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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 08 Aug 2022 at 01:38 Created: 

Publications by FHCRC Researchers

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

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

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

Citations The Papers (from PubMed®)

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RevDate: 2022-08-06

Jones SMW, Sherman KJ, Bermet Z, et al (2022)

An experimental study to inform adoption of mindfulness-based stress reduction in chronic low back pain.

Implementation science communications, 3(1):87.

BACKGROUND: Chronic low back pain is a common and sometimes disabling condition, and mindfulness-based stress reduction is recommended as a first line of therapy. This study tested whether different descriptions of mindfulness training altered based on influential intervention characteristics increased adoption intentions.

METHODS: People with chronic low back pain (n = 452) were randomized to review one of four mindfulness training descriptions in an online survey using a 2 × 2 factorial design. The first factor was evidence strength and quality with relative advantage (ER). The second factor was adaptability, trialability, complexity, and design quality and packaging (AD). Each factor had two levels: a description of standardized mindfulness training that described each intervention characteristic and a patient-centered description emphasizing flexibility and patient testimonials. The primary outcomes were intentions to try mindfulness training and practice mindfulness at home. Using structural equation modeling with a bootstrapped distribution, we tested six mediators, three of which are Theory of Planned Behavior predictors of intention-self-efficacy, norms, and attitudes- and the other three are predictors of adoption-feasibility, appropriateness, and acceptability.

RESULTS: Overall, the mindfulness training descriptions were not associated with an increase in intentions compared to the classic vignette (11/12 p's > 0.05). Most descriptions were unrelated to mediators except the classic ER with patient-centered AD was associated with higher self-efficacy/control and feasibility (p's ≤ 0.05; standardized effect range: 0.111-0.125). Self-efficacy/control (training standardized coefficient: 0.531, home: 0.686), norms (training: 0.303, home: 0.256), and attitudes (training: 0.316, home: 0.293) were all positively associated with intentions to adopt mindfulness training and home practice. Feasibility (training: 0.185; home: 0.293) and acceptability (training: 0.639; home: 0.554) were positively related to intentions to adopt mindfulness training. Appropriateness was related to intentions to adopt home practice (0.187) but not mindfulness training (0.100). None of the indirect effects from experimental group to intentions was significant (all p's > 0.05).

CONCLUSIONS: Self-efficacy/control and acceptability may be key mediators for increasing patient adoption of mindfulness. Because experimental manipulation did not substantially change intentions to adopt mindfulness, the presentation and delivery of MBSR may need to be tailored to the individual patient's needs rather than a specific format for chronic low back pain.

RevDate: 2022-08-05

Mostofi N, Shaw C, Walter RB, et al (2022)

Evaluating concordance in assessment of ECOG performance status in acute myeloid leukemia patients.

Leukemia [Epub ahead of print].

RevDate: 2022-08-05

Ramdas S, Judd J, Graham SE, et al (2022)

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

American journal of human genetics, 109(8):1366-1387.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

RevDate: 2022-08-05

Chambers LC, Morgan JL, Lowens MS, et al (2022)

The Incidence Rate of Sexual Behaviors Among Cisgender Men who have Sex with Men Attending a Sexual Health Clinic.

Archives of sexual behavior [Epub ahead of print].

Although nuanced parameterization of sexual behavior may improve estimates from mathematical models of human immunodeficiency virus and sexually transmitted infection transmission, prospective estimates of the incidence of specific sexual behaviors among men who have sex with men (MSM) are limited. From December 2014 to July 2018, MSM with and without nongonococcal urethritis (NGU) completed weekly diaries over 3-12 weeks. Incidence rates of any sex, receptive anal sex, insertive anal sex, insertive oral sex, receptive rimming, and receptive hand-penile contact were 1.19, 0.28, 0.66, 0.90, 0.24, and 0.85 episodes per person-week, respectively, among 104 MSM with NGU at baseline, and 1.33, 0.54, 0.32, 0.95, 0.44, and 0.88 episodes per person-week, respectively, among 25 MSM without NGU at baseline. Most receptive anal sex (NGU + 83%, NGU - 86%) and insertive anal sex (NGU + 85%, NGU - 76%) episodes were condomless. MSM engaged in sex just over once per week, and condom use was infrequent. Insertive oral sex and receptive hand-penile contact were the most common behaviors.

RevDate: 2022-08-05

Kumar L, Kn N, Gujral S, et al (2022)

Editorial: Real World Outcomes of Lymphoma From India.

Frontiers in oncology, 12:922370.

RevDate: 2022-08-04

Xu S, Carpenter MC, Spreng RL, et al (2022)

Impact of adjuvants on the biophysical and functional characteristics of HIV vaccine-elicited antibodies in humans.

NPJ vaccines, 7(1):90.

Adjuvants can alter the magnitude, characteristics, and persistence of the humoral response to protein vaccination. HIV vaccination might benefit from tailored adjuvant choice as raising a durable and protective response to vaccination has been exceptionally challenging. Analysis of trials of partially effective HIV vaccines have identified features of the immune response that correlate with decreased risk, including high titers of V1V2-binding IgG and IgG3 responses with low titers of V1V2-binding IgA responses and enhanced Fc effector functions, notably antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, there has been limited opportunity to compare the effect of different adjuvants on these activities in humans. Here, samples from the AVEG015 study, a phase 1 trial in which participants (n = 112) were immunized with gp120SF-2 and one of six different adjuvants or combinations thereof were assessed for antibody titer, biophysical features, and diverse effector functions. Three adjuvants, MF59 + MTP-PE, SAF/2, and SAF/2 + MDP, increased the peak magnitude and durability of antigen-specific IgG3, IgA, FcγR-binding responses and ADCP activity, as compared to alum. While multiple adjuvants increased the titer of IgG, IgG3, and IgA responses, none consistently altered the balance of IgG to IgA or IgG3 to IgA. Linear regression analysis identified biophysical features including gp120-specific IgG and FcγR-binding responses that could predict functional activity, and network analysis identified coordinated aspects of the humoral response. These analyses reveal the ability of adjuvants to drive the character and function of the humoral response despite limitations of small sample size and immune variability in this human clinical trial.

RevDate: 2022-08-04

Jang SK, Evans L, Fialkowski A, et al (2022)

Rare genetic variants explain missing heritability in smoking.

Nature human behaviour [Epub ahead of print].

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

RevDate: 2022-08-04

Bellairs JA, Redila VA, Wu P, et al (2022)

An in vivo Biomarker to Characterize Ototoxic Compounds and Novel Protective Therapeutics.

Frontiers in molecular neuroscience, 15:944846.

There are no approved therapeutics for the prevention of hearing loss and vestibular dysfunction from drugs like aminoglycoside antibiotics. While the mechanisms underlying aminoglycoside ototoxicity remain unresolved, there is considerable evidence that aminoglycosides enter inner ear mechanosensory hair cells through the mechanoelectrical transduction (MET) channel. Inhibition of MET-dependent uptake with small molecules or modified aminoglycosides is a promising otoprotective strategy. To better characterize mammalian ototoxicity and aid in the translation of emerging therapeutics, a biomarker is needed. In the present study we propose that neonatal mice systemically injected with the aminoglycosides G418 conjugated to Texas Red (G418-TR) can be used as a histologic biomarker to characterize in vivo aminoglycoside toxicity. We demonstrate that postnatal day 5 mice, like older mice with functional hearing, show uptake and retention of G418-TR in cochlear hair cells following systemic injection. When we compare G418-TR uptake in other tissues, we find that kidney proximal tubule cells show similar retention. Using ORC-13661, an investigational hearing protection drug, we demonstrate in vivo inhibition of aminoglycoside uptake in mammalian hair cells. This work establishes how systemically administered fluorescently labeled ototoxins in the neonatal mouse can reveal important details about ototoxic drugs and protective therapeutics.

RevDate: 2022-08-03

Jahn N, Jahn E, Saadati M, et al (2022)

Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial.

Leukemia [Epub ahead of print].

The aim of this study was to characterize the mutational landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3-mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene-gene interactions, and possible treatment effects of midostaurin.

RevDate: 2022-08-03

Ondersma SJ, Todd L, Jablonski S, et al (2022)

Online randomised factorial trial of electronic Screening and Brief Intervention for alcohol use in pregnancy: a study protocol.

BMJ open, 12(8):e062735 pii:bmjopen-2022-062735.

INTRODUCTION: Approximately 1 in 7 pregnant women in the USA report past-month alcohol use. Strong evidence connects prenatal alcohol exposure with a range of adverse perinatal outcomes, including the spectrum of conditions known as fetal alcohol spectrum disorders. Screening and Brief Intervention (SBI) has been recommended for pregnant women but has proven difficult to implement. This study will test the efficacy of single-session technology-delivered SBI (electronic SBI) for alcohol use in pregnancy, while simultaneously evaluating the possible additional benefit of tailored text messages and/or booster sessions in a 3×2 factorial trial.

METHOD AND ANALYSIS: This full factorial trial will use online advertising and clinic-based flyers to recruit pregnant women meeting criteria for unhealthy alcohol use, and randomly assign them to one of six conditions crossing three levels of brief intervention (none, single 120-minute session and single session plus two 5-minute boosters) with two levels of tailored text messaging (none vs twice weekly messages). The primary analysis will test for dose-response effects of the brief intervention on alcohol abstinence, defined as no self-report of alcohol use in the 90 days prior to 34 weeks' gestation, and negative results for ethyl glucuronide analysis of fingernail samples. Secondary analyses will examine main and interaction effects of tailored text messaging as well as intervention effects on birth outcomes.

ETHICS AND DISSEMINATION: Ethical approval was provided by the Michigan State University Biomedical and Health Institutional Review Board (STUDY00005298). Results will be presented at conferences and community forums, in addition to being published in a peer-reviewed journal. Intervention content demonstrating sufficient efficacy and safety will be made publicly available.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04332172).

RevDate: 2022-08-03

Hiatt JB, Sandborg H, Garrison SM, et al (2022)

Inhibition of LSD1 with bomedemstat sensitizes small cell lung cancer to immune checkpoint blockade and T cell killing.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:707373 [Epub ahead of print].

PURPOSE: The addition of immune checkpoint blockade (ICB) to platinum/etoposide chemotherapy changed the standard of care for small cell lung cancer (SCLC) treatment. However, ICB addition only modestly improved clinical outcomes, likely reflecting the high prevalence of an immunologically "cold" tumor microenvironment in SCLC, despite high mutational burden. Nevertheless, some patients clearly benefit from ICB and recent reports have associated clinical responses to ICB in SCLC with A) decreased neuroendocrine characteristics and B) activation of NOTCH signaling. We previously showed that inhibition of the LSD1 demethylase activates NOTCH and suppresses neuroendocrine features of SCLC, leading us to investigate whether LSD1 inhibition would enhance the response to PD1 inhibition in SCLC.

EXPERIMENTAL DESIGN: We employed a syngeneic immunocompetent model of SCLC, derived from a genetically engineered mouse model harboring Rb1/Trp53 inactivation, to investigate combining the LSD1 inhibitor bomedemstat with anti-PD1 therapy. In vivo experiments were complemented by cell-based studies in murine and human models.

RESULTS: Bomedemstat potentiated responses to PD1 inhibition in a syngeneic model of SCLC, resulting in increased CD8+ T cell infiltration and strong tumor growth inhibition. Bomedemstat increased MHC class I expression in mouse SCLC tumor cells in vivo and augmented MHC-I induction by interferon-ɣ and increased killing by tumor specific T cells in cell culture.

CONCLUSIONS: LSD1 inhibition increased MHC-I expression and enhanced responses to PD1 inhibition in vivo, supporting a new clinical trial to combine bomedemstat with standard of care PD1 axis inhibition in SCLC.

RevDate: 2022-08-02

Tripathi N, Jo Y, Tripathi A, et al (2022)

Genomic landscape of locally advanced or metastatic urothelial carcinoma with squamous differentiation compared to pure urothelial carcinoma.

Urologic oncology pii:S1078-1439(22)00257-5 [Epub ahead of print].

BACKGROUND: Urothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology.

METHODS: In this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction.

RESULTS: Among the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj.p >0.001, p = >0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj.p= 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups.

CONCLUSION: These findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets.

RevDate: 2022-08-02

Beaber EF, Kamineni A, Burnett-Hartman AN, et al (2022)

Evaluating and Improving Cancer Screening Process Quality in a Multilevel Context: The PROSPR II Consortium Design and Research Agenda.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 31(8):1521-1531.

BACKGROUND: Cancer screening is a complex process involving multiple steps and levels of influence (e.g., patient, provider, facility, health care system, community, or neighborhood). We describe the design, methods, and research agenda of the Population-based Research to Optimize the Screening Process (PROSPR II) consortium. PROSPR II Research Centers (PRC), and the Coordinating Center aim to identify opportunities to improve screening processes and reduce disparities through investigation of factors affecting cervical, colorectal, and lung cancer screening in U.S. community health care settings.

METHODS: We collected multilevel, longitudinal cervical, colorectal, and lung cancer screening process data from clinical and administrative sources on >9 million racially and ethnically diverse individuals across 10 heterogeneous health care systems with cohorts beginning January 1, 2010. To facilitate comparisons across organ types and highlight data breadth, we calculated frequencies of multilevel characteristics and volumes of screening and diagnostic tests/procedures and abnormalities.

RESULTS: Variations in patient, provider, and facility characteristics reflected the PROSPR II health care systems and differing target populations. PRCs identified incident diagnoses of invasive cancers, in situ cancers, and precancers (invasive: 372 cervical, 24,131 colorectal, 11,205 lung; in situ: 911 colorectal, 32 lung; precancers: 13,838 cervical, 554,499 colorectal).

CONCLUSIONS: PROSPR II's research agenda aims to advance: (i) conceptualization and measurement of the cancer screening process, its multilevel factors, and quality; (ii) knowledge of cancer disparities; and (iii) evaluation of the COVID-19 pandemic's initial impacts on cancer screening. We invite researchers to collaborate with PROSPR II investigators.

IMPACT: PROSPR II is a valuable data resource for cancer screening researchers.

RevDate: 2022-08-02

Chubak J, Burnett-Hartman AN, Barlow WE, et al (2022)

Estimating Cancer Screening Sensitivity and Specificity Using Healthcare Utilization Data: Defining the Accuracy Assessment Interval.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 31(8):1517-1520.

The effectiveness and efficiency of cancer screening in real-world settings depend on many factors, including test sensitivity and specificity. Outside of select experimental studies, not everyone receives a gold standard test that can serve as a comparator in estimating screening test accuracy. Thus, many studies of screening test accuracy use the passage of time to infer whether or not cancer was present at the time of the screening test, particularly for patients with a negative screening test. We define the accuracy assessment interval as the period of time after a screening test that is used to estimate the test's accuracy. We describe how the length of this interval may bias sensitivity and specificity estimates. We call for future research to quantify bias and uncertainty in accuracy estimates and to provide guidance on setting accuracy assessment interval lengths for different cancers and screening modalities.

RevDate: 2022-08-01

Byun J, Han Y, Li Y, et al (2022)

Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer.

Nature genetics [Epub ahead of print].

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

RevDate: 2022-08-01

Glenn BA, Nonzee NJ, Herrmann AK, et al (2022)

Impact of a Multi-Level, Multi-Component, System Intervention on HPV Vaccination in a Federally Qualified Health Center.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:707365 [Epub ahead of print].

