitivity of SPF10 PCR-DEIA-LiPA25 was higher than Linear Array, with the exception of HPV 70, for the detection of oral HPV. The prevalence ratio of SPF10 PCR-DEIA-LiPA25 to Linear Array varied between 1 and 9 for individual HPV genotypes, excluding HPV 70, and between 3.8 and 4.4 for grouped 4-valent and 9-valent HPV vaccine types, respectively. There was no association between socio-demographic-behavioral factors and discordance in results between the two tests for oral HPV 16 detection.

DISCUSSION: SPF10 PCR-DEIA-LiPA25 was more sensitive than Linear Array for detecting HPV in oral gargle samples. Given the growing importance of detecting oral HPV infection for research studies of oral HPV natural history and vaccine effectiveness evaluation, we recommend using methods with higher sensitivity such as SPF10 PCR-DEIA-LiPA25 for detecting HPV in oral gargle samples.

RevDate: 2020-05-28

Pidala J, Bhatt VR, Hamilton B, et al (2020)

Ixazomib for treatment of refractory chronic graft vs. host disease: A Chronic GVHD Consortium phase II trial: Ixazomib for chronic GVHD treatment.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30313-X [Epub ahead of print].

New interventions are needed in advanced chronic GVHD. In a phase II, single-arm, multi-center trial we examined the efficacy of ixazomib in patients with chronic GVHD that had progressed after at least one prior line of systemic immune suppressive therapy. Ixazomib was given as a 4 mg oral dose weekly on days 1, 8, and 15 of a 28-day cycle for up to 6 total cycles. The primary endpoint was 6 month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immune suppressive (IS) therapy. A total of 50 subjects were enrolled at 6 institutions. Median time from chronic GVHD onset to enrollment was 2.8 years (IQR 1.5-4.3). Chronic GVHD at enrollment was NIH moderate (16%) or severe (84%), predominantly classic (80% vs. overlap 20%), with 52% having 4 or more involved organs. Patients were heavily pretreated with 39 (78%) having 3 or more prior lines of systemic therapy for chronic GVHD. Of the 50 treated subjects, 26 completed 6 months of planned therapy. The 6 month treatment failure rate was significantly lower compared with the historical benchmark (28% vs. 44%, p=0.01) previously established in second-line therapy of chronic GVHD.16 No patient, transplant, or chronic GVHD variables were significantly associated with 6 month treatment failure. NIH-defined overall response rate was 40% at 6 months. Overall survival at 6 and 12 months was 92% and 90%. Ixazomib met the primary endpoint of low treatment failure at 6 months in the setting of advanced chronic GVHD. At 6 months the NIH CR/PR rate was 40%, and 52% remained on ixazomib suggesting the low treatment failure rate was in part due to prevention of progressive disease that would have required additional treatment.

RevDate: 2020-05-28

Woerner A, Shin DS, Chick JFB, et al (2020)

Endolymphatic exclusion for the treatment of pediatric chylous ascites secondary to neuroblastoma resection: report of two cases.

Radiology case reports, 15(7):1044-1049 pii:S1930-0433(20)30166-7.

Chylous ascites is a rare, but highly morbid complication of oncologic resection, often associated with retroperitoneal lymphadenectomy. Conservative measures with total parenteral nutrition or lipid-reduced formulas constitute the initial mainstay therapy, but not without risks and failures. This report describes 2 endolymphatic treatment strategies for iatrogenic chylous ascites following neuroblastoma resection. Lymphatic leaks were identified using intranodal lymphangiography, targeted with cone-beam computed tomographic guidance, and embolized with n-butyl cyanoacrylate. There were no adverse outcomes, with complete resolution of chylous ascites and a mean follow-up of 26 months.

RevDate: 2020-05-28

VanDeusen HR, Ramroop JR, Morel KL, et al (2020)

Targeting RET Kinase in Neuroendocrine Prostate Cancer.

Molecular cancer research : MCR pii:1541-7786.MCR-19-1245 [Epub ahead of print].

The increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR independent to AR dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR independent cell lines. Clinical NEPC patient samples and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacological inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. Implications: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in AVPC patients.

RevDate: 2020-05-27

Nyquist MD, Corella A, Coleman I, et al (2020)

Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress.

Cell reports, 31(8):107669.

Prostate cancers (PCs) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determine the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1-deficient tumors are classified as AR-active adenocarcinomas, indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss is associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 are highly resistant to all single-agent therapeutics tested, the combination of PARP and ATR inhibition is found to produce significant responses, reflecting a clinically exploitable vulnerability resulting from replication stress.

RevDate: 2020-05-27

Young AM, Gunn AL, EM Hatch (2020)

BAF facilitates interphase nuclear membrane repair through recruitment of nuclear transmembrane proteins.

Molecular biology of the cell [Epub ahead of print].

Nuclear membrane rupture during interphase occurs in a variety of cell contexts, both healthy and pathological. Membrane ruptures can be rapidly repaired, but these mechanisms are still unclear. Here we show BAF, a nuclear envelope protein that shapes chromatin and recruits membrane proteins in mitosis, also facilitates nuclear membrane repair in interphase, in part through recruitment of the nuclear membrane proteins emerin and LEMD2 to rupture sites. Characterization of GFP-BAF accumulation at nuclear membrane rupture sites confirmed BAF is a fast, accurate, and persistent mark of nucleus rupture whose kinetics are partially dictated by membrane resealing. BAF depletion significantly delayed nuclear membrane repair, with a larger effect on longer ruptures. This phenotype could be rescued by GFP-BAF, but not by a BAF mutant lacking the LEM-protein binding domain. Depletion of the BAF interactors LEMD2 or emerin, and to a lesser extent lamin A/C, increased the duration of nucleus ruptures, consistent with LEM-protein binding being a key function of BAF during membrane repair. Overall our results suggest a model where BAF is critical for timely repair of large ruptures in the nuclear membrane, potentially by facilitating membrane attachment to the rupture site. [Media: see text].

RevDate: 2020-05-27

Frigault MJ, Nikiforow S, Mansour M, et al (2020)

Tocilizumab not associated with increased infection risk after CAR T - Implications for COVID-19?.

Blood pii:457793 [Epub ahead of print].

RevDate: 2020-05-27

Short NJ, Kantarjian H, Kanagal-Shamanna R, et al (2020)

Ultra-accurate Duplex Sequencing for the assessment of pretreatment ABL1 kinase domain mutations in Ph+ ALL.

Blood cancer journal, 10(5):61 pii:10.1038/s41408-020-0329-y.

Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4-10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%-3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.

RevDate: 2020-05-27

Cowan AJ, Green DJ, Karami M, et al (2020)

KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation.

Clinical lymphoma, myeloma & leukemia pii:S2152-2650(20)30180-4 [Epub ahead of print].

BACKGROUND: Bortezomib has been incorporated into thalidomide and dexamethasone provided with cisplatin, doxorubicin, cyclophosphamide, and etoposide (PACE) as an intensive regimen before autologous stem-cell transplantation for multiple myeloma (MM). We examined MM patients at our center who received chemomobilization with a regimen that substituted carfilzomib and lenalidomide for bortezomib and thalidomide (KRD-PACE).

PATIENTS AND METHODS: This was a retrospective study of 27 MM patients who received KRD-PACE for chemomobilization. Our analysis included patients who had circulating plasma cells (CPCs) by flow cytometry, ≥ 10% bone marrow plasma cells (BMPC), a monoclonal protein ≥ 1 g/dL, or an involved serum free light chain ≥ 10 mg/dL.

RESULTS: The most common indication for KRD-PACE was BMPC ≥ 10% in 16 patients (60%), followed by CPCs in 11 (41%). The median (range) age was 61 (35-69) years, and the median (range) BMPC before treatment was 10% (5%-47%). The overall response rate was 43%, and a median (range) of 20.24 (8.08-69.88) × 106 CD34+ cells/kg were collected. CPC clearance rate was 50%, and the median reduction in BMPC was 75%. Two patients had sinus bradycardia and 5 (19%) had neutropenic fever.

CONCLUSION: KRD-PACE is an effective therapy to mobilize peripheral blood stem cells in MM patients with residual disease burden. This regimen was successful at clearing CPCs and reducing BMPC burden, with an overall response rate of 43%. Despite theoretical concern regarding the combination of 3 cardiotoxic agents, we observed a low frequency of cardiac issues.

RevDate: 2020-05-27

Hardikar S, Albrechtsen RD, Achaintre D, et al (2020)

Impact of Pre-blood Collection Factors on Plasma Metabolomic Profiles.

Metabolites, 10(5): pii:metabo10050213.

Demographic, lifestyle and biospecimen-related factors at the time of blood collection can influence metabolite levels in epidemiological studies. Identifying the major influences on metabolite concentrations is critical to designing appropriate sample collection protocols and considering covariate adjustment in metabolomics analyses. We examined the association of age, sex, and other short-term pre-blood collection factors (time of day, season, fasting duration, physical activity, NSAID use, smoking and alcohol consumption in the days prior to collection) with 133 targeted plasma metabolites (acylcarnitines, amino acids, biogenic amines, sphingolipids, glycerophospholipids, and hexoses) among 108 individuals that reported exposures within 48 h before collection. The differences in mean metabolite concentrations were assessed between groups based on pre-collection factors using two-sided t-tests and ANOVA with FDR correction. Percent differences in metabolite concentrations were negligible across season, time of day of collection, fasting status or lifestyle behaviors at the time of collection, including physical activity or the use of tobacco, alcohol or NSAIDs. The metabolites differed in concentration between the age and sex categories for 21.8% and 14.3% metabolites, respectively. In conclusion, extrinsic factors in the short period prior to collection were not meaningfully associated with concentrations of selected endogenous metabolites in a cross-sectional sample, though metabolite concentrations differed by age and sex. Larger studies with more coverage of the human metabolome are warranted.

RevDate: 2020-05-26

Davis D, Tretiakova MS, Kizzar C, et al (2020)

Abundant CD8+ tumor infiltrating lymphocytes and beta-2-microglobulin are associated with better outcome and response to interleukin-2 therapy in advanced stage clear cell renal cell carcinoma.

Annals of diagnostic pathology, 47:151537 pii:S1092-9134(20)30078-2 [Epub ahead of print].

