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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 08 Mar 2021 at 01:33 Created: 

Publications by FHCRC Researchers

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

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

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

Citations The Papers (from PubMed®)

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RevDate: 2021-03-05

Koole JL, Bours MJL, Geijsen AJMR, et al (2021)

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

The American journal of clinical nutrition pii:6154815 [Epub ahead of print].

BACKGROUND: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear.

OBJECTIVES: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis.

METHODS: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing.

RESULTS: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers.

CONCLUSIONS: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.

RevDate: 2021-03-05

Thomas M, Sakoda LC, Hoffmeister M, et al (2021)

Response to Li and Hopper.

American journal of human genetics, 108(3):527-529.

RevDate: 2021-03-05

Hahn WC, Bader JS, Braun TP, et al (2021)

An expanded universe of cancer targets.

Cell, 184(5):1142-1155.

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

RevDate: 2021-03-05

Xu Y, Miller CP, Warren EH, et al (2021)

Current status of antigen-specific T-cell immunotherapy for advanced renal-cell carcinoma.

Human vaccines & immunotherapeutics [Epub ahead of print].

In renal-cell carcinoma (RCC), tumor-reactive T-cell responses can occur spontaneously or in response to systemic immunotherapy with cytokines and immune checkpoint inhibitors. Cancer vaccines and engineered T-cell therapies are designed to selectively augment tumor antigen-specific CD8+ T-cell responses with the goal to elicit tumor regression and avoid toxicities associated with nonspecific immunotherapies. In this review, we provide an overview of the central role of T-cell immunity in the treatment of advanced RCC. Clinical outcomes for antigen-targeted vaccines or other T-cell-engaging therapies for RCC are summarized and evaluated, and emerging new strategies to enhance the effectiveness of antigen-specific therapy for RCC are discussed.

RevDate: 2021-03-05

Figuracion KCF, FM Lewis (2021)

Environmental enrichment: A concept analysis.

Nursing forum [Epub ahead of print].

OBJECTIVES: The concept analysis of environmental enrichment aims to clarify the meaning of the term contributing to a shared understanding of its use in healthcare and future research studies. Environmental enrichment has implications in health promotion in children's development and healthy aging in the general population.

METHODS: A literature search using PubMed and CINAHL databases on environmental enrichment was conducted to identify the uses of the term from various disciplines. The keywords are "environmental enrichment", "socialization", "physical activity", "cognitive stimulation", and "experience-dependent". Human studies from 2000 to 2020 were included in the search.

RESULTS: Availability of green spaces, neighborhood safety, walkability to community centers, and accessibility of community resources are antecedents of environmental enrichment. Defining attributes are positive stimulation, interpersonal interaction, and physical engagement. The consequences of environmental enrichment are improved cognitive functioning in children, decline in memory impairment, and reduced risk of developing dementia in the elderly.

CONCLUSION: Engaging and counseling patients, family members, and the community in adverse effects of a deprived environment and the benefits of an enriched environment is a vital tenet of the nursing discipline. Understanding the optimum amount of positive stimulation, interpersonal interaction duration, and frequency are needed in future research.

RevDate: 2021-03-05

Speakman JR, Yamada Y, Sagayama H, et al (2021)

A standard calculation methodology for human doubly labeled water studies.

Cell reports. Medicine, 2(2):100203 pii:S2666-3791(21)00014-8.

The doubly labeled water (DLW) method measures total energy expenditure (TEE) in free-living subjects. Several equations are used to convert isotopic data into TEE. Using the International Atomic Energy Agency (IAEA) DLW database (5,756 measurements of adults and children), we show considerable variability is introduced by different equations. The estimated rCO2 is sensitive to the dilution space ratio (DSR) of the two isotopes. Based on performance in validation studies, we propose a new equation based on a new estimate of the mean DSR. The DSR is lower at low body masses (<10 kg). Using data for 1,021 babies and infants, we show that the DSR varies non-linearly with body mass between 0 and 10 kg. Using this relationship to predict DSR from weight provides an equation for rCO2 over this size range that agrees well with indirect calorimetry (average difference 0.64%; SD = 12.2%). We propose adoption of these equations in future studies.

RevDate: 2021-03-05

Smith LP, Yamato JA, Galipeau PC, et al (2021)

Within-patient phylogenetic reconstruction reveals early events in Barrett's Esophagus.

Evolutionary applications, 14(2):399-415 pii:EVA13125.

Barrett's Esophagus is a neoplastic condition which progresses to esophageal adenocarcinoma in 5% of cases. Key events affecting the outcome likely occur before diagnosis of Barrett's and cannot be directly observed; we use phylogenetic analysis to infer such past events. We performed whole-genome sequencing on 4-6 samples from 40 cancer outcome and 40 noncancer outcome patients with Barrett's Esophagus, and inferred within-patient phylogenies of deconvoluted clonal lineages. Spatially proximate lineages clustered in the phylogenies, but temporally proximate ones did not. Lineages with inferred loss-of-function mutations in both copies of TP53 and CDKN2A showed enhanced spatial spread, whereas lineages with loss-of-function mutations in other frequently mutated loci did not. We propose a two-phase model with expansions of TP53 and CKDN2A mutant lineages during initial growth of the segment, followed by relative stasis. Subsequent to initial expansion, mutations in these loci as well as ARID1A and SMARCA4 may show a local selective advantage but do not expand far: The spatial structure of the Barrett's segment remains stable during surveillance even in patients who go on to cancer. We conclude that the cancer/noncancer outcome is strongly affected by early steps in formation of the Barrett's segment.

RevDate: 2021-03-04

Mino-Kenudson M, Le Stang N, Daigneault JB, et al (2021)

IASLC Global Survey on PD-L1 Testing for Non-Small Cell Lung Cancer.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(21)01732-9 [Epub ahead of print].

BACKGROUND: PD-L1 immunohistochemistry (IHC) is required to determine eligibility for pembrolizumab monotherapy in advanced non-small cell lung cancer (NSCLC) worldwide and for several other indications depending on the country. Four assays have been approved/CE-IVD marked, but PD-L1 IHC seems diversely implemented across regions and laboratories with the application of laboratory-developed tests (LDTs).

METHOD: To assess practice of PD-L1 IHC and identify issues and disparities, the IASLC pathology committee conducted a global survey for pathologists from January to May 2019, comprising multiple questions on pre-analytical, analytical and post-analytical conditions.

RESULT: 344 pathologists from 64 countries participated with 41% from Europe, 24% from North America, and 18% from Asia. Besides biopsies and resections, cellblocks were used by 75% of the participants and smears by 11%. The clone 22C3 was most commonly used (69%) followed by SP263 (51%). They were applied as a LDT by 40% and 30% of the users, respectively, and 76% of the participants developed at least one LDT. A half of the participants reported turnaround time (TAT) of ≤ 2 days, while 13% reported that of ≥ 5 days. Additionally, quality assurance (QA), formal training for scoring and standardized reporting were not implemented by 18%, 16% and 14% of the participants, respectively.

CONCLUSION: Heterogeneity in PD-L1 testing is marked across regions and laboratories in terms of antibody clones, IHC assays, samples, TATs and QA measures. The lack of QA, formal training and standardized reporting stated by a significant minority identifies a need for additional QA measures and training opportunities.

RevDate: 2021-03-04

Thouvenel CD, Fontana MF, Netland J, et al (2021)

Multimeric antibodies from antigen-specific human IgM+ memory B cells restrict Plasmodium parasites.

The Journal of experimental medicine, 218(4):.

Multimeric immunoglobulin-like molecules arose early in vertebrate evolution, yet the unique contributions of multimeric IgM antibodies to infection control are not well understood. This is partially due to the difficulty of distinguishing low-affinity IgM, secreted rapidly by plasmablasts, from high-affinity antibodies derived from later-arising memory cells. We developed a pipeline to express B cell receptors (BCRs) from Plasmodium falciparum-specific IgM+ and IgG+ human memory B cells (MBCs) as both IgM and IgG molecules. BCRs from both subsets were somatically hypermutated and exhibited comparable monomeric affinity. Crystallization of one IgM+ MBC-derived antibody complexed with antigen defined a linear epitope within a conserved Plasmodium protein. In its physiological multimeric state, this antibody displayed exponentially higher antigen binding than a clonally identical IgG monomer, and more effectively inhibited P. falciparum invasion. Forced multimerization of this IgG significantly improved both antigen binding and parasite restriction, underscoring how avidity can alter antibody function. This work demonstrates the potential of high-avidity IgM in both therapeutics and vaccines.

RevDate: 2021-03-04

Roesch F, M OhAinle (2020)

HIV-CRISPR: A CRISPR/Cas9 Screening Method to Identify Genes Affecting HIV Replication.

Bio-protocol, 10(9):e3614 pii:3614.

Screening with CRISPR/Cas9 technology has already led to significant discoveries in the fields of cancer biology, cell biology and virology. Because of the relatively low false discovery rates and the ability to perform high-throughput, pooled approaches, it has rapidly become the assay of choice for screening studies, including whole-genome screens. Here, we describe a CRISPR screening protocol that allows for efficient screening of the entire life cycle of HIV-1 through packaging of the HIV-CRISPR lentiviral genomes by infecting HIV-1 virus in trans.

RevDate: 2021-03-04

Malherbe DC, Vang L, Mendy J, et al (2020)

Modified Adenovirus Prime-Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge.

Frontiers in immunology, 11:626464.

Designing immunogens and improving delivery methods eliciting protective immunity is a paramount goal of HIV vaccine development. A comparative vaccine challenge study was performed in rhesus macaques using clade C HIV Envelope (Env) and SIV Gag antigens. One group was vaccinated using co-immunization with DNA Gag and Env expression plasmids cloned from a single timepoint and trimeric Env gp140 glycoprotein from one of these clones (DNA+Protein). The other group was a prime-boost regimen composed of two replicating simian (SAd7) adenovirus-vectored vaccines expressing Gag and one Env clone from the same timepoint as the DNA+Protein group paired with the same Env gp140 trimer (SAd7+Protein). The env genes were isolated from a single pre-peak neutralization timepoint approximately 1 year post infection in CAP257, an individual with a high degree of neutralization breadth. Both DNA+Protein and SAd7+Protein vaccine strategies elicited significant Env-specific T cell responses, lesser Gag-specific responses, and moderate frequencies of Env-specific TFH cells. Both vaccine modalities readily elicited systemic and mucosal Env-specific IgG but not IgA. There was a higher frequency and magnitude of ADCC activity in the SAd7+Protein than the DNA+Protein arm. All macaques developed moderate Tier 1 heterologous neutralizing antibodies, while neutralization of Tier 1B or Tier 2 viruses was sporadic and found primarily in macaques in the SAd7+Protein group. Neither vaccine approach provided significant protection from viral acquisition against repeated titered mucosal challenges with a heterologous Tier 2 clade C SHIV. However, lymphoid and gut tissues collected at necropsy showed that animals in both vaccine groups each had significantly lower copies of viral DNA in individual tissues compared to levels in controls. In the SAd7+Protein-vaccinated macaques, total and peak PBMC viral DNA were significantly lower compared with controls. Taken together, this heterologous Tier 2 SHIV challenge study shows that combination vaccination with SAd7+Protein was superior to combination DNA+Protein in reducing viral seeding in tissues in the absence of protection from infection, thus emphasizing the priming role of replication-competent SAd7 vector. Despite the absence of correlates of protection, because antibody responses were significantly higher in this vaccine group, we hypothesize that vaccine-elicited antibodies contribute to limiting tissue viral seeding.

RevDate: 2021-03-04

Merryman RW, Castagna L, Giordano L, et al (2021)

Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma.

Leukemia [Epub ahead of print].

Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.

RevDate: 2021-03-03

Zamora D, Duke ER, Xie H, et al (2021)

Cytomegalovirus-specific T-cell Reconstitution following Letermovir Prophylaxis after Hematopoietic Cell Transplantation.

Blood pii:475413 [Epub ahead of print].

Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. We compared polyfunctional CMV-specific T-cell responses in a prospective cohort of allogeneic HCT recipients who received letermovir to controls who received PCR-guided preemptive therapy prior to the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at three months post-HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen specific T-cell subsets (COMPASS). Letermovir use and reduction in viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjusting for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65; whereas CMV shedding rate was associated with greater CD4+ responses to IE-1. In conclusion, our study provides initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly due to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

RevDate: 2021-03-03

Silhol R, Geidelberg L, Mitchell KM, et al (2021)

Assessing the potential impact of disruptions due to COVID-19 on HIV among key and lower-risk populations in the largest cities of Cameroon and Benin.

Journal of acquired immune deficiency syndromes (1999) pii:00126334-900000000-95920 [Epub ahead of print].

BACKGROUND: The COVID-19 pandemic indirectly impacts HIV epidemiology in Central/West Africa. We estimated the potential impact of COVID-19-related disruptions to HIV prevention/treatment services and sexual partnerships on HIV incidence and HIV-related deaths among key populations including female sex workers (FSW), their clients, men who have sex with men (MSM), and overall.

SETTING: Yaoundé (Cameroon) and Cotonou (Benin).

METHODS: We used mathematical models of HIV calibrated to city- and risk-population-specific demographic/behavioural/epidemic data. We estimated the relative change in 1-year HIV incidence and HIV-related deaths for various disruption scenarios of HIV prevention/treatment services and decreased casual/commercial partnerships, compared to a scenario without COVID-19.

RESULTS: A 50% reduction in condom use in all partnerships over 6 months would increase 1-year HIV incidence by 39%, 42%, 31% and 23% among MSM, FSW, clients, and overall in Yaoundé respectively, and 69%, 49% and 23% among FSW, clients and overall respectively in Cotonou. Combining a 6-month interruption of ART initiation and 50% reduction in HIV prevention/treatment use would increase HIV incidence by 50% and HIV-related deaths by 20%. This increase in HIV infections would be halved by a simultaneous 50% reduction in casual and commercial partnerships.

CONCLUSIONS: Reductions in condom use following COVID-19 would increase infections among key populations disproportionately, particularly FSW in Cotonou, who need uninterrupted condom provision. Disruptions in HIV prevention/treatment services have the biggest impacts on HIV infections and deaths overall, only partially mitigated by equal reductions in casual/commercial sexual partnerships. Maintaining ART provision must be prioritised to minimise short-term excess HIV-related deaths.

RevDate: 2021-03-03

Bitman-Lotan E, Rincon-Arano H, Raz G, et al (2019)

Determination of Chromatin Accessibility in Drosophila MidgutEnterocytes by in situ 5mC Labeling.

Bio-protocol, 9(22):e3435 pii:3435.

Regulation of gene expression involves dynamic changes in chromatin organization, where in many cases open chromatin structure correlates with gene activation. Several methods enable monitoring changes in chromatin accessibility, including ATAC-seq, FAIRE-seq, MNase-seq and DNAse-seq methods, which involve Next-generation-sequencing (NGS). Focusing on the adult Drosophila differentiated gut enterocytes (ECs) we used a sequencing-free method that enables visualizing and semi-quantifying large-scale changes in chromatin structure using in vitro methylation assay with the bacterial CpG Methyltransferase, M. Sssl, that determine chromatin accessibility. In brief, as CpG methylation is minimal in differentiated somatic Drosophila cells, we used the bacterial M. SssI enzyme to methylate CpG dinucleotides in situ depending on their chromatin accessibility. The methylated dinucleotides are detected using 5mCytosine monoclonal antibody and nuclei are visualized microscopically. Thus, the 5mC method enables to monitor large-scale chromatin changes in heterogenic cellular tissue focusing on the cell type of interest and without the need for cell purification or NGS.

RevDate: 2021-03-03

Larson RA, Mandrekar SJ, Huebner LJ, et al (2021)

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

Leukemia [Epub ahead of print].