BACKGROUND: Human papillomavirus (HPV) vaccines can significantly reduce the burden of HPV-associated cancers, but remain underutilized. We evaluated a multi-component, system-level intervention to improve HPV vaccination in a large Federally Qualified Health Center (FQHC) that serves a primarily low income Latino population.

METHODS: From January 2015 through March 2017, we evaluated the effectiveness of a multi-component, system-level intervention to improve HPV vaccination rates in 8 clinics randomly assigned to study condition (4 intervention, 4 usual care). The intervention included parent reminders for HPV vaccine series completion, provider training, clinic-level audit and feedback, and workflow modifications to reduce missed opportunities for vaccination. Using a difference-in-differences approach, we compared HPV vaccination rates among patients ages 11-17 during a 12-month pre-intervention period and a 15-month intervention period. Linear mixed models were used to estimate intervention effects on vaccine initiation and completion.

RESULTS: The sample included approximately 15,000 adolescents each quarter (range 14,773-15,571; mean age 14 years, 51% female, 88% Latino). A significantly greater quarterly increase in HPV vaccine initiation was observed for intervention compared to usual care clinics (0.75 percentage point greater increase, p < 0.001), corresponding to 114 additional adolescents vaccinated per quarter. The intervention led to a greater increase in HPV vaccine completion rates among boys (0.65 percentage point greater increase, p<0.001), but not girls.

CONCLUSIONS: Our system-level intervention was associated with modest improvements in HPV vaccine initiation overall and completion among boys Impact: Study findings have implications for reducing HPV-related cancers in safety net populations.

RevDate: 2022-08-01

Kanabolo D, True L, Vakar-Lopez F, et al (2022)

Prostate Specific Antigen (PSA) Screening and a Lifesaving Cardiac Transplant.

Urology pii:S0090-4295(22)00633-1 [Epub ahead of print].

RevDate: 2022-08-01

Huang H, Peng L, Zhang B, et al (2022)

Combination of Low-Dose Gemcitabine and PD-1 Inhibitors for Treatment in Patients With Advanced Malignancies.

Frontiers in immunology, 13:882172.

Purpose: This study determined the efficacy of low-dose gemcitabine combined with programmed death-1 (PD-1) inhibitors for treating multiple malignancies, providing a cost-effective and safe treatment option.

Study Design: This study included 61 patients with advanced solid tumors treated with low-dose gemcitabine combined with PD-1 inhibitors at the Henan Cancer Hospital between January 2018 and February 2022. We retrospectively reviewed medical records to evaluate several clinical factors, including progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and objective response to treatment.

Results: Sixty-one patients received treatment with low-dose gemcitabine combined with PD-1 inhibitors. The objective response rate (ORR) was 29.5% and the disease control rate (DCR) was 62.3%. The median PFS was 4.3 months (95% confidence interval, 2.3 to 6.3 months) and the median OS was 15.0 months (95% confidence interval, 8.8 to 21.2 months). Hematological toxicity, mainly leukopenia or thrombocytopenia, was the most common AE, with any-grade and grade 3/4 hematological toxicity reported in 60.7 and 13.1% of patients, respectively.

Conclusions: Low-dose gemcitabine combined with PD-1 inhibitors may offer a novel treatment option for patients with advanced malignancies.

RevDate: 2022-07-31

MacKay EJ, Zhang B, Neuman MD, et al (2022)

Impact of Hospital Practice and Staffing Differences on Transesophageal Echocardiography Use in Cardiac Valve or Coronary Artery Bypass Graft Surgery.

Journal of cardiothoracic and vascular anesthesia pii:S1053-0770(22)00519-5 [Epub ahead of print].

OBJECTIVES: To identify and quantify the predictors of intraoperative transesophageal echocardiography (TEE) use among the patients undergoing cardiac valve or isolated coronary artery bypass graft (CABG) surgery.

DESIGN: An observational cohort study.

SETTING: This study used the Centers for Medicare and Medicaid Services administrative claims dataset of the beneficiaries undergoing valve or isolated CABG surgery between 2013 to 2015.

PARTICIPANTS: Adults aged ≥65 years of age undergoing cardiac valve or isolated CABG surgery.

INTERVENTIONS: Generalized linear mixed-model (GLMM) analyses were used to examine the relationship between the TEE and patient characteristics, hospital factors, and staffing differences, while accounting for clustering within hospitals. The proportion of variation in TEE use attributable to patient-level characteristics was quantified using odds ratios. Hospital-level factors and staffing differences were quantified using the median odds ratios (MOR) and interval odds ratios (IOR).

MEASUREMENTS AND MAIN RESULTS: Among 261,860 patients (123,702 valve procedures and 138,158 isolated CABG), the GLMM analysis demonstrated that the strongest predictor for intraoperative TEE use was the hospital where the surgery occurred (MOR for TEE of 2.57 in valve and 4.16 in isolated CABG). The TEE staffing variable reduced the previously unexplained across-hospital variability by 9% in valve and 21% in isolated CABG, and hospitals with anesthesiologist TEE staffing (versus mixed) were more likely to use TEE in both valve and CABG (MOR for TEE of 1.21 in valve and 1.84 in isolated CABG).

CONCLUSION: Hospital practice was the strongest predictor for TEE use overall. In isolated CABG surgery, hospitals with anesthesiologist TEE staffing were a primary predictor for TEE use.

RevDate: 2022-07-30

Holtan SG, Yu J, Choe HK, et al (2022)

Disease progression, treatments, hospitalization, and clinical outcomes in acute GVHD: a multicenter chart review.

Bone marrow transplantation [Epub ahead of print].

Acute graft-versus-host disease (GVHD) remains a barrier to successful allogeneic hematopoietic cell transplantation (HCT) outcomes. This multicenter, retrospective chart review describes disease progression, treatment patterns, hospitalizations, and clinical outcomes among 475 patients (≥12 years old) who developed grades II-IV acute GVHD after their first HCT (January 2014-June 2016). Median (interquartile range) age at HCT was 55 (44-63) years. From the date of acute GVHD diagnosis, 190 patients (40.0%) experienced progression to more severe disease and/or developed new organ involvement. Among 431 patients with grades II-IV acute GVHD at diagnosis, 73.1% received first-line systemic corticosteroids. During follow-up (median 524 days since acute GVHD diagnosis), 23.4% of patients had an increase in steroid dose and 44.4% were unable to taper below 10 mg/day. Over half of patients (54.9%) required ≥1 hospital readmission within 100 days post-HCT (≥2 readmissions in 22.3%); mean inpatient length of stay upon readmission was 27.5 days. Approximately half of patients (52.8%) died during follow-up; 1-year overall mortality from date of acute GVHD diagnosis and nonrelapse mortality rates were 35.2% and 25.5%, respectively. Overall, patients who developed acute GVHD following HCT had poor clinical outcomes, highlighting the unmet need for early and effective treatment strategies.

RevDate: 2022-07-19

Cranmer LD, Hess LM, Sugihara T, et al (2022)

Cardiac events among patients with sarcoma treated with doxorubicin by method of infusion: A real-world database study.

Cancer reports (Hoboken, N.J.) [Epub ahead of print].

BACKGROUND: Administration of doxorubicin by continuous intravenous (CIV) infusion, versus bolus (BOL) administration, has been proposed to mitigate the risk of cardiac events. This study used real-world data to explore the association between mode of doxorubicin administration and duration of treatment, time-to-treatment failure (TTF), and cardiac events.

METHODS: Occurrence of cardiac events after initiation of BOL versus CIV doxorubicin for sarcoma in the International Business Machines MarketScan claims database were compared. Duration of doxorubicin treatment, TTF, and time-to-first-cardiac event (TCE) were evaluated using Kaplan-Meier method and unadjusted and adjusted Cox regression models.

RESULTS: A total of 196 patients were included in the BOL group and 399 in the CIV group. In unadjusted analyses, there were significant differences between BOL versus CIV for duration of doxorubicin treatment (median 1.4 vs. 2.1 months, p = .002), TTF (median 8.8 vs. 5.6 months, p = .002), and TCE (medians not reached, p = .03). Adjusting for baseline covariates, only TTF remained significant (hazard ratio: 0.71, 95% confidence interval 0.59-0.86, p = .0004), favoring BOL.

CONCLUSIONS: While the risk of cardiac complications was higher with BOL in unadjusted analysis, the risk was no longer present in the adjusted analysis. While we cannot draw causal inferences due to the retrospective, nonrandomized study design, these data suggest that replacing BOL with prolonged CIV administration has not been effective as a strategy to mitigate cardiac events, given community standards of oncologic practice.

RevDate: 2022-07-30

DeZern AE, Eapen M, Wu J, et al (2022)

Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial.

The Lancet. Haematology pii:S2352-3026(22)00206-X [Epub ahead of print].

BACKGROUND: Relapsed severe aplastic anaemia is a marrow failure disorder with high morbidity and mortality. It is often treated with bone marrow transplantation at relapse post-immunosuppressive therapy, but under-represented minorities often cannot find a suitably matched donor. This study aimed to understand the 1-year overall survival in patients with relapsed or refractory severe aplastic anaemia after haploidentical bone marrow transplantation.

METHODS: We report the outcomes of BMT CTN 1502, a single-arm, phase 2 clinical trial done at academic bone marrow transplantation centres in the USA. Included patients were children and adults (75 years or younger) with severe aplastic anaemia that was refractory (fulfilment of severe aplastic anaemia disease criteria at least 3 months after initial immunosuppressive therapy) or relapsed (initial improvement of cytopenias after first-line immunosuppressive therapy but then a later return to fulfilment of severe aplastic anaemia disease criteria), adequate performance status (Eastern Cooperative Oncology Group score 0 or 1, Karnofsky or Lansky score ≥60%), and the presence of an eligible related haploidentical donor. The regimen used reduced-intensity conditioning (rabbit anti-thymocyte globulin 4·5 mg/kg in total, cyclophosphamide 14·5 mg/kg daily for 2 days, fludarabine 30 mg/kg daily for 5 days, total body irradiation 200 cGy in a single fraction), related HLA-haploidentical donors, and post-transplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. Additionally, for GVHD prophylaxis, mycophenolate mofetil was given orally at a dose of 15 mg/kg three times a day up to 1 g three times a day (maximum dose 3000 mg per day) from day 5 to day 35, and tacrolimus was given orally or intravenously from day 5 to day 180 as per institutional standards to maintain a serum concentration of 10-15 ng/mL. The primary endpoint was overall survival 1 year after bone marrow transplantation. All patients treated per protocol were analysed. This study is complete and is registered with ClinicalTrials.gov, NCT02918292.

FINDINGS: Between May 1, 2017, and Aug 30, 2020, 32 patients with relapsed or refractory severe aplastic anaemia were enrolled from 14 centres, and 31 underwent bone marrow transplantation. The median age was 24·9 years (IQR 10·4-51·3), and median follow-up was 24·3 months (IQR 12·1-29·2). Of the 31 patients who received a transplant, 19 (61%) were male and 12 (39%) female. 13 (42%) patients were site-reported as non-White, and 19 (61%) were from under-represented racial and ethnic groups; there were four (13%) patients who were Asian, seven (23%) Black, one (3%) Hawaiian/Pacific Islander, and one (3%) more than one race, with seven (23%) patients reporting Hispanic ethnicity. 24 (77%) of 31 patients were alive with engraftment at 1 year, and one (3%) patient alive with autologous recovery. The 1-year overall survival was 81% (95% CI 62-91). The most common grade 3-5 adverse events (seen in seven or more patients) included seven (23%) patients with abnormal liver tests, 15 (48%) patients with cardiovascular changes (including sinus tachycardia, heart failure, pericarditis), ten (32%) patients with gastrointestinal issues, seven (23%) patients with nutritional disorders, and eight (26%) patients with respiratory disorders. Six (19%) deaths, due to disease and unsuccessful bone marrow transplantation, were reported after transplantation.

INTERPRETATION: Haploidentical bone marrow transplantation using this approach results in excellent overall survival with minimal GVHD in patients who have not responded to immunosuppressive therapy, and can expand access to bone marrow transplantation across all populations. In clinical practice, this could now be considered a standard approach for salvage treatment of severe aplastic anaemia. Attention to obtaining high cell doses (>2·5 × 108 nucleated marrow cells per kg of recipient ideal bodyweight) from bone marrow harvests is crucial to the success of this approach.

FUNDING: US National Heart, Lung, and Blood Institute and US National Cancer Institute.

RevDate: 2022-07-30

An M, Wang W, Zhang J, et al (2022)

Association of hepatitis B virus DNA levels with overall survival for advanced hepatitis B virus-related hepatocellular carcinoma under immune checkpoint inhibitor therapy.

Cancer immunology, immunotherapy : CII [Epub ahead of print].

BACKGROUND: High hepatitis B virus (HBV) DNA level is an independent risk factor for postoperative HBV-associated liver cancer recurrence. We sought to examine whether HBV DNA level and antiviral therapy are associated with survival outcomes in patients with advanced hepatocellular carcinoma (HCC) treated with anti-programmed cell death protein 1 (PD-1)based immunotherapy.

METHODS: This single-institution retrospective analysis included 217 patients with advanced HBV-related HCC treated from 1 June 2018, through 30 December 2020. Baseline information was compared between patients with low and high HBV DNA levels. Overall survival (OS) and progression-free survival (PFS) were compared, and univariate and multivariate analyses were applied to identify potential risk factors for oncologic outcomes.

RESULTS: The 217 patients included in the analysis had a median survival time of 20.6 months. Of these HBV-associated HCC patients, 165 had known baseline HBV DNA levels. Baseline HBV DNA level was not significantly associated with OS (P = 0.59) or PFS (P = 0.098). Compared to patients who did not receive antiviral therapy, patients who received antiviral therapy had significantly better OS (20.6 vs 11.1 months, P = 0.020), regardless of HBV DNA levels. Moreover, antiviral status (adjusted HR = 0.24, 95% CI 0.094-0.63, P = 0.004) was an independent protective factor for OS in a multivariate analysis of patients with HBV-related HCC.

CONCLUSIONS: HBV viral load does not compromise the clinical outcome of patients with HBV-related HCC treated with anti-PD-1-based immunotherapy. The use of antiviral therapy significantly improves survival time of HBV-related HCC patients.

RevDate: 2022-07-30

Huynh HH, Forrest K, Becker JO, et al (2022)

A Targeted Liquid Chromatography-Tandem Mass Spectrometry Method for Simultaneous Quantification of Peptides from the Carboxyl-terminal Region of Type III Procollagen, Biomarkers of Collagen Turnover.

Clinical chemistry pii:6652162 [Epub ahead of print].

BACKGROUND: The development of analytical approaches to help reduce the risk of growth hormone (GH) doping is important to fair competition and the health of athletes. However, the reliable detection of GH use remains challenging. The identification of novel biomarkers of GH administration could lead to a better understanding of the physiological response to GH, more sensitive detection of the illicit use of GH in sport, and better management of patients treated for GH disorders.

METHODS: We developed a targeted liquid chromatography-tandem mass spectrometry method to simultaneously quantify the carboxyl-terminal propeptide of type III procollagen (P-III-CP) and type III collagen degradation products in human serum. Following proteolysis, we instituted a simple acid precipitation step to reduce digested sample complexity before peptide immunoenrichment, which improved the recovery of one target peptide from serum. We evaluated the concentration of each biomarker at different age ranges and after GH administration in healthy participants.