Studies assessing tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC) and clinical outcomes have mixed results. Given fundamental interaction of MHC class I with CD8+ T-cells, we hypothesized that expression of MHC class I associated protein, beta-2-microglobulin (B2M), may be an important immunologic marker in RCC. We sought to understand potential implications of CD8 + TILs and tumor B2M expression on overall survival and response to high-dose interleukin-2 (IL-2) therapy, in a cohort of patients with high-stage (clinical stage III and IV) ccRCC. Four tumor regions from 56 patients with ccRCC were retrospectively assessed immunohistochemically. At a median follow-up time of 33 months, 22 (39%) patients had died of disease, 23 (41%) were alive disease, and 11 (20%) had no evidence of disease. Tumors with high CD8 + TILs had a significantly lower death rate [hazard ratio (HR): 0.33, p = 0.02]. CD8 + TILs correlated with B2M expression (p = 0.007). On multivariable analyses, patients with both high B2M and CD8 + TILs had lower death rate (HR: 0.27, p = 0.03). Within the subgroup treated with IL-2 (n = 27, 48%), tumors with high CD8 + TILs were more likely to respond to IL-2 therapy [coefficient (coef): 1.6, p = 0.05]. On multivariable analyses, tumors with a combination of both high B2M expression and high CD8 + TILs also showed trend to responding to IL-2 therapy (coef: 2.5, p = 0.06). In conclusion, abundant CD8+ TILs and high tumor expression of beta-2-microglobulin were good prognostic indicators associated with longer survival in patients with high-stage ccRCC. Abundant CD8+ TILs may predict response to IL-2 therapy.

RevDate: 2020-05-26

Perchetti GA, Nalla AK, Huang ML, et al (2020)

Validation of SARS-CoV-2 detection across multiple specimen types.

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 128:104438 pii:S1386-6532(20)30180-3 [Epub ahead of print].

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused considerable disruption across the world, resulting in more than 235,000 deaths since December 2019. SARS-CoV-2 has a wide tropism and detection of the virus has been described in multiple specimen types, including various respiratory secretions, cerebrospinal fluid, and stool.

OBJECTIVE: To evaluate the accuracy and sensitivity of a laboratory modified CDCbased SARS-CoV-2 N1 and N2 assay across a range of sample types. Study Design We compared the matrix effect on the analytical sensitivity of SARS-CoV-2 detection by qRT-PCR in nasal swabs collected in viral transport medium (VTM), bronchoalveolar lavage (BAL), sputum, plasma, cerebral spinal fluid (CSF), stool, VTM, phosphate buffered saline (PBS), and Hanks' Balanced Salt Solution (HBSS). Initial limits of detection (LoD) were subsequently narrowed to confirm an LoD for each specimen type and target gene.

RESULTS: LoDs were established using a modified CDC-based laboratory developed test and ranged from a mean CT cut-off of 33.8-35.7 (10-20 copies/reaction) for the N1 gene target, and 34.0-36.2 (1-10 copies/reaction) for N2. Alternatives to VTM such as PBS and HBSS had comparable LoDs. The N2 gene target was found to be most sensitive in CSF.

CONCLUSION: A modified CDC-based laboratory developed test is able to detect SARSCoV- 2 accurately with similar sensitivity across all sample types tested.

RevDate: 2020-05-26

Levoir L, L Goo (2020)

A (class-)switch in the antibody response may distinguish primary from secondary dengue virus infection.

EBioMedicine, 56:102790 pii:S2352-3964(20)30165-1 [Epub ahead of print].

RevDate: 2020-05-26

Wiercioch W, Nieuwlaat R, Akl EA, et al (2020)

Methodology for the American Society of Hematology VTE guidelines: current best practice, innovations, and experiences.

Blood advances, 4(10):2351-2365.

BACKGROUND: Methods for the development of clinical guidelines have advanced dramatically over the past 2 decades to strive for trustworthiness, transparency, user-friendliness, and rigor. The American Society of Hematology (ASH) guidelines on venous thromboembolism (VTE) have followed these advances, together with application of methodological innovations.

OBJECTIVE: In this article, we describe methods and methodological innovations as a model to inform future guideline enterprises by ASH and others to achieve guideline standards. Methodological innovations introduced in the development of the guidelines aim to address current challenges in guideline development.

METHODS: We followed ASH policy for guideline development, which is based on the Guideline International Network (GIN)-McMaster Guideline Development Checklist and current best practices. Central coordination, specialist working groups, and expert panels were established for the development of 10 VTE guidelines. Methodological guidance resources were developed to guide the process across guidelines panels. A methods advisory group guided the development and implementation of methodological innovations to address emerging challenges and needs.

RESULTS: The complete set of VTE guidelines will include >250 recommendations. Methodological innovations include the use of health-outcome descriptors, online voting with guideline development software, modeling of pathways for diagnostic questions, application of expert evidence, and a template manuscript for publication of ASH guidelines. These methods advance guideline development standards and have already informed other ASH guideline projects.

CONCLUSIONS: The development of the ASH VTE guidelines followed rigorous methods and introduced methodological innovations during guideline development, striving for the highest possible level of trustworthiness, transparency, user-friendliness, and rigor.

RevDate: 2020-05-26

Graham LS, Montgomery B, Cheng HH, et al (2020)

Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies.

PloS one, 15(5):e0233260 pii:PONE-D-20-01628.

BACKGROUND: While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment.

METHODS: We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (≥50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported.

RESULTS: 27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score ≥8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months).

CONCLUSIONS: MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.

RevDate: 2020-05-26

Nodler JL, DiVasta AD, Vitonis AF, et al (2020)

Supplementation with vitamin D or ω-3 fatty acids in adolescent girls and young women with endometriosis (SAGE): a double-blind, randomized, placebo-controlled trial.

The American journal of clinical nutrition pii:5846052 [Epub ahead of print].

BACKGROUND: Adolescents with endometriosis are a particularly underserved population who struggle with chronic pain. Despite widespread use, there are no published trials examining the individual effects of vitamin D and omega-3 (n-3) fatty acid supplementation on endometriosis-associated pain in adolescents.

OBJECTIVES: We aimed to determine whether supplementation with vitamin D or ω-3 fatty acids remediates pain, changes frequency of pain medication usage, or affects quality of life in young women with endometriosis.

METHODS: Women (aged 12-25 y) with surgically confirmed endometriosis and pelvic pain enrolled in a double-blind, randomized, placebo-controlled trial. The primary outcome was pain measured by the visual analog scale (VAS). Secondary outcomes were quality of life, pain catastrophizing, and pain medication usage. Participants were randomly assigned to receive 2000 IU vitamin D3, 1000 mg fish oil, or placebo daily for 6 mo.

RESULTS: A total of 147 women were screened and 69 were randomly assigned as follows: 27 to vitamin D3; 20 to fish oil; and 22 to placebo. Participants in the vitamin D arm experienced significant improvement in VAS pain [mean (95% CI) worst pain in the past month, from baseline to 6 mo: 7.0 (6.2, 7.8) to 5.5 (4.2, 6.8), P = 0.02]; however, an improvement of nearly identical magnitude was observed in the placebo arm [6.0 (5.1, 6.9) to 4.4 (3.0, 5.8), P = 0.07]. A more modest improvement was observed in the fish oil arm [5.9 (4.8, 7.0) to 5.2 (3.7, 6.8), P = 0.39]. Neither of the intervention arms were statistically different from placebo.

CONCLUSIONS: In young women with endometriosis, supplementation with vitamin D led to significant changes in pelvic pain; however, these were similar in magnitude to placebo. Supplementation with fish oil resulted in about half of the VAS pain reduction of the other 2 arms. Studies are needed to better define the physiology underlying the observed reduction in pain score in the placebo arm that persisted across 6 mo.This trial was registered at clinicaltrials.gov as NCT02387931.

RevDate: 2020-05-26

Blair CS, Li S, Chau G, et al (2020)

Hormonal Contraception Use and Cabotegravir Pharmacokinetics in HIV-Uninfected Women Enrolled in HPTN 077.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

OBJECTIVES: To evaluate whether hormonal contraceptive use among cisgender women is associated with differences in pharmacokinetic (PK) parameters of a long-acting injectable formulation of the integrase strand transfer inhibitor, cabotegravir (CAB-LA).

SETTING: This is a secondary analysis of 85 cisgender women enrolled in HPTN 077, a phase 2a multicenter study that enrolled HIV-uninfected, low-risk individuals in Malawi, Brazil, South Africa, and the United States.

METHODS: Participants received 4-weeks daily oral cabotegravir lead-in, followed by CAB-LA 800mg injection every 12 weeks (Cohort 1) or 600mg every 8 weeks (after 4-week initial interval between injections, Cohort 2), over 41 weeks. Participants were followed 52-76 weeks subsequent to final injection. GEE and linear regression were used to evaluate differences in CAB-LA PK parameters (peak concentration, trough concentration, area under the curve, apparent terminal half-life, and time to lower limit of quantification) and self-reported hormonal contraceptive stratified by type (oral, injectable, implants, other), controlling for BMI and cohort.

RESULTS: Compared to women reporting no hormonal contraception (n=6), oral contraceptive use (n=18) was associated with lower CAB-LA peak concentration but was not associated with differences in other PK parameters. No other hormonal contraceptive type (injectable, implants, other) was associated with significant differences in CAB-LA PK parameters.

CONCLUSION: While oral contraceptive use was associated with differences in CAB-LA peak concentration, no differences were observed in other PK parameters, suggesting this association is not likely to be clinically significant. However, these data highlight the need for further research exploring potential drug-drug interactions between CAB-LA and hormonal contraceptives.

RevDate: 2020-05-26

Okafor CN, Hucks-Ortiz C, Hightow-Weidman LB, et al (2020)

Associations between Self-Reported Substance Use Behaviors and PrEP Acceptance and Adherence among Black MSM in the HPTN 073 Study.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

BACKGROUND: Preexposure prophylaxis (PrEP) is efficacious for HIV prevention. Black Men who have Sex with Men (MSM) accounted for the largest proportion of new HIV diagnoses in the U.S relative to other racial/ethnic groups. Black MSM who use substances are at an increased risk for HIV infection and are ideal candidates for PrEP, but barriers to maintaining PrEP adherence remain a concern. We assessed whether substance use behaviors are associated with initiation and adherence to PrEP among a sample of Black MSM in the U.S.