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

RevDate: 2021-03-03

Sasamoto N, Wang T, Townsend MK, et al (2021)

Prospective analyses of lifestyle factors related to energy balance and ovarian cancer risk by infiltration of tumor associated macrophages.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1686 [Epub ahead of print].

BACKGROUND: Lifestyle factors related to energy balance have been associated with ovarian cancer risk and influence the tumor immune microenvironment, including tumor-associated macrophages (TAMs). However, no studies have assessed whether these factors differentially impact ovarian cancer risk by TAM densities.

METHODS: We conducted a prospective analysis in the Nurses' Health Studies to examine the associations of physical activity, sitting time, and a food-based empirical dietary inflammatory pattern (EDIP) score with invasive epithelial ovarian cancer risk by TAM density assessed by immunohistochemistry. We considered density of CD68 (marker of total TAMs) and CD163 (marker of pro-carcinogenic M2-type TAMs), and their ratios. We used multivariable Cox proportional hazards regression to calculate hazard ratios (HR) and 95% confidence intervals (CIs) of exposures with risk of ovarian tumors with high versus low TAMs, including analyses stratified by body mass index.

RESULTS: Analyses included 312 incident ovarian cancer cases with TAM measurements. Physical activity, sitting time, and EDIP score were not differentially associated with ovarian cancer risk by TAM densities (Pheterogeneity>0.05). Among overweight and obese women, higher EDIP score was associated with increased risk of CD163 low density tumors (HR comparing extreme tertiles=1.57, 95%CI=0.88-2.80; Ptrend=0.01), but not CD163 high density tumors (comparable HR=1.16, 95%CI=0.73-1.86; Ptrend=0.24), though this difference was not statistically significant (Pheterogeneity=0.22).

CONCLUSIONS: We did not observe differential associations between lifestyle factors and ovarian cancer risk by TAM densities.

IMPACT: Future investigations examining the interplay between other ovarian cancer risk factors and the tumor immune microenvironment may help provide insight into ovarian cancer etiology.

RevDate: 2021-03-03

Dimou N, Yarmolinsky J, Bouras E, et al (2021)

Causal effects of lifetime smoking on breast and colorectal cancer risk: Mendelian randomization study.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1218 [Epub ahead of print].

BACKGROUND: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.

METHODS: Genome-wide association study summary data were used to identify genetic variants associated with lifetime amount of smoking (n=126 variants) and ever having smoked regularly (n=112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).

RESULTS: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [odds ratio [OR] per 1-standard deviation (SD) increment: 1.13 (95% confidence interval [CI]: 1.00-1.26); P: 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer [OR per 1-SD increment: 1.21 (95% CI: 1.04-1.40); P: 0.01], colon cancer [OR: 1.31 (95% CI: 1.11-1.55); P: <0.01], and rectal cancer [OR: 1.36 (95% CI: 1.07-1.73); P: 0.01]. Ever having smoked regularly was not associated with risks of breast [OR: 1.01 (95% CI: 0.90-1.14); P: 0.85] or colorectal cancer [OR: 0.97 (95% CI: 0.86-1.10); P: 0.68].

CONCLUSIONS: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.

IMPACT: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.

RevDate: 2021-03-03

Marron TU, Ryan AE, Reddy SM, et al (2021)

Considerations for treatment duration in responders to immune checkpoint inhibitors.

Journal for immunotherapy of cancer, 9(3):.

Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.

RevDate: 2021-02-26

Huyghe JR, Harrison TA, Bien SA, et al (2021)

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Gut pii:gutjnl-2020-321534 [Epub ahead of print].

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

RevDate: 2021-02-25

Brasky TM, Flores KF, Larson JC, et al (2021)

Associations of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with colorectal cancer risk in the Women's Health Initiative.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1401 [Epub ahead of print].

BACKGROUND: Use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) has been postulated to reduce cancer risk by inhibition of tumor progression, vascularization, and metastasis. The renin-angiotensin system is upregulated in colorectal cancers; however, the association of ACEi and ARB use with colorectal cancer risk is not well understood.

METHODS: The study population was 142,812 Women's Health Initiative participants free of colorectal cancer who reported on ACEi and ARB use at baseline; 2,216 incident colorectal cancers were diagnosed during 10 years of follow-up. Cox regression models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for associations relative to non-use among normotensive women, untreated hypertensive women, and hypertensive women treated with other antihypertensive medications.

RESULTS: HRs among women who used any ACEi or ARB compared to non-use in the 3 referent groups ranged between 0.97 and 1.01. Findings were similar for increased ACEi/ARB duration and for medications examined as separate classes or individually.

CONCLUSIONS: In this large prospective study of women, no associations of ACEi or ARB use with colorectal cancer risk were observed.

IMPACT: Choice of drug in the large population of aging women who will be prescribed ACEi and ARB should be made without factoring in any benefit on colorectal cancer risk.

RevDate: 2021-03-02

Haring B, Reiner AP, Liu J, et al (2021)

Healthy Lifestyle and Clonal Hematopoiesis of Indeterminate Potential: Results From the Women's Health Initiative.

Journal of the American Heart Association, 10(5):e018789.

Background Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship between a healthy lifestyle and CHIP is unknown. Methods and Results This analysis included 8709 postmenopausal women (mean age, 66.5 years) enrolled in the WHI (Women's Health Initiative), free of cancer or cardiovascular disease, with deep-coverage whole genome sequencing data available. Information on lifestyle factors (body mass index, smoking, physical activity, and diet quality) was obtained, and a healthy lifestyle score was created on the basis of healthy criteria met (0 point [least healthy] to 4 points [most healthy]). CHIP was derived on the basis of a prespecified list of leukemogenic driver mutations. The prevalence of CHIP was 8.6%. A higher healthy lifestyle score was not associated with CHIP (multivariable-adjusted odds ratio [OR] [95% CI], 0.99 [0.80-1.23] and 1.13 [0.93-1.37]) for the upper (3 or 4 points) and middle category (2 points), respectively, versus referent (0 or 1 point). Across score components, a normal and overweight body mass index compared with obese was significantly associated with a lower odds for CHIP (OR, 0.71 [95% CI, 0.57-0.88] and 0.83 [95% CI, 0.68-1.01], respectively; P-trend 0.0015). Having never smoked compared with being a current smoker tended to be associated with lower odds for CHIP. Conclusions A healthy lifestyle, based on a composite score, was not related to CHIP among postmenopausal women. However, across individual lifestyle factors, having a normal body mass index was strongly associated with a lower prevalence of CHIP. These findings support the idea that certain healthy lifestyle factors are associated with a lower frequency of CHIP.

RevDate: 2021-02-26

Phan IQ, Subramanian S, Kim D, et al (2021)

In silico detection of SARS-CoV-2 specific B-cell epitopes and validation in ELISA for serological diagnosis of COVID-19.

Scientific reports, 11(1):4290.

Rapid generation of diagnostics is paramount to understand epidemiology and to control the spread of emerging infectious diseases such as COVID-19. Computational methods to predict serodiagnostic epitopes that are specific for the pathogen could help accelerate the development of new diagnostics. A systematic survey of 27 SARS-CoV-2 proteins was conducted to assess whether existing B-cell epitope prediction methods, combined with comprehensive mining of sequence databases and structural data, could predict whether a particular protein would be suitable for serodiagnosis. Nine of the predictions were validated with recombinant SARS-CoV-2 proteins in the ELISA format using plasma and sera from patients with SARS-CoV-2 infection, and a further 11 predictions were compared to the recent literature. Results appeared to be in agreement with 12 of the predictions, in disagreement with 3, while a further 5 were deemed inconclusive. We showed that two of our top five candidates, the N-terminal fragment of the nucleoprotein and the receptor-binding domain of the spike protein, have the highest sensitivity and specificity and signal-to-noise ratio for detecting COVID-19 sera/plasma by ELISA. Mixing the two antigens together for coating ELISA plates led to a sensitivity of 94% (N = 80 samples from persons with RT-PCR confirmed SARS-CoV-2 infection), and a specificity of 97.2% (N = 106 control samples).

RevDate: 2021-03-01

McFadden SM, Ko LK, Shankar M, et al (2021)

Development and Evaluation of an Online Continuing Education Course to Increase Healthcare Provider Self-Efficacy to Make Strong HPV Vaccine Recommendations to East African Immigrant Families.

Tumour virus research pii:S2666-6790(21)00004-5 [Epub ahead of print].

OBJECTIVE: To develop and evaluate an online continuing education (CE) course designed to improve healthcare provider self-efficacy to make strong adolescent HPV vaccine recommendations to East African immigrant families.

METHODS: Focus groups with providers and East African immigrant mothers informed course development. Providers serving East African immigrant families were recruited to view the course and complete pre-/post-test and two-month follow-up surveys. Pre-/post differences were compared with paired t-tests.

RESULTS: 202 providers completed the course and pre-/post-test; 158 (78%) completed two-month follow-up. Confidence to make strong HPV vaccine recommendations to East African families increased from 68% pre-test to 98% post-test. Confidence to address common parental concerns also increased: safety, 54% pre-test, 92% post-test; fertility, 55% pre-test, 90% post-test; child too young, 68% pre-test, 92% post-test; and pork gelatin in vaccine manufacturing, 38% pre-test, 90% post-test. Two-month follow-up scores remained high (97% for overall confidence, 94%-98% for addressing parental concerns). All pre-/post-test and pre-test/two-month follow-up comparisons were statistically significant (p<0.05).

CONCLUSIONS: The online CE course focused on culturally appropriate strategies for making strong recommendations and addressing specific parental concerns was effective for increasing provider self-efficacy to recommend HPV vaccination to East African families. Similar courses could be tailored to other priority populations.

RevDate: 2021-03-01

Li C, Goncalves KA, Raskó T, et al (2021)

Single-dose MGTA-145/plerixafor leads to efficient mobilization and in vivo transduction of HSCs with thalassemia correction in mice.

Blood advances, 5(5):1239-1249.

We have developed an in vivo hemopoietic stem cell (HSC) gene therapy approach without the need for myelosuppressive conditioning and autologous HSC transplantation. It involves HSC mobilization and IV injection of a helper-dependent adenovirus HDAd5/35++ vector system. The current mobilization regimen consists of granulocyte colony-stimulating factor (G-CSF) injections over a 4-day period, followed by the administration of plerixafor/AMD3100. We tested a simpler, 2-hour, G-CSF-free mobilization regimen using truncated GRO-β (MGTA-145; a CXCR2 agonist) and plerixafor in the context of in vivo HSC transduction in mice. The MGTA-145+plerixafor combination resulted in robust mobilization of HSCs. Importantly, compared with G-CSF+plerixafor, MGTA-145+plerixafor led to significantly less leukocytosis and no elevation of serum interleukin-6 levels and was thus likely to be less toxic. With both mobilization regimens, after in vivo selection with O6-benzylguanine (O6BG)/BCNU, stable GFP marking was achieved in >90% of peripheral blood mononuclear cells. Genome-wide analysis showed random, multiclonal vector integration. In vivo HSC transduction after mobilization with MGTA-145+plerixafor in a mouse model for thalassemia resulted in >95% human γ-globin+ erythrocytes at a level of 36% of mouse β-globin. Phenotypic analyses showed a complete correction of thalassemia. The γ-globin marking percentage and level were maintained in secondary recipients, further demonstrating that MGTA145+plerixafor mobilizes long-term repopulating HSCs. Our study indicates that brief exposure to MGTA-145+plerixafor may be advantageous as a mobilization regimen for in vivo HSC gene therapy applications across diseases, including thalassemia and sickle cell disease.

RevDate: 2021-03-01

Held L, Siu C, M Shadman (2021)

Venetoclax as a therapeutic option for the treatment of chronic lymphocytic leukemia: the evidence so far.

Expert opinion on pharmacotherapy [Epub ahead of print].

INTRODUCTION: Venetoclax, an oral, BCL-2 inhibitor, is approved by the FDA for treatment of CLL in all lines of therapy. Data from landmark studies, including the CLL14 and MURANO trials, demonstrated marked improvement in clinical outcomes compared to chemoimmunotherapy when venetoclax was used in combination with CD20 monoclonal antibodies for fixed treatment duration.

AREAS COVERED: This article reviews the mechanism of action of venetoclax and discusses how curtailing the BCL signaling pathway undermines CLL pathophysiology. The authors also give their clinical experience with the drug, with emphasis on assessing and managing the risk of venetoclax-associated tumor lysis syndrome (TLS).

EXPERT OPINION: Venetoclax has positioned itself as one of the primary treatment options for CLL, given the consistent efficacy and deep remissions it has elicited across multiple settings of the disease with a time-limited schedule. Accurate TLS risk evaluation and stringent adherence to the dose-escalation protocols will help optimize patient outcomes. Finally, we expect that current and future studies will (1) ascertain the ideal treatment duration using the minimal residual disease state as a guide and (2) help us understand the optimal role of venetoclax in combination or in sequence with other novel targeted therapies in the treatment of CLL.

RevDate: 2021-03-01

Tripathi A, Khaki AR, P Grivas (2021)

Perioperative Immunotherapy in Muscle-invasive Bladder Cancer.

Immune checkpoint inhibitors (ICIs) have already been approved for the treatment of metastatic urothelial carcinoma and are now being investigated for perioperative treatment of muscle-invasive bladder cancer (MIBC). Ongoing trials are assessing ICIs as monotherapy and in combination with other treatments. Early data are promising, and long-term survival data are awaited to confirm the potential of ICIs in MIBC.

RevDate: 2021-02-28

Hughes SM, Pandey U, Johnston C, et al (2021)

Impact of the menstrual cycle and ethinyl estradiol/etonogestrel contraceptive vaginal ring on granulysin and other mucosal immune mediators.

American journal of reproductive immunology (New York, N.Y. : 1989) [Epub ahead of print].

PROBLEM: Changes in sex hormones during the menstrual cycle and contraceptive vaginal ring (CVR) use influence immunity within the female genital tract, but the magnitude of these effects and their anatomical location are unclear.

METHOD OF STUDY: In a prospective study, 29 women were assessed at three time points: follicular phase, luteal phase, and one month after initiation of the ethinyl estradiol/etonogestrel CVR (NuvaRing®, Merck). We performed microarrays on endocervical cytobrushes and measured immune mediators in cervicovaginal fluid, adjusting for bacterial vaginosis and presence of blood. We compared these results to public gene expression data from the fallopian tubes, endometrium, endo- and ectocervix, and vagina.

RESULTS: Immune-related gene expression in the endocervix and immune mediators in cervicovaginal fluid increased during CVR use versus both menstrual phases, and in the follicular versus luteal phase. The antimicrobial protein granulysin was high during CVR use, intermediate in the follicular phase, and nearly absent from the luteal phase. Re-analysis of public gene expression data confirmed increased immune-related gene expression in the endocervix during the follicular phase. However, in the fallopian tube, endometrium and vagina, the follicular phase showed immunosuppression.

CONCLUSIONS: Immune-related genes in the cervicovaginal tract were highest during CVR use, intermediate in the follicular phase, and lowest in the luteal phase. Granulysin is a potential biomarker of menstrual phase: frequently detected in follicular samples, but rare in luteal. Lastly, immunological differences between the follicular and luteal phases vary throughout the female genital tract.

RevDate: 2021-02-28

Rane MS, Page LC, McVeigh E, et al (2021)

Improving adolescent human papillomavirus (HPV) immunization uptake in school-based health centers through awareness campaigns.

Vaccine pii:S0264-410X(21)00152-3 [Epub ahead of print].

PURPOSE: The aim of this study was to measure the effect of a multicomponent human papillomavirus (HPV) vaccine promotion campaign on adolescent HPV vaccine uptake at school-based health centers (SBHCs) in Seattle, WA.