RESULTS: The assay was linear over an estimated concentration range of 0.3 to1.0 nM and 0.1 to 0.4 nM for each surrogate peptide of P-III-CP and collagen fragments, respectively. Intra-day and inter-day coefficients of variation were ≤15%. Biomarker concentrations appeared to vary with age and to reflect age-specific collagen turnover. Moreover, their concentrations changed after GH administration.

CONCLUSIONS: Our method quantifies the proteins belonging to the family of P-III-CP and type III collagen degradation products in human serum, which could be used to detect GH administration in athletes and better understand diseases involving GH therapy or altered type III collagen turnover.

RevDate: 2022-07-29

Peters BA, Hanna DB, Sharma A, et al (2022)

Menopausal hormone therapy and subclinical cardiovascular disease in women with and without HIV.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6651468 [Epub ahead of print].

BACKGROUND: Estrogen-based hormone therapy (HT) may have beneficial cardiovascular effects when initiated in early menopause. This has not been examined in women with HIV who have heightened immune activation and cardiovascular risks.

METHODS: Among 609 post-menopausal women (1,234 person-visits) in the Women's Interagency HIV Study, we examined the relationship of ever HT use (oral, patch, or vaginal) with subclinical atherosclerosis - carotid artery intima-media thickness (CIMT), distensibility, and plaque assessed via repeated B-mode ultrasound imaging (2004-2013). We also examined associations of HT with cross-sectional biomarkers of immune activation and D-dimer. Statistical models were adjusted for sociodemographic, behavioral, and cardiometabolic factors.

RESULTS: Women (mean age = 51, 80% HIV+) who ever used HT at baseline were older, and more likely to be non-Hispanic White and report higher income, than never users. Women who ever used HT had 43% lower prevalence of plaque (prevalence ratio = 0.57; 95% CI = [0.40, 0.80]; p < 0.01), 2.51 µm less progression of CIMT per year (95% CI = [-4.60, -0.41]; p = 0.02), and marginally lower incidence of plaque over ∼7 years (risk ratio = 0.38; 95% CI = [0.14, 1.03]; p = 0.06), compared with never users, adjusting for covariates; ever HT use was not associated with distensibility. These findings were similar for women with and without HIV. Ever HT use was associated with lower serum D-dimer, but not with biomarkers of immune activation after covariate adjustment.

CONCLUSIONS: HT may confer a subclinical cardiovascular benefit in women with HIV. These results begin to fill a knowledge gap in menopausal care for women with HIV, in whom uptake of HT is very low.

RevDate: 2022-07-28

Wang Z, Xiao H, Lin L, et al (2022)

Publisher Correction: Geographic social inequalities in information-seeking response to the COVID-19 pandemic in China: longitudinal analysis of Baidu Index.

Scientific reports, 12(1):12927 pii:10.1038/s41598-022-17295-9.

RevDate: 2022-07-28

DiCorpo D, Gaynor SM, Russell EM, et al (2022)

Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.

Communications biology, 5(1):756.

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

RevDate: 2022-07-28

Forman R, Viscoli CM, Bath PM, et al (2022)

Central vs site outcome adjudication in the IRIS trial.

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association, 31(9):106667 pii:S1052-3057(22)00361-5 [Epub ahead of print].

BACKGROUND: Central adjudication of outcome events is the standard in clinical trial research. We examine the benefit of central adjudication in the Insulin Resistance Intervention after Stroke (IRIS) trial and show how the benefit is influenced by outcome definition and features of the adjudicated events.

METHODS: IRIS tested pioglitazone for prevention of stroke and myocardial infarction in patients with a recent transient ischemic attack or ischemic stroke. We compared the hazard ratios for study outcomes classified by site and central adjudication. We repeated the analysis for an updated stroke definition.

RESULTS: The hazard ratios for the primary outcome were identical (0.76) and statistically significant regardless of adjudicator. The hazard ratios for stroke alone were nearly identical with site and central adjudication, but only reached significance with site adjudication (HR, 0.80; p = 0.049 vs. HR, 0.82; p = 0.09). Using the updated stroke definition, all hazard ratios were lower than with the original IRIS definition and statistically significant regardless of adjudication method. Agreement was higher when stroke type was certain, subtype was large vessel or cardioembolic, signs or symptoms lasted > 24 h, imaging showed a stroke, and when NIHSS was ≥3.

DISCUSSION: Central stroke adjudication caused the hazard ratio for a main secondary outcome in IRIS (stroke alone) to be higher and lose statistical significant compared with site review. The estimate of treatment effects were larger with the updated stroke definition. There may be benefit of central adjudication for events with specific features, such as shorter symptom duration or normal brain imaging.

RevDate: 2022-07-28

Glanville AR, Benden C, Bergeron A, et al (2022)

Bronchiolitis obliterans syndrome after lung or haematopoietic stem cell transplantation: current management and future directions.

ERJ open research, 8(3): pii:00185-2022.

Bronchiolitis obliterans syndrome (BOS) may develop after either lung or haematopoietic stem cell transplantation (HSCT), with similarities in histopathological features and clinical manifestations. However, there are differences in the contributory factors and clinical trajectories between the two conditions. BOS after HSCT occurs due to systemic graft-versus-host disease (GVHD), whereas BOS after lung transplantation is limited to the lung allograft. BOS diagnosis after HSCT is more challenging, as the lung function decline may occur due to extrapulmonary GVHD, causing sclerosis or inflammation in the fascia or muscles of the respiratory girdle. Treatment is generally empirical with no established effective therapies. This review provides rare insights and commonalities of both conditions, which are not well elaborated elsewhere in contemporary literature, and highlights the importance of cross disciplinary learning from experts in other transplant modalities. Treatment algorithms for each condition are presented, based on the published literature and consensus clinical opinion. Immunosuppression should be optimised, and other conditions or contributory factors treated where possible. When initial treatment fails, the ultimate therapeutic option is lung transplantation (or re-transplantation in the case of BOS after lung transplantation) in carefully selected candidates. Novel therapies under investigation include aerosolised liposomal cyclosporine, Janus kinase inhibitors, antifibrotic therapies and (in patients with BOS after lung transplantation) B-cell-directed therapies. Effective novel treatments that have a tangible impact on survival and thereby avoid the need for lung transplantation or re-transplantation are urgently required.

RevDate: 2022-07-27

Yuan Z, Yu X, Chen W, et al (2022)

Correction: Epigenetic silencing and tumor suppressor gene of HAND2 by targeting ERK signaling in colorectal cancer.

Cell communication and signaling : CCS, 20(1):113.

RevDate: 2022-07-27

Wingood M, Jones S, Gell NM, et al (2022)

Evaluation of Electronic and Pen-and-Paper Formats of the Inventory of Physical Activity Barriers: A Randomized Crossover Study.

Journal of physical activity & health [Epub ahead of print].

BACKGROUND: The Inventory of Physical Activity Barriers (IPAB) assesses physical activity participation barriers. Development, refinement, and psychometric evaluation of the IPAB occurred via an electronic format. However, various circumstances may require using a pen-and-paper format. As instrument formats are not always interchangeable, the authors aimed to establish whether 2 different formats (electronic and pen and paper) can be used interchangeably for the IPAB.

METHODS: This randomized crossover study included 66 community-dwelling adults aged 50 years and older (mean age = 73 [SD = 7.6]). Half the sample completed the electronic format of the IPAB first and the pen-and-paper format second, and the other half completed them in reverse order. Tests of equivalence and a Bland-Altman plot were performed.

RESULTS: The intraclass correlation coefficient between formats was .94, and kappa was .68. The mean difference between the 2 administration forms of the IPAB was 0.002 (P = .96). Both administration formats had high internal consistency (Cronbach alpha = .92 and .93) and illustrated construct validity (P ≤ .001 for both administration formats).

CONCLUSION: Pen-and-paper and electronic formats of the IPAB are equivalent and, thus, can be used interchangeably among non-Hispanic whites who are highly educated. The format should be used consistently if completing preintervention and postintervention evaluations or comparing scores.

RevDate: 2022-07-27

Stoddard CI, Sung K, Ojee E, et al (2022)

Distinct Antibody Responses to Endemic Coronaviruses Pre- and Post-SARS-CoV-2 Infection in Kenyan Infants and Mothers.

Viruses, 14(7): pii:v14071517.

Pre-existing antibodies that bind endemic human coronaviruses (eHCoVs) can cross-react with SARS-CoV-2, which is the betacoronavirus that causes COVID-19, but whether these responses influence SARS-CoV-2 infection is still under investigation and is particularly understudied in infants. In this study, we measured eHCoV and SARS-CoV-1 IgG antibody titers before and after SARS-CoV-2 seroconversion in a cohort of Kenyan women and their infants. Pre-existing eHCoV antibody binding titers were not consistently associated with SARS-CoV-2 seroconversion in infants or mothers; however, we observed a very modest association between pre-existing HCoV-229E antibody levels and a lack of SARS-CoV-2 seroconversion in the infants. After seroconversion to SARS-CoV-2, antibody binding titers to the endemic betacoronaviruses HCoV-OC43 and HCoV-HKU1, and the highly pathogenic betacoronavirus SARS-CoV-1, but not the endemic alphacoronaviruses HCoV-229E and HCoV-NL63, increased in the mothers. However, eHCoV antibody levels did not increase following SARS-CoV-2 seroconversion in the infants, suggesting the increase seen in the mothers was not simply due to cross-reactivity to naively generated SARS-CoV-2 antibodies. In contrast, the levels of antibodies that could bind SARS-CoV-1 increased after SARS-CoV-2 seroconversion in both the mothers and infants, both of whom were unlikely to have had a prior SARS-CoV-1 infection, supporting prior findings that SARS-CoV-2 responses cross-react with SARS-CoV-1. In summary, we found evidence of increased eHCoV antibody levels following SARS-CoV-2 seroconversion in the mothers but not the infants, suggesting eHCoV responses can be boosted by SARS-CoV-2 infection when a prior memory response has been established, and that pre-existing cross-reactive antibodies are not strongly associated with SARS-CoV-2 infection risk in mothers or infants.

RevDate: 2022-07-27

Hua X, Song L, Yu G, et al (2022)

MicrobiomeGWAS: A Tool for Identifying Host Genetic Variants Associated with Microbiome Composition.

Genes, 13(7): pii:genes13071224.

The microbiome is the collection of all microbial genes and can be investigated by sequencing highly variable regions of 16S ribosomal RNA (rRNA) genes. Evidence suggests that environmental factors and host genetics may interact to impact human microbiome composition. Identifying host genetic variants associated with human microbiome composition not only provides clues for characterizing microbiome variation but also helps to elucidate biological mechanisms of genetic associations, prioritize genetic variants, and improve genetic risk prediction. Since a microbiota functions as a community, it is best characterized by β diversity; that is, a pairwise distance matrix. We develop a statistical framework and a computationally efficient software package, microbiomeGWAS, for identifying host genetic variants associated with microbiome β diversity with or without interacting with an environmental factor. We show that the score statistics have positive skewness and kurtosis due to the dependent nature of the pairwise data, which makes p-value approximations based on asymptotic distributions unacceptably liberal. By correcting for skewness and kurtosis, we develop accurate p-value approximations, whose accuracy was verified by extensive simulations. We exemplify our methods by analyzing a set of 147 genotyped subjects with 16S rRNA microbiome profiles from non-malignant lung tissues. Correcting for skewness and kurtosis eliminated the dramatic deviation in the quantile-quantile plots. We provided preliminary evidence that six established lung cancer risk SNPs were collectively associated with microbiome composition for both unweighted (p = 0.0032) and weighted (p = 0.011) UniFrac distance matrices. In summary, our methods will facilitate analyzing large-scale genome-wide association studies of the human microbiome.

RevDate: 2022-07-27

Knight TE, Edwards H, Meshinchi S, et al (2022)

"FLipping" the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors.

Cancers, 14(14): pii:cancers14143398.

The treatment of many types of cancers, including acute myeloid leukemia (AML), has been revolutionized by the development of therapeutics targeted at crucial molecular drivers of oncogenesis. In contrast to broad, relatively indiscriminate conventional chemotherapy, these targeted agents precisely disrupt key pathways within cancer cells. FMS-like tyrosine kinase 3 (FLT3)-encoding a critical regulator of hematopoiesis-is the most frequently mutated gene in patients with AML, and these mutations herald reduced survival and increased relapse in these patients. Approximately 30% of newly diagnosed AML carries an FLT3 mutation; of these, approximately three-quarters are internal tandem duplication (ITD) mutations, and the remainder are tyrosine kinase domain (TKD) mutations. In contrast to its usual, tightly controlled expression, FLT3-ITD mutants allow constitutive, "run-away" activation of a large number of key downstream pathways which promote cellular proliferation and survival. Targeted inhibition of FLT3 is, therefore, a promising therapeutic avenue. In April 2017, midostaurin became both the first FLT3 inhibitor and the first targeted therapy of any kind in AML to be approved by the US FDA. The use of FLT3 inhibitors has continued to grow as clinical trials continue to demonstrate the efficacy of this class of agents, with an expanding number available for use as both experimental standard-of-care usage. This review examines the biology of FLT3 and its downstream pathways, the mechanism of FLT3 inhibition, the development of the FLT3 inhibitors as a class and uses of the agents currently available clinically, and the mechanisms by which resistance to FLT3 inhibition may both develop and be overcome.

RevDate: 2022-07-26

Schröder J, Chegwidden L, Maj C, et al (2022)

GWAS meta-analysis of 16 790 patients with Barrett's oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level.

Gut pii:gutjnl-2021-326698 [Epub ahead of print].

OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.

DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.

RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.

CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.

RevDate: 2022-07-26

Hopp CS, Taylor JJ, PD Crompton (2022)

Assessment of Plasmodium falciparum Antigen-Specific B Cells.

Methods in molecular biology (Clifton, N.J.), 2470:689-713.

This protocol describes methods that exploit the specificity of binding between the B cell receptor and cognate antigen to detect and characterize Plasmodium-specific human B cells. Importantly, this approach allows for the isolation and study of B cells without activating the cells or requiring them to secrete antibodies. The protocol describes how antigen "probes" are generated and used in flow cytometry to identify and sort antigen-specific B cells, and includes methods for enrichment of antigen-specific B cells prior to flow cytometry. Finally, we detail techniques to optimize the exclusion of B cells that are not specific for the antigen of interest.

RevDate: 2022-07-26

Gao F, Glidden DV, Hughes JP, et al (2021)

Sample size calculation for active-arm trial with counterfactual incidence based on recency assay.

Statistical communications in infectious diseases, 13(1):20200009 pii:scid-2020-0009.

Objectives: The past decade has seen tremendous progress in the development of biomedical agents that are effective as pre-exposure prophylaxis (PrEP) for HIV prevention. To expand the choice of products and delivery methods, new medications and delivery methods are under development. Future trials of non-inferiority, given the high efficacy of ARV-based PrEP products as they become current or future standard of care, would require a large number of participants and long follow-up time that may not be feasible. This motivates the construction of a counterfactual estimate that approximates incidence for a randomized concurrent control group receiving no PrEP.

Methods: We propose an approach that is to enroll a cohort of prospective PrEP users and aug-ment screening for HIV with laboratory markers of duration of HIV infection to indicate recent infections. We discuss the assumptions under which these data would yield an estimate of the counterfactual HIV incidence and develop sample size and power calculations for comparisons to incidence observed on an investigational PrEP agent.

Results: We consider two hypothetical trials for men who have sex with men (MSM) and transgender women (TGW) from different regions and young women in sub-Saharan Africa. The calculated sample sizes are reasonable and yield desirable power in simulation studies.