METHODS: Data for this analysis comes from the HIV Prevention Trails Network Study 073 (HPTN 073). Substance use behaviors - including alcohol, marijuana, poppers (i.e. alkyl nitrites) and stimulants (i.e. methamphetamine/cocaine use) including use of these substances before/during condomless anal intercourse (CAI) - were assessed longitudinally via self-report. PrEP adherence was assessed by pharmacological testing in blood. Generalized estimating equations were used to evaluate association between substance use behaviors and PrEP initiation and adherence.

RESULTS: Among 226 HIV-negative Black MSM, the majority (60%) were 25+ years of age. Most of the substance use behaviors, were not significantly associated with PrEP initiation or adherence. However, stimulant use before/during CAI was significantly associated with lower odds of PrEP adherence (Adjusted odds ratio=0.21, 95% confidence interval=0.07, 0.61; p=<0.01).

CONCLUSIONS: These findings suggest that PrEP adherence is feasible among Black MSM who use substances. However, Black MSM who engage in stimulant use before/during CAI may present a unique group for additional study and support with enhanced behavioral health and support services.

RevDate: 2020-05-25

Hohl SD, Shankaran V, Bell-Brown A, et al (2020)

Text Message Preferences for Surveillance Colonoscopy Reminders Among Colorectal Cancer Survivors.

Health education & behavior : the official publication of the Society for Public Health Education [Epub ahead of print].

Background. Surveillance colonoscopy 1-year after colorectal cancer (CRC) surgery effectively reduces CRC mortality, yet less than half of survivors undergo this procedure. Text message reminders can improve CRC screening and other health behaviors, but use of this strategy to address barriers to CRC surveillance has not been reported. Objectives. The goal of this qualitative study was to assess CRC survivor perspectives on barriers to colonoscopy to inform the design of a theory-based, short message service (SMS) intervention to increase surveillance colonoscopy utilization. Method. CRC survivors in Western Washington participated in one of two focus groups to explore perceived barriers to completing surveillance colonoscopy and preferences for SMS communication. Content analysis using codes representative of the health belief model and prospect theory constructs were applied to qualitative data. Results. Thirteen CRC survivors reported individual-, interpersonal-, and system-level barriers to surveillance colonoscopy completion. Participants were receptive to receiving SMS reminders to mitigate these barriers. They suggested that reminders offer supportive, loss-framed messaging; include educational content; and be personalized to communication preferences. Finally, they recommended that reminders begin no earlier than 9 months following CRC surgery and not include response prompts. Conclusions. Our study demonstrates that CRC survivors perceive SMS reminders as an acceptable, valuable tool for CRC surveillance. Furthermore, there may be value in integrating theoretical frameworks to design, implement, and evaluate SMS interventions to address barriers to CRC surveillance. As physicians play a key role in CRC surveillance, provider- and system-level interventions that could additively improve the impact of SMS interventions are also worth exploring.

RevDate: 2020-05-24

Panattoni L, Phelps CE, Lieu TA, et al (2020)

Feasibility of Measuring Preferences for Chemotherapy Among Early-Stage Breast Cancer Survivors Using a Direct Rank Ordering Multicriteria Decision Analysis Versus a Time Trade-Off.

The patient pii:10.1007/s40271-020-00423-w [Epub ahead of print].

OBJECTIVES: Chemotherapy is increasingly a preference-based choice among women diagnosed with early-stage breast cancer. Multicriteria decision analysis (MCDA) is a promising but underutilized method to facilitate shared decision making. We explored the feasibility of conducting an MCDA using direct rank ordering versus a time trade-off (TTO) to assess chemotherapy choice in a large population-based sample.

METHODS: We surveyed 904 early-stage breast cancer survivors who were within 5 years of diagnosis and reported to the Western Washington State Cancer System and Kaiser Permanente Northern California registries. Direct rank ordering of 11 criteria and TTO surveys were conducted from September 2015 to July 2016; clinical data were obtained from registries or medical records. Multivariable regressions estimated post hoc associations between the MCDA, TTO, and self-reported chemotherapy receipt, considering covariates.

RESULTS: Survivors ranged in age from 25 to 74 years and 73.9% had stage I tumors. The response rate for the rank ordering was 81.0%; TTO score was 94.2%. A one-standard deviation increase in the difference between the chemotherapy and no chemotherapy MCDA scores was associated with a 75.1% (95% confidence interval 43.9-109.7%; p < 0.001) increase in the adjusted odds of having received chemotherapy; no association was found between the TTO score and chemotherapy receipt.

CONCLUSIONS: A rank-order-based MCDA was feasible and was associated with chemotherapy choice. Future research should consider developing and testing this MCDA for use in clinical encounters. Additional research is required to develop a TTO-based model and test its properties against a pragmatic MCDA to inform future shared decision-making tools.

RevDate: 2020-05-23

Buckner FS, McCulloch DJ, Atluri V, et al (2020)

Clinical Features and Outcomes of 105 Hospitalized patients with COVID-19 in Seattle, Washington.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5842263 [Epub ahead of print].

BACKGROUND: Washington State served as the initial epicenter of the SARS-CoV-2 pandemic in the United States. An understanding of the risk factors and clinical outcomes of hospitalized patients with COVID-19 may provide guidance for management.

METHODS: All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, WA between March 2 and March 26, 2020 were included. We evaluated individuals with and without severe disease, defined as admission to the intensive care unit or death.

RESULTS: One-hundred-five COVID-19 patients were hospitalized. Thirty-five percent were admitted from a senior home or skilled nursing facility. The median age was 69 years and half were women.Three or more comorbidities were present in 55% of patients, with hypertension (59%), obesity (47%), cardiovascular disease (38%) and diabetes (33%) being the most prevalent. Most (63%) had symptoms for 5 days or longer prior to admission. Only 39% had fever in the first 24 hours, whereas 41% had hypoxia at admission. Seventy-three percent of patients had lymphopenia. Of 50 samples available for additional testing, no viral coinfections were identified. Severe disease occurred in 49%. Eighteen percent of patients were placed on mechanical ventilation and the overall mortality rate was 33%.

CONCLUSIONS: During the early days of the COVID-19 epidemic in Washington State, the disease had its greatest impact on elderly patients with medical comorbidities. We observed high rates of severe disease and mortality in our hospitalized patients.

RevDate: 2020-05-23

Hung KF, Sidorova JM, Nghiem P, et al (2020)

The 6-4 photoproduct is the trigger of UV-induced replication blockage and ATR activation.

Proceedings of the National Academy of Sciences of the United States of America pii:1917196117 [Epub ahead of print].

The most prevalent human carcinogen is sunlight-associated ultraviolet (UV), a physiologic dose of which generates thousands of DNA lesions per cell, mostly of two types: cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). It has not been possible, in living cells, to precisely characterize the respective contributions of these two lesion types to the signals that regulate cell cycle progression, DNA replication, and cell survival. Here we coupled multiparameter flow cytometry with lesion-specific photolyases that eliminate either CPDs or 6-4PPs and determined their respective contributions to DNA damage responses. Strikingly, only 6-4PP lesions activated the ATR-Chk1 DNA damage response pathway. Mechanistically, 6-4PPs, but not CPDs, impeded DNA replication across the genome as revealed by microfluidic-assisted replication track analysis. Furthermore, single-stranded DNA accumulated preferentially at 6-4PPs during DNA replication, indicating selective and prolonged replication blockage at 6-4PPs. These findings suggest that 6-4PPs, although eightfold fewer in number than CPDs, are the trigger for UV-induced DNA damage responses.

RevDate: 2020-05-23

Cheong M, Gartlan KH, Lee JS, et al (2020)

ASC modulates CTL cytotoxicity and transplant outcome independent of the inflammasome.

Cancer immunology research pii:2326-6066.CIR-19-0653 [Epub ahead of print].

The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1β and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome-independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.

RevDate: 2020-05-22

Perchetti GA, Nalla AK, Huang ML, et al (2020)

Validation of SARS-CoV-2 detection across multiple specimen types.

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 128:104438 pii:S1386-6532(20)30180-3 [Epub ahead of print].

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused considerable disruption across the world, resulting in more than 235,000 deaths since December 2019. SARS-CoV-2 has a wide tropism and detection of the virus has been described in multiple specimen types, including various respiratory secretions, cerebrospinal fluid, and stool.

OBJECTIVE: To evaluate the accuracy and sensitivity of a laboratory modified CDCbased SARS-CoV-2 N1 and N2 assay across a range of sample types. Study Design We compared the matrix effect on the analytical sensitivity of SARS-CoV-2 detection by qRT-PCR in nasal swabs collected in viral transport medium (VTM), bronchoalveolar lavage (BAL), sputum, plasma, cerebral spinal fluid (CSF), stool, VTM, phosphate buffered saline (PBS), and Hanks' Balanced Salt Solution (HBSS). Initial limits of detection (LoD) were subsequently narrowed to confirm an LoD for each specimen type and target gene.

RESULTS: LoDs were established using a modified CDC-based laboratory developed test and ranged from a mean CT cut-off of 33.8-35.7 (10-20 copies/reaction) for the N1 gene target, and 34.0-36.2 (1-10 copies/reaction) for N2. Alternatives to VTM such as PBS and HBSS had comparable LoDs. The N2 gene target was found to be most sensitive in CSF.

CONCLUSION: A modified CDC-based laboratory developed test is able to detect SARSCoV- 2 accurately with similar sensitivity across all sample types tested.

RevDate: 2020-05-22

Moodie Z, Walsh SR, Laher F, et al (2020)

Antibody and cellular responses to HIV vaccine regimens with DNA plasmid as compared with ALVAC priming: An analysis of two randomized controlled trials.

PLoS medicine, 17(5):e1003117 pii:PMEDICINE-D-19-04284.

BACKGROUND: DNA plasmids promise a pragmatic alternative to viral vectors for prime-boost HIV-1 vaccines. We evaluated DNA plasmid versus canarypox virus (ALVAC) primes in 2 randomized, double-blind, placebo-controlled trials in southern Africa with harmonized trial designs. HIV Vaccine Trials Network (HVTN) 111 tested DNA plasmid prime by needle or needleless injection device (Biojector) and DNA plasmid plus gp120 protein plus MF59 adjuvant boost. HVTN 100 tested ALVAC prime and ALVAC plus gp120 protein plus MF59 adjuvant boost (same protein/adjuvant as HVTN 111) by needle.