METHODS: Youth-led HPV vaccine promotion campaigns were introduced in 2016 in 13 schools with SBHCs in Seattle. Five other schools with SBHCs served as controls. Vaccination records for students were obtained from the Washington Immunization Information System from September 2012 to August 2018. We compared increase in HPV vaccine uptake in SBHCs between 1) intervention and control schools, and 2) pre- and post-intervention periods in intervention schools using generalized estimating equations.

RESULTS: HPV vaccine uptake was high at baseline among students that use SBHCs for vaccines and has steadily increased between 2012 and 2018. Implementing the promotion campaign resulted in 14% higher (95% Confidence Interval (CI): 1%, 30%) HPV vaccine uptake in intervention SBHCs compared to control SBHCs, adjusting for time and confounders. Comparing pre-and post-intervention periods in intervention SBHCs, HPV vaccine uptake was 14% higher (95% CI: -4%, 35%) in the post-intervention period. SBHCs that received more active intervention activities saw 9% higher (95% CI: 1%, 21%) vaccine uptake compared to those that received passive intervention.

CONCLUSION: The vaccination promotion program implemented in a school-based setting resulted in higher HPV vaccine uptake in the post-intervention period compared to pre-intervention period, but this increase was not statistically significant. Even so, schools that received more intervention activities for longer periods of time had higher HPV vaccine uptake.

RevDate: 2021-02-27

Kanvinde PP, Malla AP, Connolly NP, et al (2021)

Leveraging the replication-competent avian-like sarcoma virus/tumor virus receptor-A system for modeling human gliomas.

Glia [Epub ahead of print].

Gliomas are the most common primary intrinsic brain tumors occurring in adults. Of all malignant gliomas, glioblastoma (GBM) is considered the deadliest tumor type due to diffuse brain invasion, immune evasion, cellular, and molecular heterogeneity, and resistance to treatments resulting in high rates of recurrence. An extensive understanding of the genomic and microenvironmental landscape of gliomas gathered over the past decade has renewed interest in pursuing novel therapeutics, including immune checkpoint inhibitors, glioma-associated macrophage/microglia (GAMs) modulators, and others. In light of this, predictive animal models that closely recreate the conditions and findings found in human gliomas will serve an increasingly important role in identifying new, effective therapeutic strategies. Although numerous syngeneic, xenograft, and transgenic rodent models have been developed, few include the full complement of pathobiological features found in human tumors, and therefore few accurately predict bench-to-bedside success. This review provides an update on how genetically engineered rodent models based on the replication-competent avian-like sarcoma (RCAS) virus/tumor virus receptor-A (tv-a) system have been used to recapitulate key elements of human gliomas in an immunologically intact host microenvironment and highlights new approaches using this model system as a predictive tool for advancing translational glioma research.

RevDate: 2021-02-27

Nakamichi K, Shen JZ, Lee CS, et al (2021)

Hospitalization and mortality associated with SARS-CoV-2 viral clades in COVID-19.

Scientific reports, 11(1):4802.

The COVID-19 epidemic of 2019-20 is due to the novel coronavirus SARS-CoV-2. Following first case description in December, 2019 this virus has infected over 10 million individuals and resulted in at least 500,000 deaths world-wide. The virus is undergoing rapid mutation, with two major clades of sequence variants emerging. This study sought to determine whether SARS-CoV-2 sequence variants are associated with differing outcomes among COVID-19 patients in a single medical system. Whole genome SARS-CoV-2 RNA sequence was obtained from isolates collected from patients registered in the University of Washington Medicine health system between March 1 and April 15, 2020. Demographic and baseline clinical characteristics of patients and their outcome data including their hospitalization and death were collected. Statistical and machine learning models were applied to determine if viral genetic variants were associated with specific outcomes of hospitalization or death. Full length SARS-CoV-2 sequence was obtained 190 subjects with clinical outcome data. 35 (18.4%) were hospitalized and 14 (7.4%) died from complications of infection. A total of 289 single nucleotide variants were identified. Clustering methods demonstrated two major viral clades, which could be readily distinguished by 12 polymorphisms in 5 genes. A trend toward higher rates of hospitalization of patients with Clade 2 infections was observed (p = 0.06, Fisher's exact). Machine learning models utilizing patient demographics and co-morbidities achieved area-under-the-curve (AUC) values of 0.93 for predicting hospitalization. Addition of viral clade or sequence information did not significantly improve models for outcome prediction. In summary, SARS-CoV-2 shows substantial sequence diversity in a community-based sample. Two dominant clades of virus are in circulation. Among patients sufficiently ill to warrant testing for virus, no significant difference in outcomes of hospitalization or death could be discerned between clades in this sample. Major risk factors for hospitalization and death for either major clade of virus include patient age and comorbid conditions.

RevDate: 2021-02-26

Wagner DL, Fritsche E, Pulsipher MA, et al (2021)

Immunogenicity of CAR T cells in cancer therapy.

Nature reviews. Clinical oncology [Epub ahead of print].

Patient-derived T cells genetically reprogrammed to express CD19-specific chimeric antigen receptors (CARs) have shown remarkable clinical responses and are commercially available for the treatment of patients with certain advanced-stage B cell malignancies. Nonetheless, several trials have revealed pre-existing and/or treatment-induced immune responses to the mouse-derived single-chain variable fragments included in these constructs. These responses might have contributed to both treatment failure and the limited success of redosing strategies observed in some patients. Data from early phase clinical trials suggest that CAR T cells are also associated with immunogenicity-related events in patients with solid tumours. Generally, the clinical implications of anti-CAR immune responses are poorly understood and highly variable between different CAR constructs and malignancies. These observations highlight an urgent need to uncover the mechanisms of immunogenicity in patients receiving CAR T cells and develop validated assays to enable clinical detection. In this Review, we describe the current clinical evidence of anti-CAR immune responses and discuss how new CAR T cell technologies might impact the risk of immunogenicity. We then suggest ways to reduce the risks of anti-CAR immune responses to CAR T cell products that are advancing towards the clinic. Finally, we summarize measures that investigators could consider in order to systematically monitor and better comprehend the possible effects of immunogenicity during trials involving CAR T cells as well as in routine clinical practice.

RevDate: 2021-02-26

Cai EY, Garcia J, Liu Y, et al (2021)

A bladder cancer patient-derived xenograft displays aggressive growth dynamics in vivo and in organoid culture.

Scientific reports, 11(1):4609.

Bladder cancer is among the most prevalent cancers worldwide. Currently, few bladder cancer models have undergone thorough characterization to assess their fidelity to patient tumors, especially upon propagation in the laboratory. Here, we establish and molecularly characterize CoCaB 1, an aggressive cisplatin-resistant muscle-invasive bladder cancer patient-derived xenograft (PDX) and companion organoid system. CoCaB 1 was a subcutaneous PDX model reliably transplanted in vivo and demonstrated an acceleration in growth upon serial transplantation, which was reflected in organoid and 2D cell culture systems. Transcriptome analysis revealed progression towards an increasingly proliferative and stem-like expression profile. Gene expression differences between organoid and PDX models reflected expected differences in cellular composition, with organoids enriched in lipid biosynthesis and metabolism genes and deprived of extracellular components observed in PDXs. Both PDX and organoid models maintained the histological fidelity and mutational heterogeneity of their parental tumor. This study establishes the CoCaB 1 PDX and organoid system as companion representative tumor models for the development of novel bladder cancer therapies.

RevDate: 2021-02-26

Borowsky J, Haruki K, Lau MC, et al (2021)

Association of Fusobacterium nucleatum with Specific T Cell Subsets in the Colorectal Carcinoma Microenvironment.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-4009 [Epub ahead of print].

PURPOSE: While evidence indicates that Fusobacterium nucleatum may promote colorectal carcinogenesis through its suppressive effect on T-cell-mediated antitumor immunity, the specific T-cell subsets involved remain uncertain.

EXPERIMENTAL DESIGN: We measured F. nucleatum DNA within tumor tissue by quantitative PCR on 933 cases (including 128 F. nucleatum-positive cases) among 4,465 incident colorectal carcinoma cases in two prospective cohorts. Multiplex immunofluorescence combined with digital image analysis and machine learning algorithms for CD3, CD4, CD8, CD45RO (PTPRC isoform), and FOXP3 measured various T-cell subsets. We leveraged data on Bifidobacterium, microsatellite instability (MSI), tumor whole exome sequencing, and M1/M2-type tumor-associated macrophages [by CD68, CD86, IRF5, MAF, and MRC1 (CD206) multimarker assay]. Using the 4,465 cancer cases and inverse probability weighting method to control for selection bias due to tissue availability, multivariable-adjusted logistic regression analysis assessed the association between F. nucleatum and T-cell subsets.

RESULTS: The amount of F. nucleatum was inversely associated with tumor stromal CD3+ lymphocytes (multivariable odds ratio, 0.47, 95% confidence interval, 0.28-0.79, for F. nucleatum-high vs. negative category; Ptrend=0.0004) and specifically stromal CD3+CD4+CD45RO+ cells (corresponding multivariable odds ratio, 0.52, 95% confidence interval, 0.32-0.85; Ptrend=0.003). These relationships did not substantially differ by MSI status, neoantigen loads, or exome-wide tumor mutational burden. F. nucleatum was not significantly associated with T-cell subset densities in tumor intraepithelial regions or with macrophage densities.

CONCLUSIONS: The amount of tissue F. nucleatum is associated with lower densities of stromal memory helper T cells. Our findings provide evidence for the interactive pathogenic roles of microbiota and specific immune cells.

RevDate: 2021-02-25

Sandfort TGM, Mbilizi Y, Sanders EJ, et al (2021)

HIV incidence in a multinational cohort of men and transgender women who have sex with men in sub-Saharan Africa: Findings from HPTN 075.

PloS one, 16(2):e0247195 pii:PONE-D-20-19800.

Few studies have assessed HIV incidence in men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA). We assessed HIV incidence and its correlates among MSM and TGW in SSA enrolled in the prospective, multi-country HIV Prevention Trials Network (HPTN) 075 study, conducted from 2015 to 2017. Participants were enrolled at four sites in SSA (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Eligible participants reported male sex assignment at birth, were 18 to 44 years of age, and had engaged in anal intercourse with a man in the preceding three months. Participation involved five study visits over 12 months. Visits included behavioral assessments and testing for HIV and sexually transmitted infections. Twenty-one of 329 persons acquired HIV during the study [incidence rate: 6.96/100 person-years (PY) (95% CI: 4.3, 10.6)]. Among TGW, HIV incidence was estimated to be 8.4/100 PY (95% CI: 2.3, 21.5). Four participants were found to have acute HIV infection at their first HIV-positive visit. HIV incidence varied among the four study sites, ranging from 1.3/100 PY to 14.4/100 PY. In multivariate longitudinal analysis, factors significantly associated with HIV acquisition were engagement in unprotected receptive anal intercourse [adjusted hazard ratio (AHR) 5.8, 95% confidence interval (CI): 2.4, 14.4] and incident rectal gonorrhea and/or chlamydia (AHR: 2.7, 95% CI: 1.1, 6.8). The higher HIV incidence in Cape Town compared to Blantyre could be explained by the higher prevalence of several risk factors for HIV infection among participants in Cape Town. Annual HIV incidence observed in this study is substantially higher than reported HIV incidence in the general populations in the respective countries and among MSM in the United States. Intensification of HIV prevention efforts for MSM and TGW in SSA is urgently needed.

RevDate: 2021-02-25

Okoye AA, Duell DD, Fukazawa Y, et al (2021)

CD8+ T cells fail to limit SIV reactivation following ART withdrawal until after viral amplification.

The Journal of clinical investigation pii:141677 [Epub ahead of print].

To define the contribution of CD8+ T cell responses to control of SIV reactivation during and following antiretroviral therapy (ART), we determined the effect of long-term CD8+ T cell depletion using a rhesusized anti-CD8β monoclonal antibody (mAb) on barcoded SIVmac239 dynamics on stable ART and after ART cessation in Rhesus Macaques (RMs). Among the RMs with full CD8+ T cell depletion in both blood and tissue, there were no significant differences in the frequency of viral blips in plasma, the number of SIV RNA+ cells and the average number of RNA copies/infected cell in tissue, and levels of cell-associated SIV RNA and DNA in blood and tissue relative to control-treated RM during ART. Upon ART cessation, both CD8+ T cell-depleted and control RMs rebounded in <12 days with no difference in the time to viral rebound, or in either the number or growth rate of rebounding SIVmac239M barcode clonotypes. However, effectively CD8+ T cell-depleted RMs showed a stable ~2-log increase in post-ART plasma viremia relative to controls. These results indicate that while potent anti-viral CD8+ T cell responses can develop during ART-suppressed SIV infection, these responses effectively intercept post-ART SIV rebound only after systemic viral replication, too late to limit reactivation frequency or the early spread of reactivating SIV reservoirs.

RevDate: 2021-02-25

Oeffinger KC, Stratton KL, Hudson MM, et al (2021)

Impact of Risk-Adapted Therapy for Pediatric Hodgkin Lymphoma on Risk of Long-Term Morbidity: A Report From the Childhood Cancer Survivor Study.

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

PURPOSE: To determine the incidence of serious chronic health conditions among survivors of pediatric Hodgkin lymphoma (HL), compare by era of therapy and by selected cancer therapies, and provide estimates of risks associated with contemporary therapy.

METHODS: Assessing 2,996 5-year HL survivors in the Childhood Cancer Survivor Study diagnosed from 1970 to 1999, we examined the cumulative incidence of severe to fatal chronic conditions (grades 3-5) using self-report conditions, medically confirmed subsequent malignant neoplasms, and cause of death based on the National Death Index. We used multivariable regression models to estimate hazard ratios (HRs) per decade and by key treatment exposures.

RESULTS: HL survivors were of a mean age of 35.6 years (range, 12-58 years). The cumulative incidence of any grade 3-5 condition by 35 years of age was 31.4% (95% CI, 29.2 to 33.5). Females were twice as likely (HR, 2.1; 95% CI, 1.8 to 2.4) to have a grade 3-5 condition compared with males. From the 1970s to the 1990s, there was a 20% reduction (HR, 0.8; 95% CI, 0.7 to 0.9) in decade-specific risk of a grade 3-5 condition (P trend = .002). In survivors who had a recurrence and/or hematopoietic cell transplant, the risk of a grade 3-5 condition was substantially elevated, similar to that of survivors treated with high-dose, extended-field radiotherapy (HR, 1.2; 95% CI, 0.9 to 1.5). Compared with survivors treated with chest radiotherapy ≥ 35 Gy in combination with an anthracycline or alkylator, a contemporary regimen for low-intermediate risk HL was estimated to lead to a 40% reduction in risk of a grade 3-5 condition (HR, 0.6; 95% CI, 0.4 to 0.8).

CONCLUSION: This study demonstrates that risk-adapted therapy for pediatric HL has resulted in a significant reduction in serious long-term outcomes.

RevDate: 2021-02-25

Shortliffe EH, Lyman GH, FK Amankwah (2021)

Medications in Single-Dose Vials and Implications of Discarded Injectable Drugs: A National Academies Report.

JAMA pii:2777040 [Epub ahead of print].

RevDate: 2021-02-25

Hershman DL, Neugut AI, Moseley A, et al (2021)

Patient Reported Outcomes and Long-Term Non-Adherence to Aromatase Inhibitors.

Journal of the National Cancer Institute pii:6149351 [Epub ahead of print].

BACKGROUND: Non-adherence to aromatase inhibitors (AIs) is common and increases risk of breast cancer (BC) recurrence. We analyzed factors associated with non-adherence among patients enrolled in S1105, a randomized trial of text-messaging.