Conclusions: Future one-arm trials with counterfactual placebo incidence based on a recency assay can be conducted with reasonable total screening sample sizes and adequate power to determine treatment efficacy.

RevDate: 2022-07-25

Sapkota Y, Qiu W, Dixon SB, et al (2022)

Genetic risk score enhances the risk prediction of severe obesity in adult survivors of childhood cancer.

Nature medicine [Epub ahead of print].

Adult survivors of childhood cancer have high rates of obesity, which, in combination with the cardiotoxic effects of specific cancer therapies, places them at high risk for cardiovascular morbidity. Here we show the contribution of genetic risk scores (GRSs) to increase prediction of those survivors of childhood cancer who are at risk for severe obesity (body mass index ≥40 kg m-2) as an adult. Among 2,548 individuals of European ancestry from the St. Jude Lifetime Cohort Study who were 5-year survivors of childhood cancer, the GRS was found to be associated with 53-fold-higher odds of severe obesity. Addition of GRSs to risk prediction models based on cancer treatment exposures and lifestyle factors significantly improved model prediction (area under the curve increased from 0.68 to 0.75, resulting in the identification of 4.3-times more high-risk survivors), which was independently validated in 6,064 individuals from the Childhood Cancer Survivor Study. Genetic predictors improve identification of patients who could benefit from heightened surveillance and interventions to mitigate the risk of severe obesity and associated cardio-metabolic complications.

RevDate: 2022-07-25

Zhu Y, Shen R, Vuong I, et al (2022)

Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression.

Nature communications, 13(1):4282.

Lipid nanoparticles hold great potential as an effective non-viral vector for nucleic acid-based gene therapy. Plasmid DNA delivery can result in extended transgene expression compared to mRNA-based technologies, yet there is a lack of systematic investigation into lipid nanoparticle compositions for plasmid DNA delivery. Here, we report a multi-step screening platform to identify optimized plasmid DNA lipid nanoparticles for liver-targeted transgene expression. To achieve this, we analyze the role of different helper lipids and component ratios in plasmid DNA lipid nanoparticle-mediated gene delivery in vitro and in vivo. Compared to mRNA LNPs and in vivo-jetPEI/DNA nanoparticles, the identified plasmid DNA lipid nanoparticles successfully deliver transgenes and mediate prolonged expression in the liver following intravenous administration in mice. By addressing different physiological barriers in a stepwise manner, this screening platform can efficiently down select effective lipid nanoparticle candidates from a lipid nanoparticle library of over 1000 formulations. In addition, we substantially extend the duration of plasmid DNA nanoparticle-mediated transgene expression using a DNA/siRNA co-delivery approach that targets transcription factors regulating inflammatory response pathways. This lipid nanoparticle-based co-delivery strategy further highlights the unique advantages of an extended transgene expression profile using plasmid DNA delivery and offers new opportunities for DNA-based gene medicine applications.

RevDate: 2022-07-25

Goldsmith SR, Ghobadi A, Dipersio JF, et al (2022)

CAR T versus HCT: An Evolving Perspective.

Transplantation and cellular therapy pii:S2666-6367(22)01477-4 [Epub ahead of print].

Cellular therapy modalities, including autologous (Auto) hematopoietic cell transplantation (HCT), allogeneic (Allo) HCT, and now chimeric antigen receptor (CAR) T therapy, have demonstrated long term remissions in advanced hematologic malignancies. Auto and AlloHCT, through hematopoietic rescue, have permitted the use of higher doses of chemotherapy. AlloHCT also introduced nonspecific immune-mediated targeting of malignancy resulting in protection from relapse, although at the expense of similar targeting of normal host cells. In contrast, CAR T therapy, through genetically-engineered immunotherapeutic precision, allows for redirection of autologous immune effector cells against malignancy in an antigen-specific and MHC-independent fashion, with demonstrated efficacy in patients who are refractory to cytotoxic chemotherapy. It too has unique toxicities and challenges. Non-Hodgkin lymphoma (including large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma), B-cell acute lymphoblastic leukemia, and multiple myeloma are the three main diseases with fully developed CAR T products with widespread deployment. Recent and ongoing clinical trials are examining the interface between the three cellular therapy modalities (AutoHCT, AlloHCT, and CAR T), to determine whether they should be "complementary" or "competitive". In this review, we examine the current state of this interface with respect to the most recent data and delve into the controversies and conclusions that may inform clinical decision-making.

RevDate: 2022-07-25

Chehab L, Doody DR, Esbenshade AJ, et al (2022)

A Population-Based Study of the Long-Term Risk of Infections Associated With Hospitalization in Childhood Cancer Survivors.

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

PURPOSE: Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer.

METHODS: We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators.

RESULTS: On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9).

CONCLUSION: Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

RevDate: 2022-07-25

Mao Z, Nesterenko PA, McLaughlin J, et al (2022)

Physical and in silico immunopeptidomic profiling of a cancer antigen prostatic acid phosphatase reveals targets enabling TCR isolation.

Proceedings of the National Academy of Sciences of the United States of America, 119(31):e2203410119.

Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide-major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.

RevDate: 2022-07-25

Cheng EL, Cardle II, Kacherovsky N, et al (2022)

Discovery of a Transferrin Receptor 1-Binding Aptamer and Its Application in Cancer Cell Depletion for Adoptive T-Cell Therapy Manufacturing.

Journal of the American Chemical Society [Epub ahead of print].

The clinical manufacturing of chimeric antigen receptor (CAR) T cells includes cell selection, activation, gene transduction, and expansion. While the method of T-cell selection varies across companies, current methods do not actively eliminate the cancer cells in the patient's apheresis product from the healthy immune cells. Alarmingly, it has been found that transduction of a single leukemic B cell with the CAR gene can confer resistance to CAR T-cell therapy and lead to treatment failure. In this study, we report the identification of a novel high-affinity DNA aptamer, termed tJBA8.1, that binds transferrin receptor 1 (TfR1), a receptor broadly upregulated by cancer cells. Using competition assays, high resolution cryo-EM, and de novo model building of the aptamer into the resulting electron density, we reveal that tJBA8.1 shares a binding site on TfR1 with holo-transferrin, the natural ligand of TfR1. We use tJBA8.1 to effectively deplete B lymphoma cells spiked into peripheral blood mononuclear cells with minimal impact on the healthy immune cell composition. Lastly, we present opportunities for affinity improvement of tJBA8.1. As TfR1 expression is broadly upregulated in many cancers, including difficult-to-treat T-cell leukemias and lymphomas, our work provides a facile, universal, and inexpensive approach for comprehensively removing cancerous cells from patient apheresis products for safe manufacturing of adoptive T-cell therapies.

RevDate: 2022-07-25

Ng RH, Lee JW, Baloni P, et al (2022)

Constraint-Based Reconstruction and Analyses of Metabolic Models: Open-Source Python Tools and Applications to Cancer.

Frontiers in oncology, 12:914594.

The influence of metabolism on signaling, epigenetic markers, and transcription is highly complex yet important for understanding cancer physiology. Despite the development of high-resolution multi-omics technologies, it is difficult to infer metabolic activity from these indirect measurements. Fortunately, genome-scale metabolic models and constraint-based modeling provide a systems biology framework to investigate the metabolic states and define the genotype-phenotype associations by integrations of multi-omics data. Constraint-Based Reconstruction and Analysis (COBRA) methods are used to build and simulate metabolic networks using mathematical representations of biochemical reactions, gene-protein reaction associations, and physiological and biochemical constraints. These methods have led to advancements in metabolic reconstruction, network analysis, perturbation studies as well as prediction of metabolic state. Most computational tools for performing these analyses are written for MATLAB, a proprietary software. In order to increase accessibility and handle more complex datasets and models, community efforts have started to develop similar open-source tools in Python. To date there is a comprehensive set of tools in Python to perform various flux analyses and visualizations; however, there are still missing algorithms in some key areas. This review summarizes the availability of Python software for several components of COBRA methods and their applications in cancer metabolism. These tools are evolving rapidly and should offer a readily accessible, versatile way to model the intricacies of cancer metabolism for identifying cancer-specific metabolic features that constitute potential drug targets.

RevDate: 2022-07-25

Rotz SJ, Yi JC, Hamilton BK, et al (2022)

Health Related Quality of Life in Young Adults Survivors of Hematopoietic Cell Transplantation.

Transplantation and cellular therapy pii:S2666-6367(22)01480-4 [Epub ahead of print].

BACKGROUND: Young adults, age 18-39, are at a stage of life which may make them more vulnerable than older adults to impairments in health-related quality of life (HRQOL) during and after hematopoietic cell transplantation (HCT). Health self-efficacy (HSE) is the belief that one can implement strategies to produce a desired health outcome and has been associated with health outcomes in oncology research. Little is known about HRQOL or HSE in young adult HCT survivors compared to older HCT survivors.

OBJECTIVE: Given the age-specific psychosocial challenges facing young adult HCT recipients and research on non-transplant young adult cancer survivors, we hypothesized that young adult survivors would have worse post-HCT HRQOL compared to older adults and that among young adult HCT survivors, higher levels of HSE would be associated with higher HRQOL and lower levels of cancer-related distress.

STUDY DESIGN: This is a cross-sectional secondary analysis of two combined baseline datasets from multi-center studies of HCT survivors approached for participation in clinical trials of survivorship interventions. Participants from 20 transplant centers in the US were 1-10 years post-HCT, ≥18 years of age at the time of study enrollment, had no evidence of disease relapse/progression or subsequent malignancies, and read English adequate to consent and complete assessments. Medical record and patient-reported data were obtained for demographics and HCT-related clinical factors and complications (e.g. total body irradiation, chronic graft-versus-host disease). Participants completed surveys on HRQOL (Short-form [SF]-12), HSE, and Cancer and Treatment Distress (CTXD), which includes six subscales and an overall mean score. SF-12 was calculated for both mental (MCS) and physical (PCS) component scores. Participants were compared between two cohorts: young adults (age 18 to 39 at transplant) and older adults (age ≥40 at transplant). Multiple linear regression analyses determined factors associated with HSE, PCS, MCS and CTXD within young adults.

RESULTS: In this analysis of N=979 survivors, compared to older adults, young adult participants had lower mental health scores (SF-12 MCS: 48.40 vs. 50.23, P=0.04) and higher cancer-related distress (CTXD: 0.96 vs. 0.85, P=0.04), though better physical health (SF-12 PCS: 48.99 vs. 47.18, P=0.049). Greater overall cancer-related distress was driven by higher levels of uncertainty, financial concern, and medical demand subscales for young adults compared with older adults. Young adults also had lower HSE (2.93 vs. 3.08, P=0.0004). In a multivariate model, HSE was strongly associated with age group (p=0.0005) after adjusting for multiple other transplant related factors. Among young adults, HSE was associated with mental and physical components of the SF-12 and the CTXD, and HSE remained significant after adjusting for other transplant-related factors.

CONCLUSIONS: Overall, young adult HCT survivors have lower mental health, increased cancer-related distress, and lower levels of HSE compared to older adults. Although the direction of these effects cannot be determined with these data, the strong association between HSE and HRQOL among young adults suggests that targeting interventions to improve HSE may have broad impact on health outcomes.

RevDate: 2022-07-24

DeCotes D, Baron S, Hoffman J, et al (2022)

Highly mutated monoclonal antibody 3F2 targets a conformational and strain-restricted epitope in human immunodeficiency virus gp41 with significant antibody-dependent cell cytotoxicity.

Archives of virology [Epub ahead of print].

Identifying epitope targets by studying the native antibody (Ab) response can identify potential novel vaccine constructs. Studies suggest that long-term non-progressor (LTNP) subjects have inherent immune mechanisms that help to control viremia and disease progression. To explore a role for antibodies (Abs) in LTNP progression, our lab has previously characterized a number of highly mutated Abs that target conformational epitopes of the human immunodeficiency virus (HIV) envelope protein from a single LTNP subject (10076). One Ab clone, 10076-Q3-2C6, had significant cross-clade Ab-dependent cell cytotoxicity. To assess if other LTNP subjects produced similar Abs, we expressed another highly mutated Ab from another subject; subject 10002, clone 10002-Q1-3F2 (variable heavy chain, 63.2% amino acid sequence identity to predicted germline). After expression with its native light chain, the recombinant Ab 3F2 bound to the trimeric envelope protein of HIV (trimer), as well as to the ectodomain of gp41. 3F2 binding to gp41 peptide libraries was consistent with non-linear epitope binding and showed possible overlap with the epitope of 2C6. Ab competition assays suggested that 3F2 may bind near the immunodominant epitope 1 loop region (ID1) of gp41. 2C6 blocked the binding of ID1-loop-binding Abs and 3F2 to the trimer, but 3F2 failed to block 2C6 binding. Together, these results suggest that 3F2 binds to a non-linear conformational epitope primarily localized between the epitope of 2C6 and the ID1. Since they are targeted by functional Abs, a more complete understanding of these ID1 and near-ID1 epitopes may be exploited in future immunization strategies.

RevDate: 2022-07-25

Yuan Z, Yu X, Chen W, et al (2022)

Epigenetic silencing and tumor suppressor gene of HAND2 by targeting ERK signaling in colorectal cancer.

Cell communication and signaling : CCS, 20(1):111.

BACKGROUND: The screening biomarkers for early detection of colorectal cancer (CRC) is lacking. The aim is to identify epigenetic silenced genes and clarify its roles and underlying mechanism in CRC. We conducted integrative analyses of epigenome-wide Human Methylation 450 K arrays and transcriptome to screen out candidate epigenetic driver genes with transcription silencing. Methylated silencing HAND2 were identified and verified in large CRC cohort. The mechanism of HAND2 expression by promoter inhibition were clarified both in vitro and vivo assays. Cell biofunctional roles of HAND2 methylation was investigated in CRC cells. HAND2 reconstitution were constructed by lentivirus plasmid and tumor xenograft model of HAND2 were built subcutaneously. Genomic mRNA analysis by RNA-sequencing and subsequent GSEA analysis were performed to identify potential target of HAND2 and qPCR/WB was conducted to identify the results.

RESULTS: We firstly reported high frequency of HAND2 methylation in promoter in CRC and hypermethylation was negatively correlated with expression silencing and leaded to poor survival in several CRC cohort patients. 5-Aza treatment to demethylated HAND2 could revert its expression in CRC cells. Functionally, HAND2 reconstitution can inhibit cell proliferation, invasion and migration in vitro. In tumor xenograft, HAND2 reconstruction significantly repressed tumor growth when compared to control vector. Thousands of aberrant expressed genes were observed in the heatmap of RNA-sequencing data. HAND2 reconstitution could bind to ERK and reduce its phosphorylation by CoIP assay. These above results showed HAND2 reconstitution perturbed the activation of MAPK/ERK signaling by reduction of ERK phosphorylation.

CONCLUSIONS: HAND2 is one tumor suppressor by targeting ERK signaling and one potential epigenetic driver gene in CRC. Video Abstract.

RevDate: 2022-07-23

Mdluli T, Li Y, Pinyakorn S, et al (2022)

Acute HIV-1 infection viremia associate with rebound upon treatment interruption.

Med (New York, N.Y.) pii:S2666-6340(22)00276-8 [Epub ahead of print].

BACKGROUND: Analytic treatment interruption (ATI) studies evaluate strategies to potentially induce remission in people living with HIV-1 but are often limited in sample size. We combined data from four studies that tested three interventions (vorinostat/hydroxychloroquine/maraviroc before ATI, Ad26/MVA vaccination before ATI, and VRC01 antibody infusion during ATI).