METHODS AND FINDINGS: The primary endpoints for this analysis were binding antibody (bAb) responses to HIV antigens (gp120 from strains ZM96, 1086, and TV1; variable 1 and 2 [V1V2] regions of gp120 from strains TV1, 1086, and B.CaseA, as 1086 V1V2 and B.CaseA were correlates of risk in the RV144 efficacy trial), neutralizing antibody (nAb) responses to pseudoviruses TV1c8.2 and MW925.26, and cellular responses to vaccine-matched antigens (envelope [Env] from strains ZM96, 1086, and TV1; and Gag from strains LAI and ZM96) at month 6.5, two weeks after the fourth vaccination. Per-protocol cohorts included vaccine recipients from HVTN 100 (n = 186, 60% male, median age 23 years) enrolled between February 9, 2015, and May 26, 2015 and from HVTN 111 (n = 56, 48% male, median age 24 years) enrolled between June 21, 2016, and July 13, 2017. IgG bAb response rates were 100% to 3 Env gp120 antigens in both trials. Response rates to V1V2 were lower and similar in both trials except to vaccine-matched 1086 V1V2, with rates significantly higher for the DNA-primed regimen than the ALVAC-primed regimen: 96.6% versus 72.7% (difference = 23.9%, 95% CI 15.6%-32.2%, p < 0.001). Among positive responders, bAb net mean fluorescence intensity (MFI) was significantly higher with the DNA-primed regimen than ALVAC-primed for 1086 V1V2 (geometric mean [GM] 2,833.3 versus 1,200.9; ratio = 2.36, 95% CI 1.42-3.92, p < 0.001) and B.CaseA V1V2 (GM 2314.0 versus 744.6, ratio = 3.11, 95% CI 1.51-6.38, p = 0.002). nAb response rates were >98% in both trials, with significantly higher 50% inhibitory dilution (ID50) among DNA-primed positive responders (n = 53) versus ALVAC-primed (n = 182) to tier 1A MW965.26 (GM 577.7 versus 265.7, ratio = 2.17, 95% CI 1.67-2.83, p < 0.001) and to TV1c8.2 (GM 187.3 versus 100.4, ratio = 1.87, 95% CI 1.48-2.35, p < 0.001). CD4+ T-cell response rates were significantly higher with DNA plasmid prime via Biojector than ALVAC prime (91.4% versus 52.8%, difference = 38.6%, 95% CI 20.5%-56.6%, p < 0.001 for ZM96.C; 88.0% versus 43.1%, difference = 44.9%, 95% CI 26.7%-63.1%, p < 0.001 for 1086.C; 55.5% versus 2.2%, difference = 53.3%, 95% CI 23.9%-82.7%, p < 0.001 for Gag LAI/ZM96). The study's main limitations include the nonrandomized comparison of vaccines from 2 different trials, the lack of data on immune responses to other non-vaccine-matched antigens, and the uncertain clinical significance of the observed immunological effects.

CONCLUSIONS: In this study, we found that further investigation of DNA/protein regimens is warranted given enhanced immunogenicity to the V1V2 correlates of decreased HIV-1 acquisition risk identified in RV144, the only HIV vaccine trial to date to show any efficacy.

RevDate: 2020-05-22

Ntalla I, Weng LC, Cartwright JH, et al (2020)

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nature communications, 11(1):2542 pii:10.1038/s41467-020-15706-x.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

RevDate: 2020-05-22

Zhu J, Shu X, Guo X, et al (2020)

Associations between genetically predicted blood protein biomarkers 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-20-0091 [Epub ahead of print].

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments.

METHODS: To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci (pQTL).

RESULTS: We observed associations between predicted concentrations of 38 proteins and PDAC risk at a false discovery rate of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (odds ratio ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL-15 production.

CONCLUSIONS: We identified 38 candidates of protein biomarkers for PDAC risk.

IMPACT: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiological understanding of PDAC development.

RevDate: 2020-05-22

Diab A, Tannir NM, Bentebibel SE, et al (2020)

Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02).

Cancer discovery pii:2159-8290.CD-19-1510 [Epub ahead of print].

This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempeg-a-ldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.

RevDate: 2020-05-21

D'Souza A, Fretham C, Lee SJ, et al (2020)

Current Use and Trends in Hematopoietic Cell Transplantation in the United States.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30225-1 [Epub ahead of print].

Hematopoietic cell transplantation (HCT) is a well-established treatment to control and/or cure many malignant and non-malignant diseases involving the hematopoietic system and some solid tumors. We report information about HCT procedures performed in the United States (US) in 2018 and analyze trends and outcomes of HCT as reported to the Center for International Blood and Marrow Transplant Research® (CIBMTR®). Overall, compared to 2017, the numbers of allogeneic transplant in the US increased by 1% and numbers of autologous transplants decreased by 5%. Key findings are fewer autologous transplants performed for non-Hodgkin lymphoma and increasing numbers of haploidentical transplants, nearly all of which use post-transplant cyclophosphamide for graft-versus-host disease prophylaxis. There is a continuing increase in transplantations in adults older than 70 years, particularly for acute myeloid leukemia and myelodysplastic syndromes. Survival rates by disease, disease stage, donor type and age are presented. This report, prepared annually by the CIBMTR, provides a snapshot of current transplant activity in the US.

RevDate: 2020-05-21

Jackson SS, Adami HO, Andreotti G, et al (2020)

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

Journal of hepatology pii:S0168-8278(20)30292-0 [Epub ahead of print].

BACKGROUND: Gallbladder cancer (GBC) has a female predominance, although other biliary tract cancers (BTCs) such as extrahepatic and intrahepatic bile duct (EHBDC and IHBDC) and ampulla of Vater (AVC) have a male predominance. The role of female reproductive factors in BTC etiology remains unclear.

METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

RESULTS: During 21,681,798 person-years of follow-up, 875 GBC, 379 IHBDC, 450 EHBDC, and 261 AVC cases occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births: 1.72, 95% CI: 1.25, 2.38). Age at menarche (HR per year increase: 1.15, 95% CI: 1.06, 1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years: 1.13, 95% CI: 1.04, 1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR: 1.19, 95% CI: 1.09, 1.31) and EHBDC HR: 1.11, 95% CI: 1.01, 1.22) in Asian women only.

CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest sex hormones may have distinct effects on cancers across the biliary tract and vary by geography.

RevDate: 2020-05-21

Roxby AC, Greninger AL, Hatfield KM, et al (2020)

Outbreak Investigation of COVID-19 Among Residents and Staff of an Independent and Assisted Living Community for Older Adults in Seattle, Washington.

JAMA internal medicine pii:2766448 [Epub ahead of print].

Importance: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused epidemic spread of coronavirus disease 2019 (COVID-19) in the Seattle, Washington, metropolitan area, with morbidity and mortality concentrated among residents of skilled nursing facilities. The prevalence of COVID-19 among older adults in independent/assisted living is not understood.

Objectives: To conduct surveillance for SARS-CoV-2 and describe symptoms of COVID-19 among residents and staff of an independent/assisted living community.

In March 2020, public health surveillance of staff and residents was conducted on site at an assisted and independent living residence for older adults in Seattle, Washington, after exposure to 2 residents who were hospitalized with COVID-19.

Exposures: Surveillance for SARS-CoV-2 infection in a congregate setting implementing social isolation and infection prevention protocols.

Main Outcomes and Measures: SARS-CoV-2 real-time polymerase chain reaction was performed on nasopharyngeal swabs from residents and staff; a symptom questionnaire was completed assessing fever, cough, and other symptoms for the preceding 14 days. Residents were retested for SARS-CoV-2 7 days after initial screening.

Results: Testing was performed on 80 residents; 62 were women (77%), with mean age of 86 (range, 69-102) years. SARS-CoV-2 was detected in 3 of 80 residents (3.8%); none felt ill, 1 male resident reported resolved cough and 1 loose stool during the preceding 14 days. Virus was also detected in 2 of 62 staff (3.2%); both were symptomatic. One week later, resident SARS-CoV-2 testing was repeated and 1 new infection detected (asymptomatic). All residents remained in isolation and were clinically stable 14 days after the second test.

Conclusions and Relevance: Detection of SARS-CoV-2 in asymptomatic residents highlights challenges in protecting older adults living in congregate settings. In this study, symptom screening failed to identify residents with infections and all 4 residents with SARS-CoV-2 remained asymptomatic after 14 days. Although 1 asymptomatic infection was found on retesting, a widespread facility outbreak was avoided. Compared with skilled nursing settings, in assisted/independent living communities, early surveillance to identify asymptomatic persons among residents and staff, in combination with adherence to recommended preventive strategies, may reduce viral spread.

RevDate: 2020-05-21

DeRosa S, Edupuganti S, Huang Y, et al (2020)

Robust antibody and cellular responses induced by DNA-only vaccination for HIV.

JCI insight pii:137079 [Epub ahead of print].

BACKGROUND: HVTN 098, a randomized, double-blind, placebo-controlled trial, evaluated the safety, tolerability and immunogenicity of PENNVAX®-GP HIV DNA vaccine, administered with or without plasmid IL-12 (pIL-12), via intradermal (ID) or intramuscular (IM) electroporation (EP) in healthy, HIV-uninfected adults. The study tested whether PENNVAX®-GP delivered via ID/EP at 1/5th the dose could elicit equivalent immune responses to delivery via IM/EP, and if inclusion of pIL-12 provided additional benefit.

METHODS: Participants received DNA encoding HIV-1 env/gag/pol in three groups: 1.6mg ID (ID no IL-12 group, n=20), 1.6mg ID + 0.4mg pIL-12 (ID+IL-12 group, n=30), 8mg IM + 1mg pIL-12 (IM+IL-12 group, n=30) or placebo (n=9) via EP at 0, 1, 3 and 6 months. Results of cellular and humoral immunogencity assessments are reported.

RESULTS: Following vaccination, the frequency of responders (response rate) to any HIV protein based on CD4+ T-cells expressing IFN-γ and/or IL-2 was 96% for both the ID+IL-12 and IM+IL-12 groups; CD8+ T-cell response rates were 64% and 44%, respectively. For ID delivery, the inclusion of pIL-12 increased CD4+ T-cell response rate from 56% to 96%. The frequency of responders was similar (>90%) for IgG binding Ab to gp140 consensus Env across all groups, but the magnitude was higher in the ID+IL-12 group compared to the IM+IL-12 group.