METHODS: At enrollment, BC patients were required to have been on an adjuvant AI for ≥30 days and were asked about financial, medication and demographic factors. They completed Patient-Reported Outcomes (PROs) representing pain (Brief Pain Inventory), endocrine symptoms (FACT-Endocrine Symptoms), and beliefs about medications (Treatment Satisfaction Questionnaire for Medicine; Brief Medication Questionnaire). Our primary endpoint was AI non-adherence at 36 months, defined as urine AI metabolite assay <10 ng/mL or no submitted specimen. We evaluated the association between individual baseline characteristics and non-adherence with logistic regression. A composite risk score reflecting the number of statistically significant baseline characteristics was examined.

RESULTS: We analyzed data from 702 patients; median age was 60.9 years. Overall, 35.9% patients were non-adherent at 36 months. Younger patients (< age 65 years) were more non-adherent (38.8% vs.28.6%, OR = 1.51,95% CI = 1.05-2.16, p = .02). Fourteen baseline PRO scales were each statistically significantly associated with non-adherence. In a composite risk model categorized into quartile levels, each increase in risk level was associated with a 46.5% increase in the odds of non-adherence (OR = 1.47,95% CI = 1.26-1.70, p < .001). The highest risk patients were more than three times more likely to be non-adherent than the lowest risk patients (OR = 3.14, 95% CI = 1.97-5.02, p < .001).

CONCLUSIONS: The presence of multiple baseline PRO-specified risk factors was statistically significantly associated with AI non-adherence. The use of these assessments can help identify patients for targeted interventions to improve adherence.

RevDate: 2021-02-24

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

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nature communications, 12(1):1236.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

RevDate: 2021-02-23

Goyal A, Reeves DB, Cardozo-Ojeja EF, et al (2021)

Viral load and contact heterogeneity predict SARS-CoV-2 transmission and super-spreading events.

eLife, 10: pii:63537 [Epub ahead of print].

SARS-CoV-2 is difficult to contain because many transmissions occur during pre-symptomatic infection. Unlike influenza, most SARS-CoV-2 infected people do not transmit while a small percentage infect large numbers of people. We designed mathematical models which link observed viral loads with epidemiologic features of each virus, including distribution of transmissions attributed to each infected person and duration between symptom onset in the transmitter and secondarily infected person. We identify that people infected with SARS-CoV-2 or influenza can be highly contagious for less than one day, congruent with peak viral load. SARS-CoV-2 super-spreader events occur when an infected person is shedding at a very high viral load and has a high number of exposed contacts. The higher predisposition of SARS-CoV-2 towards super-spreading events cannot be attributed to additional weeks of shedding relative to influenza. Rather, a person infected with SARS-CoV-2 exposes more people within equivalent physical contact networks, likely due to aerosolization.

RevDate: 2021-02-22

Mitchell KM, Dimitrov D, Silhol R, et al (2021)

The potential effect of COVID-19-related disruptions on HIV incidence and HIV-related mortality among men who have sex with men in the USA: a modelling study.

The lancet. HIV pii:S2352-3018(21)00022-9 [Epub ahead of print].

BACKGROUND: During the COVID-19 pandemic, men who have sex with men (MSM) in the USA have reported similar or fewer sexual partners and reduced HIV testing and care access compared with before the pandemic. Pre-exposure prophylaxis (PrEP) use has also declined. We aimed to quantify the potential effect of COVID-19 on HIV incidence and HIV-related mortality among US MSM.

METHODS: We used a calibrated, deterministic, compartmental HIV transmission model for MSM in Baltimore (MD, USA) and available data on COVID-19-related disruptions to HIV services to predict effects of reductions in sexual partners (0%, 25%, 50%), condom use (5%), HIV testing (20%), viral suppression (10%), PrEP initiations (72%), PrEP adherence (9%), and antiretroviral therapy (ART) initiations (50%). In our main analysis, we modelled disruptions due to COVID-19 starting Jan 1, 2020, and lasting 6 months. We estimated the median change in cumulative new HIV infections and HIV-related deaths among MSM over 1 and 5 years, compared with a base case scenario without COVID-19-related disruptions.

FINDINGS: A 25% reduction in sexual partners for 6 months among MSM in Baltimore, without HIV service changes, could reduce new HIV infections by median 12·2% (95% credible interval 11·7 to 12·8) over 1 year and median 3·0% (2·6 to 3·4) over 5 years. In the absence of changes in sexual behaviour, the 6-month estimated reductions in condom use, HIV testing, viral suppression, PrEP initiations, PrEP adherence, and ART initiations combined are predicted to increase new HIV infections by median 10·5% (5·8 to 16·5) over 1 year, and by median 3·5% (2·1 to 5·4) over 5 years. Disruptions to ART initiations and viral suppression are estimated to substantially increase HIV-related deaths (ART initiations by median 1·7% [0·8 to 3·2], viral suppression by median 9·5% [5·2 to 15·9]) over 1 year, with smaller proportional increases over 5 years. The other individual disruptions (to HIV testing, PrEP and condom use, PrEP initiation, and partner numbers) were estimated to have little effect on HIV-related deaths (<1% change over 1 or 5 years). A 25% reduction in sexual partnerships is estimated to offset the effect of the combined service disruptions on new HIV infections (change over 1 year: median -3·9% [-7·4 to 1·0]; over 5 years: median 0·0% [-0·9 to 1·4]), but not on HIV deaths (change over 1 year: 11·0% [6·2 to 17·7]; over 5 years: 2·6% [1·5 to 4·3]).

INTERPRETATION: Maintaining access to ART and adherence support is of the utmost importance to maintain viral suppression and minimise excess HIV-related mortality due to COVID-19 restrictions in the USA, even if disruptions to services are accompanied by reductions in sexual partnerships.

FUNDING: National Institutes of Health.

RevDate: 2021-02-22

Srinivasan S, Beamer MA, Fiedler TL, et al (2021)

Megasphaera lornae sp. nov., Megasphaera hutchinsoni sp. nov., and Megasphaera vaginalis sp. nov.: novel bacteria isolated from the female genital tract.

International journal of systematic and evolutionary microbiology [Epub ahead of print].

Six strictly anaerobic Gram-negative bacteria representing three novel species were isolated from the female reproductive tract. The proposed type strains for each species were designated UPII 199-6T, KA00182T and BV3C16-1T. Phylogenetic analyses based on 16S rRNA gene sequencing indicated that the bacterial isolates were members of the genus Megasphaera. UPII 199-6T and KA00182T had 16S rRNA gene sequence identities of 99.9 % with 16S rRNA clone sequences previously amplified from the human vagina designated as Megasphaera type 1 and Megasphaera type 2, members of the human vaginal microbiota associated with bacterial vaginosis, preterm birth and HIV acquisition. UPII 199-6T exhibited sequence identities ranging from 92.9 to 93.6 % with validly named Megasphaera isolates and KA00182T had 16S rRNA gene sequence identities ranging from 92.6-94.2 %. BV3C16-1T was most closely related to Megasphaera cerevisiae with a 16S rRNA gene sequence identity of 95.4 %. Cells were coccoid or diplococcoid, non-motile and did not form spores. Genital tract isolates metabolized organic acids but were asaccharolytic. The isolates also metabolized amino acids. The DNA G+C content for the genome sequences of UPII 199-6T, KA00182T and BV3C16-1T were 46.4, 38.9 and 49.8 mol%, respectively. Digital DNA-DNA hybridization and average nucleotide identity between the genital tract isolates and other validly named Megasphaera species suggest that each isolate type represents a new species. The major fatty acid methyl esters include the following: C12 : 0, C16 : 0, C16 : 0 dimethyl acetal (DMA) and summed feature 5 (C15 : 0 DMA and/or C14 : 0 3-OH) in UPII 199-6T; C16 : 0 and C16 : 1cis 9 in KA00182T; C12 : 0; C14 : 0 3-OH; and summed feature 5 in BV3C16-1T. The isolates produced butyrate, isobutyrate, and isovalerate but there were specific differences including production of formate and propionate. Together, these data indicate that UPII 199-6T, KA00182T and BV3C16-1T represent novel species within the genus Megasphaera. We propose the following names: Megasphaera lornae sp. nov. for UPII 199-6T representing the type strain of this species (=DSM 111201T=ATCC TSD-205T), Megasphaera hutchinsoni sp. nov. for KA00182T representing the type strain of this species (=DSM 111202T=ATCC TSD-206T) and Megasphaera vaginalis sp. nov. for BV3C16-1T representing the type strain of this species (=DSM 111203T=ATCC TSD-207T).

RevDate: 2021-02-22

Connelly-Smith L, ML Linenberger (2020)

Leukocytapheresis for AML hyperleukocytosis: Failing to make the grade.

Transfusion, 60(10):2161-2163.

RevDate: 2021-02-22

Nuechterlein N, Li B, Feroze A, et al (2021)

Radiogenomic modeling predicts survival-associated prognostic groups in glioblastoma.

Neuro-oncology advances, 3(1):vdab004 pii:vdab004.

Background: Combined whole-exome sequencing (WES) and somatic copy number alteration (SCNA) information can separate isocitrate dehydrogenase (IDH)1/2-wildtype glioblastoma into two prognostic molecular subtypes, which cannot be distinguished by epigenetic or clinical features. The potential for radiographic features to discriminate between these molecular subtypes has yet to be established.

Methods: Radiologic features (n = 35 340) were extracted from 46 multisequence, pre-operative magnetic resonance imaging (MRI) scans of IDH1/2-wildtype glioblastoma patients from The Cancer Imaging Archive (TCIA), all of whom have corresponding WES/SCNA data. We developed a novel feature selection method that leverages the structure of extracted MRI features to mitigate the dimensionality challenge posed by the disparity between a large number of features and the limited patients in our cohort. Six traditional machine learning classifiers were trained to distinguish molecular subtypes using our feature selection method, which was compared to least absolute shrinkage and selection operator (LASSO) feature selection, recursive feature elimination, and variance thresholding.

Results: We were able to classify glioblastomas into two prognostic subgroups with a cross-validated area under the curve score of 0.80 (±0.03) using ridge logistic regression on the 15-dimensional principle component analysis (PCA) embedding of the features selected by our novel feature selection method. An interrogation of the selected features suggested that features describing contours in the T2 signal abnormality region on the T2-weighted fluid-attenuated inversion recovery (FLAIR) MRI sequence may best distinguish these two groups from one another.

Conclusions: We successfully trained a machine learning model that allows for relevant targeted feature extraction from standard MRI to accurately predict molecularly-defined risk-stratifying IDH1/2-wildtype glioblastoma patient groups.

RevDate: 2021-02-22

Seneviratne HK, Hamlin AN, Li S, et al (2021)

Identification of Novel UGT1A1 Variants Including UGT1A1 454C>A through the Genotyping of Healthy Participants of the HPTN 077 Study.

ACS pharmacology & translational science, 4(1):226-239.

Cabotegravir (CAB) is an integrase strand-transfer inhibitor of HIV that has proven effective for HIV treatment and prevention in a long-acting injectable formulation, typically preceded by an oral formulation lead-in phase. Previous in vitro studies have demonstrated that CAB is primarily metabolized via glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9. In this study, we performed next-generation sequencing of genomic DNA isolated from the HPTN 077 participants to explore the variants within UGT1A1 and UGT1A9. Additionally, to enable correlation of UGT1A1 and UGT1A9 genotypes with plasma CAB-glucuronide levels, we quantified glucuronidated CAB following both oral administration of CAB and intramuscular injection of long-acting CAB. From these studies, 48 previously unreported variants of UGT1A1 and UGT1A9 were detected. Notably, 5/68 individuals carried a UGT1A1 454C>A variant that resulted in amino acid substitution P152T, and the use of in silico tools predicted a deleterious effect of the P152T substitution. Thus, the impact of this mutant on a range of UGT1A1 substrates was tested using a COS-7 cell-based assay. The glucuronide conjugates of CAB, dolutegravir, and raltegravir, were not formed in the COS-7 cells expressing the UGT1A1 P152T mutant. Further, formation of glucuronides of raloxifene and 7-ethyl-10-hydroxycamptothecin were reduced in the cells expressing the UGT1A1 P152T mutant. Using the same approach, we tested the activities of two UGT1A9 mutants, UGT1A9 H217Y and UGT1A9 R464G, and found that these mutations were tolerated and decreased function, respectively. These data provide insight into previously unreported genetic variants of UGT1A1 and UGT1A9.

RevDate: 2021-02-20

Granadier D, Iovino L, Kinsella S, et al (2021)

Dynamics of thymus function and T cell receptor repertoire breadth in health and disease.

Seminars in immunopathology [Epub ahead of print].

T cell recognition of unknown antigens relies on the tremendous diversity of the T cell receptor (TCR) repertoire; generation of which can only occur in the thymus. TCR repertoire breadth is thus critical for not only coordinating the adaptive response against pathogens but also for mounting a response against malignancies. However, thymic function is exquisitely sensitive to negative stimuli, which can come in the form of acute insult, such as that caused by stress, infection, or common cancer therapies; or chronic damage such as the progressive decline in thymic function with age. Whether it be prolonged T cell deficiency after hematopoietic cell transplantation (HCT) or constriction in the breadth of the peripheral TCR repertoire with age; these insults result in poor adaptive immune responses. In this review, we will discuss the importance of thymic function for generation of the TCR repertoire and how acute and chronic thymic damage influences immune health. We will also discuss methods that are used to measure thymic function in patients and strategies that have been developed to boost thymic function.

RevDate: 2021-02-20

Ragoonanan D, Khazal SJ, Abdel-Azim H, et al (2021)

Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer.

Nature reviews. Clinical oncology [Epub ahead of print].

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

RevDate: 2021-02-20

Lurain K, Ramaswami R, Mangusan R, et al (2021)

Use of pembrolizumab with or without pomalidomide in HIV-associated non-Hodgkin's lymphoma.

Journal for immunotherapy of cancer, 9(2):.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control.

METHODS: We conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute.

RESULTS: We identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1-21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2-3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide.

CONCLUSIONS: Treatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL.

RevDate: 2021-02-19

Parrish PCR, AH Berger (2021)

CRISPR base editor screens identify variant function at scale.

Molecular cell, 81(4):647-648.

Cuella-Martin et al. (2021) and Hanna et al. (2021) showcase CRISPR base editing in large-scale pooled screens in human cells to discover both loss- and gain-of-function variants, enabling protein structure/function insights and clinical variant interpretation.

RevDate: 2021-02-19

Zhao YQ, Norton D, L Hanrahan (2021)

Small area estimation and childhood obesity surveillance using electronic health records.

PloS one, 16(2):e0247476 pii:PONE-D-20-13740.

There is an urgent need for childhood surveillance systems to design, implement, and evaluate interventions at the local level. We estimated obesity prevalence for individuals aged 5-17 years using a southcentral Wisconsin EHR data repository, Public Health Information Exchange (PHINEX, 2007-2012). The prevalence estimates were calculated by aggregating the estimated probability of each individual being obese, which was obtained via a generalized linear mixed model. We incorporated the random effects at the area level into our model. A weighted procedure was employed to account for missingness in EHR data. A non-parametric kernel smoothing method was used to obtain the prevalence estimates for locations with no or little data (<20 individuals) from the EHR. These estimates were compared to results from newly available obesity atlas (2015-2016) developed from various EHRs with greater statewide representation. The mean of the zip code level obesity prevalence estimates for males and females aged 5-17 years is 16.2% (SD 2.72%); 17.9% (SD 2.14%) for males and 14.4% (SD 2.00%) for females. The results were comparable to the Wisconsin Health Atlas (WHA) estimates, a much larger dataset of local community EHRs in Wisconsin. On average, prevalence estimates were 2.12% lower in this process than the WHA estimates, with lower estimation occurring more frequently for zip codes without data in PHINEX. Using this approach, we can obtain estimates for local areas that lack EHRs data. Generally, lower prevalence estimates were produced for those locations not represented in the PHINEX database when compared to WHA estimates. This underscores the need to ensure that the reference EHRs database can be made sufficiently similar to the geographic areas where synthetic estimates are being created.