METHODS: The statistical validity of combining data from these participants was evaluated. Eleven variables, including HIV-1 viral load at diagnosis, Fiebig stage, and CD4+ T cell count were evaluated using pairwise correlations, statistical tests, and Cox survival models.

FINDINGS: Participants had homogeneous demographic and clinical characteristics. Because an antiviral effect was seen in participants who received VRC01 infusion post-ATI, these participants were excluded from the analysis, permitting a pooled analysis of 53 participants. Time to viral rebound was significantly associated with variables measured at the beginning of infection: pre-antiretroviral therapy (ART) viral load (HR = 1.34, p = 0.022), time to viral suppression post-ART initiation (HR = 1.07, p < 0.001), and area under the viral load curve (HR = 1.34, p = 0.026).

CONCLUSIONS: We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later.

FUNDING: This work was supported by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of the Army (W81XWH-18-2-0040). This research was funded, in part, by the US National Institute of Allergy and Infectious Diseases (AAI20052001) and the I4C Martin Delaney Collaboratory (5UM1AI126603-05).

RevDate: 2022-07-22

Hurwitz LM, Townsend MK, Jordan SJ, et al (2022)

Modification of the Association Between Frequent Aspirin Use and Ovarian Cancer Risk: A Meta-Analysis Using Individual-Level Data From Two Ovarian Cancer Consortia.

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

PURPOSE: Frequent aspirin use has been associated with reduced ovarian cancer risk, but no study has comprehensively assessed for effect modification. We leveraged harmonized, individual-level data from 17 studies to examine the association between frequent aspirin use and ovarian cancer risk, overall and across subgroups of women with other ovarian cancer risk factors.

METHODS: Nine cohort studies from the Ovarian Cancer Cohort Consortium (n = 2,600 cases) and eight case-control studies from the Ovarian Cancer Association Consortium (n = 5,726 cases) were included. We used Cox regression and logistic regression to assess study-specific associations between frequent aspirin use (≥ 6 days/week) and ovarian cancer risk and combined study-specific estimates using random-effects meta-analysis. We conducted analyses within subgroups defined by individual ovarian cancer risk factors (endometriosis, obesity, family history of breast/ovarian cancer, nulliparity, oral contraceptive use, and tubal ligation) and by number of risk factors (0, 1, and ≥ 2).

RESULTS: Overall, frequent aspirin use was associated with a 13% reduction in ovarian cancer risk (95% CI, 6 to 20), with no significant heterogeneity by study design (P = .48) or histotype (P = .60). Although no association was observed among women with endometriosis, consistent risk reductions were observed among all other subgroups defined by ovarian cancer risk factors (relative risks ranging from 0.79 to 0.93, all P-heterogeneity > .05), including women with ≥ 2 risk factors (relative risk, 0.81; 95% CI, 0.73 to 0.90).

CONCLUSION: This study, the largest to-date on aspirin use and ovarian cancer, provides evidence that frequent aspirin use is associated with lower ovarian cancer risk regardless of the presence of most other ovarian cancer risk factors. Risk reductions were also observed among women with multiple risk factors, providing proof of principle that chemoprevention programs with frequent aspirin use could target higher-risk subgroups.

RevDate: 2022-07-22

Parikh ND, Tayob N, Al-Jarrah T, et al (2022)

Barriers to Surveillance for Hepatocellular Carcinoma in a Multicenter Cohort.

JAMA network open, 5(7):e2223504 pii:2794480.

Importance: Hepatocellular carcinoma (HCC) surveillance is underused in clinical practice, which may be owing to patient and clinician barriers.

Objective: To characterize HCC surveillance barriers and associations with clinical outcomes in a multicenter cohort of patients with cirrhosis.

This retrospective, multicenter cohort study included 5 medical centers in the United States. Patients with cirrhosis and newly diagnosed HCC treated from 2014 to 2018 were included. Data were analyzed from June 2021 to February 2022.

Exposure: Surveillance completion in the 36-month period prior to HCC diagnosis.

Main Outcomes and Measures: Surveillance receipt was classified as semiannual, annual, or no surveillance. Multivariable logistic regression analysis was used to identify factors associated with semiannual surveillance. We conducted multivariable logistic and Cox regression analyses to characterize associations between surveillance completion with curative treatment and overall survival.

Results: A total 629 eligible patients (median [IQR] age, 63.6 [56.2-71.0] years; 491 [78.1%] men) were assessed, including 7 American Indian or Alaska Native patients (1.1%), 14 Asian patients (2.2), 176 Black patients (28.0%), 86 Hispanic patients (13.1%), and 340 White patients (54.1%). Nearly two-thirds of the cohort had no surveillance prior to HCC diagnosis (mean [range by site] 63.7% [37.9%-80.4%]), with a mean (range by site) of 14.0% (5.3%-33.3%) of patients having received semiannual surveillance and 22.3% (14.3%-28.8%) of patients having received annual surveillance. The most common reasons for no surveillance were lack of surveillance orders or nonadherence (mean [range by site], 82.4% [66.7%-92.4%], although a mean (range by site) of 17.6% (10.2%-22.1%) of patients had unrecognized cirrhosis at HCC presentation. Semiannual surveillance was associated with hepatitis B infection (odds ratio [OR], 3.06 [95% CI, 1.24-7.23]) and inversely associated with Black race (OR, 0.41 [95% CI, 0.20-0.80]) and lack of cirrhosis recognition (OR, 0.14 [95% CI, 0.02-0.46]). Semiannual HCC surveillance was significantly associated with curative treatment receipt (OR, 2.73 [95% CI, 1.60-4.70]) but not overall survival (HR, 0.81 [95% CI, 0.55-1.18]).

Conclusions and Relevance: In this cohort study of patients with cirrhosis, HCC surveillance was underused in more than 80% of patients and associated with failures across the screening process. Dedicated programs to improve cirrhosis detection and HCC surveillance attainment are needed.

RevDate: 2022-07-22

Dintwe OB, De Rosa SC, Huang Y, et al (2022)

Achieving intracellular cytokine staining assay concordance on two continents to assess HIV vaccine-induced T-cell responses.

Journal of leukocyte biology [Epub ahead of print].

The HIV Vaccine Trials Network (HVTN) conducts clinical trials on 4 continents in pursuit of a safe and effective HIV vaccine. Cellular immune responses to vaccination that define vaccine immunogenicity and/or immune correlates of protection can be measured using multiparameter intracellular cytokine staining (ICS) assays. The HVTN cellular immunology laboratory, located in Seattle, WA, conducts ICS assays for vaccine trials according to Good Clinical Laboratory Practices (GCLP). In 2013, the HVTN established a second GCLP compliant cellular immunology laboratory in Cape Town, South Africa to assess vaccine immunogenicity for HVTN trials conducted on the African continent. To ensure ICS readouts in the 2 laboratories were directly comparable, we conducted concordance testing using PBMC from healthy controls and vaccine trial participants. Despite standardized procedures and instrumentation, shared quality control measures and quality assurance oversight, several factors impacted our ability to obtain close agreement in T-cell responses measured in the 2 laboratories. One of these was the type of fetal bovine serum (FBS) used in the assay, which impacted lymphocyte cell viability and background responses. In addition, the differences in supernatant removal technique also significantly affected our ability to detect positive responses to vaccine antigens. Standardization of these factors allowed us to achieve and maintain ICS assay concordance across the 2 laboratories over multiple years, accelerating our efforts to evaluate HIV vaccines. The insights gained in this process are valuable for assay transfer efforts by groups of investigators that need to directly compare data generated in different laboratories around the globe.

RevDate: 2022-07-21

Lee CJ, Wang T, Chen K, et al (2022)

Association of Chronic Graft-versus-Host Disease with Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy.

Transplantation and cellular therapy pii:S2666-6367(22)01475-0 [Epub ahead of print].

BACKGROUND: Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality-of-life among long-term survivors of pediatric HCT. Late effects of HCT are well documented in this population and cGVHD has been reported as a risk factor for subsequent neoplasms (SN) and several non-malignant late effects. However, the correlation between cGVHD and late effects varies between studies.

OBJECTIVE: We compared late effects occurring ≥ 2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of late effects.

STUDY DESIGN: This was a systematic retrospective analysis using data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large and representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant and non-malignant late effects following a diagnosis of cGVHD versus those who never developed cGVHD. The cumulative incidence (CI) of any first LE, subsequent neoplasm (SN), and non-malignant LE (NM-LE) was estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD vs. no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first late effects.

RESULTS: The estimated 10-year cumulative incidence of any late effect in patients with and without cGVHD was 43% (95% CI, 38%-48.2%) vs. 32% (95% CI, 28.5%-36.3%) (P<0.001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any late effect (HR 1.38, 95% CI, 1.13-1.68, P=.001) and non-malignant late effects (HR 1.37, 95% CI, 1.10-1.70, P=.006), but not SN (HR 1.30, 95% CI, 0.73-2.31, P=.38). Chronic GVHD-related factors linked with the development of a non-malignant late effect included having extensive grade (HR 1.60, 95% CI 1.23 - 2.08, P=.0005), severe cGVHD (HR 2.25, 95% CI 1.60 - 3.17, P<.0001), interrupted onset type (HR 1.57, 95% CI 1.21 - 2.05, P=.0008), and both mucocutaneous and visceral organ involvement (HR 1.59, 95% CI 1.24 - 2.03, P=.0002). No significant association between cGVHD-specific variables and SN was identified. Lastly, duration of cGVHD treatment with systemic immunosuppression was not significantly associated with SN or non-malignant late effects.

CONCLUSIONS: cGVHD was more closely associated with non-malignant late effects than SN amongst survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SN was strongly associated with myeloablative total body irradiation. Chronic GVHD-related characteristics consistent with a state of higher immune dysregulation were more closely linked to non-malignant late effects.

RevDate: 2022-07-21

Shrestha L, Lin MJ, Xie H, et al (2022)

Clinical performance characteristics of the Swift Normalase Amplicon Panel for sensitive recovery of SARS-CoV-2 genomes.

The Journal of molecular diagnostics : JMD pii:S1525-1578(22)00191-X [Epub ahead of print].

Amplicon-based sequencing methods have been central in characterizing the diversity, transmission, and evolution of SARS-CoV-2, but need to be rigorously assessed for clinical utility. Here, we validated the Swift Biosciences' SARS-CoV-2 Swift Normalase Amplicon Panels using remnant clinical specimens. High quality genomes meeting our established library and sequence quality criteria were recovered from positive specimens with 95% limit of detection of 40.08 SARS-CoV-2 copies/PCR reaction. Breadth of genome recovery ≥was evaluated across a range of Ct values (11.3 - 36.7, median 21.6). Out of 428 positive samples, 413 (96.5%) generated genomes with < 10% Ns, with a mean genome coverage of 13,545X ± SD 8,382X. No genomes were recovered from PCR-negative specimens (n = 30), or from specimens positive for non-SARS-CoV-2 respiratory viruses (n = 20). Compared to whole-genome shotgun metagenomic sequencing (n = 14) or Sanger sequencing for the spike gene (n = 11), pairwise identity between consensus sequences was 100% in all cases, with highly concordant allele frequencies (R2 = 0.99) between Swift and shotgun libraries. When samples from different clades were mixed at varying ratios, expected variants were detected even in 1:99 mixtures. When deployed as a clinical test, 268 tests were performed in the first 23 weeks with a median turnaround time of 11 days, ordered primarily for outbreak investigations and infection control.

RevDate: 2022-07-21

Dunk CE, Bucher M, Zhang J, et al (2022)

Human Leukocyte Antigen HLA-C, HLA-G, HLA-F and HLA-E placental profiles are altered in Early Severe Preeclampsia and Preterm Birth with Chorioamnionitis.

American journal of obstetrics and gynecology pii:S0002-9378(22)00575-0 [Epub ahead of print].

BACKGROUND: The extravillous trophoblast expresses each of the non-classical MHC class I antigens - HLA-E, F, and G and a single classical class I antigen HLA-C. We recently demonstrated dynamic expression patterns of HLA-C, G and F during early EVT invasion and placentation.

OBJECTIVE: In this study we investigate the hypothesis that the immune inflammatory mediated complications of pregnancy such as early preeclampsia and preterm labor, may show altered expression profiles of non-classical HLA.

STUDY DESIGN: Real time q-PCR, western blot and immunohistochemistry were performed on placental villous tissues and basal plate sections from term non-laboring deliveries, preterm deliveries and severe early onset preeclampsia both with and without small for gestational age neonates.

RESULTS: HLA-G is strongly and exclusively expressed by the EVT within the placental basal plate and its levels increase in pregnancies complicated by severe early onset PE with SGA neonates as compared to healthy term controls. HLA-C shows a similar profile in the EVT of PE pregnancies, but significantly decreases in the villous placenta. HLA-F protein levels are decreased in both EVT and villous placenta of severe early onset PE pregnancies both with and without SGA babies as compared to Term and PTB deliveries. HLA-E decreases in blood vessels in placentas from PE pregnancies as compared to Term and PTB deliveries. HLA-F and HLA-C are increased in the placenta of PTBs with chorioamnionitis as compared to idiopathic PTB.

CONCLUSION: Dysregulation of placental HLA expression at the maternal fetal interface may contribute to the compromised maternal tolerance in PTB with chorioamnionitis and excessive maternal systemic inflammation associated with severe early onset PE.

RevDate: 2022-07-21

Farooq Z, Kusuma F, Burke P, et al (2022)

The amino acid sensor GCN2 suppresses Terminal Oligopyrimidine (TOP) mRNA translation via La-related Protein 1 (LARP1).

The Journal of biological chemistry pii:S0021-9258(22)00719-0 [Epub ahead of print].

La-related protein 1 (LARP1) has been identified as a key translational inhibitor of terminal oligopyrimidine (TOP) mRNAs downstream of the nutrient sensing protein kinase complex, mTORC1. LARP1 exerts this inhibitory effect on TOP mRNA translation by binding to the mRNA cap and the adjacent 5'TOP motif, resulting in the displacement of the cap-binding protein eIF4E from TOP mRNAs. However, the involvement of additional signaling pathway in regulating LARP1-mediated inhibition of TOP mRNA translation is not clear. In the present study, we identify a second nutrient sensing kinase GCN2 that converges on LARP1 to control TOP mRNA translation. Using chromatin-immunoprecipitation followed by massive parallel sequencing (ChIP-seq) analysis of activating transcription factor 4 (ATF4), an effector of GCN2 in nutrient stress conditions, in WT and GCN2 KO mouse embryonic fibroblasts (MEFs) we determined that LARP1 is a GCN2-dependent transcriptional target of ATF4. Moreover, we identified GCN1, a GCN2 activator, participates in a complex with LARP1 on stalled ribosomes, suggesting a role for GCN1 in LARP1-mediated translation inhibition in response to ribosome stalling. Therefore, our data suggest that the GCN2 pathway controls LARP1 activity via two mechanisms: ATF4-dependent transcriptional induction of LARP1 mRNA, and GCN1-mediated recruitment of LARP1 to stalled ribosomes.

RevDate: 2022-07-21

Hicks DR, Kennedy MA, Thompson KA, et al (2022)

De novo design of protein homodimers containing tunable symmetric protein pockets.

Proceedings of the National Academy of Sciences of the United States of America, 119(30):e2113400119.