CONCLUSION: PENNVAX®-GP DNA induced robust cellular and humoral immune responses, demonstrating that immunogenicity of DNA vaccines can be enhanced by EP route and inclusion of pIL-12. ID/EP was dose-sparing, inducing equivalent, or in some aspects superior, immune responses compared to IM/EP.

TRIAL REGISTRATION: ClinicalTrials.gov NCT02431767Funding: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID, https://www.niaid.nih.gov/) U.S. Public Health Service Grants UM1 AI068618 [LC: HIV 75 Vaccine Trials Network], UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068635 76 [SDMC: HIV Vaccine Trials Network], , U01 AI069418-ˇ08 [Emory-ˇCDC Clinical Trials Unit], UM AI069511 [University of Rochester HIV/AIDS Clinical Trials Unit], UM1 AI069439 77 [Vanderbilt Clinical Trial Unit], UM1 AI069481 [Seattle-ˇLausanne Clinical Trials Unit] and HVDDT Contract HHSN2722008000063C (Inovio Pharmaceuticals). This work was also supported, in part, by IPCAVD award U19 AI09646-ˇ03 (DBW) and NIH award P01 AI120756 (GDT). The opinions expressed in this article are those of the authors and do not necessarily represent the official views of the NIAID or the National Institutes of Health (NIH).

RevDate: 2020-05-21

Lofterød T, Frydenberg H, Flote V, et al (2020)

Exploring the effects of lifestyle on breast cancer risk, age at diagnosis, and survival: the EBBA-Life study.

Breast cancer research and treatment pii:10.1007/s10549-020-05679-2 [Epub ahead of print].

PURPOSE: Whether an unfavorable lifestyle not only affects breast cancer risk, but also influences age at onset of breast cancer and survival, is under debate.

METHODS: In a population-based cohort, the Energy Balance and Breast Cancer Aspects throughout life (EBBA-Life) study, a total of 17,145 women were included. During follow-up, 574 women developed invasive breast cancer. Breast cancer cases were followed for an additional 9.1 years. Detailed medical records were obtained. Cox's proportional hazard regression models were used to study the association between pre-diagnostic lifestyle factors (weight, physical activity, alcohol use, smoking, and hypertension), breast cancer risk, age at diagnosis, and survival.

RESULTS: At study entry, 34.3% of the participating women were overweight and 30.7% were physically inactive. Mean age at breast cancer diagnosis was 58.0 years, and 78.9% of the tumors were estrogen receptor positive. Among menopausal women who did not use hormone therapy and had an unfavorable lifestyle (3-5 unfavorable factors), compared with women who had a favorable lifestyle, we observed a twofold higher risk for postmenopausal breast cancer (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.23-3.69), and they were 3.4 years younger at diagnosis (64.8 versus 68.2 years, P = 0.032). Breast cancer patients with an unfavorable lifestyle, compared with patients with a favorable lifestyle, had almost a two times higher overall mortality risk (HR 1.96, 95% CI 1.01-3.80).

CONCLUSIONS: Our study supports a healthy lifestyle improving breast cancer prevention, postponing onset of disease, and extending life expectancy among breast cancer patients.

RevDate: 2020-05-21

Kessler RC, Bauer MS, Bishop TM, et al (2020)

Using Administrative Data to Predict Suicide After Psychiatric Hospitalization in the Veterans Health Administration System.

Frontiers in psychiatry, 11:390.

There is a very high suicide rate in the year after psychiatric hospital discharge. Intensive postdischarge case management programs can address this problem but are not cost-effective for all patients. This issue can be addressed by developing a risk model to predict which inpatients might need such a program. We developed such a model for the 391,018 short-term psychiatric hospital admissions of US veterans in Veterans Health Administration (VHA) hospitals 2010-2013. Records were linked with the National Death Index to determine suicide within 12 months of hospital discharge (n=771). The Super Learner ensemble machine learning method was used to predict these suicides for time horizon between 1 week and 12 months after discharge in a 70% training sample. Accuracy was validated in the remaining 30% holdout sample. Predictors included VHA administrative variables and small area geocode data linked to patient home addresses. The models had AUC=.79-.82 for time horizons between 1 week and 6 months and AUC=.74 for 12 months. An analysis of operating characteristics showed that 22.4%-32.2% of patients who died by suicide would have been reached if intensive case management was provided to the 5% of patients with highest predicted suicide risk. Positive predictive value (PPV) at this higher threshold ranged from 1.2% over 12 months to 3.8% per case manager year over 1 week. Focusing on the low end of the risk spectrum, the 40% of patients classified as having lowest risk account for 0%-9.7% of suicides across time horizons. Variable importance analysis shows that 51.1% of model performance is due to psychopathological risk factors accounted, 26.2% to social determinants of health, 14.8% to prior history of suicidal behaviors, and 6.6% to physical disorders. The paper closes with a discussion of next steps in refining the model and prospects for developing a parallel precision treatment model.

RevDate: 2020-05-20

Vijay S, TS Gujral (2020)

Non-linear Deep Neural Network for Rapid and Accurate Prediction of Phenotypic Responses to Kinase Inhibitors.

iScience, 23(5):101129 pii:S2589-0042(20)30314-X [Epub ahead of print].

Protein kinase inhibitors are one of the most successful targeted therapies to date. Despite this progress, additional kinase inhibitors are needed to expand the target space as well as overcome drug resistance that has emerged in clinical setting. Here, we developed KiDNN (Kinase inhibitor prediction using Deep Neural Networks). KiDNN utilizes non-linear, multilayer feedforward network that mimics complex and dynamic kinase-driven signaling pathways. We used KiDNN to predict the effect of ∼200 kinase inhibitors on migration of breast and liver cancer cells. We show that the prediction accuracy of KiDNN outperformed other prediction tools based on linear models. We validated that an inhibitor of tyrosine kinase receptors, and an inhibitor of Src family kinases, decreased migration of triple-negative breast cancer cells, consistent with the role of these kinases in driving motility. Overall, we show that non-linear, DNN-based models provide a powerful approach to in silico screen hundreds of kinase inhibitors.

RevDate: 2020-05-20

Myers SP, Dasari M, Brown JB, et al (2020)

Effects of Gender Bias and Stereotypes in Surgical Training: A Randomized Clinical Trial.

JAMA surgery pii:2765984 [Epub ahead of print].

Importance: Factors contributing to underrepresentation of women in surgery are incompletely understood. Pro-male bias and stereotype threat appear to contribute to gender imbalance in surgery.

Objectives: To evaluate the association between pro-male gender bias and career engagement and the effect of stereotype threat on skill performance among trainees in academic surgery.

A 2-phase study with a double-blind, randomized clinical trial component was conducted in 3 academic general surgery training programs. Residents were recruited between August 1 and August 15, 2018, and the study was completed at the end of that academic year. In phase 1, surveys administered 5 to 6 months apart investigated the association of gender bias with career engagement. In phase 2, residents were randomized 1:1 using permuted-block design stratified by site, training level, and gender to receive either a trigger of or protection against stereotype threat. Immediately after the interventions, residents completed the Fundamentals of Laparoscopic Surgery (FLS) assessment followed by a final survey. A total of 131 general surgery residents were recruited; of these 96 individuals with academic career interests met eligibility criteria; 86 residents completed phase 1. Eighty-five residents were randomized in phase 2, and 4 residents in each arm were lost to follow-up.

Intervention: Residents read abstracts that either reported that women had worse laparoscopic skill performance than men (trigger of stereotype threat [A]) or had no difference in performance (protection against stereotype threat [B]).

Main Outcomes and Measures: Association between perception of pro-male gender bias and career engagement survey scores (phase 1) and stereotype threat intervention and FLS scores (phase 2) were the outcomes. Intention-to-treat analysis was conducted.

Results: Seventy-seven residents (38 women [49.4%]) completed both phases of the study. The association between pro-male gender bias and career engagement differed by gender (interaction coefficient, -1.19; 95% CI, -1.90 to -0.49; P = .02); higher perception of bias was associated with higher engagement among men (coefficient, 1.02; 95% CI, 0.19-2.24; P = .04), but no significant association was observed among women (coefficient, -0.25; 95% CI, -1.59 to 1.08; P = .50). There was no evidence of a difference in FLS score between interventions (mean [SD], A: 395 [150] vs B: 367 [157]; P = .51). The response to stereotype threat activation was similar in men and women (interaction coefficient, 15.1; 95% CI, -124.5 to 154.7; P = .39). The association between stereotype threat activation and FLS score differed by gender across levels of susceptibility to stereotype threat (interaction coefficient, -35.3; 95% CI, -47.0 to -23.6; P = .006). Higher susceptibility to stereotype threat was associated with lower FLS scores among women who received a stereotype threat trigger (coefficient, -43.4; 95% CI, -48.0 to -38.9; P = .001).

Conclusions and Relevance: Perception of pro-male bias and gender stereotypes may influence career engagement and skill performance, respectively, among surgical trainees.

Trial Registration: ClinicalTrials.gov Identifier: NCT03623009.

RevDate: 2020-05-20

Vora SB, Waghmare A, Englund JA, et al (2020)

Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults.

Open forum infectious diseases, 7(5):ofaa121 pii:ofaa121.

Background: Infectious complications of chimeric antigen receptor (CAR) T-cell immunotherapy in children and young adults have not been well described.

Methods: Medical records of patients ≤26 years old receiving CD19 CAR T-cell infusion (CTI) at a single institution between 2014 and 2017 were reviewed. The number of infections per 100 days-at-risk (infection density) in the 90 days preceding and 0-28 and 29-90 days after CTI was calculated. Poisson regression and Cox analyses were utilized to identify risk factors for infections.

Results: Eighty-three patients received CTI during the study period. Most patients (98%) had refractory or relapsed acute lymphoblastic leukemia (ALL). Infections occurred in 54% of patients in the 90 days before CTI (infection density, 1.23) and in 40% of patients in the first 28 days following CTI (infection density, 2.89). Infection density decreased to 0.55 in the 29-90 days post-CTI. Most infections were bacteremias (39%) or respiratory viral infections (43%). Pre-CTI risk factors associated with infection included prior hematopoietic cell transplantation (HCT), immunoglobulin G (IgG) level <400 mg/dL, and lymphodepletion other than cyclophosphamide plus fludarabine; post-CTI risk factors included higher-severity CRS and IgG <400 mg/dL.