RevDate: 2021-02-19

Flores LE, Frontera WR, Andrasik MP, et al (2021)

Assessment of the Inclusion of Racial/Ethnic Minority, Female, and Older Individuals in Vaccine Clinical Trials.

JAMA network open, 4(2):e2037640 pii:2776562.

Importance: Medical research has not equitably included members of racial/ethnic minority groups or female and older individuals. There are limited data on participant demographic characteristics in vaccine trials despite the importance of these data to current trials aimed at preventing coronavirus disease 2019.

Objective: To investigate whether racial/ethnic minority groups and female and older adults are underrepresented among participants in vaccine clinical trials.

This cross-sectional study examined data from completed US-based vaccine trials registered on ClinicalTrials.gov from July 1, 2011, through June 30, 2020. The terms vaccine, vaccination, immunization, and inoculation were used to identify trials. Only those addressing vaccine immunogenicity or efficacy of preventative vaccines were included.

Main Outcomes and Measures: The numbers and percentages of racial/ethnic minority, female, and older individuals compared with US census data from 2011 and 2018. Secondary outcome measures were inclusion by trial phase and year of completion.

Results: A total of 230 US-based trials with 219 555 participants were included in the study. Most trials were randomized (180 [78.3%]), included viral vaccinations (159 [69.1%]), and represented all trial phases. Every trial reported age and sex; 134 (58.3%) reported race and 79 (34.3%) reported ethnicity. Overall, among adult study participants, White individuals were overrepresented (77.9%; 95% CI, 77.4%-78.4%), and Black or African American individuals (10.6%; 95% CI, 10.2%-11.0%) and American Indian or Alaska Native individuals (0.4%; 95% CI, 0.3%-0.5%) were underrepresented compared with US census data; enrollment of Asian individuals was similar (5.7%; 95% CI, 5.5%-6.0%). Enrollment of Hispanic or Latino individuals (11.6%; 95% CI, 11.1%-12.0%) was also low even among the limited number of adult trials reporting ethnicity. Adult trials were composed of more female participants (75 325 [56.0%]), but among those reporting age as a percentage, enrollment of participants who were aged 65 years or older was low (12.1%; 95% CI, 12.0%-12.3%). Black or African American participants (10.1%; 95% CI, 9.7%-10.6%) and Hispanic or Latino participants (22.5%; 95% CI, 21.6%-23.4%) were also underrepresented in pediatric trials. Among trials reporting race/ethnicity, 65 (48.5%) did not include American Indian or Alaska Native participants and 81 (60.4%) did not include Hawaiian or Pacific Islander participants.

Conclusions and Relevance: This cross-sectional study found that among US-based vaccine clinical trials, members of racial/ethnic minority groups and older adults were underrepresented, whereas female adults were overrepresented. These findings suggest that diversity enrollment targets should be included for all vaccine trials targeting epidemiologically important infections.

RevDate: 2021-02-19

Chen JG, Zhu J, Zhang YH, et al (2021)

Liver cancer mortality over six decades in an epidemic area: what we have learned.

PeerJ, 9:e10600 pii:10600.

Background and aims: Liver cancer is one of the most dominant malignant tumors in the world. The trends of liver cancer mortality over the past six decades have been tracked in the epidemic region of Qidong, China. Using epidemiological tools, we explore the dynamic changes in age-standardized rates to characterize important aspects of liver cancer etiology and prevention.

Methods: Mortality data of liver cancer in Qidong from 1958 to 1971 (death retrospective survey) and from 1972 to 2017 (cancer registration) were tabulated for the crude rate (CR), and age-standardized rate and age-birth cohorts. The average annual percentage change was calculated by the Joinpoint Regression Program.

Results: The natural death rate during 1958-2017 decreased from 9‰ to 5.4‰ and then increased to 8‰ as the population aged; cancer mortality rates rose continuously from 57/105 to 240/105. Liver cancer mortality increased from 20/105 to 80/105, and then dropped to less than 52/105 in 2017. Liver cancer deaths in 1972-2017 accounted for 30.53% of all cancers, with a CR of 60.48/105, age-standardized rate China (ASRC) of 34.78/105, and ASRW (world) of 45.71/105. Other key features were the CR for males and females of 91.86/105 and 29.92/105, respectively, with a sex ratio of 3.07:1. Period analysis showed that the ASRs for mortality of the age groups under 54 years old had a significant decreasing trend. Importantly, birth cohort analysis showed that the mortality rate of liver cancer in 40-44, 35-39, 30-34, 25-29, 20-24, 15-19 years cohort decreased considerably, but the rates in 70-74, and 75+ increased.

Conclusions: The crude mortality rate of liver cancer in Qidong has experienced trends from lower to higher levels, and from continued increase at a high plateau to most recently a gradual decline, and a change greatest in younger people. Many years of comprehensive prevention and intervention measures have influenced the decline of the liver cancer epidemic in this area. The reduction of intake levels of aflatoxin might be one of the most significant factors as evidenced by the dramatic decline of exposure biomarkers in this population during the past three decades.

RevDate: 2021-02-19

Solan JL, Hingorani SR, PD Lampe (2021)

Cx43 phosphorylation sites regulate pancreatic cancer metastasis.

Oncogene [Epub ahead of print].

Pancreatic ductal adenocarcinoma (PDA) is aggressive, highly metastatic and characterized by a robust desmoplasia. Connexin proteins that form gap junctions have been implicated in tumor suppression for over 30 years. Cx43, the most widely expressed connexin, regulates cell behaviors, including migration and proliferation. Thus, we hypothesized that Cx43 could regulate PDA progression. Phosphorylation of Cx43 by Casein Kinase 1 (CK1) regulates gap junction assembly. We interbred the well-established KrasLSL-G12D/+;p48Cre/+ (KC) mouse model of PDA with homozygous "knock-in" mutant Cx43 mice bearing amino acid substitution at CK1 sites (Cx43CK1A) and found profound and surprising effects on cancer progression. Crossing the Cx43CK1A mouse onto the KC background (termed KC;CxCK1A) led to significant extension of lifespan, from a median of 370 to 486 days (p = 0.03) and a decreased incidence of metastasis (p = 0.045). However, when we examined early stages of disease, we found more rapid onset of tissue remodeling in the KC;CxCK1A mouse followed by divergence to a cystic phenotype. During tumorigenesis, gap junctions are increasingly present in stromal cells of the KC mice but are absent from the KC;Cx43CK1A mice. Tail vein metastasis assays with cells derived from KC or KC;CxCK1A tumors showed that KC;CxCK1A cells could efficiently colonize the lung and downregulate Cx43 expression, arguing that inhibition of metastasis was not occurring at the distal site. Instead, stromal gap junctions, their associated signaling events or other unknown Cx43-dependent events facilitate metastatic capacity in the primary tumor.

RevDate: 2021-02-18

Díez-Obrero V, Dampier CH, Moratalla-Navarro F, et al (2021)

Genetic effects on transcriptome profiles in colon epithelium provide functional insights for genetic risk loci.

Cellular and molecular gastroenterology and hepatology pii:S2352-345X(21)00036-9 [Epub ahead of print].

BACKGROUND & AIMS: The association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait associated loci and may suggest novel genes implicated in disease. Here, we aimed to 1) generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse and descending), 2) identify expression and splicing quantitative trait loci (QTLs), 3) find traits for which identified QTLs contribute to single nucleotide polymorphism (SNP)-based heritability, 4) propose candidate effector genes, and 5) provide a web-based visualization resource.

METHODS: We collected colonic mucosal biopsies from 485 healthy adults and performed bulk RNA sequencing (RNA-Seq). We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses.

RESULTS: We provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer (CoTrEx).

CONCLUSIONS: We provided the largest characterization to date of gene expression and splicing across colon subsites. Our findings provide greater etiological insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.

RevDate: 2021-02-18

Guilcher GMT, Rivard L, Huang JT, et al (2021)

Immune function in childhood cancer survivors: a Children's Oncology Group review.

The Lancet. Child & adolescent health pii:S2352-4642(20)30312-6 [Epub ahead of print].

Childhood cancer and its treatment often impact the haematopoietic and lymphatic systems, with immunological consequences. Immunological assessments are not routinely included in surveillance guidelines for most survivors of childhood cancer, although a robust body of literature describes immunological outcomes, testing recommendations, and revaccination guidelines after allogeneic haematopoietic cell transplantation. Survivorship care providers might not fully consider the impaired recovery of a child's immune system after cancer treatment if the child has not undergone haematopoietic cell transplantation. We did a scoping review to collate the existing literature describing immune function after childhood cancer therapy, including both standard-dose chemotherapy and high-dose chemotherapy with haematopoietic cell rescue. This Review aims to summarise: the principles of immunology and testing of immune function; the body of literature describing immunological outcomes after childhood cancer therapy, with an emphasis on the risk of infection, when is testing indicated, and preventive strategies; and knowledge gaps and opportunities for future research.

RevDate: 2021-02-19

Shadman M, A Goodrich (2020)

Improving Outcomes for Patients With Chronic Lymphocytic Leukemia.

Journal of the advanced practitioner in oncology, 11(3):312-315.

Mazyar Shadman, MD, MPH, and Amy Goodrich, CRNP, reviewed data regarding the mechanistic activity, efficacy, and safety of approved and emerging therapeutic options for chronic lymphocytic leukemia (CLL) and strategies for managing adverse events associated with approved therapies for CLL.

RevDate: 2021-02-19

Grivas P, J Hammond (2020)

Improving Outcomes for Patients With Advanced Urothelial Carcinoma.

Journal of the advanced practitioner in oncology, 11(3):285-289.

At JADPRO Live 2019, Petros Grivas, MD, PhD, and Jeannette Hammond, PA-C, reviewed data regarding mechanistic activity, efficacy, and safety of approved and emerging therapies for advanced or metastatic urothelial carcinoma, the selection of appropriate lines of therapy, and strategies for managing adverse events.

RevDate: 2021-02-18

Straub TJ, Chou WC, Manson AL, et al (2021)

Limited effects of long-term daily cranberry consumption on the gut microbiome in a placebo-controlled study of women with recurrent urinary tract infections.

BMC microbiology, 21(1):53.

BACKGROUND: Urinary tract infections (UTIs) affect 15 million women each year in the United States, with > 20% experiencing frequent recurrent UTIs. A recent placebo-controlled clinical trial found a 39% reduction in UTI symptoms among recurrent UTI sufferers who consumed a daily cranberry beverage for 24 weeks. Using metagenomic sequencing of stool from a subset of these trial participants, we assessed the impact of cranberry consumption on the gut microbiota, a reservoir for UTI-causing pathogens such as Escherichia coli, which causes > 80% of UTIs.

RESULTS: The overall taxonomic composition, community diversity, carriage of functional pathways and gene families, and relative abundances of the vast majority of observed bacterial taxa, including E. coli, were not changed significantly by cranberry consumption. However, one unnamed Flavonifractor species (OTU41), which represented ≤1% of the overall metagenome, was significantly less abundant in cranberry consumers compared to placebo at trial completion. Given Flavonifractor's association with negative human health effects, we sought to determine OTU41 characteristic genes that may explain its differential abundance and/or relationship to key host functions. Using comparative genomic and metagenomic techniques, we identified genes in OTU41 related to transport and metabolism of various compounds, including tryptophan and cobalamin, which have been shown to play roles in host-microbe interactions.

CONCLUSION: While our results indicated that cranberry juice consumption had little impact on global measures of the microbiome, we found one unnamed Flavonifractor species differed significantly between study arms. This suggests further studies are needed to assess the role of cranberry consumption and Flavonifractor in health and wellbeing in the context of recurrent UTI.

TRIAL REGISTRATION: Clinical trial registration number: ClinicalTrials.gov NCT01776021 .

RevDate: 2021-02-17

Luedtke A, RC Kessler (2021)

New Directions in Research on Heterogeneity of Treatment Effects for Major Depression.

JAMA psychiatry pii:2776610 [Epub ahead of print].

RevDate: 2021-02-17

Dobersch S, Rubio K, Singh I, et al (2021)

Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation.

Nature communications, 12(1):1072.

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.

RevDate: 2021-02-16

Pal SK, Tangen C, Thompson IM, et al (2021)

A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial.

Lancet (London, England) pii:S0140-6736(21)00152-5 [Epub ahead of print].

BACKGROUND: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC.

METHODS: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057.

FINDINGS: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group.

INTERPRETATION: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC.

FUNDING: National Institutes of Health and National Cancer Institute.

RevDate: 2021-02-16

Greaney AJ, Loes AN, Crawford KHD, et al (2021)

Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies.

Cell host & microbe pii:S1931-3128(21)00082-2 [Epub ahead of print].

The evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent plasma antibodies are impacted by all mutations to the spike's receptor-binding domain (RBD), the main target of plasma neutralizing activity. Binding by polyclonal plasma antibodies is affected by mutations in three main epitopes in the RBD, but longitudinal samples reveal that the impact of these mutations on antibody binding varies substantially both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD's receptor-binding motif. The most important site is E484, where neutralization by some plasma is reduced >10-fold by several mutations, including one in the emerging 20H/501Y.V2 and 20J/501Y.V3 SARS-CoV-2 lineages. Going forward, these plasma escape maps can inform surveillance of SARS-CoV-2 evolution.

RevDate: 2021-02-16

Godwin CD, Laszlo GS, Fiorenza S, et al (2021)

Targeting the membrane-proximal C2-set domain of CD33 for improved CD33-directed immunotherapy.

Leukemia [Epub ahead of print].

There is increasing interest in targeting CD33 in malignant and non-malignant disorders. In acute myeloid leukemia, longer survival with the CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO) validates this strategy. Still, GO benefits only some patients, prompting efforts to develop more potent CD33-directed therapeutics. As one limitation, CD33 antibodies typically recognize the membrane-distal V-set domain. Using various artificial CD33 proteins, in which this domain was differentially positioned within the extracellular portion of the molecule, we tested whether targeting membrane-proximal epitopes enhances the effector functions of CD33 antibody-based therapeutics. Consistent with this idea, a CD33V-set/CD3 bispecific antibody (BsAb) and CD33V-set-directed chimeric antigen receptor (CAR)-modified T cells elicited substantially greater cytotoxicity against cells expressing a CD33 variant lacking the entire C2-set domain than cells expressing full-length CD33, whereas cytotoxic effects induced by GO were independent of the position of the V-set domain. We therefore raised murine and human antibodies against the C2-set domain of human CD33 and identified antibodies that bound CD33 regardless of the presence/absence of the V-set domain ("CD33PAN antibodies"). These antibodies internalized when bound to CD33 and, as CD33PAN/CD3 BsAb, had potent cytolytic effects against CD33+ cells. Together, our data provide the rationale for further development of CD33PAN antibody-based therapeutics.

RevDate: 2021-02-15

Witlox WJA, Ramaekers BLT, Lacas B, et al (2021)

Individual patient data meta-analysis of prophylactic cranial irradiation in locally advanced non-small cell lung cancer.

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology pii:S0167-8140(21)06048-5 [Epub ahead of print].

BACKGROUND: Prophylactic cranial irradiation (PCI) was compared to observation in several randomized trials (RCTs), and a reduction greater than 50% was shown regarding the incidence of brain metastases (BM). However, none of these studies showed an improvement of overall survival (OS), possibly related to relatively small sample sizes and short follow-up. The aim of this meta-analysis was therefore to assess the impact of PCI on long term OS for stage III non-small cell lung cancer (NSCLC) compared to observation based on the pooled updated individual patient RCT data.