Function follows form in biology, and the binding of small molecules requires proteins with pockets that match the shape of the ligand. For design of binding to symmetric ligands, protein homo-oligomers with matching symmetry are advantageous as each protein subunit can make identical interactions with the ligand. Here, we describe a general approach to designing hyperstable C2 symmetric proteins with pockets of diverse size and shape. We first designed repeat proteins that sample a continuum of curvatures but have low helical rise, then docked these into C2 symmetric homodimers to generate an extensive range of C2 symmetric cavities. We used this approach to design thousands of C2 symmetric homodimers, and characterized 101 of them experimentally. Of these, the geometry of 31 were confirmed by small angle X-ray scattering and 2 were shown by crystallographic analyses to be in close agreement with the computational design models. These scaffolds provide a rich set of starting points for binding a wide range of C2 symmetric compounds.

RevDate: 2022-07-21

Chang A, Sholukh AM, Wieland A, et al (2022)

Herpes simplex virus lymphadenitis is associated with tumor reduction in a chronic lymphocytic leukemia patient.

The Journal of clinical investigation pii:161109 [Epub ahead of print].

BACKGROUND: Herpes simplex virus lymphadenitis (HSVL) is an unusual presentation of HSV reactivation in chronic lymphocytic leukemia (CLL) patients characterized by systemic symptoms and no herpetic lesions. The immune responses during HSVL have not been studied.

METHODS: Peripheral blood and lymph node samples of a patient with HSVL were obtained. HSV-2 viral load, antibody levels, B and T cell responses, cytokine levels, and tumor burden were measured.

RESULTS: This patient showed HSV-2 viremia for at least 6 weeks. During this period, she had a robust HSV-specific antibody response with neutralizing and antibody-dependent cellular phagocytosis activity. Activated (HLA-DR+, CD38+) CD4+ and CD8+ T cells increased 18-fold and HSV-specific CD8+ T cells were detected in the blood at higher numbers. HSV-specific B and T cell responses in the lymph node were also detected. Markedly elevated levels of pro-inflammatory cytokines in the blood were also observed. Surprisingly, a sustained decrease in CLL tumor burden without CLL-directed therapy was observed with this and also a prior episode of HSVL.

CONCLUSION: HSVL should be considered as part of the differential diagnosis in CLL patients who present with signs and symptoms of aggressive lymphoma transformation. An interesting finding was the sustained tumor control after 2 episodes of HSVL in this patient. This tumor burden reduction may be due to the HSV-specific response serving as an adjuvant for activating tumor-specific or bystander T cells. Studies in additional CLL patients are needed to confirm and extend these findings.

FUNDING: National Institutes of Health and Winship Cancer Institute.

RevDate: 2022-07-21
CmpDate: 2022-07-21

Wang Z, Xiao H, Lin L, et al (2022)

Geographic social inequalities in information-seeking response to the COVID-19 pandemic in China: longitudinal analysis of Baidu Index.

Scientific reports, 12(1):12243.

The outbreak of the COVID-19 pandemic alarmed the public and initiated the uptake of preventive measures. However, the manner in which the public responded to these announcements, and whether individuals from different provinces responded similarly during the COVID-19 pandemic in China, remains largely unknown. We used an interrupted time-series analysis to examine the change in Baidu Search Index of selected COVID-19 related terms associated with the COVID-19 derived exposure variables. We analyzed the daily search index in Mainland China using segmented log-normal regressions with data from Jan 2017 to Mar 2021. In this longitudinal study of nearly one billion internet users, we found synchronous increases in COVID-19 related searches during the first wave of the COVID-19 pandemic and subsequent local outbreaks, irrespective of the location and severity of each outbreak. The most precipitous increase occurred in the week when most provinces activated their highest level of response to public health emergencies. Search interests increased more as Human Development Index (HDI) -an area level measure of socioeconomic status-increased. Searches on the index began to decline nationwide after the initiation of mass-scale lockdowns, but statistically significant increases continued to occur in conjunction with the report of major sporadic local outbreaks. The intense interest in COVID-19 related information at virtually the same time across different provinces indicates that the Chinese government utilizes multiple channels to keep the public informed of the pandemic. Regional socioeconomic status influenced search patterns.

RevDate: 2022-07-20

Müller NF, Kistler KE, T Bedford (2022)

A Bayesian approach to infer recombination patterns in coronaviruses.

Nature communications, 13(1):4186.

As shown during the SARS-CoV-2 pandemic, phylogenetic and phylodynamic methods are essential tools to study the spread and evolution of pathogens. One of the central assumptions of these methods is that the shared history of pathogens isolated from different hosts can be described by a branching phylogenetic tree. Recombination breaks this assumption. This makes it problematic to apply phylogenetic methods to study recombining pathogens, including, for example, coronaviruses. Here, we introduce a Markov chain Monte Carlo approach that allows inference of recombination networks from genetic sequence data under a template switching model of recombination. Using this method, we first show that recombination is extremely common in the evolutionary history of SARS-like coronaviruses. We then show how recombination rates across the genome of the human seasonal coronaviruses 229E, OC43 and NL63 vary with rates of adaptation. This suggests that recombination could be beneficial to fitness of human seasonal coronaviruses. Additionally, this work sets the stage for Bayesian phylogenetic tracking of the spread and evolution of SARS-CoV-2 in the future, even as recombinant viruses become prevalent.

RevDate: 2022-07-21

Menghi F, Banda K, Kumar P, et al (2022)

Genomic and epigenomic BRCA alterations predict adaptive resistance and response to platinum-based therapy in patients with triple-negative breast and ovarian carcinomas.

Science translational medicine, 14(652):eabn1926.

Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1 promoter methylation (BRCA1meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1 and BRCA2 (BRCAmut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCA perturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with BRCA1meth and BRCAmut states, BRCA1meth uniformly associates with poor outcomes. Exposure of BRCA1meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1 methylation and increased BRCA1 expression and platinum resistance. These data suggest that, unlike BRCAmut cancers, where BRCA loss is a genetically "fixed" deficiency state, BRCA1meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of BRCA mutations results in more accurate predictions of patient response when compared to either HRD status or BRCA status alone. This underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa.

RevDate: 2022-07-20

Cohen AA, van Doremalen N, Greaney AJ, et al (2022)

Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models.

Science (New York, N.Y.) [Epub ahead of print].

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded, rather than variable, immunodominant, and exposed. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicrons and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers.

RevDate: 2022-07-20

Tang J, Zeng C, Cox TM, et al (2022)

Respiratory mucosal immunity against SARS-CoV-2 following mRNA vaccination.

Science immunology [Epub ahead of print].

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19 vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2) and Omicron BA.1.1 in the BAL compared to COVID-19 convalescents, despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses, not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during re-infection, but offer limited protection against breakthrough infection, especially by Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by Omicron sublineage and future VOCs.

RevDate: 2022-07-20

Bowen JE, Addetia A, Dang HV, et al (2022)

Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines.

Science (New York, N.Y.) [Epub ahead of print].

The SARS-CoV-2 Omicron variant of concern comprises several sublineages with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1, and BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations lead to enhanced ACE2 binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, and BA.4/5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

RevDate: 2022-07-20

Dacon C, Tucker C, Peng L, et al (2022)

Broadly neutralizing antibodies target the coronavirus fusion peptide.

Science (New York, N.Y.) [Epub ahead of print].

The potential for future coronavirus outbreaks highlights the need to broadly target this group of pathogens. We use an epitope-agnostic approach to identify six monoclonal antibodies that bind to spike proteins from all seven human-infecting coronaviruses. All six antibodies target the conserved fusion peptide region adjacent to the S2' cleavage site. COV44-62 and COV44-79 broadly neutralize alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.2 and BA.4/5, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2' cleavage site. COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings highlight the fusion peptide as a candidate epitope for next-generation coronavirus vaccine development.

RevDate: 2022-07-20

Crary IL, Parker EU, Lowry KP, et al (2022)

ASO Visual Abstract: Risk of Lobular Neoplasia Upgrade with Synchronous Carcinoma.

Annals of surgical oncology pii:10.1245/s10434-022-12213-9 [Epub ahead of print].

RevDate: 2022-07-21

Rivera CG, Beieler AM, Childs-Kean LM, et al (2022)

A Bundle of the Top 10 OPAT Publications in 2021.

Open forum infectious diseases, 9(7):ofac242.

As outpatient parenteral antimicrobial therapy (OPAT) becomes more common, it may be difficult to stay current with recent related publications. A group of multidisciplinary OPAT clinicians reviewed and ranked all OPAT publications published in 2021. This article provides a high-level summary of the OPAT manuscripts that were voted the "top 10" publications of 2021.

RevDate: 2022-07-21

Zimmer AJ, Stohs E, Meza J, et al (2022)

Bloodstream Infections in Hematologic Malignancy Patients With Fever and Neutropenia: Are Empirical Antibiotic Therapies in the United States Still Effective?.

Open forum infectious diseases, 9(7):ofac240.

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant.

Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation.

Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with variability across centers. Cefepime and piperacillin-tazobactam were the most commonly prescribed empirical antibiotics for FN, at 62% and 23%, respectively; a GP-directed agent was empirically included in nearly half of all FN episodes within the first 24 hours. Susceptibility to fluoroquinolones, cefepime, piperacillin-tazobactam, and carbapenems was 49%, 84%, 88%, and 96%, respectively, among GN isolates. Critical illness (CrI), defined as a new requirement for mechanical ventilation, vasopressor, or death within 30 days, occurred in 15% and did not correlate with fluoroquinolone prophylaxis, organism type, initial antibiotics, or adequacy of coverage. Only severity of illness at presentation, signified by a Pitt bacteremia score ≥2, predicted for critical illness within 30 days. Mortality was 4% by day 7 and 10% overall.

Conclusions: In accordance with US guidelines, cefepime or piperacillin-tazobactam remain effective agents or empirical treatment for high-risk cancer patients with FN who are stable at presentation, maintaining high GN pathogen susceptibility and yielding excellent outcomes.

RevDate: 2022-07-18

Joo JH, Wang X, Singh S, et al (2022)

Intraosseous delivery of platelet-targeted FVIII lentiviral vector in humanized NBSGW mice.

Blood advances pii:485952 [Epub ahead of print].

We previously showed that intraosseous (IO) delivery of factor VIII (FVIII, gene F8) lentiviral vector (LV) driven by the megakaryocyte-specific promoter, Gp1bα, (G-F8-LV) partially corrected the bleeding phenotype in hemophilia A mice for up to 5 months. In this study, we further characterized and confirmed the successful transduction of self-regenerating hematopoietic stem and progenitor cells (HSPCs) in treated mice. Additionally, secondary transplant of HSPCs isolated from G-F8-LV treated mice corrected the bleeding phenotype of the recipient HemA mice, indicating the potential of long-term transgene expression following IO-LV therapy. To facilitate the translation of this technology to human applications, we evaluated the safety and efficacy of this gene transfer therapy into human HSPCs. In vitro transduction of human HSPCs by the platelet-targeted G-F8-LV confirmed megakaryocyte-specific gene expression after preferential differentiation of HSPCs to megakaryocyte lineages. Lentiviral integration analysis detected a polyclonal integration pattern in G-F8-LV transduced human cells, profiling the clinical safety for hemophilia treatment. Most importantly, IO delivery of G-F8-LV to humanized NBSGW mice produced persistent FVIII expression in human platelets after gene therapy, and the megakaryocytes differentiated from human CD34+ HSPCs isolated from LV-treated humanized mice showed up to 10.2% FVIII expression, indicating efficient transduction of self-regenerating human HSPCs. Collectively, these results indicate the long-term safety and efficacy of IO-LV gene therapy strategy for hemophilia A in a humanized model, adding further evidence to the feasibility of translating this method for clinical applications.

RevDate: 2022-07-18

Vutien P, Berry K, Feng Z, et al (2022)

Combining FIB-4 and liver stiffness into the FIB-5, a single model that accurately predicts complications of portal hypertension.

The American journal of gastroenterology pii:00000434-990000000-00435 [Epub ahead of print].

OBJECTIVES: We aimed to combine the fibrosis-4 (FIB-4) score and fibroscan-derived liver stiffness (LS) into a single score (FIB-5) that predicts incident complications of portal hypertension (PH) in persons with compensated liver disease.

METHODS: In this retrospective cohort study, we identified 5849 US veterans who underwent LS measurement from 05/01/2014 to 06/30/2019 and had laboratory tests enabling FIB-4 calculation within 6 months of LS measurement. Patients were followed from LS date until 02/05/2020 for incident complications of PH. We combined LS values and the individual components of the FIB-4 score (i.e. age, aspartate aminotransferase, alanine aminotransferase, platelet count) using multivariable Cox proportional hazards modeling or the machine learning algorithm eXtreme gradient boosting (XGBoost) to develop the C-FIB-5 and X-FIB-5 models, respectively. Models were internally validated using optimism-corrected measures.

RESULTS: Among 5849 patients, the mean age was 62.8 years, 95.9% were male, and the mean follow-up time was 2.14 ± 1.21 years. Within 3 years after LS measurement date, 116 (2.0%) patients developed complications of PH. The X-FIB-5 (Area Under the Receiver Operating Characteristic [AUROC] 0.845) and C-FIB-5 scores (AUROC 0.868) demonstrated superior discrimination over LS (AUROC 0.688) and FIB-4 (AUROC 0.672) for predicting incident complications of PH. Both the X-FIB-5 and C-FIB-5 models demonstrated higher classification accuracy across all sensitivity cut-offs as compared to LS or FIB-4 alone.

CONCLUSIONS: We combined LS and the individual components of the FIB-4 into a single scoring system (FIB-5, www.fib5.net), which can help identify patients with compensated liver disease at risk of developing complications of PH.

RevDate: 2022-07-19

Pollyea DA, George TI, Abedi M, et al (2020)

Diagnostic and molecular testing patterns in patients with newly diagnosed acute myeloid leukemia in the Connect® MDS/AML Disease Registry.

EJHaem, 1(1):58-68.

Diagnostic and molecular genetic testing are key in advancing the treatment of acute myeloid leukemia (AML), yet little is known about testing patterns outside of clinical trials, especially in older patients. We analyzed diagnostic and molecular testing patterns over time in 565 patients aged ≥ 55 years with newly diagnosed AML enrolled in the Connect® MDS/AML Disease Registry (NCT01688011) in the United States. Diagnostic data were recorded at enrolment and compared with published guidelines. The percentage of bone marrow blasts was reported for 82.1% of patients, and cellularity was the most commonly reported bone marrow morphological feature. Flow cytometry, karyotyping, molecular testing, and fluorescence in situ hybridization were performed in 98.8%, 95.4%, 75.9%, and 75.7% of patients, respectively. Molecular testing was done more frequently at academic than community/government sites (84.3% vs 70.2%; P < .001). Enrolment to the Registry after 2016 was significantly associated with molecular testing at academic sites (odds ratio [OR] 2.59; P = .023) and at community/government sites (OR 4.85; P < .001) in logistic regression analyses. Better understanding of practice patterns may identify unmet needs and inform institutional protocols regarding the diagnosis of patients with AML.

RevDate: 2022-07-17

Hiatt JB, Romine PE, DY Wu (2022)

Improving the efficacy of immunotherapy in small cell lung cancer: Leveraging recent scientific discoveries and tumor-specific antigens.

Seminars in oncology pii:S0093-7754(22)00043-4 [Epub ahead of print].