Conclusions: Infection rates in children and young adults receiving CD19 CAR T-cell therapy increase in the first month and then decline. Understanding types and timing of infections and contributing risk factors may help inform prophylactic and monitoring strategies. Specific attention should be given to patients with prior HCT, severe hypogammaglobulinemia, and severe CRS.

RevDate: 2020-05-19

Nyame YA (2020)

Editorial Comment.

The Journal of urology [Epub ahead of print].

RevDate: 2020-05-19

Zomerdijk N, Turner J, Hill GR, et al (2020)

Experiences and unmet needs of family members requested to donate haematopoietic stem cells to an ill relative: findings from a prospective multi-centre study.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer pii:10.1007/s00520-020-05520-y [Epub ahead of print].

BACKGROUND: Despite well-documented physical effects of haematopoietic stem cell (HSC) donation, far less attention has been focused on the psychosocial impact for family donors. This study aimed to better understand the psychosocial aspects of HSC donation by family members, focusing, in particular on their needs for information and supportive care.

METHODS: Thirty-one adult HSC family donors from two clinical hospitals were interviewed before, during and 1 month after HSC donation. Interviews explored ambivalence, motivation, perceived pressure, preparedness, the donor-recipient relationship, information and support received and suggestions for improvement.

RESULTS: Three main themes about the donation experience were identified: 'call to arms' (focused on the recipient, stressful urgency, making meaning of being a donor, decisional ambivalence), 'proceeding with donation' (living in limbo, unsettling uncertainty, pervasive pain, feeling supported) and 'after the dust settles' (feeling discarded, downplaying role, residual symptoms, dealing with adverse recipient outcomes). Underlying system and communication issues included time for consideration prior to donor work-up, management of confidentiality, information inadequacy and access to support. Donors wanted information about the emotional challenges specific to being a family donor, such as ways in which previous donors coped with recipient death. For donors whose recipient had died, the priority for improved care was follow-up support.

CONCLUSION: Our findings emphasise a gap in information and supportive care for family donors and the need for a protocol specifically designed to inform and support family donors before, during and after HSC donation.

RevDate: 2020-05-19

Zhang H, Ahearn TU, Lecarpentier J, et al (2020)

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nature genetics pii:10.1038/s41588-020-0609-2 [Epub ahead of print].

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

RevDate: 2020-05-19

Garancher A, Suzuki H, Haricharan S, et al (2020)

Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma.

Nature neuroscience pii:10.1038/s41593-020-0628-4 [Epub ahead of print].

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.

RevDate: 2020-05-18

Dieffenbach BV, Li N, Madenci AL, et al (2020)

Incidence of and risk factors for late cholecystectomy in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.

European journal of cancer (Oxford, England : 1990), 133:4-13 pii:S0959-8049(20)30145-3 [Epub ahead of print].

BACKGROUND: Gallbladder disease and need for cholecystectomy are common and significant contributors to patient morbidity and healthcare costs. Childhood cancer survivors are at elevated risk for developing cholelithiasis. However, their incidence of and risk factors for late (>5 years from diagnosis) cholecystectomy have not been studied.

METHODS: A total of 25,549 survivors (median age at diagnosis 6.9 years, range 0-21.0; current age 30.7 years, range 5.6-65.9) diagnosed between 1970 and 1999 and 5037 siblings were queried for self-reported cholecystectomy occurring five or more years from primary cancer diagnosis. Piecewise exponential models evaluated associations between cancer treatment exposures and late cholecystectomy.

RESULTS: Over a median follow-up period of 21.9 and 26.0 years, respectively, 789 survivors and 168 siblings underwent late cholecystectomy (cumulative incidence 7.2%, 95% confidence interval [CI] = 6.5-7.8% and 6.6%, 95% CI = 5.4-7.6%, respectively; rate ratio [RR] = 1.3, 95% CI = 1.1-1.5). Compared with siblings, survivors of acute lymphoblastic leukaemia (RR = 1.4, 95% CI = 1.2-1.8), soft tissue sarcoma (RR = 1.4, 95% CI = 1.0-1.8) and bone cancer (RR = 1.3, 95% CI = 1.0-1.8) were at the greatest risk. In addition to attained age, female sex and increasing body mass index, exposure to high-dose (≥750 mg/m2) platinum chemotherapy (RR = 2.6, 95% CI = 1.5-4.5), vinca alkaloid chemotherapy (RR = 1.4, 95% CI = 1.1-1.8) or total body irradiation (TBI; RR = 2.2, 95% CI = 1.2-4.2) were each associated with late cholecystectomy.

CONCLUSIONS: Independent of traditional risk factors for gallbladder disease, exposure to high-dose platinum chemotherapy, vinca alkaloid chemotherapy or TBI increased risk for late cholecystectomy. These findings should inform current long-term follow-up guidelines and education regarding risk for late cholecystectomy.

RevDate: 2020-05-18

Huang Y, Zhang Y, Zhang Z, et al (2020)

Generating Survival Times Using Cox Proportional Hazards Models with Cyclic and Piecewise Time-Varying Covariates.

Statistics in biosciences pii:9266 [Epub ahead of print].

Time-to-event outcomes with cyclic time-varying covariates are frequently encountered in biomedical studies that involve multiple or repeated administrations of an intervention. In this paper, we propose approaches to generating event times for Cox proportional hazards models with both time-invariant covariates and a continuous cyclic and piecewise time-varying covariate. Values of the latter covariate change over time through cycles of interventions and its relationship with hazard differs before and after a threshold within each cycle. The simulations of data are based on inverting the cumulative hazard function and a log link function for relating the hazard function to the covariates. We consider closed-form derivations with the baseline hazard following the exponential, Weibull, or Gompertz distribution. We propose two simulation approaches: one based on simulating survival data under a single-dose regimen first before data are aggregated over multiple-dosing cycles and another based on simulating survival data directly under a multiple-dose regimen. We consider both fixed intervals and varying intervals of the drug administration schedule. The method's validity is assessed in simulation experiments. The results indicate that the proposed procedures perform well in generating data that conform to their cyclic nature and assumptions of the Cox proportional hazards model.

RevDate: 2020-05-19

Nishida-Aoki N, Bondesson AJ, TS Gujral (2020)

Measuring Real-time Drug Response in Organotypic Tumor Tissue Slices.

Journal of visualized experiments : JoVE.

Tumor tissues are composed of cancerous cells, infiltrated immune cells, endothelial cells, fibroblasts, and extracellular matrix. This complex milieu constitutes the tumor microenvironment (TME) and can modulate response to therapy in vivo or drug response ex vivo. Conventional cancer drug discovery screens are carried out on cells cultured in a monolayer, a system critically lacking the influence of TME. Thus, experimental systems that integrate sensitive and high-throughput assays with physiological TME will strengthen the preclinical drug discovery process. Here, we introduce ex vivo tumor tissue slice culture as a platform for medium-high-throughput drug screening. Organotypic tissue slice culture constitutes precisely-cut, thin tumor sections that are maintained with the support of a porous membrane in a liquid-air interface. In this protocol, we describe the preparation and maintenance of tissue slices prepared from mouse tumors and tumors from patient-derived xenograft (PDX) models. To assess changes in tissue viability in response to drug treatment, we leveraged a biocompatible luminescence-based viability assay that enables real-time, rapid, and sensitive measurement of viable cells in the tissue. Using this platform, we evaluated dose-dependent responses of tissue slices to the multi-kinase inhibitor, staurosporine, and cytotoxic agent, doxorubicin. Further, we demonstrate the application of tissue slices for ex vivo pharmacology by screening 17 clinical and preclinical drugs on tissue slices prepared from a single PDX tumor. Our physiologically-relevant, highly-sensitive, and robust ex vivo screening platform will greatly strengthen preclinical oncology drug discovery and treatment decision making.

RevDate: 2020-05-18

Kidd S, Christiansen K, Coumar A, et al (2020)

A Dedicated Education Unit and a Novel Resident Nurse Transition-to-Practice Program in an Ambulatory Oncology Setting.

Seminars in oncology nursing pii:S0749-2081(20)30042-5 [Epub ahead of print].

OBJECTIVE: To summarize an innovative initiative in oncology nurse workforce development that addresses critical current and future gaps and encompasses use of dedicated education units for student nurse rotation and a transition-to-practice residency program.

DATA SOURCES: Review of institutional data including original pilot analysis and ongoing programmatic metrics (N=8 years), consensus, professional guidelines, and published literature.

CONCLUSION: The dedicated education unit serves as a conduit for recruitment into institutional oncology nurse residency positions, and retention rates in the residency program continue to exceed national averages. Subsequent mentoring of these nurses in transition to practice has manifested high rates of promotion into nurse leadership roles year over year.

Oncology nurse practice incorporates state-of-the-science approved therapies, early phase clinical trial implementation, and evidence-based complex oncology patient care management. A new model of student clinical nurse rotations in ambulatory settings, nurse resident transition to practice, and ongoing leadership mentoring is essential in creating a sustainable, highly skilled, and robust oncology nurse work force.

RevDate: 2020-05-18

Carone M, Luedtke AR, MJ van der Laan (2019)

Toward computerized efficient estimation in infinite-dimensional models.

Journal of the American Statistical Association, 114(527):1174-1190.

Despite the risk of misspecification they are tied to, parametric models continue to be used in statistical practice because they are simple and convenient to use. In particular, efficient estimation procedures in parametric models are easy to describe and implement. Unfortunately, the same cannot be said of semiparametric and nonparametric models. While the latter often reflect the level of available scientific knowledge more appropriately, performing efficient inference in these models is generally challenging. The efficient influence function is a key analytic object from which the construction of asymptotically efficient estimators can potentially be streamlined. However, the theoretical derivation of the efficient influence function requires specialized knowledge and is often a difficult task, even for experts. In this paper, we present a novel representation of the efficient influence function and describe a numerical procedure for approximating its evaluation. The approach generalizes the nonparametric procedures of Frangakis et al. (2015) and Luedtke et al. (2015) to arbitrary models. We present theoretical results to support our proposal, and illustrate the method in the context of several semiparametric problems. The proposed approach is an important step toward automating efficient estimation in general statistical models, thereby rendering more accessible the use of realistic models in statistical analyses.

RevDate: 2020-05-16

Erijman A, Kozlowski L, Sohrabi-Jahromi S, et al (2020)

A High-Throughput Screen for Transcription Activation Domains Reveals Their Sequence Features and Permits Prediction by Deep Learning.