METHODS: Seven RCTs were eligible, and data from the four most recent trials (924 patients) could be retrieved. The log-rank observed minus expected number of events and its variance were used to calculate individual and overall pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) with a fixed effects model. Inter-trial heterogeneity was studied using the I2 test. In addition, the 5-year absolute survival difference between arms was calculated for all endpoints. The pre-specified toxicities were reported descriptively.

RESULTS: The median follow-up was 97 months (74-108). Compared to observation, no statistically significant impact of PCI on OS was observed (HR 0.90 [0.76-1.07] p=0.23, 5-year absolute difference 1.8% [-5.2-8.8]). PCI significantly prolonged progression-free survival (HR 0.77 [0.66-0.91] p=0.002) and BM-free survival (HR 0.82 [0.69-0.97] p=0.02). The number of patients with high-grade (≥3) toxicity was 6.4% (21/330) for PCI.

CONCLUSION: No OS benefit by PCI was observed, but PCI prolonged the progression-free survival and BM-free survival at an increased risk of late memory impairment and fatigue.

RevDate: 2021-02-15

Mgodi NM, Takuva S, Edupuganti S, et al (2021)

A phase 2b study to evaluate the safety and efficacy of VRC01 broadly neutralizing monoclonal antibody in reducing acquisition of HIV-1 infection in women in sub-Saharan Africa: baseline findings.

Journal of acquired immune deficiency syndromes (1999) pii:00126334-900000000-95944 [Epub ahead of print].

BACKGROUND: HIV Vaccine Trials Network (HVTN) 703/HIV Prevention Trials Network (HPTN) 081 is a phase 2b randomized, double-blind placebo-controlled trial to assess the safety and efficacy of passively infused monoclonal antibody (mAb) VRC01 in preventing HIV acquisition in heterosexual women between the ages of 18 and 50 at risk of HIV. Participants were enrolled at 20 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania and Zimbabwe. It is one of two Antibody Mediated Prevention (AMP) efficacy trials, with HVTN 704/HPTN 085, evaluating VRC01 for HIV prevention.

METHODS: Intense community engagement was utilized to optimize participant recruitment and retention. Participants were randomly assigned to receive intravenous (IV) VRC01 10 mg/kg, VRC01 30 mg/kg, or placebo in a 1:1:1 ratio. Infusions were given every eight weeks with a total of 10 infusions and 104 weeks of follow-up after the first infusion.

RESULTS: Between May 2016 and September 2018, 1924 women from sub-Saharan Africa were enrolled. The median age was 26 (IQR: 22-30) and 98.9% were Black. Sexually transmitted infection prevalence at enrollment included chlamydia (16.9%), trichomonas (7.2%), gonorrhea (5.7%) and syphilis (2.2%). External condoms (83.2%) and injectable contraceptives (61.1%) were the methods of contraception most frequently used by participants. In total, through April 3, 2020, 38,490 clinic visits were completed with a retention rate of 96% and 16,807 infusions administered with an adherence rate of 98%.

CONCLUSIONS: This proof-of-concept, large-scale mAb study demonstrates the feasibility of conducting complex trials involving IV infusions in high-incidence populations in sub-Saharan Africa.

RevDate: 2021-02-15

Edupuganti S, Mgodi N, Karuna ST, et al (2021)

Feasibility and Successful Enrollment in a Proof-of-Concept HIV Prevention Trial of VRC01, a Broadly Neutralizing HIV-1 Monoclonal Antibody.

Journal of acquired immune deficiency syndromes (1999) pii:00126334-900000000-95939 [Epub ahead of print].

BACKGROUND: The Antibody Mediated Prevention (AMP) trials (HVTN 704/HPTN 085 & HVTN 703/HPTN 081) are the first efficacy trials to evaluate whether VRC01, a broadly neutralizing monoclonal antibody (mAb) targeting the CD4 binding site of the HIV envelope protein, prevents sexual transmission of HIV-1. HVTN 704/HPTN 085 enrolled 2,701 cisgender men and transgender (TG) individuals who have sex with men at 26 sites in Brazil, Peru, Switzerland and the United States.

METHODS: Participants were recruited and retained through early, extensive community engagement. Eligible participants were randomized 1:1:1 to 10 mg/kg or 30 mg/kg of VRC01 or saline placebo. Visits occurred monthly, with intravenous (IV) infusions every 8 weeks over 2 years, for a total of ten infusions. Participants were followed for 104 weeks after first infusion.

RESULTS: The median HVTN 704/HPTN 085 participant age was 28; 99% were assigned male sex; 90% identified as cisgender male, 5% as TG female and the remaining as other genders. Thirty-two percent were White, 15% Black and 57% Hispanic/Latinx. Twenty-eight percent had a sexually transmitted infection at enrollment. Over 23,000 infusions were administered with no serious IV administration complications. Overall retention and adherence to the study schedule exceeded 90%, and the drop-out rate was below 10% annually (7.3 per 100-person years) through Week 80, the last visit for the primary endpoint.

CONCLUSIONS: HVTN 704/HPTN 085 exceeded accrual and retention expectations. With exceptional safety of IV administration and operational feasibility, it paves the way for future large-scale mAb trials for HIV prevention and/or treatment.

RevDate: 2021-02-15

Singh N, Winston DJ, Razonable RR, et al (2020)

Association of HHV-6 With Outcomes in CMV-Seronegative Liver Transplant Recipients With CMV-Seropositive Donors Receiving Preemptive Antiviral Therapy.

Transplantation pii:00007890-900000000-95428 [Epub ahead of print].

BACKGROUND: Risk factors, virologic parameters and outcomes associated with HHV-6 viremia in high-risk donor CMV-seropositive and recipient CMV-seronegative (D+R-) liver transplant recipients in the current era are incompletely defined.

METHODS: The study population consisted of patients in the preemptive therapy (PET) arm of a randomized, controlled trial of PET versus valganciclovir prophylaxis for CMV prevention in D+R- liver transplant recipients. Weekly blood samples through 100 days in the PET group were tested for HHV-6 viremia using a real-time quantitative PCR. Assessments included virologic characteristics and relationship with CMV, risk factors and impact of HHV-6 viremia with outcomes through 12 months post-transplant.

RESULTS: HHV-6 viremia at any level developed in 42% (40/96). Older patient age (p=0.03), longer hospitalization (p=0.015), and ICU stay at transplantation (p=0.029) were significantly associated with high-grade viremia. Concurrent HHV-6 and CMV viremia was associated with earlier onset of HHV-6 viremia (p=0.004), higher HHV-6 AUC (p=0.043), and higher peak HHV-6 viral load (p=0.006) vs HHV-6 viremia alone. High-grade viremia was independently associated with biopsy-proven rejection within 12 months (p=0.045) post-transplant.

CONCLUSIONS: Among D+R- liver transplant recipients receiving valganciclovir as PET, high-grade HHV-6 viremia was associated with increased age and critical-illness in ICU at time of transplant and was independently associated with allograft rejection.

RevDate: 2021-02-15

Shen T, Wang W, Zhou W, et al (2021)

MAPK4 promotes prostate cancer by concerted activation of androgen receptor and AKT.

The Journal of clinical investigation, 131(4):.

Prostate cancer (PCa) is the second leading cause of cancer death in American men. Androgen receptor (AR) signaling is essential for PCa cell growth/survival and remains a key therapeutic target for lethal castration-resistant PCa (CRPC). GATA2 is a pioneer transcription factor crucial for inducing AR expression/activation. We recently reported that MAPK4, an atypical MAPK, promotes tumor progression via noncanonical activation of AKT. Here, we demonstrated that MAPK4 activated AR by enhancing GATA2 transcriptional expression and stabilizing GATA2 protein through repression of GATA2 ubiquitination/degradation. MAPK4 expression correlated with AR activation in human CRPC. Concerted activation of both GATA2/AR and AKT by MAPK4 promoted PCa cell proliferation, anchorage-independent growth, xenograft growth, and castration resistance. Conversely, knockdown of MAPK4 decreased activation of both AR and AKT and inhibited PCa cell and xenograft growth, including castration-resistant growth. Both GATA2/AR and AKT activation were necessary for MAPK4 tumor-promoting activity. Interestingly, combined overexpression of GATA2 plus a constitutively activated AKT was sufficient to drive PCa growth and castration resistance, shedding light on an alternative, MAPK4-independent tumor-promoting pathway in human PCa. We concluded that MAPK4 promotes PCa growth and castration resistance by cooperating parallel pathways of activating GATA2/AR and AKT and that MAPK4 is a novel therapeutic target in PCa, especially CRPC.

RevDate: 2021-02-15

Owonikoko TK, Redman MW, Byers LA, et al (2021)

Phase 2 Study of Talazoparib in Patients With Homologous Recombination Repair-Deficient Squamous Cell Lung Cancer: Lung-MAP Substudy S1400G.

Clinical lung cancer pii:S1525-7304(21)00004-8 [Epub ahead of print].

PURPOSE: This signal finding study (S1400G) was designed to evaluate the efficacy of talazoparib in advanced stage squamous cell lung cancer harboring homologous recombination repair deficiency.

PATIENTS AND METHODS: The full eligible population (FEP) had tumors with a deleterious mutation in any of the study-defined homologous recombination repair genes and without prior exposure to a PARP inhibitor. The primary analysis population (PAP) is a subset of FEP with alteration in ATM, ATR, BRCA1, BRCA2, or PALB2. Treatment consisted of talazoparib 1 mg daily continuously in 21-day cycles. A 2-stage design with exact 93% power and 1-sided 0.07 type I error required enrollment of 40 patients in the PAP in order to rule out an overall response rate (ORR) of 15% or less if the true ORR is ≥ 35%.

RESULTS: The study enrolled 47 patients in the FEP, of whom 24 were in the PAP. The median age for the FEP was 66.7 years; 83% were male and 85% white. ORR in the PAP was 4% (95% confidence interval [CI], 0, 21) with disease control rate of 54% (95% CI, 33, 74). Median progression-free survival and overall survival were 2.4 months (95% CI, 1.5-2.8) and 5.2 months (95% CI, 4.0-10), respectively. In the FEP, ORR was 11% (95% CI, 3.6, 23), the disease control rate was 51% (95% CI, 36, 66), and the median duration of response was 1.8 months (95% CI, 1.3, 4.2). Median progression-free and overall survival were 2.5 months and 5.7 months, respectively.

CONCLUSIONS: S1400G failed to show sufficient level of efficacy for single agent talazoparib in a biomarker defined subset of squamous lung cancer with homologous recombination repair deficiency.

RevDate: 2021-02-13

Labadie KP, Ludwig AD, Lehnert AL, et al (2021)

Glypican-3 targeted delivery of 89Zr and 90Y as a theranostic radionuclide platform for hepatocellular carcinoma.

Scientific reports, 11(1):3731.

Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (89Zr) and yttrium-90 (90Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUVmax by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R2 = 0.90). Serum AFP was significantly lower 30 days after RIT in 90Y-αGPC3 treated animals compared to those untreated (p = 0.01) or treated with non-radiolabeled αGPC3 (p = 0.02). Immuno-PET GTV measurements strongly correlated with tumor burden after RIT (R2 = 0.87), and GTV of animals treated with 90Y-αGPC3 was lower than in animals who did not receive treatment or were treated with non-radiolabeled αGPC3, although this only trended toward statistical significance. A theranostic platform utilizing GPC3 targeted 89Zr and 90Y effectively imaged, treated, and assessed response after radioimmunotherapy in a GPC3-expressing HCC xenograft model.

RevDate: 2021-02-12

Desroches B, Porter J, Bhayani S, et al (2021)

Comparison of the Safety and Efficacy of Valveless and Standard Insufflation During Robotic Partial Nephrectomy: A Prospective, Randomized, Multi-Institutional Trial.

Urology pii:S0090-4295(21)00156-4 [Epub ahead of print].

OBJECTIVE: To use a randomized, prospective, multi-institutional study to compare the safety and efficacy of conventional insufflation (CIS) and valveless insufflation (AirSeal Insufflation - AIS) at the conventional pressure of 15 mmHg in robot-assisted partial nephrectomy - a surgery where AIS has gained popularity for maintaining visualization despite suction. This study was also powered to evaluate the effect of decreasing pneumoperitoneum by 20% in the valveless system.

MATERIALS AND METHODS: Three high-volume institutions randomized subjects into CIS 15, AIS 15, and AIS 12 mmHg cohorts. Endpoints included rates of subcutaneous emphysema (SCE), pneumothorax (PTX), pneumomediastinum (PMS), intraoperative end-tidal carbon dioxide (ET CO2), and peak airway pressure (PAP), as well as hospital stay, post-operative pain, and complications. Given the substantial proportion of retroperitoneal surgery, a secondary analysis evaluated the effect of surgical approach.

RESULTS: 202 patients were accrued. SCE was decreased in the AIS 12 mmHg group (p=0.003). PTX and PMS rates were not statistically significantly different across the three insufflation groups. Higher rates of SCE and PMS, although not PTX, were noted in all retroperitoneal surgery groups - with lower SCE rates for AIS 12 mmHg regardless of surgical approach.

CONCLUSIONS: AIS is often preferred for complex procedures including retroperitoneal and transperitoneal robotic-assisted partial nephrectomy, for its maintenance of pneumoperitoneum despite continuous suction necessary for visualization. This study shows that AIS is safe when compared to CIS at 15 mmHg, and shows improvement in outcomes when pneumoperitoneum pressure is reduced by 20% to 12 mmHg.

RevDate: 2021-02-12

Grunwald MR, Zhang MJ, Elmariah H, et al (2021)

Alternative donor transplantation for myelodysplastic syndromes: haploidentical relative and matched unrelated donors.

Blood advances, 5(4):975-983.

We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.

RevDate: 2021-02-12

Severson TM, Zhu Y, De Marzo AM, et al (2021)

Epigenetic and transcriptional analysis reveals a core transcriptional program conserved in clonal prostate cancer metastases.

Molecular oncology [Epub ahead of print].

The epigenomic regulation of transcriptional programs in metastatic prostate cancer is poorly understood. We studied the epigenomic landscape of prostate cancer drivers using transcriptional profiling and chromatin immunoprecipitation sequencing (ChIP-seq) in four clonal metastatic tumors derived from a single prostate cancer patient. Our epigenomic analyses focused on Androgen Receptor (AR), which is a key oncogenic driver in prostate cancer , the AR pioneer factor FOXA1, chromatin insulator CTCF, as well as for modified histones H3K27ac and H3K27me3. The vast majority of AR binding sites were shared among healthy prostate, primary prostate cancer and metastatic tumor samples, signifying core AR-driven transcriptional regulation within the prostate cell lineage. Genes associated with core AR-binding events were significantly enriched for essential genes in prostate cancer cell proliferation. Remarkably, the metastasis-specific active AR binding sites showed no differential transcriptional output, indicating a robust transcriptional program across metastatic samples. Combined, our data reveal a core transcriptional program in clonal metastatic prostate cancer, despite epigenomic differences in the AR cistrome.

RevDate: 2021-02-13

Lee S, Lee C, Nam JW, et al (2020)

School Walkability Index: Application of Environmental Audit Tool and GIS.

Journal of transport & health, 18:.

Introduction: Active school travel is an important way to promote children's physical activity, but it requires supportive environments that can safely and comfortably accommodate children's walking and biking. Few existing indices explicitly consider school neighborhood environmental factors related to children's walking to school. In this study, we used a street audit tool and Geographic Information System (GIS) to evaluate walkability near low-income elementary schools in Seattle, WA.

Methods: The audit-based school walkability index was developed based on all street segments (n=841) within a 0.4km network buffer from each study school (n=18). The GIS-based school walkability, a combination of road connectivity, vehicular traffic exposure, and residential density, was also measured in a 2km network buffer around each school. The participants were individuals aged 8-11 years (n=315) who participated in the Walking School Bus randomized controlled trial project. Mixed-effects logistic and linear models were used to examine the association of the index's representations of the built environment with children's school travel mode (walking or biking to school 1+ times per week) and with objectively measured moderate-to-vigorous physical activity (MVPA, average weekday minutes during the 90-min before-school period). These associations were tested with the total sample as well as the subsample of children living within 1.5km from their schools.