Small cell lung cancer (SCLC) is an aggressive neuroendocrine neoplasm with poor survival outcomes and little change to treatment standards over decades. SCLC is associated with heavy tobacco exposure and a high rate of somatic mutations in tumor cells, leading to hope that immune checkpoint inhibitors would dramatically reshape the treatment landscape of SCLC. Instead, immune checkpoint inhibitors have led to real but modest gains in outcomes, with only a small minority of patients deriving more durable benefit. Furthermore, biomarkers of ICI efficacy that have succeeded in other tumor types have not been validated in SCLC. However, recent research advances have suggested that epigenetic heterogeneity and plasticity play especially key roles in SCLC biology. Leveraging this emerging perspective, a new slate of candidate biomarkers of immune checkpoint inhibitor benefit have been described, and the novel treatment strategies combining rational epigenetic perturbation with immune checkpoint inhibitors are being developed. Finally, other immunotherapy strategies targeting SCLC-specific mechanisms are being tested. Together, these developments may lead to a second generation of much more efficacious immunotherapies in SCLC.

RevDate: 2022-07-17

Caliebe A, Tekola-Ayele F, Darst BF, et al (2022)

Including diverse and admixed populations in genetic epidemiology research.

Genetic epidemiology [Epub ahead of print].

The inclusion of ancestrally diverse participants in genetic studies can lead to new discoveries and is important to ensure equitable health care benefit from research advances. Here, members of the Ethical, Legal, Social, Implications (ELSI) committee of the International Genetic Epidemiology Society (IGES) offer perspectives on methods and analysis tools for the conduct of inclusive genetic epidemiology research, with a focus on admixed and ancestrally diverse populations in support of reproducible research practices. We emphasize the importance of distinguishing socially defined population categorizations from genetic ancestry in the design, analysis, reporting, and interpretation of genetic epidemiology research findings. Finally, we discuss the current state of genomic resources used in genetic association studies, functional interpretation, and clinical and public health translation of genomic findings with respect to diverse populations.

RevDate: 2022-07-15

Hettmer S, Linardic CM, Kelsey A, et al (2022)

Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children's Oncology Group and Cooperative Weichteilsarkom-Studiengruppe.

European journal of cancer (Oxford, England : 1990), 172:367-386 pii:S0959-8049(22)00324-0 [Epub ahead of print].

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.

RevDate: 2022-07-15

Muffly L, Yin J, Jacobson S, et al (2022)

Disparities in trial enrollment and outcomes of Hispanic adolescent and young adult acute lymphoblastic leukemia.

Blood advances, 6(14):4085-4092.

In this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients.

RevDate: 2022-07-15

Nomburg J, Bullman S, Nasrollahzadeh D, et al (2022)

An international report on bacterial communities in esophageal squamous cell carcinoma.

International journal of cancer [Epub ahead of print].

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella, and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

RevDate: 2022-07-14

LaMonte MJ, Manson JE, Anderson GL, et al (2022)

Contributions of the Women's Health Initiative to Cardiovascular Research: JACC State-of-the-Art Review.

Journal of the American College of Cardiology, 80(3):256-275.

The WHI (Women's Health Initiative) enrolled 161,808 racially and ethnically diverse postmenopausal women, ages 50-79 years, from 1993 to 1998 at 40 clinical centers across the United States. In its clinical trial component, WHI evaluated 3 randomized interventions (menopausal hormone therapy; diet modification; and calcium/vitamin D supplementation) for the primary prevention of major chronic diseases, including cardiovascular disease, in older women. In the WHI observational study, numerous clinical, behavioral, and social factors have been evaluated as predictors of incident chronic disease and mortality. Although the original interventions have been completed, the WHI data and biomarker resources continue to be leveraged and expanded through ancillary studies to yield novel insights regarding cardiovascular disease prevention and healthy aging in women.

RevDate: 2022-07-14

Symonds L, Konnick E, Vakar-Lopez F, et al (2022)

BRCA2 Alterations in Neuroendocrine/Small-Cell Carcinoma Prostate Cancer: A Case Series.

JCO precision oncology, 6:e2200091.

RevDate: 2022-07-14

Zurko J, Ramdial J, Shadman M, et al (2022)

Allogeneic transplant following CAR T-cell therapy for large B-cell lymphoma.

Haematologica [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR-T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR-T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR-T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR-T failure. The median number of lines of therapy between CAR-T infusion and alloHCT was 1 (range 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis.

RevDate: 2022-07-14

Stephens DM, Li H, Constine LS, et al (2022)

Extranodal presentation in limited stage diffuse large B-cell lymphoma as a prognostic marker in three SWOG trials S0014, S0313 and S1001.

Haematologica [Epub ahead of print].

Not available.

RevDate: 2022-07-14

Othus M, Garcia-Manero G, Godwin JE, et al (2022)

Improved outcomes with 7+3 induction chemotherapy for acute myeloid leukemia over the past four decades: analysis of SWOG trial data.

Haematologica [Epub ahead of print].

We have previously shown that complete response (CR) rates and overall survival (OS) of patients with acute myeloid leukemia (AML) have improved since the 1980s. However, we have not previously evaluated how the length of first CR (CR1) has changed over this time period. To address this, we analyzed 1,247 patients age 65 or younger randomized to 7+3 arms from 5 SWOG studies: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). We evaluated length of CR1 and survival after relapse from CR1 over the 4 decades these studies represent. Both length of CR1 and survival after relapse from CR1 have improved over the last four decades. The relative benefit associated with CR1 and the relative detriment associated with relapse have decreased over this period; while achieving CR1 and relapse from CR1 still have strong prognostic associations with outcomes, the magnitude of the association has decreased over time. Possible explanations for these patterns include higher CR rates with salvage therapies after relapse, more frequent use of hematopoietic cell transplant, and better supportive care.

RevDate: 2022-07-13

Bricker J, Mull K, Santiago-Torres M, et al (2022)

Smoking cessation smartphone application use over time: Do usage patterns predict 12-month cessation outcomes?.

Journal of medical Internet research [Epub ahead of print].

BACKGROUND: Little is known about how individuals engage over time with smartphone application interventions and whether this engagement predicts health outcomes.

OBJECTIVE: In the context of a randomized trial comparing two smartphone applications (apps) for smoking cessation, to determine: (1) distinct groups of smartphone app login trajectories over a 6-month period, (2) their association with smoking cessation outcomes at 12-months, and (3) baseline user characteristics that predict data-driven trajectory group membership.

METHODS: Functional clustering of 182 consecutive days of smoothed login data from both arms of a large (N = 2415) randomized trial of two smartphone apps for smoking cessation (iCanQuit and QuitGuide) was used to identify distinct trajectory groups. Logistic regression was used to determine the association of group membership with the primary outcome of 30-day point prevalence smoking abstinence at 12 months. Finally, baseline characteristics associated with group membership were examined using logistic and multinomial logistic regression. Analyses were conducted separately for each app.

RESULTS: For iCanQuit, participants were clustered into three groups: "1-week users" (n=610, 57% of the sample), "4-week users" (n=303, 28%), and "26-week users" (n=156, 15%). For smoking cessation rates at the 12-month follow-up, compared to 1-week users, 4-week users had 50% higher odds of cessation (30% vs. 23%; OR = 1.50; 95% CI = 1.05, 2.14; p = .027) whereas 26-week users had 397% higher odds (56% vs. 23%; OR = 4.97; 95% CI = 3.31, 7.52; p < .001). For QuitGuide, participants were clustered into two groups: "1-week users" (n=695, 65% of the sample), and "3-week users" (n=369, 35%). The difference in the odds of being abstinent at 12-months for 3-week users vs. 1-week users was minimal (23% vs. 21%; OR = 1.16; 95% CI = 0.84, 1.62; p = .370). Different baseline characteristics predicted trajectory group membership for each app.

CONCLUSIONS: Patterns of 1-, 3-, and 4-week usage of smartphone apps for smoking cessation may be common for how people engage in digital health interventions. There were significant higher odds of quitting smoking among 4-week users, and especially among 26-week users of the iCanQuit application. To improve study outcomes, strategies for detecting users who disengage early from these interventions (1-week users) and proactively offering them a more intensive intervention could be fruitful.

CLINICALTRIAL: Clinical Trials.gov Registration Number: NCT02724462.

RevDate: 2022-07-14

von Mehren M, Kane JM, Agulnik M, et al (2022)

Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 20(7):815-833.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.

RevDate: 2022-07-14

Wood DE, Kazerooni EA, Aberle D, et al (2022)

NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2022.

Journal of the National Comprehensive Cancer Network : JNCCN, 20(7):754-764.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

RevDate: 2022-07-13

Filson CP, Zhu K, Huang Y, et al (2022)

Impact of Prostate Health Index Results for Prediction of Biopsy Grade Reclassification During Active Surveillance.

The Journal of urology [Epub ahead of print].

OBJECTIVE: We assessed whether Prostate Health Index (phi) results improve prediction of grade reclassification for men on active surveillance.

METHODS/MATERIALS: We identified men in Canary Prostate Active Surveillance Study with Grade Group (GG) 1 cancer. Outcome was grade reclassification to GG2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R1) vs clinical data+phi (R3). We considered an "or"-logic rule combining clinical score and phi (R4), and a "two-step" rule using clinical data followed by risk stratification based on phi (R2). Rules were applied to a validation set, where values of R2 - R4 vs R1 for specificity and sensitivity were evaluated.

RESULTS: We included 1532 biopsies (n=610 discovery; n=922 validation) among 1142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among discovery set, at 95% sensitivity, R2 yielded highest specificity at 27% vs 17% for R1. In validation set, R3 had best performance vs R1 with Δsensitivity = -4% and Δspecificity = +6%. There was slight improvement for R3 vs R1 for confirmatory biopsy (AUC 0.745 vs R1 0.724, ΔAUC=0.021, 95%CI 0.002-0.041) but not for subsequent biopsies (ΔAUC=-0.012, 95%CI -0.031-0.006). R3 did not have better discrimination vs R1 among the biopsy cohort overall (ΔAUC=0.007, 95%CI -0.007-0.020).

CONCLUSIONS: Among active surveillance patients, using phi with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.

RevDate: 2022-07-13

Traxinger B, Vick SC, Woodward-Davis A, et al (2022)

Mucosal viral infection induces a regulatory T cell activation phenotype distinct from tissue residency in mouse and human tissues.

Mucosal immunology [Epub ahead of print].

Regulatory T cells (Tregs) mediate immune homeostasis, yet also facilitate nuanced immune responses during infection, balancing pathogen control while limiting host inflammation. Recent studies have identified Treg populations in non-lymphoid tissues that are phenotypically distinct from Tregs in lymphoid tissues (LT), including performance of location-dependent roles. Mucosal tissues serve as critical barriers to microbes while performing unique physiologic functions, so we sought to identify distinct phenotypical and functional aspects of mucosal Tregs in the female reproductive tract. In healthy human and mouse vaginal mucosa, we found that Tregs are highly activated compared to blood or LT Tregs. To determine if this phenotype reflects acute activation or a general signature of vaginal tract (VT)-residency, we infected mice with HSV-2 to discover that VT Tregs express granzyme-B (GzmB) and acquire a VT Treg signature distinct from baseline. To determine the mechanisms that drive GzmB expression, we performed ex vivo assays to reveal that a combination of type-I interferons and interleukin-2 is sufficient for GzmB expression. Together, we highlight that VT Tregs are activated at steady state and become further activated in response to infection; thus, they may exert robust control of local immune responses, which could have implications for mucosal vaccine design.

RevDate: 2022-07-13

Hoge ACH, Getz M, Zimmer A, et al (2022)

Publisher Correction: DNA-based copy number analysis confirms genomic evolution of PDX models.

NPJ precision oncology, 6(1):50 pii:10.1038/s41698-022-00293-5.

RevDate: 2022-07-12

Jelley L, Douglas J, Ren X, et al (2022)

Genomic epidemiology of Delta SARS-CoV-2 during transition from elimination to suppression in Aotearoa New Zealand.

Nature communications, 13(1):4035.

New Zealand's COVID-19 elimination strategy heavily relied on the use of genomics to inform contact tracing, linking cases to the border and to clusters during community outbreaks. In August 2021, New Zealand entered its second nationwide lockdown after the detection of a single community case with no immediately apparent epidemiological link to the border. This incursion resulted in the largest outbreak seen in New Zealand caused by the Delta Variant of Concern. Here we generated 3806 high quality SARS-CoV-2 genomes from cases reported in New Zealand between 17 August and 1 December 2021, representing 43% of reported cases. We detected wide geographical spread coupled with undetected community transmission, characterised by the apparent extinction and reappearance of genomically linked clusters. We also identified the emergence, and near replacement, of genomes possessing a 10-nucleotide frameshift deletion that caused the likely truncation of accessory protein ORF7a. By early October, New Zealand moved from an elimination strategy to a suppression strategy and the role of genomics changed markedly from being used to track and trace, towards population-level surveillance.

RevDate: 2022-07-12

Moser R, Annis J, Nikolova O, et al (2022)

Pharmacological targeting of TFIIH suppresses KRAS mutant pancreatic ductal adenocarcinoma and synergizes with TRAIL.

Cancer research pii:706975 [Epub ahead of print].

Pancreatic ductal adenocarcinoma (PDAC) typically presents as metastatic disease at diagnosis and remains refractory to treatment. Next generation sequencing efforts have described the genomic landscape, classified molecular subtypes, and confirmed frequent alterations in major driver genes, with coexistent alterations in KRAS and TP53 correlating with the highest metastatic burden and poorest outcomes. However, translating this information to guide therapy remains a challenge. By integrating genomic analysis with an arrayed RNAi druggable genome screen and drug profiling of a KRAS/TP53 mutant PDAC cell line derived from a patient-derived xenograft (PDCL), we identified numerous targetable vulnerabilities that reveal both known and novel functional aspects of pancreatic cancer biology. A dependence on the general transcription and DNA repair factor TFIIH complex, particularly the XPB subunit and the CAK complex (CDK7/CyclinH/MAT1), was identified and further validated utilizing a panel of genomically subtyped KRAS mutant PDCLs. TFIIH function was inhibited with a covalent inhibitor of CDK7/12/13 (THZ1), a CDK7/CDK9 kinase inhibitor (SNS-032), and a covalent inhibitor of XPB (Triptolide), which led to disruption of the protein stability of the RNA polymerase II subunit RPB1. Loss of RPB1 following TFIIH inhibition led to downregulation of key transcriptional effectors of KRAS mutant signaling and negative regulators of apoptosis, including MCL1, XIAP, and CFLAR, initiating caspase-8 dependent apoptosis. All three drugs exhibited synergy in combination with a multivalent TNF-related apoptosis inducing ligand (TRAIL), effectively reinforcing mitochondrial-mediated apoptosis. These findings present a novel combination therapy with direct translational implications for current clinical trials on metastatic pancreatic cancer patients.

RevDate: 2022-07-13
CmpDate: 2022-07-13

Hargreaves JR, Pliakas T, Hoddinott G, et al (2022)

The association between HIV stigma and HIV incidence in the context of universal testing and treatment: analysis of data from the HPTN 071 (PopART) trial in Zambia and South Africa.

Journal of the International AIDS Society, 25 Suppl 1:e25931.

INTRODUCTION: To investigate the association between individual and community-level measures of HIV stigma and HIV incidence within the 21 communities participating in the HPTN (071) PopART trial in Zambia and South Africa.

METHODS: Secondary analysis of data from a population-based cohort followed-up over 36 months between 2013 and 2018. The outcome was rate of incident HIV infection among individuals who were HIV negative at cohort entry. Individual-level exposures, measured in a random sample of all participants, were: (1) perception of stigma in the community, (2) perception of stigma in health settings and (3) fear and judgement towards people living with HIV. Individual-level analyses were conducted with adjusted, individual-level Poisson regression. Community-level HIV stigma exposures drew on data reported by people living with HIV, health workers and community members. We used linear regression to explore the association between HIV stigma and community-level HIV incidence.

RESULTS: Among 8172 individuals who were HIV negative and answered individual-level stigma questions at enrolment to the cohort, there was no evidence of a statistically significant association between any domain of HIV stigma and risk of incident HIV infection. Among the full cohort of 26,110 individuals among whom HIV incidence was measured, there was no evidence that community-level HIV incidence was associated with any domain of HIV stigma.

CONCLUSIONS: HIV stigma is often cited as a barrier to the effectiveness of HIV prevention programming. However, in the setting for the HPTN 071 "PopART trial," measured stigma alone was not associated with the risk of HIV infection.

RevDate: 2022-07-12

Sapkota Y, Liu Q, Li N, et al (2022)

Contribution of Genome-Wide Polygenic Score to Risk of Coronary Artery Disease in Childhood Cancer Survivors.

JACC. CardioOncology, 4(2):258-267 pii:S2666-0873(22)00222-8.

Background: Adverse cardiovascular outcomes such as coronary artery disease (CAD) are the leading noncancer causes of morbidity and mortality among childhood cancer survivors.

Objectives: The aim of this study was to assess the role of a genome-wide polygenic score (GPS) for CAD, well validated in the general population, and its interplay with cancer-related risk factors among childhood cancer survivors.

Methods: In a cohort study of 2,472 5-year childhood cancer survivors from the St. Jude Lifetime Cohort, the association between the GPS and the risk of CAD was performed using Cox regression models adjusted for age at cancer diagnosis, sex, cumulative dose of anthracyclines, and mean heart radiation dose.

Results: Among survivors of European ancestry, the GPS was significantly associated with the risk of CAD (HR per 1 SD of the GPS: 1.25; 95% CI: 1.04-1.49; P = 0.014). Compared with the first tertile, survivors in the upper tertile had a greater risk of CAD (1.51-fold higher HR of CAD [95% CI: 0.96-2.37; P = 0.074]), although the difference was not statistically significant. The GPS-CAD association was stronger among survivors diagnosed with cancer at age <10 years exposed to >25 Gy heart radiation (HR top vs. bottom tertile of GPS: 15.49; 95% CI: 5.24-45.52; P trend = 0.005) but not among those diagnosed at age ≥10 years (P trend ≥ 0.77) and not among those diagnosed at age <10 years exposed to ≤25 Gy heart radiation (P trend = 0.23). Among high-risk survivors, defined by an estimated relative hazard ≥3.0 from fitted Cox models including clinical risk factors alone, the cumulative incidence of CAD at 40 years from diagnosis was 29% (95% CI: 13%-45%). After incorporating the GPS into the model, the cumulative incidence increased to 48% (95% CI: 26%-69%).

Conclusions: Childhood cancer survivors are at risk for premature CAD. A GPS may help identify those who may benefit from targeted screening and personalized preventive interventions.

RevDate: 2022-07-05

Sesso HD, Manson JE, Aragaki AK, et al (2022)

Reply to Ramírez PC and Diaz-Quijano FA (AJCN-D-22-00631).

The American journal of clinical nutrition pii:6631549 [Epub ahead of print].

RevDate: 2022-07-12
CmpDate: 2022-07-12

Hirko KA, Xu H, Rogers LQ, et al (2022)

Cancer disparities in the context of rurality: risk factors and screening across various U.S. rural classification codes.

Cancer causes & control : CCC, 33(8):1095-1105.

PURPOSE: Prior cancer research is limited by inconsistencies in defining rurality. The purpose of this study was to describe the prevalence of cancer risk factors and cancer screening behaviors across various county-based rural classification codes, including measures reflecting a continuum, to inform our understanding of cancer disparities according to the extent of rurality.

METHODS: Using an ecological cross-sectional design, we examined differences in cancer risk factors and cancer screening behaviors from the Behavioral Risk Factor Surveillance System and National Health Interview Survey (2008-2013) across rural counties and between rural and urban counties using four rural-urban classification codes for counties and county-equivalents in 2013: U.S. Office of Management and Budget, National Center for Health Statistics, USDA Economic Research Service's rural-urban continuum codes, and Urban Influence Codes.

RESULTS: Although a rural-to-urban gradient was not consistently evident across all classification codes, the prevalence of smoking, obesity, physical inactivity, and binge alcohol use increased (all ptrend < 0.03), while colorectal, cervical and breast cancer screening decreased (all ptrend < 0.001) with increasing rurality. Differences in the prevalence of risk factors and screening behaviors across rural areas were greater than differences between rural and urban counties for obesity (2.4% vs. 1.5%), physical activity (2.9% vs. 2.5%), binge alcohol use (3.4% vs. 0.4%), cervical cancer screening (6.8% vs. 4.0%), and colorectal cancer screening (4.4% vs. 3.8%).

CONCLUSIONS: Rural cancer disparities persist across multiple rural-urban classification codes, with marked variation in cancer risk factors and screening evident within rural regions. Focusing only on a rural-urban dichotomy may not sufficiently capture subpopulations of rural residents at greater risk for cancer and cancer-related mortality.

RevDate: 2022-07-01
CmpDate: 2022-07-01

Cheng J, Clayton JS, Acemel RD, et al (2022)

Regulatory Architecture of the RCA Gene Cluster Captures an Intragenic TAD Boundary, CTCF-Mediated Chromatin Looping and a Long-Range Intergenic Enhancer.

Frontiers in immunology, 13:901747.

The Regulators of Complement Activation (RCA) gene cluster comprises several tandemly arranged genes with shared functions within the immune system. RCA members, such as complement receptor 2 (CR2), are well-established susceptibility genes in complex autoimmune diseases. Altered expression of RCA genes has been demonstrated at both the functional and genetic level, but the mechanisms underlying their regulation are not fully characterised. We aimed to investigate the structural organisation of the RCA gene cluster to identify key regulatory elements that influence the expression of CR2 and other genes in this immunomodulatory region. Using 4C, we captured extensive CTCF-mediated chromatin looping across the RCA gene cluster in B cells and showed these were organised into two topologically associated domains (TADs). Interestingly, an inter-TAD boundary was located within the CR1 gene at a well-characterised segmental duplication. Additionally, we mapped numerous gene-gene and gene-enhancer interactions across the region, revealing extensive co-regulation. Importantly, we identified an intergenic enhancer and functionally demonstrated this element upregulates two RCA members (CR2 and CD55) in B cells. We have uncovered novel, long-range mechanisms whereby autoimmune disease susceptibility may be influenced by genetic variants, thus highlighting the important contribution of chromatin topology to gene regulation and complex genetic disease.

RevDate: 2022-07-11

Mishra A, Tamari R, DeZern AE, et al (2022)

Eprenetapopt Plus Azacitidine After Allogeneic Hematopoietic Stem-Cell Transplantation for TP53-Mutant Acute Myeloid Leukemia and Myelodysplastic Syndromes.

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

PURPOSE: Outcomes are poor in TP53-mutant (mTP53) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), even after allogeneic hematopoietic stem-cell transplant (HCT). Eprenetapopt (APR-246) is a first-in-class, small-molecule p53 reactivator.

PATIENTS AND METHODS: We conducted a phase II, multicenter, open-label trial to assess efficacy and safety of eprenetapopt combined with azacitidine as maintenance therapy after HCT (ClinicalTrials.gov identifier: NCT03931291). Patients with mTP53 MDS or AML received up to 12 cycles of eprenetapopt 3.7 g once daily intravenously on days 1-4 and azacitidine 36 mg/m2 once daily intravenously/subcutaneously on days 1-5 in 28-day cycles. The primary outcomes were relapse-free survival (RFS) and safety.

RESULTS: Of the 84 patients screened for eligibility before HCT, 55 received a transplant. Thirty-three patients ultimately received maintenance treatment (14 AML and 19 MDS); the median age was 65 (range 40-74) years. The median number of eprenetapopt cycles was 7 (range 1-12). With a median follow-up of 14.5 months, the median RFS was 12.5 months (95% CI, 9.6 to not estimable) and the 1-year RFS probability was 59.9% (95% CI, 41 to 74). With a median follow-up of 17.0 months, the median overall survival (OS) was 20.6 months (95% CI, 14.2 to not estimable) and the 1-year OS probability was 78.8% (95% CI, 60.6 to 89.3). Thirty-day and 60-day mortalities from the first dose were 0% and 6% (n = 2), respectively. Acute and chronic (all grade) graft-versus-host disease adverse events were reported in 12% (n = 4) and 33% (n = 11) of patients, respectively.

CONCLUSION: In patients with mTP53 AML and MDS, post-HCT maintenance therapy with eprenetapopt combined with azacitidine was well tolerated. RFS and OS outcomes were encouraging in this high-risk population.

RevDate: 2022-07-11

Romieu I, Khandpur N, Katsikari A, et al (2022)

Consumption of industrial processed foods and risk of premenopausal breast cancer among Latin American women: the PRECAMA study.

BMJ nutrition, prevention & health, 5(1):1-9 pii:bmjnph-2021-000335.

Ultra-processed food intake has been linked to an increased risk of breast cancer in Western populations. No data are available in the Latin American population although the consumption of ultra-processed foods is increasing rapidly in this region. We evaluated the association of ultra-processed food intake to breast cancer risk in a case-control study including 525 cases (women aged 20-45 years) and 525 matched population-based controls from Chile, Colombia, Costa Rica and Mexico. The degree of processing of foods was classified according to the NOVA classification. Overall, the major contributors to ultra-processed food intake were ready-to-eat/heat foods (18.2%), cakes and desserts (16.7%), carbonated and industrial fruit juice beverages (16.7%), breakfast cereals (12.9%), sausages and reconstituted meat products (12.1%), industrial bread (6.1%), dairy products and derivatives (7.6%) and package savoury snacks (6.1%). Ultra-processed food intake was positively associated with the risk of breast cancer in adjusted models (OR T3-T1=1.93; 95% CI=1.11 to 3.35). Specifically, a higher risk was observed with oestrogen receptor positive breast cancer (ORT3-T1=2.44, (95% CI=1.01 to 5.90, P-trend=0.049), while no significant association was observed with oestrogen receptor negative breast cancer (ORT3-T1=1.87, 95% CI=0.43 to 8.13, P-trend=0.36). Our findings suggest that the consumption of ultra-processed foods might increase the risk of breast cancer in young women in Latin America. Further studies should confirm these findings and disentangle specific mechanisms relating ultra-processed food intake and carcinogenic processes in the breast.

RevDate: 2022-07-11

Hwang WH, Stoklosa J, CY Wang (2022)

Population Size Estimation using Zero-truncated Poisson Regression with Measurement Error.

Journal of agricultural, biological, and environmental statistics, 27(2):303-320.

Population size estimation is an important research field in biological sciences. In practice, covariates are often measured upon capture on individuals sampled from the population. However, some biological measurements, such as body weight may vary over time within a subject's capture history. This can be treated as a population size estimation problem in the presence of covariate measurement error. We show that if the unobserved true covariate and measurement error are both normally distributed, then a naïve estimator without taking into account measurement error will under-estimate the population size. We then develop new methods to correct for the effect of measurement errors. In particular, we present a conditional score and a nonparametric corrected score approach that are both consistent for population size estimation. Importantly, the proposed approaches do not require the distribution assumption on the true covariates, furthermore the latter does not require normality assumptions on the measurement errors. This is highly relevant in biological applications, as the distribution of covariates is often non-normal or unknown. We investigate finite sample performance of the new estimators via extensive simulated studies. The methods are applied to real data from a capture-recapture study.

RevDate: 2022-07-11

Buszkiewicz JH, Rose CM, Ko LK, et al (2022)

Associations between neighborhood built environment, residential property values, and adult BMI change: The Seattle Obesity Study III.

SSM - population health, 19:101158 pii:S2352-8273(22)00137-9.

Objective: To examine associations between neighborhood built environment (BE) variables, residential property values, and longitudinal 1- and 2-year changes in body mass index (BMI).

Methods: The Seattle Obesity Study III was a prospective cohort study of adults with geocoded residential addresses, conducted in King, Pierce, and Yakima Counties in Washington State. Measured heights and weights were obtained at baseline (n = 879), year 1 (n = 727), and year 2 (n = 679). Tax parcel residential property values served as proxies for individual socioeconomic status. Residential unit and road intersection density were captured using Euclidean-based SmartMaps at 800 m buffers. Counts of supermarket (0 versus. 1+) and fast-food restaurant availability (0, 1-3, 4+) were measured using network based SmartMaps at 1600 m buffers. Density measures and residential property values were categorized into tertiles. Linear mixed-effects models tested whether baseline BE variables and property values were associated with differential changes in BMI at year 1 or year 2, adjusting for age, gender, race/ethnicity, education, home ownership, and county of residence. These associations were then tested for potential disparities by age group, gender, race/ethnicity, and education.

Results: Road intersection density, access to food sources, and residential property values were inversely associated with BMI at baseline. At year 1, participants in the 3rd tertile of density metrics and with 4+ fast-food restaurants nearby showed less BMI gain compared to those in the 1st tertile or with 0 restaurants. At year 2, higher residential property values were predictive of lower BMI gain. There was evidence of differential associations by age group, gender, and education but not race/ethnicity.

Conclusion: Inverse associations between BE metrics and residential property values at baseline demonstrated mixed associations with 1- and 2-year BMI change. More work is needed to understand how individual-level sociodemographic factors moderate associations between the BE, property values, and BMI change.

RevDate: 2022-07-11

Panaite L, Wu QV, Voutsinas J, et al (2022)

Predictors of cytopenias after treatment with axicabtagene ciloleucel in patients with large B-cell lymphoma.

Leukemia & lymphoma [Epub ahead of print].

Cytopenias are important but less studied adverse events following chimeric antigen receptor-engineered T cell (CAR-T) therapy. In our analysis of patients with large cell lymphoma who received axicabtagene ciloleucel (axi-cel), we sought to determine the rate and risk factors of clinically significant short term cytopenias defined as grade ≥3 neutropenia, anemia, or thrombocytopenia, or treatment with growth factors or blood product transfusions between days 20-30 after axi-cel. Fifty-three pts received axi-cel during the study period and severe cytopenias were observed in 32 (60%) pts. Significant cytopenias were more common in non-responders (stable or progressive disease) vs. responders (partial or complete response) (100% vs. 70%; p = .01). In the multivariable model, platelet transfusion within a month before leukapheresis, number of red blood cell and platelet transfusions between leukapheresis to lymphodepletion, pre-lymphodepletion absolute neurophil count, pre-lymphodepletion lactate dehydrogenase, and number of dexamethasone treatments after CAR-T were significantly associated with severe cytopenias after axi-cel.

RevDate: 2022-07-10

Tam CS, Brown JR, Kahl BS, et al (2022)

Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial.

The Lancet. Oncology pii:S1470-2045(22)00293-5 [Epub ahead of print].

BACKGROUND: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL.

METHODS: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment.

FINDINGS: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B).

INTERPRETATION: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL.

FUNDING: BeiGene.

RevDate: 2022-07-09

Goga A, Bekker LG, Garrett N, et al (2022)

Breakthrough SARS-CoV-2 infections during periods of delta and omicron predominance, South Africa.

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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.

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

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

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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.

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

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

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Papers in Classical Genetics

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.

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

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