Molecular cell pii:S1097-2765(20)30262-8 [Epub ahead of print].

Acidic transcription activation domains (ADs) are encoded by a wide range of seemingly unrelated amino acid sequences, making it difficult to recognize features that promote their dynamic behavior, "fuzzy" interactions, and target specificity. We screened a large set of random 30-mer peptides for AD function in yeast and trained a deep neural network (ADpred) on the AD-positive and -negative sequences. ADpred identifies known acidic ADs within transcription factors and accurately predicts the consequences of mutations. Our work reveals that strong acidic ADs contain multiple clusters of hydrophobic residues near acidic side chains, explaining why ADs often have a biased amino acid composition. ADs likely use a binding mechanism similar to avidity where a minimum number of weak dynamic interactions are required between activator and target to generate biologically relevant affinity and in vivo function. This mechanism explains the basis for fuzzy binding observed between acidic ADs and targets.

RevDate: 2020-05-16

Dean NE, Halloran ME, IM Longini (Jr) (2020)

Temporal Confounding in the Test Negative Design.

American journal of epidemiology pii:5837778 [Epub ahead of print].

In the test negative design, routine testing at healthcare facilities is leveraged to estimate the effectiveness of an intervention such as a vaccine. The odds of vaccination for individuals who test positive for a target pathogen is compared to the odds of vaccination for individuals who test negative for that pathogen, adjusting for key confounders. The design is rapidly growing in popularity, but many open questions remain about its properties. In this paper, we examine temporal confounding by generalizing derivations to allow for time-varying vaccine status, including out of season controls, and open populations. We confirm that calendar time is an important confounder when vaccine status varies during the study. We demonstrate that, where time is not a confounder, including out of season controls can improve precision. We generalize these results to open populations. We use our theoretical findings to interpret three recent papers utilizing the test negative design. Through careful examination of the theoretical properties of this study design, we provide key insights that can directly inform the implementation and analysis of future test negative studies.

RevDate: 2020-05-16

Hertoghs N, Schwedhelm KV, Stuart KD, et al (2020)

OMIP-064: A 27-Color Flow Cytometry Panel to Detect and Characterize Human NK Cells and Other Innate Lymphoid Cell Subsets, MAIT Cells, and γδ T Cells.

Cytometry. Part A : the journal of the International Society for Analytical Cytology [Epub ahead of print].

This 27-color flow cytometry panel was developed in order to assess immunological changes over the course of an immunization and challenge regimen in two experimental malaria vaccine trials. The aim of the study was to find correlates of vaccine-induced protection. Several studies have indicated that protection against malaria appears to involve immune responses at various immunological sites, with liver-resident responses playing an essential role. As it is not feasible to monitor the immune responses within the liver in humans, this panel is developed with the aim to thoroughly characterize the immune responses over time in blood in addition to detecting changes that might reflect what happens in other immunological sites like the liver. The focus of this panel is to detect several innate lymphoid cell populations, including NK cells and their activation status. Moreover, unconventional T cells like mucosal associated invariant T cells and γδ T cells are assessed in the panel. © 2020 International Society for Advancement of Cytometry.

RevDate: 2020-05-16

Perchetti GA, Huang ML, Peddu V, et al (2020)

Stability of SARS-CoV-2 in PBS for Molecular Detection.

RNA viruses often require "cold-chains" of transportation to prevent the breakdown of genetic material.….

RevDate: 2020-05-16

Patel SP, Othus M, Chae YK, et al (2020)

Ipilimumab and Nivolumab in Rare Tumors S1609: Neuroendocrine-Response.

Clinical cancer research : an official journal of the American Association for Cancer Research, 26(10):2434.

RevDate: 2020-05-15

Ziegler CGK, Allon SJ, Nyquist SK, et al (2020)

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.

Cell pii:S0092-8674(20)30500-6 [Epub ahead of print].

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.

RevDate: 2020-05-15

Snoeyenbos Newman G, Bauer K, Karpenko A, et al (2020)

Evaluation of the National Sexually Transmitted Disease Curriculum: Reach, Utilization, and Engagement.

Sexually transmitted diseases, 47(6):412-418.

BACKGROUND: With increasing rates of sexually transmitted infections in the United States, there is a critical need to educate health professionals on the prevention, diagnosis, and treatment of sexually transmitted infections. The National Sexually Transmitted Disease Curriculum (NSTDC, https://www.std.uw.edu) is a free, online curriculum, funded by the Centers for Disease Control and Prevention. The purpose of this article is to evaluate the reach, utilization, and engagement of users with the curriculum.

METHODS: Data on NSTDC utilization was collected for 24 months after the February 1, 2017 launch. For all users, Google Analytics was used to determine total number of users, geographic location, age and sex, and average session duration. For registered users, additional data analysis included work-role, demographics, and completion of self-study modules, check-on-learning questions, and question banks. User satisfaction was measured on a 5-point Likert scale.

RESULTS: During the evaluation period, 136,270 individual users accessed the NSTDC, including 24,652 registered users. Among all registered users, 10,660 (43.2%) were registered nurses, 2810 (11.4%) physicians, 4942 (20.1%) Advanced Practice Nurses and Physician Assistants, and 6213 (25.2%) nonclinicians. Among registered users, 18,533 (75.2%) completed at least 1 module, 7898 (32.0%) completed all 7 modules, and 19,804 (80.4%) answered optional check-on-learning questions. Median satisfaction with the content was (5) very satisfied (interquartile range, 4-5).

CONCLUSIONS: The NSTDC is a free, guideline-based, online curriculum with novel dual functionality that has achieved extensive reach with a broad array of health professionals who engage deeply with the material. The wide usage of NSTDC demonstrates the need for high-quality, unbiased, free content in user-focused formats.

RevDate: 2020-05-15

Tran Q, Warren JL, Barrett MJ, et al (2020)

An Evaluation of the Utility of Big Data to Supplement Cancer Treatment Information: Linkage Between IQVIA Pharmacy Database and the Surveillance, Epidemiology, and End Results Program.

Journal of the National Cancer Institute. Monographs, 2020(55):72-81.

Oral anticancer medications (OAMs) are increasingly utilized. We evaluated the representativeness and completeness of IQVIA, a large aggregator of pharmacy data, for breast cancer, colon cancer, chronic myeloid leukemia, and myeloma cases diagnosed in six Surveillance, Epidemiology, and End Results Program (SEER) registries between 2007 and 2011. Patient's SEER and SEER-Medicare data were linked and compared with IQVIA pharmacy data from 2006 to 2012 for specific OAMs. Overall, 67.6% of SEER cases had a pharmacy claim in IQVIA during the treatment assessment window. This varied by location, race and ethnicity, and insurance status. IQVIA consistently identified fewer cases who received an OAM of interest than SEER-Medicare. The difference was least pronounced for breast cancer agents and most pronounced for myeloma agents. The IQVIA pharmacy database included a large portion of persons in the SEER areas. Future studies should assess receipt of OAMs for other cancer sites and in different SEER registries.

RevDate: 2020-05-15

Mikhael J, Richter J, Vij R, et al (2020)

A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma.

Leukemia pii:10.1038/s41375-020-0857-2 [Epub ahead of print].

A Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ≥3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38-85), 5 (2-14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ≥10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade ≤2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ≤2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ≥10 mg/kg.

RevDate: 2020-05-15

Darst BF, Wan P, Sheng X, et al (2020)

A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry.

European urology pii:S0302-2838(20)30328-6 [Epub ahead of print].

Although men of African ancestry have a high risk of prostate cancer (PCa), no genes or mutations have been identified that contribute to familial clustering of PCa in this population. We investigated whether the African ancestry-specific PCa risk variant at 8q24, rs72725854, is enriched in men with a PCa family history in 9052 cases, 143 cases from high-risk families, and 8595 controls of African ancestry. We found the risk allele to be significantly associated with earlier age at diagnosis, more aggressive disease, and enriched in men with a PCa family history (32% of high-risk familial cases carried the variant vs 23% of cases without a family history and 12% of controls). For cases with two or more first-degree relatives with PCa who had at least one family member diagnosed at age <60 yr, the odds ratios for TA heterozygotes and TT homozygotes were 3.92 (95% confidence interval [CI] = 2.13-7.22) and 33.41 (95% CI = 10.86-102.84), respectively. Among men with a PCa family history, the absolute risk by age 60 yr reached 21% (95% CI = 17-25%) for TA heterozygotes and 38% (95% CI = 13-65%) for TT homozygotes. We estimate that in men of African ancestry, rs72725854 accounts for 32% of the total familial risk explained by all known PCa risk variants. PATIENT SUMMARY: We found that rs72725854, an African ancestry-specific risk variant, is more common in men with a family history of prostate cancer and in those diagnosed with prostate cancer at younger ages. Men of African ancestry may benefit from the knowledge of their carrier status for this genetic risk variant to guide decisions about prostate cancer screening.

RevDate: 2020-05-14

Perchetti GA, Nalla AK, Huang ML, et al (2020)

Validation of SARS-CoV-2 detection across multiple specimen types.

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology pii:104438 [Epub ahead of print].

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused considerable disruption across the world, resulting in more than 235,000 deaths since December 2019. SARS-CoV-2 has a wide tropism and detection of the virus has been described in multiple specimen types, including various respiratory secretions, cerebrospinal fluid, and stool.

Objective: To evaluate the accuracy and sensitivity of a laboratory modified CDCbased SARS-CoV-2 N1 and N2 assay across a range of sample types. Study Design We compared the matrix effect on the analytical sensitivity of SARS-CoV-2 detection by qRT-PCR in nasal swabs collected in viral transport medium (VTM), bronchoalveolar lavage (BAL), sputum, plasma, cerebral spinal fluid (CSF), stool, VTM, phosphate buffered saline (PBS), and Hanks' Balanced Salt Solution (HBSS). Initial limits of detection (LoD) were subsequently narrowed to confirm an LoD for each specimen type and target gene.

Results: LoDs were established using a modified CDC-based laboratory developed test and ranged from a mean CT cut-off of 33.8-35.7 (10-20 copies/reaction) for the N1 gene target, and 34.0-36.2 (1-10 copies/reaction) for N2. Alternatives to VTM such as PBS and HBSS had comparable LoDs. The N2 gene target was found to be most sensitive in CSF.