Results: The audit-based school walkability index (WI) was positively associated with both active commuting to school among the subsample living within 1.5km from their schools and with children's before-school MVPA among the subsample and the total sample. The GIS-based school WI showed significant associations with children's before-school MVPA but no relationships with active school travel among the subsample and the total sample.

Conclusion: The audit-based school walkability index can be used as a complementary tool for measuring walkability near low-income elementary schools along with existing GIS-based school walkability index.

RevDate: 2021-02-12

Mocci E, Kundu P, Wheeler W, et al (2021)

Smoking modifies pancreatic cancer risk loci on 2q21.3.

Cancer research pii:0008-5472.CAN-20-3267 [Epub ahead of print].

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% CI 0.82-0.93; former smokers 1.00, 95 CI 0.91-1.07; current smokers 1.25, 95%CI 1.12-1.40, interaction P-value=3.08x10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high LD with rs1818613 (r2=0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.

RevDate: 2021-02-13

Wang Y, Zhou W, Wang J, et al (2021)

Pre-HCT mosaicism increases relapse risk and lowers survival in acute lymphoblastic leukemia patients post-unrelated HCT.

Blood advances, 5(1):66-70.

RevDate: 2021-02-13

Martens KL, da Costa WL, Amos CI, et al (2021)

HIGH-2-LOW risk model to predict venous thromboembolism in allogeneic transplant patients after platelet engraftment.

Blood advances, 5(1):167-175.

Venous thromboembolism (VTE) after allogeneic hematopoietic cell transplantation (HCT) is a significant treatment-associated complication, although optimal timing of thromboprophylaxis remains uncertain when weighing concurrent risks of bleeding. We aimed to derive and internally validate a risk assessment model (RAM) using patients who underwent first allogeneic HCT from 2006 through 2015 (n = 1703). Index date was defined as the 30th day after transplant, at which point we estimated >75% of patients would have achieved platelet engraftment >50 × 109/L. Stepwise logistic regression modeling was used for model development, and internal validation was achieved by fitting a logistic regression model with 1000 bootstrapped resamples to estimate the optimism-corrected c-statistic. The final RAM, "HIGH-2-LOW," included 7 predictors obtained at 30 days after transplant: History of catheter-related deep venous thrombosis (DVT), Inpatient at day 30, Graft-versus-host disease grade 3 to 4, History of pulmonary embolism or lower-extremity DVT, Lymphoma diagnosis, Obesity with body mass index ≥35 kg/m2, and White blood cell count ≥11 × 109/L. Approximately 16% of patients were stratified as high risk, with incident VTE rate of 10.3% at 100 days compared with 1.5% for those at low risk. VTE odds ratios at 100 days were 5.87 (95% confidence interval [CI], 2.98-11.57) and 2.71 (95% CI, 1.38-5.35) in the high- and intermediate-risk vs low-risk groups, respectively. HIGH-2-LOW model serves as a novel and potentially clinically meaningful tool to identify high-risk allogeneic HCT patients who may benefit from early thromboprophylaxis after platelet engraftment.

RevDate: 2021-02-12

Lyman GH, Carrier M, Ay C, et al (2021)

American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer.

Blood advances, 5(4):927-974.

BACKGROUND: Venous thromboembolism (VTE) is a common complication among patients with cancer. Patients with cancer and VTE are at a markedly increased risk for morbidity and mortality.

OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about the prevention and treatment of VTE in patients with cancer.

METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The guideline development process was supported by updated or new systematic evidence reviews. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess evidence and make recommendations.

RESULTS: Recommendations address mechanical and pharmacological prophylaxis in hospitalized medical patients with cancer, those undergoing a surgical procedure, and ambulatory patients receiving cancer chemotherapy. The recommendations also address the use of anticoagulation for the initial, short-term, and long-term treatment of VTE in patients with cancer.

CONCLUSIONS: Strong recommendations include not using thromboprophylaxis in ambulatory patients receiving cancer chemotherapy at low risk of VTE and to use low-molecular-weight heparin (LMWH) for initial treatment of VTE in patients with cancer. Conditional recommendations include using thromboprophylaxis in hospitalized medical patients with cancer, LMWH or fondaparinux for surgical patients with cancer, LMWH or direct oral anticoagulants (DOAC) in ambulatory patients with cancer receiving systemic therapy at high risk of VTE and LMWH or DOAC for initial treatment of VTE, DOAC for the short-term treatment of VTE, and LMWH or DOAC for the long-term treatment of VTE in patients with cancer.

RevDate: 2021-02-12

Li L, Liu H, Krout M, et al (2021)

A novel dual Ca2+ sensor system regulates Ca2+-dependent neurotransmitter release.

The Journal of cell biology, 220(4):.

Ca2+-dependent neurotransmitter release requires synaptotagmins as Ca2+ sensors to trigger synaptic vesicle (SV) exocytosis via binding of their tandem C2 domains-C2A and C2B-to Ca2+. We have previously demonstrated that SNT-1, a mouse synaptotagmin-1 (Syt1) homologue, functions as the fast Ca2+ sensor in Caenorhabditis elegans. Here, we report a new Ca2+ sensor, SNT-3, which triggers delayed Ca2+-dependent neurotransmitter release. snt-1;snt-3 double mutants abolish evoked synaptic transmission, demonstrating that C. elegans NMJs use a dual Ca2+ sensor system. SNT-3 possesses canonical aspartate residues in both C2 domains, but lacks an N-terminal transmembrane (TM) domain. Biochemical evidence demonstrates that SNT-3 binds both Ca2+ and the plasma membrane. Functional analysis shows that SNT-3 is activated when SNT-1 function is impaired, triggering SV release that is loosely coupled to Ca2+ entry. Compared with SNT-1, which is tethered to SVs, SNT-3 is not associated with SV. Eliminating the SV tethering of SNT-1 by removing the TM domain or the whole N terminus rescues fast release kinetics, demonstrating that cytoplasmic SNT-1 is still functional and triggers fast neurotransmitter release, but also exhibits decreased evoked amplitude and release probability. These results suggest that the fast and slow properties of SV release are determined by the intrinsically different C2 domains in SNT-1 and SNT-3, rather than their N-termini-mediated membrane tethering. Our findings therefore reveal a novel dual Ca2+ sensor system in C. elegans and provide significant insights into Ca2+-regulated exocytosis.

RevDate: 2021-02-11

Chemaly RF, Marty FM, Wolfe CR, et al (2021)

DAS181 Treatment of Severe Lower Respiratory Tract Parainfluenza Virus Infection in Immunocompromised Patients: A Phase 2 Randomized, Placebo-Controlled Study.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:6132834 [Epub ahead of print].

BACKGROUND: There are no antiviral therapies for Parainfluenza virus (PIV) infections. DAS181, a sialidase fusion protein, has demonstrated activity in in vitro and in animal models of PIV.

METHODS: Adult immunocompromised patients diagnosed with PIV lower respiratory tract infection (LRTI) who required oxygen supplementation were randomized 2:1 to nebulized DAS181 (4.5 mg/day) or matching placebo for up to 10 days. Randomization was stratified by need for mechanical ventilation (MV) or supplemental oxygen (SO). The primary endpoint was the proportion of patients reaching clinical stability survival (CSS) defined as returning to breathing room air (RTRA), normalization of vital signs for at least 24 hours, and survival up to day 45 from enrollment.

RESULTS: A total of 111 patients were randomized to DAS181 (n=74) or placebo (n=37). CSS was achieved by 45.0% DAS181 treated patients in the SO stratum compared with 31.0% for placebo (p=0.15), while patients on MV had no benefit from DAS181. The proportion of patients achieving RTRA was numerically higher for SO stratum DAS181 patients (51.7%) compared with Placebo (34.5%) at Day 28 (p=0.17). In a post-hoc analysis of solid organ transplant, hematopoietic cell transplantation within one year, or chemotherapy within one year, more SO stratum patients achieved RTRA on DAS181 (51.8%) when compared to placebo (15.8%) by day 28 (p=0.012).

CONCLUSION: The primary endpoint was not met, but post-hoc analysis of the RTRA component suggests DAS181 may have clinical activity in improving oxygenation in select severely immunocompromised patients with PIV LRTI who are not on mechanical ventilation.

RevDate: 2021-02-12

Taliun D, Harris DN, Kessler MD, et al (2021)

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.

Nature, 590(7845):290-299.

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

RevDate: 2021-02-11

Liu Q, Palomero L, Moore J, et al (2021)

Loss of TGFβ signaling increases alternative end-joining DNA repair that sensitizes to genotoxic therapies across cancer types.

Science translational medicine, 13(580):.

Among the pleotropic roles of transforming growth factor-β (TGFβ) signaling in cancer, its impact on genomic stability is least understood. Inhibition of TGFβ signaling increases use of alternative end joining (alt-EJ), an error-prone DNA repair process that typically functions as a "backup" pathway if double-strand break repair by homologous recombination or nonhomologous end joining is compromised. However, the consequences of this functional relationship on therapeutic vulnerability in human cancer remain unknown. Here, we show that TGFβ broadly controls the DNA damage response and suppresses alt-EJ genes that are associated with genomic instability. Mechanistically based TGFβ and alt-EJ gene expression signatures were anticorrelated in glioblastoma, squamous cell lung cancer, and serous ovarian cancer. Consistent with error-prone repair, more of the genome was altered in tumors classified as low TGFβ and high alt-EJ, and the corresponding patients had better outcomes. Pan-cancer analysis of solid neoplasms revealed that alt-EJ genes were coordinately expressed and anticorrelated with TGFβ competency in 16 of 17 cancer types tested. Moreover, regardless of cancer type, tumors classified as low TGFβ and high alt-EJ were characterized by an insertion-deletion mutation signature containing short microhomologies and were more sensitive to genotoxic therapy. Collectively, experimental studies revealed that loss or inhibition of TGFβ signaling compromises the DNA damage response, resulting in ineffective repair by alt-EJ. Translation of this mechanistic relationship into gene expression signatures identified a robust anticorrelation that predicts response to genotoxic therapies, thereby expanding the potential therapeutic scope of TGFβ biology.

RevDate: 2021-02-11

Flaig TW, Tangen CM, Daneshmand S, et al (2021)

A randomized phase II study of coexpression extrapolation (COXEN) with neoadjuvant chemotherapy for bladder cancer (SWOG S1314; NCT02177695).

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-2409 [Epub ahead of print].

PURPOSE: Dose-dense Methotrexate-Vinblastine-Adriamycin-Cisplatin (ddMVAC) and Gemcitabine-Cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer (BC). The aim of this study was to validate the score from a Coexpression extrapolation (COXEN) algorithm-generated gene expression model (GEM) as a biomarker in patients undergoing radical cystectomy.

EXPERIMENTAL DESIGN: Eligibility included cT2-T4a N0 M0, urothelial BC, {greater than or equal to} 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy; 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. The primary objective assessed pre-specified dichotomous treatment specific COXEN score as predictive of pT0 rate or {less than or equal to} pT1 (downstaging) at surgery.

RESULTS: Among 167 evaluable patients, the odds ratio for pT0 with the GC GEM score in GC-treated patients was 2.63 (p=0.10; 95% CI [0.82,8.36]); for the ddMVAC COXEN GEM score with ddMVAC treatment, the OR was 1.12 (p=0.82, 95% CI [0.42, 2.95]). The GC GEM score was applied to pooled arms (GC and ddMVAC) for downstaging with an OR of 2.33 (p=0.02; 95% CI [1.11, 4.89]). In an intention to treat analysis of eligible patients (n=227), pT0 rates for ddMVAC and GC were 28% and 30% (p = 0.75); downstaging was 47% and 40% (p = 0.27), respectively.

CONCLUSIONS: Treatment-specific COXEN scores were not significantly predictive for response to individual chemotherapy treatment. The COXEN GEM GC score was significantly associated with downstaging in the pooled arms. Additional biomarker development is planned.

RevDate: 2021-02-10

Zhu Y, Dalrymple SL, Coleman I, et al (2021)

Correction to: Role of androgen receptor splice variant-7 (AR-V7) in prostate cancer resistance to 2nd-generation androgen receptor signaling inhibitors.

RevDate: 2021-02-10

Tuazon SA, Holmberg LA, Nadeem O, et al (2021)

A clinical perspective on plasma cell leukemia; current status and future directions.

Blood cancer journal, 11(2):23.

Primary plasma cell leukemia (pPCL) is an aggressive plasma cell disorder with a guarded prognosis. The diagnosis is confirmed when peripheral blood plasma cells (PCs) exceed 20% of white blood cells or 2000/μL. Emerging data demonstrates that patients with lower levels of circulating (PCs) have the same adverse prognosis, challenging the clinical disease definition, but supporting the adverse impact of circulating PCs. The cornerstone of treatment consists of combination therapy incorporating a proteasome inhibitor, an immunomodulatory agent, steroids, and/or anthracyclines and alkylators as part of more-intensive chemotherapy, followed by consolidative autologous hematopoietic cell transplantation in eligible patients and then maintenance therapy. Monoclonal antibodies are also currently being evaluated in this setting with a strong rationale for their use based on their activity in multiple myeloma (MM). Due to limited therapeutic studies specifically evaluating pPCL, patients with pPCL should be considered for clinical trials. In contrast to MM, the outcomes of patients with pPCL have only modestly improved with novel therapies, and secondary PCL arising from MM in particular is associated with a dismal outlook. Newer drug combinations, immunotherapy, and cellular therapy are under investigation, and these approaches hopefully will demonstrate efficacy to improve the prognosis of pPCL.

RevDate: 2021-02-12

Harvey RD, Mileham KF, Bhatnagar V, et al (2021)

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Washout Period and Concomitant Medication Work Group.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-3855 [Epub ahead of print].

PURPOSE: Washout periods and concomitant medication exclusions are common in cancer clinical trial protocols. These exclusion criteria are often applied inconsistently and without evidence to justify their use. The authors sought to determine how washout period and concomitant medication allowances can be broadened to speed trial enrollment and improve the generalizability of trial data to a larger oncology practice population without compromising the safety of trial participants.

EXPERIMENTAL DESIGN: A multistakeholder working group was convened to define problems associated with excessively long washout periods and exclusion of patients due to concomitant medications. The group performed a literature search and evaluated study data from the Pancreatic Cancer Action Network (PanCAN), Emory University School of Medicine (Atlanta, GA), and the FDA to understand recent approaches to these eligibility criteria. The group convened to develop consensus recommendations for broadened eligibility criteria.

RESULTS: The data analysis found that exclusion criteria based on washout periods and concomitant medications are frequently inconsistent and lack scientific rationale. Scientific rationale for appropriate eligibility criteria are presented in the article; for washout periods, rationale is presented by treatment type.

CONCLUSIONS: Arbitrary or blanket washout and concomitant medication exclusions should be eliminated. Where there is evidence to support them, clinically relevant washout periods and concomitant medication-related eligibility criteria may be included.

RevDate: 2021-02-10

Harvey RD, Bruinooge SS, Chen L, et al (2021)

Impact of Broadening Trial Eligibility Criteria for Patients with Advanced Non-Small Cell Lung Cancer: Real-World Analysis of Select ASCO-Friends Recommendations.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-3857 [Epub ahead of print].

PURPOSE: Cancer clinical trials often accrue slowly or miss enrollment targets. Strict eligibility criteria are a major reason. Restrictive criteria also limit opportunities for patient participation while compromising external validity of trial results. We examined the impact of broadening select eligibility criteria on characteristics and number of patients eligible for trials, using recommendations of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research.

EXPERIMENTAL DESIGN: A retrospective, observational analysis used electronic health record data from ASCO's CancerLinQ Discovery database. Study cohort included patients with advanced non-small cell lung cancer treated from 2011 to 2018. Patients were grouped by traditional criteria [no brain metastases, no other malignancies, and creatinine clearance (CrCl) ≥ 60 mL/minute] and broadened criteria (including brain metastases, other malignancies, and CrCl ≥ 30 mL/minute).

RESULTS: The analysis cohort included 10,500 patients. Median age was 68 years, and 73% of patients were White. Most patients had stage IV disease (65%). A total of 5,005 patients (48%) would be excluded from trial participation using the traditional criteria. The broadened criteria, however, would allow 98% of patients (10,346) to be potential participants. Examination of patients included by traditional criteria (5,495) versus those added (4,851) by broadened criteria showed that the number of women, patients aged 75+ years, and those with stage IV cancer was significantly greater using broadened criteria.

CONCLUSIONS: This analysis of real-world data demonstrated that broadening three common eligibility criteria has the potential to double the eligible patient population and include trial participants who are more representative of those encountered in practice.

RevDate: 2021-02-10

Magnuson A, Bruinooge SS, Singh H, et al (2021)

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the ASCO-Friends of Cancer Research Performance Status Work Group.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-3868 [Epub ahead of print].

PURPOSE: Performance status (PS) is one of the most common eligibility criteria. Many trials are limited to patients with high-functioning PS, resulting in important differences between trial participants and patient populations with the disease. In addition, existing PS measures are subjective and susceptible to investigator bias.

EXPERIMENTAL DESIGN: A multidisciplinary working group of the American Society of Clinical Oncology and Friends of Cancer Research evaluated how PS eligibility criteria could be more inclusive. The working group recommendations are based on a literature search, review of trials, simulation study, and multistakeholder consensus. The working group prioritized inclusiveness and access to investigational therapies, while balancing patient safety and study integrity.

RESULTS: Broadening PS eligibility criteria may increase the number of potentially eligible patients for a given clinical trial, thus shortening accrual time. It may also result in greater participant diversity, potentially reduce trial participant and patient disparities, and enable clinicians to more readily translate trial results to patients with low-functioning PS. Potential impact on outcomes was explored through a simulation trial demonstrating that when the number of Eastern Cooperative Oncology Group PS2 participants was relatively small, the effect on the estimated HR and power was modest, even when PS2 patients did not derive a treatment benefit.

CONCLUSIONS: Expanding PS eligibility criteria to be more inclusive may be justified in many cases and could result in faster accrual rates and more representative trial populations.

RevDate: 2021-02-10

Kim ES, Uldrick TS, Schenkel C, et al (2021)

Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO-Friends of Cancer Research Joint Research Statement.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-3852 [Epub ahead of print].

PURPOSE: Restrictive clinical trial eligibility criteria (EC) limit the number of patients who can enroll and potentially benefit from protocol-driven, investigational treatment plans and reduce the generalizability of trial results to the broader population. Following publication of expert stakeholder recommendations for broadening EC in 2017, the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) convened working groups to produce additional recommendations and analyze the potential impact on clinical trials using real-world data.

EXPERIMENTAL DESIGN: Multistakeholder working groups were appointed by an ASCO-Friends leadership group to propose recommendations for more inclusive EC related to: washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status.

RESULTS: The four working groups, ASCO Board of Directors, and Friends leadership support the recommendations included in this statement to modernize EC related to washout periods, concomitant medications, prior therapies, laboratory references ranges and test intervals, and performance status to make trial populations more inclusive and representative of cancer patient populations.

CONCLUSIONS: Implementation of the recommendations is intended to result in greater ease of determining patient eligibility. Increased opportunities for patient participation in research will help address longstanding underrepresentation of certain groups in clinical trials and produce evidence that is more informative for a broader patient population. More patients eligible will also likely speed clinical trial accrual.

RevDate: 2021-02-10

Kim AE, Brandstetter E, Wilcox N, et al (2021)

Evaluating Specimen Quality and Results from a Community-Wide, Home-Based Respiratory Surveillance Study.

Journal of clinical microbiology pii:JCM.02934-20 [Epub ahead of print].

Introduction. While influenza and other respiratory pathogens cause significant morbidity and mortality, the community-based burden of these infections remains incompletely understood. The development of novel methods to detect respiratory infections is essential for mitigating epidemics and developing pandemic-preparedness infrastructure.Methods. From October 2019 to March 2020, we conducted a home-based cross-sectional study in the greater Seattle area, utilizing electronic consent and data collection instruments. Participants received nasal swab collection kits via rapid delivery within 24 hours of self-reporting respiratory symptoms. Samples were returned to the laboratory and were screened for 26 respiratory pathogens and a housekeeping gene. Participant data were recorded via online survey at the time of sample collection and one week later.Results. Of the 4,572 consented participants, 4,359 (95.3%) received a home swab kit, and 3,648 (83.7%) returned a nasal specimen for respiratory pathogen screening. The 3,638 testable samples had a mean RNase P CRT value of 19.0 (SD: 3.4) and 1,232 (33.9%) samples had positive results for one or more pathogens, including 645 (17.7%) influenza-positive specimens. Among the testable samples, the median time between shipment of the home swab kit and completion of laboratory testing was 8 days [IQR: 7.0-14.0]. A single adverse event occurred and did not cause long-term effects or require medical attention.Discussion. Home-based surveillance using online participant enrollment and specimen self-collection is a safe and feasible method for community-level monitoring of influenza and other respiratory pathogens, which can readily be adapted for use during pandemics.

RevDate: 2021-02-10

Lange J, Remmers S, Gulati R, et al (2021)

Impact of cancer screening on metastasis: A prostate cancer case study.

Journal of medical screening [Epub ahead of print].

BACKGROUND: Trials of cancer screening present results in terms of deaths prevented, but metastasis is also a key endpoint that screening seeks to prevent. We developed a framework for projecting overall (de novo and progressive) metastases prevented in a screening trial using prostate cancer screening as a case study.

METHODS: Mechanistic simulation model in which screening shifts a fraction of cases that would be metastatic at diagnosis to being non-metastatic. This shift increases the incidence of non-overdiagnosed, organ-confined cases. We use estimates of the risk of metastatic progression for these cases to project how many progress to metastasis after diagnosis and tally the projected de novo and progressive metastatic cases with and without screening. We use data on stage shift from the European Randomized Study of Screening for Prostate Cancer (ERSPC) and data on the risk of metastatic progression from the Scandinavian Prostate Cancer Group-4 trial. We estimate the relative risk and absolute risk reductions in metastatic disease at diagnosis and compare these with reductions in overall metastases.

RESULTS: Assuming no effect of screening beyond initial stage shift at diagnosis, the model projects a 43% reduction in metastasis at diagnosis but a 22% reduction in the cumulative probability of metastasis over 12 years in favor of screening. These results are consistent with the empirical findings from the ERSPC.

CONCLUSION: Any reduction in metastatic disease at diagnosis under screening is likely to be an overly optimistic predictor of the impact of screening on overall metastasis and disease-specific mortality.

RevDate: 2021-02-09

Ni Y, Szpiro A, Loftus C, et al (2021)

Associations Between Maternal Nutrition in Pregnancy and Child Blood Pressure at 4-6 Years: A Prospective Study in a Community-Based Pregnancy Cohort.

The Journal of nutrition pii:6131861 [Epub ahead of print].

BACKGROUND: The intrauterine environment may influence offspring blood pressure, with effects possibly extending into adulthood. The associations between prenatal nutrition and offspring blood pressure, alone or in combination with other sociodemographic or behavioral factors, are unclear.

OBJECTIVES: To investigate the associations of maternal dietary patterns and plasma folate concentrations with blood pressure in children aged 4-6 years, and assess the potential effect modifications by child sex, maternal race, pre-pregnancy overweight or obesity, maternal smoking, and breastfeeding.

METHODS: Participants were 846 mother-child dyads from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) study. Maternal nutrition was characterized by the Healthy Eating Index 2010 (HEI) scores and plasma folate concentrations in pregnancy. We calculated the systolic blood pressure (SBP) and diastolic blood pressure percentiles, incorporating sex, age, and height, and categorized children as either having high blood pressure (HBP; ≥90th percentile) or normal blood pressure. Linear regressions were performed to quantify the associations between maternal nutrition and continuous blood pressure percentiles, and Poisson regressions were used to estimate the incidence rate ratio (IRR) of binary HBP. We examined the effect modifications using interaction models.

RESULTS: Mean HEI scores and folate concentrations were 60.0 (SD, 11.3) and 23.1 ng/mL (SD, 11.1), respectively. Based on measurements at 1 visit, 29.6% of the children were defined as having HBP. Maternal HEI scores and plasma folate concentrations were not associated with child blood pressure percentiles or HBP in the full cohort. Among mothers self-identified as white, there was an inverse relationship between maternal HEI score and child SBP percentile (β, -0.40; 95%CI: -0.75 to -0.06). A maternal HEI score above 59 was associated with a reduced risk of HBP in girls (IRR, 0.53; 95% CI: 0.32-0.88). No modified associations by pre-pregnancy overweight or obesity, maternal smoking, or breastfeeding were indicated.

CONCLUSIONS: We found little evidence for effects of maternal nutrition during pregnancy on childhood blood pressure, but detected sex- and race-specific associations. The study contributes to the evolving scientific inquiry regarding developmental origins of disease.

RevDate: 2021-02-12

Beygi S, Fernandez-Pol S, Duran G, et al (2021)

Pembrolizumab in mycosis fungoides with PD-L1 structural variants.

Blood advances, 5(3):771-774.

RevDate: 2021-02-12

Krutein MC, Hart MR, Anderson DJ, et al (2021)

Restoring RUNX1 deficiency in RUNX1 familial platelet disorder by inhibiting its degradation.

Blood advances, 5(3):687-699.

RUNX1 familial platelet disorder (RUNX1-FPD) is an autosomal dominant disorder caused by a monoallelic mutation of RUNX1, initially resulting in approximately half-normal RUNX1 activity. Clinical features include thrombocytopenia, platelet functional defects, and a predisposition to leukemia. RUNX1 is rapidly degraded through the ubiquitin-proteasome pathway. Moreover, it may autoregulate its expression. A predicted kinetic property of autoregulatory circuits is that transient perturbations of steady-state levels result in continued maintenance of expression at adjusted levels, even after inhibitors of degradation or inducers of transcription are withdrawn, suggesting that transient inhibition of RUNX1 degradation may have prolonged effects. We hypothesized that pharmacological inhibition of RUNX1 protein degradation could normalize RUNX1 protein levels, restore the number of platelets and their function, and potentially delay or prevent malignant transformation. In this study, we evaluated cell lines, induced pluripotent stem cells derived from patients with RUNX1-FPD, RUNX1-FPD primary bone marrow cells, and acute myeloid leukemia blood cells from patients with RUNX1 mutations. The results showed that, in some circumstances, transient expression of exogenous RUNX1 or inhibition of steps leading to RUNX1 ubiquitylation and proteasomal degradation restored RUNX1 levels, thereby advancing megakaryocytic differentiation in vitro. Thus, drugs retarding RUNX1 proteolytic degradation may represent a therapeutic avenue for treating bleeding complications and preventing leukemia in RUNX1-FPD.

RevDate: 2021-02-12

Shustov A, Cabrera ME, Civallero M, et al (2021)

ALK-negative anaplastic large cell lymphoma: features and outcomes of 235 patients from the International T-Cell Project.

Blood advances, 5(3):640-648.

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK- ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P = .05) but not PFS (P = .18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK- ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.

RevDate: 2021-02-09

Moseley A, Othus M, Garcia-Manero G, et al (2021)

Predicting severe toxicities with intensive induction chemotherapy for adult acute myeloid leukemia: analysis of SWOG Cancer Research Network trials S0106 and S1203.

RevDate: 2021-02-09

Elghazaly H, Aref AT, Anderson BO, et al (2021)

The first BGICC consensus and recommendations for breast cancer awareness, early detection and risk reduction in low- and middle-income countries and the MENA Region.

International journal of cancer [Epub ahead of print].

In Low-middle income countries (LMICs) and the Middle East and North Africa (MENA) region, there is an unmet need to establish and improve breast cancer (BC) awareness, early diagnosis and risk reduction programs. During the 12th BGICC - Egypt 2020, 26 experts from 7 countries worldwide voted to establish the first consensus for BC awareness, early detection and risk reduction in LMICs/MENA region. The panel advised that there is an extreme necessity for a well-developed BC data registries and prospective clinical studies that address alternative modalities/ modified BC screening programs in areas of limited resources. The most important recommendations of the panel were: 1-BC awareness campaigns should be promoted to public and all adult age groups; 2-early detection programs should combine geographically distributed mammographic facilities with clinical breast examination (CBE); 3- breast awareness should be encouraged; and 4- intensive surveillance and chemoprevention strategies should be fostered for high risk women. The panel defined some areas for future clinical research, which included the role of CBE and breast self-examination as an alternative to radiological screening in areas of limited resources, the interval and methodology of BC surveillance in women with increased risk of BC and the use of low dose tamoxifen in BC risk reduction. In LMICs/MENA region, BC awareness and early detection campaigns should take into consideration the specific disease criteria and the socio-economic status of the target population. The statements with no consensus reached, should serve as potential catalyst for future clinical research.

RevDate: 2021-02-12

Klima JC, Doyle LA, Lee JD, et al (2021)

Incorporation of sensing modalities into de novo designed fluorescence-activating proteins.

Nature communications, 12(1):856.

Through the efforts of many groups, a wide range of fluorescent protein reporters and sensors based on green fluorescent protein and its relatives have been engineered in recent years. Here we explore the incorporation of sensing modalities into de novo designed fluorescence-activating proteins, called mini-fluorescence-activating proteins (mFAPs), that bind and stabilize the fluorescent cis-planar state of the fluorogenic compound DFHBI. We show through further design that the fluorescence intensity and specificity of mFAPs for different chromophores can be tuned, and the fluorescence made sensitive to pH and Ca2+ for real-time fluorescence reporting. Bipartite split mFAPs enable real-time monitoring of protein-protein association and (unlike widely used split GFP reporter systems) are fully reversible, allowing direct readout of association and dissociation events. The relative ease with which sensing modalities can be incorporated and advantages in smaller size and photostability make de novo designed fluorescence-activating proteins attractive candidates for optical sensor engineering.

RevDate: 2021-02-09

Zhang P, Katzaroff AJ, Buttitta LA, et al (2021)

The Krüppel-like factor Cabut has cell cycle regulatory properties similar to E2F1.

Proceedings of the National Academy of Sciences of the United States of America, 118(7):.

Using a gain-of-function screen in Drosophila, we identified the Krüppel-like factor Cabut (Cbt) as a positive regulator of cell cycle gene expression and cell proliferation. Enforced cbt expression is sufficient to induce an extra cell division in the differentiating fly wing or eye, and also promotes intestinal stem cell divisions in the adult gut. Although inappropriate cell proliferation also results from forced expression of the E2f1 transcription factor or its target, Cyclin E, Cbt does not increase E2F1 or Cyclin E activity. Instead, Cbt regulates a large set of E2F1 target genes independently of E2F1, and our data suggest that Cbt acts via distinct binding sites in target gene promoters. Although Cbt was not required for cell proliferation during wing or eye development, Cbt is required for normal intestinal stem cell divisions in the midgut, which expresses E2F1 at relatively low levels. The E2F1-like functions of Cbt identify a distinct mechanism for cell cycle regulation that may be important in certain normal cell cycles, or in cells that cycle inappropriately, such as cancer cells.

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ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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

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Papers in Classical Genetics

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

Digital Books

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

Timelines

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

Biographies

Biographical information about many key scientists.

Selected Bibliographies

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

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