Conclusion: A modified CDC-based laboratory developed test is able to detect SARSCoV- 2 accurately with similar sensitivity across all sample types tested.

RevDate: 2020-05-14

Lyman GH, N Kuderer (2020)

Personalized Cancer Supportive Care in COVID-19 Era.

RevDate: 2020-05-14

Shore N, Higano CS, George DJ, et al (2020)

Concurrent or layered treatment with radium-223 and enzalutamide or abiraterone/prednisone: real-world clinical outcomes in patients with metastatic castration-resistant prostate cancer.

Prostate cancer and prostatic diseases pii:10.1038/s41391-020-0236-0 [Epub ahead of print].

BACKGROUND: In this study, we evaluated real-world data on radium-223 plus abiraterone/prednisone or enzalutamide. Previously, the ERA 223 trial (NCT02043678) demonstrated increased fracture risk with concurrent treatment with radium-223 and abiraterone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer (mCRPC).

METHODS: We used the Flatiron Health database to perform a retrospective study of patients with mCRPC treated with radium-223. Treatment with radium-223 plus abiraterone/prednisone or enzalutamide was defined as concurrent if both drugs started within 30 days of one another, or layered when the second drug started ≥30 days after the first. The index date was defined as the day of the first radium-223 dose. Outcome measures included symptomatic skeletal events (SSEs), overall survival (OS), and patterns of treatments received.

RESULTS: Of the 625 patients treated with radium-223, 22% received it together with abiraterone/prednisone and 27% with enzalutamide. When these agents were combined, they were often initiated in a layered fashion (73% layered, 23% concurrent). Prior or concomitant bone health agents (BHAs) were received by 67% and 55% of patients, respectively. Median follow-up was 9 months. Overall, incidence rates for SSEs and pathologic fractures were 0.35 and 0.11 patients per person-year, respectively. Median OS from mCRPC diagnosis was 28.1 months.

CONCLUSIONS: In this real-world setting, combination treatments with radium-223 and abiraterone/prednisone or enzalutamide were common. These agents were more commonly given in a layered than a concurrent fashion. Incidence rates for SSEs were reduced when BHAs were used; however, BHAs were underutilized.

RevDate: 2020-05-13

Coleman DJ, Sampson DA, Sehrawat A, et al (2020)

Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4.

Neoplasia (New York, N.Y.), 22(6):253-262 pii:S1476-5586(20)30114-7 [Epub ahead of print].

Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1's role in NEPC. Recently, a neural-specific transcript variant of LSD1-LSD1+8a-was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.

RevDate: 2020-05-13

D'Arcy ME, Pfeiffer RM, Rivera DR, et al (2020)

Voriconazole and the Risk of Keratinocyte Carcinomas Among Lung Transplant Recipients in the United States.

JAMA dermatology pii:2765342 [Epub ahead of print].

Importance: The antifungal medication voriconazole is used to prevent and treat aspergillosis, a major cause of mortality among recipients of lung transplants (hereinafter referred to as lung recipients). Small studies suggest that voriconazole increases risk of cutaneous squamous cell carcinoma (SCC).

Objective: To examine associations of voriconazole and other antifungal medications with risk of keratinocyte carcinomas (SCC and cutaneous basal cell carcinoma [BCC]) in lung recipients.

This population-based cohort study included non-Hispanic white patients (n = 9599) who underwent lung transplant in the United States from January 1, 2007, to December 31, 2016, identified through the national Scientific Registry of Transplant Recipients with data linkable to pharmacy claims. Data were analyzed from March 1, 2018, to February 13, 2019.

Exposures: Antifungal medication use, including voriconazole, itraconazole, posaconazole, and other antifungals, was ascertained from pharmacy claims and treated as a time-varying exposure (assessed every 30 days). Cumulative antifungal exposure was calculated as the total number of exposed months.

Main Outcomes and Measures: Primary outcomes were the first SCC or BCC reported to the transplant registry by transplant centers. Follow-up began at transplant and ended at SCC or BCC diagnosis, transplant failure or retransplant, death, loss to follow-up, or December 31, 2016. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (AHRs) for each antifungal medication.

Results: Among the 9793 lung transplants in 9599 recipients included in the analysis, median age at transplant was 59 (interquartile range [IQR], 48-65) years, 5824 (59.5%) were male, and 5721 (58.4%) reported ever smoking. During a median follow-up of 3.0 (IQR, 1.4-5.0) years after transplant, 1031 SCCs (incidence, 322 per 10 000 person-years) and 347 BCCs (incidence, 101 per 10 000 person-years) were reported. Compared with lung recipients with no observed voriconazole use, those with 1 to 3 months of voriconazole use experienced increased AHR for SCC of 1.09 (95% CI, 0.90-1.31); 4 to 7 months, 1.42 (95% CI, 1.16-1.73); 8 to 15 months, 2.04 (95% CI, 1.67-2.50); and more than 15 months, 3.05 (95% CI, 2.37-3.91). Ever itraconazole exposure was associated with increased SCC risk (AHR, 1.20; 95% CI, 1.00-1.45). For BCC, risk was not associated with voriconazole use but was increased with itraconazole use (AHR, 1.74; 95% CI, 1.27-2.37) or posaconazole use (AHR, 1.55; 95% CI, 1.00-2.41).

Conclusions and Relevance: In this study, voriconazole use was associated with increased SCC risk among lung recipients, especially after prolonged exposure. Further research evaluating the risk-benefit ratio of shorter courses or alternative medications in transplant recipients at high risk for SCC should be considered.

RevDate: 2020-05-13

Ceballos RM, Hohl SD, Molina Y, et al (2020)

Oncology provider and African-American breast cancer survivor perceptions of the emotional experience of transitioning to survivorship.

Journal of psychosocial oncology [Epub ahead of print].

Purpose: To examine the emotional experience of African American breast cancer survivors (BCS), and the information exchange between providers and patients, during transitioning to post-treatment survivorshipResearch Approach: We conducted a qualitative study using interviews and focus groups.Participants: We sought perspectives of oncology providers (n = 27) and African-American breast cancer survivors (BCS) (n = 45) who provided and received care in three counties in Washington State.Methods: African-American community consultants conducted interviews and focus groups. Thematic coding and constant comparison were applied to identify emergent themes.Findings: Participants reported emotional health information and support were needed but not consistently provided, resulting in a sense of survivor isolation. Systemic challenges limited providers' ability to deliver emotional support information. Survivors and providers expressed similar understandings of the emotional impact of transition, but each group highlighted different, yet complementary priorities to address emotional needs of African-American BCS.Conclusions: There is congruence between African-American BCS and oncology providers perceptions of the emotional experience of transitioning to post-treatment survivorship, but patients are not receiving adequate information and resources to help them adequately address their emotional needs.Implications for Policy: Improved care continuity, team-based approaches, and partnerships between health systems and community organization partnerships may help patients and providers recognize and address emotional needs during the transition.

RevDate: 2020-05-13

Ventresca M, Schünemann HJ, Macbeth F, et al (2020)

Obtaining and managing data sets for individual participant data meta-analysis: scoping review and practical guide.

BMC medical research methodology, 20(1):113 pii:10.1186/s12874-020-00964-6.

BACKGROUND: Shifts in data sharing policy have increased researchers' access to individual participant data (IPD) from clinical studies. Simultaneously the number of IPD meta-analyses (IPDMAs) is increasing. However, rates of data retrieval have not improved. Our goal was to describe the challenges of retrieving IPD for an IPDMA and provide practical guidance on obtaining and managing datasets based on a review of the literature and practical examples and observations.

METHODS: We systematically searched MEDLINE, Embase, and the Cochrane Library, until January 2019, to identify publications focused on strategies to obtain IPD. In addition, we searched pharmaceutical websites and contacted industry organizations for supplemental information pertaining to recent advances in industry policy and practice. Finally, we documented setbacks and solutions encountered while completing a comprehensive IPDMA and drew on previous experiences related to seeking and using IPD.

RESULTS: Our scoping review identified 16 articles directly relevant for the conduct of IPDMAs. We present short descriptions of these articles alongside overviews of IPD sharing policies and procedures of pharmaceutical companies which display certification of Principles for Responsible Clinical Trial Data Sharing via Pharmaceutical Research and Manufacturers of America or European Federation of Pharmaceutical Industries and Associations websites. Advances in data sharing policy and practice affected the way in which data is requested, obtained, stored and analyzed. For our IPDMA it took 6.5 years to collect and analyze relevant IPD and navigate additional administrative barriers. Delays in obtaining data were largely due to challenges in communication with study sponsors, frequent changes in data sharing policies of study sponsors, and the requirement for a diverse skillset related to research, administrative, statistical and legal issues.

CONCLUSIONS: Knowledge of current data sharing practices and platforms as well as anticipation of necessary tasks and potential obstacles may reduce time and resources required for obtaining and managing data for an IPDMA. Sufficient project funding and timeline flexibility are pre-requisites for successful collection and analysis of IPD. IPDMA researchers must acknowledge the additional and unexpected responsibility they are placing on corresponding study authors or data sharing administrators and should offer assistance in readying data for sharing.

RevDate: 2020-05-13

Castro D, Manger R, Vilariño O, et al (2020)

Evaluation of Matrix Issues in the Applicability of the Neuro-2a Cell Based Assay on the Detection of CTX in Fish Samples.

Toxins, 12(5): pii:toxins12050308.

Ciguatoxins (CTXs) are a group of neurotoxins responsible for the syndrome ciguatera fish poisoning (CFP) as a result of the consumption of contaminated fish. The presence of these toxins has been detected around the Pacific, Caribbean and Indian coasts. Recent reports indicate the emergence of CFP in other geographic areas, in particular in European coasts, of the Canary Islands (Spain) and Madeira (Portugal). A neuroblastoma cell line of murine origin (N2a) has been applied to assay different groups of neurotoxins, acting on voltage-gated sodium channel (VGSC) of excitable cells, N2a-MTT. The great potential of N2a-MTT as a sensitive tool for the CTXs screening is clearly recognized, notably because it allows the detection of these toxins at levels below recommended as security levels. However, the complexity of the matrix is a critical point on the application of N2a-MTT, which needs to be evaluated. The aim of this work is to provide recommendations for an implemented N2a-MTT method for CTXs determination in fish that avoids matrix effects, particularly those related to high lipid content.

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ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

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

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

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

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

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )